Aims. The preventive effects of bisphosphonates on articular cartilage in non-arthritic joints are unclear. This study aimed to investigate the effects of oral bisphosphonates on the rate of joint space narrowing in the non-arthritic hip. Methods. We retrospectively reviewed standing whole-leg radiographs from patients who underwent knee arthroplasties from 2012 to 2020 at our institute. Patients with previous hip surgery, Kellgren–Lawrence grade ≥ II hip osteoarthritis, hip dysplasia, or rheumatoid arthritis were excluded. The rate of hip joint space narrowing was measured in 398 patients (796 hips), and the effects of the use of bisphosphonates were examined using the multivariate regression model and the propensity score matching (1:2) model. Results. A total of 45 of 398 (11.3%) eligible patients were taking an oral bisphosphonate at the time of knee surgery, with a mean age of 75.8 years (SD 6.2) in bisphosphonate users and 75.7 years (SD 6.8) in non-users. The mean joint space narrowing rate was 0.04 mm/year (SD 0.11) in bisphosphonate users and 0.12 mm/year (SD 0.25) in non-users (p < 0.001). In the multivariate model, age (standardized coefficient = 0.0867, p = 0.016) and the use of a bisphosphonate (standardized coefficient = −0.182, p < 0.001) were associated with the joint space narrowing rate. After successfully matching 43 bisphosphonate users and 86 non-users, the joint narrowing rate was smaller in bisphosphonate users (p < 0.001). Conclusion. The use of bisphosphonates is associated with decreased joint degeneration in non-arthritic hips after knee arthroplasty. Bisphosphonates slow joint degeneration, thus maintaining the thickness of joint cartilage in the normal joint or during the early phase of osteoarthritis. Cite this article: Bone Joint Res 2022;11(11):826–834

Aims. This study was designed to develop a model for predicting bone mineral density (BMD) loss of the femur after total hip arthroplasty (THA) using artificial intelligence (AI), and to identify factors that influence the prediction. Additionally, we virtually examined the efficacy of administration of bisphosphonate for cases with severe BMD loss based on the predictive model. Methods. The study included 538 joints that underwent primary THA. The patients were divided into groups using unsupervised time series clustering for five-year BMD loss of Gruen zone 7 postoperatively, and a machine-learning model to predict the BMD loss was developed. Additionally, the predictor for BMD loss was extracted using SHapley Additive exPlanations (SHAP). The patient-specific efficacy of bisphosphonate, which is the most important categorical predictor for BMD loss, was examined by calculating the change in predictive probability when hypothetically switching between the inclusion and exclusion of bisphosphonate. Results. Time series clustering allowed us to divide the patients into two groups, and the predictive factors were identified including patient- and operation-related factors. The area under the receiver operating characteristic (ROC) curve (AUC) for the BMD loss prediction averaged 0.734. Virtual administration of bisphosphonate showed on average 14% efficacy in preventing BMD loss of zone 7. Additionally, stem types and preoperative triglyceride (TG), creatinine (Cr), estimated glomerular filtration rate (eGFR), and creatine kinase (CK) showed significant association with the estimated patient-specific efficacy of bisphosphonate. Conclusion. Periprosthetic BMD loss after THA is predictable based on patient- and operation-related factors, and optimal prescription of bisphosphonate based on the prediction may prevent BMD loss. Cite this article: Bone Joint Res 2024;13(4):184–192

There is conjecture on the optimal timing to administer bisphosphonate therapy following operative fixation of low- trauma hip fractures. Factors include recommendations for early opportunistic commencement of osteoporosis treatment, and clinician concern regarding the effect of bisphosphonates on fracture healing. We performed a systematic review and meta-analysis to determine if early administration of bisphosphonate therapy within the first month post-operatively following proximal femur fracture fixation is associated with delay in fracture healing or rates of delayed or non-union. We included randomised controlled trials examining fracture healing and union rates in adults with proximal femoral fractures undergoing osteosynthesis fixation methods and administered bisphosphonates within one month of operation with a control group. Data was pooled in meta-analyses where possible. The Cochrane Risk of Bias Tool and the GRADE approach were used to assess validity. For the outcome of time to fracture union, meta-analysis of three studies (n= 233) found evidence for earlier average time to union for patients receiving early bisphosphonate intervention (MD = −1.06 weeks, 95% CI −2.01 – −0.12, I. 2. = 8%). There was no evidence from two included studies comprising 718 patients of any difference in rates of delayed union (RR 0.61, 95% CI 0.25–1.46). Meta-analyses did not demonstrate a difference in outcomes of mortality, function, or pain. We provide low-level evidence that there is no reduction in time to healing or delay in bony union for patients receiving bisphosphonates within one month of proximal femur fixation

Aims. The aim of this study was to investigate the effects of preoperative bisphosphonate treatment on the intra- and postoperative outcomes of arthroplasty of the shoulder. The hypothesis was that previous bisphosphonate treatment would adversely affect both intra- and postoperative outcomes. Patients and Methods. A retrospective cohort study was conducted involving patients undergoing arthroplasty of the shoulder, at a single institution. Two patients with no previous bisphosphonate treatment were matched to each patient who had received this treatment preoperatively by gender, age, race, ethnicity, body mass index (BMI), and type of arthroplasty. Previous bisphosphonate treatment was defined as treatment occurring during the three-year period before the arthroplasty. The primary outcome measure was the incidence of intraoperative complications and those occurring at one and two years postoperatively. A total of 87 patients were included: 29 in the bisphosphonates-exposed (BP. +. ) group and 58 in the non-exposed (BP. -. ) group. In the BP. +. group, there were 26 female and three male patients, with a mean age of 71.4 years (51 to 87). In the BP. -. group, there were 52 female and six male patients, with a mean age of 72.1 years (53 to 88). Results. Previous treatment with bisphosphonates was positively associated with intraoperative complications (fracture; odds ratio (OR) 39.40, 95% confidence interval (CI) 2.42 to 6305.70) and one-year postoperative complications (OR 7.83, 95% CI 1.11 to 128.82), but did not achieve statistical significance for complications two years postoperatively (OR 3.45, 95% CI 0.65 to 25.28). The power was 63% for complications at one year. Conclusion. Patients who are treated with bisphosphonates during the three-year period before shoulder arthroplasty have a greater risk of intraoperative and one-year postoperative complications compared with those without this previous treatment

Aims. Currently, periprosthetic fractures are excluded from the American Society for Bone and Mineral Research (ASBMR) definition of atypical femoral fracture (AFFs). This study aims to report on a series of periprosthetic femoral fractures (PFFs) that otherwise meet the criteria for AFFs. Secondary aims were to identify predictors of periprosthetic atypical femoral fractures (PAFFs) and quantify the complications of treatment. Patients and Methods. This was a retrospective case control study of consecutive patients with periprosthetic femoral fractures between 2007 and 2017. Two observers identified 16 PAFF cases (mean age 73.9 years (44 to 88), 14 female patients) and 17 typical periprosthetic fractures in patients on bisphosphonate therapy as controls (mean age 80.7 years (60 to 86, 13 female patients). Univariate and multivariate analysis was performed to identify predictors of PAFF. Management and complications were recorded. Results. Interobserver agreement for the PAFF classification was excellent (kappa = 0.944; p < 0.001). On univariate analysis compared with controls, patients with PAFFs had higher mean body mass indices (28.6 kg/m. 2. (. sd. 8.9) vs 21.5 kg/m. 2. (. sd. 3.3); p = 0.009), longer durations of bisphosphonate therapy (median 5.5 years (IQR 3.2 to 10.6) vs 2.4 years (IQR 1.0 to 6.4); p = 0.04), and were less likely to be on alendronate (50% vs 94%; p = 0.02) with an indication of secondary osteoporosis (19% vs 0%; p = 0.049). Duration of bisphosphonate therapy was an independent predictor of PAFF on multivariate analysis (R. 2. = 0.733; p = 0.05). Following primary fracture management, complication rates were higher in PAFFs (9/16, 56%) than controls (5/17, 29%; p = 0.178) with a relative risk of any complication following PAFF of 1.71 (95% confidence interval (CI) 0.77 to 3.8) and of reoperation 2.56 (95% CI 1.3 to 5.2). Conclusion. AFFs do occur in association with prostheses. Longer duration of bisphosphonate therapy is an independent predictor of PAFF. Complication rates are higher following PAFFs compared with typical PFFs, particularly of reoperation and infection. Cite this article: Bone Joint J 2019;101-B:1285–1291

Soaking bone grafts in a bisphosphonate solution before implantation can prevent their resorption and increase the local bone density in rats and humans. However, recent studies suggest that pre-treatment of allografts with bisphosphonate can prevent bone ingrowth into impaction grafts. We tested the hypothesis that excessive amounts of bisphosphonate would also cause a negative response in less dense grafts. We used a model where non-impacted metaphyseal bone grafts were randomised into three groups with either no bisphosphonate, alendronate followed by rinsing, and alendronate without subsequent rinsing, and inserted into bone chambers in rats. The specimens were evaluated histologically at one week, and by histomorphometry and radiology at four weeks. At four weeks, both bisphosphonate groups showed an increase in the total bone content, increased newly formed bone, and higher radiodensity than the controls. In spite of being implanted in a chamber with a limited opportunity to diffuse, even an excessive amount of bisphosphonate improved the outcome. We suggest that the negative results seen by others could be due to the combination of densely compacted bone and a bisphosphonate. We suggest that bisphosphonates are likely to have a negative influence where resorption is a prerequisite to create space for new bone ingrowth

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions. Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2

We performed a retrospective review of all patients admitted to two large University Hospitals in the United Kingdom over a 24-month period from January 2008 to January 2010 to identify the incidence of atypical subtrochanteric and femoral shaft fractures and their relationship to bisphosphonate treatment. Of the 3515 patients with a fracture of the proximal femur, 156 fractures were in the subtrochanteric region. There were 251 femoral shaft fractures. The atypical fracture pattern was seen in 27 patients (7%) with 29 femoral shaft or subtrochanteric fractures. A total of 22 patients with 24 atypical fractures were receiving bisphosphonate treatment at the time of fracture. Prodromal pain was present in nine patients (11 fractures); 11 (50%) of the patients on bisphosphonates suffered 12 spontaneous fractures, and healing of these fractures was delayed in a number of patients. This large dual-centre review has established the incidence of atypical femoral fractures at 7% of the study population, 81% of whom had been on bisphosphonate treatment for a mean of 4.6 years (0.04 to 12.1). This study does not advocate any change in the use of bisphosphonates to prevent fragility fractures but attempts to raise awareness of this possible problem so symptomatic patients will be appropriately investigated. However, more work is required to identify the true extent of this new and possibly increasing problem

Aims. The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones. Methods. Three groups (seven per group) of 12-week-old mice were: 1) ovariectomized and 20 weeks thereafter treated weekly for 24 weeks with 100 μm/kg subcutaneous ibandronate (OVX+IBN); 2) ovariectomized (OVX); or 3) sham-operated (SHAM). Quantitative fracture analysis generated biomechanical properties for the femoral neck. Tibiae were microCT scanned and trabecular (proximal metaphysis) and cortical parameters along almost its whole length measured. Results. Fracture analyses revealed that OVX+IBN significantly reduced yield displacement (vs SHAM/OVX) and resilience, and increased stiffness (vs SHAM). OVX+IBN elevated tibial trabecular parameters and also increased cortical cross-sectional area and second moment of area around minor axis, and diminished ellipticity proximally. Conclusion. These data indicate that combined ovariectomy and bisphosphonate generates cortical changes linked with greater bone brittleness and modified fracture characteristics, which may provide a basis in mice for interrogating the mechanisms and genetics of atypical fracture aetiology. Cite this article: Bone Joint Open 2020;1-9:512–519

Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing. A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague–Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology. The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm. -2. (. sd. 7.63) vs 24.65 Nmm. -2. (. sd. 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (. sd. 0.75) vs 4.6 mmAl (. sd. 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007). . Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing. Cite this article: Bone Joint J 2013;95-B:1263–8

Aims. Post-operative migration of cemented acetabular components as measured by radiostereometric analysis (RSA) has a strong predictive power for late, aseptic loosening. Also, radiolucent lines predict late loosening. Migration has been reduced by systemic bisphosphonate treatment in randomised trials of hip and knee arthroplasty. Used as a local treatment, a higher local dose of bisphosphonate can be achieved without systemic exposure. We wished to see if this principle could be applied usefully in total hip arthroplasty (THA). Patients and Methods. In this randomised placebo-controlled, double-blinded trial with 60 participants, we compressed gauze soaked in bisphosphonate solution (ibandronate) or saline against the acetabular bone bed immediately before cementing the acetabular component. RSA, classification of radiolucent lines, the Harris Hip Score (HHS) and the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) were carried out at three-, six-, 12-, and 24-month follow-up. Results. Migration of the cemented acetabular component relative to the pelvis was reduced by movement almost half in the ibandronate group, when measured as maximum total point or as movement of the femoral head (p = 0.001 and 0.004, respectively). Radiolucent lines after one year were classified as absent, partial or complete, and correlated with treatment (rho 0.37; p = 0.004). Only three of 30 patients in the ibandronate group had complete lines, compared with 13 of 28 in the placebo group (p = 0.002). There were no significant effects on HHS or WOMAC score. Conclusion. Considering the power of RSA to predict loosening of cemented acetabular components, and the likelihood that radiolucent lines indicate risk of loosening, these data suggest that local treatment with a bisphosphonate can reduce the risk of late aseptic loosening. Cite this article: Bone Joint J 2017;99-B:317–24

Aims. The aim of this study was to evaluate the outcomes of a salvage procedure using a 95° angled blade plate for failed osteosynthesis of atypical subtrochanteric femoral fractures associated with the long-term use of bisphosphonates. These were compared with those for failed osteosynthesis of subtrochanteric fractures not associated with bisphosphonate treatment. Patients and Methods. Between October 2008 and July 2016, 14 patients with failed osteosynthesis of an atypical subtrochanteric femoral fracture were treated with a blade plate (atypical group). Their mean age was 67.8 years (60 to 74); all were female. During the same period, 21 patients with failed osteosynthesis of a typical subtrochanteric fracture underwent restabilization using a blade plate (typical group). Outcome variables included the time of union, postoperative complications, Harris Hip Score, and Sanders functional rating scale. Results. In the atypical group, union was achieved in 12 patients (85.7%) at a mean of 8.4 months (4 to 12). The mean follow-up was 31.2 months (12 to 92) The plate broke in one patient requiring further stabilization with a longer plate and strut-allograft. Another patient with failure of fixation and varus angulation at the fracture site declined further surgery. In the typical group, union was achieved in 18 patients (85.7%) at a mean of 7.9 months (4 to 12). There was no difference in the mean Harris Hip Score between the two groups (83.1 points vs 86.8 points; p = 0.522) at the time of final follow-up. Sanders functional rating scores were good or excellent in 78.6% of the atypical group and in 81.0% of the typical group. Conclusion. The 95° angled blade plate was shown to be an effective fixation modality for nonunion of atypical subtrochanteric fractures with a high rate of union and functional improvement, comparable to those after fractures not associated with bisphosphonate treatment. Cite this article: Bone Joint J 2018;100-B:1511–17

Objectives. Bisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls. Methods. Trabecular bone from hip fracture patients treated with BP (n = 10) was compared with naïve fractured (n = 14) and non-fractured controls (n = 6). Trabecular cores were synchrotron scanned and micro-CT scanned for microstructural analysis, including quantification of bone volume fraction, microarchitecture and microcracks. The specimens were then mechanically tested in compression. Results. BP bone was 28% lower in strength than untreated hip fracture bone, and 48% lower in strength than non-fractured control bone (4.6 MPa vs 6.4 MPa vs 8.9 MPa). BP-treated bone had 24% more microcracks than naïve fractured bone and 51% more than non-fractured control (8.12/cm. 2. vs 6.55/cm. 2. vs 5.25/cm. 2. ). BP and naïve fracture bone exhibited similar trabecular microarchitecture, with significantly lower bone volume fraction and connectivity than non-fractured controls. Conclusion. BP therapy had no detectable mechanical benefit in the specimens examined. Instead, its use was associated with substantially reduced bone strength. This low strength may be due to the greater accumulation of microcracks and a lack of any discernible improvement in bone volume or microarchitecture. This preliminary study suggests that the clinical impact of BP-induced microcrack accumulation may be significant. Cite this article: A. Jin, J. Cobb, U. Hansen, R. Bhattacharya, C. Reinhard, N. Vo, R. Atwood, J. Li, A. Karunaratne, C. Wiles, R. Abel. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res 2017;6:602–609. DOI: 10.1302/2046-3758.610.BJR-2016-0321.R1

During revision total hip replacement using morcellised compacted bone allograft, 16 patients were randomised to receive a graft which had been rinsed in either an ibandronate solution or in saline. Patients were assessed by dual energy x-ray absorptiometry after operation and at 3, 6, 12 and 24 months. A region of interest between the tip of the femoral stem and the distal plastic plug was chosen to measure the changes in bone density over time. The study was double-blinded. In all the control patients the bone density decreased during the first three months and then remained constant at this lower level. A large proportion of the mass of the bone graft was lost. In contrast, all patients with grafts treated with bisphosphonate showed a slight increase in bone density. The difference between the groups was highly significant at all points in time. We conclude that rinsing the graft in a bisphosphonate solution prevents its resorption and may therefore reduce the risk of mechanical failure. The treatment is simple, inexpensive, and appears virtually free of risk

Aims. The incidence of atypical femoral fractures (AFFs) continues to increase. However, there are currently few long-term studies on the complications of AFFs and factors affecting them. Therefore, we attempted to investigate the outcomes, complications, and risk factors for complication through mid-term follow-up of more than three years. Methods. From January 2003 to January 2016, 305 patients who underwent surgery for AFFs at six hospitals were enrolled. After exclusion, a total of 147 patients were included with a mean age of 71.6 years (48 to 89) and 146 of whom were female. We retrospectively evaluated medical records, and reviewed radiographs to investigate the fracture site, femur bowing angle, presence of delayed union or nonunion, contralateral AFFs, and peri-implant fracture. A statistical analysis was performed to identify the significance of associated factors. Results. The mean follow-up period was 70.2 months (36 to 191). There were 146 AFFs (99.3%) in female patients and the mean age was 71.6 years (48 to 89). The AFFs were located in the subtrochanter and shaft in 52 cases (35.4%) and 95 (64.6%), respectively. The preoperative mean anterior/lateral femoral bowing angles were 10.5° (SD 5.7°)/6.1° (SD 6.2°). The postoperative mean anterior/lateral bowing values were changed by 8.7° (SD 5.4°)/4.6° (SD 5.9°). Bisphosphonates had been used contemporarily in 115 AFFs (78.2%) for a mean of 52.4 months (1 to 204; SD 45.5) preoperatively. Nailing was performed in 133 AFFs (90.5%), and union was obtained at a mean of 23.6 weeks (7 to 85). Delayed union occurred in 41 (27.9%), and nonunion occurred in 13 (8.8%). Contralateral AFF occurred in 79 patients (53.7%), and the use of a bisphosphonate significantly influenced the occurrence of contralateral AFFs (p = 0.019). Peri-implant fractures occurred in a total of 13 patients (8.8%), and a significant increase was observed in cases with plating (p = 0.021) and high grade of postoperative anterolateral bowing (p = 0.044). Conclusion. The use of a bisphosphonate was found to be a risk factor for contralateral AFF, and high-grade postoperative anterolateral bowing and plate fixation significantly increased the occurrence of peri-implant fractures. Long-term follow-up studies on the bilaterality of AFFs and peri-implant fractures are warranted. Cite this article: Bone Joint J 2021;103-B(11):1648–1655

The April 2024 Hip & Pelvis Roundup. 360. looks at: Impaction bone grafting for femoral revision hip arthroplasty with the Exeter stem; Effect of preoperative corticosteroids on postoperative glucose control in total joint replacement; Tranexamic acid in patients with a history of venous thromboembolism; Bisphosphonate use may be associated with an increased risk of periprosthetic hip fracture; A balanced approach: exploring the impact of surgical techniques on hip arthroplasty outcomes; A leap forward in hip arthroplasty: dual-mobility bearings reduce groin pain; A new perspective on complications: the link between blood glucose and joint infection risks

Introduction: Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour of bone which contains numerous osteoclast-like giant cells. GCTB is a locally aggressive tumour which can cause extensive bone destruction that can be difficult to control surgically, up to 35% of cases recurring after simple curettage. Bisphosphonates are anti-resorptive agents that have proved effective in the treatment of a number of osteolytic conditions. Methods: This study reports results from four European centres where bisphosphonates are being used to treat problematic GCTBs. Details of treatment with bisphosphonates of 25 cases of primary, recurrent and metastatic GCTBs was assessed clinically and radiologically. Results: Most primary/recurrent tumours did not exhibit progressive enlargement and, in some cases, both primary and metastatic GCTBs showed a degree of radiological improvement following treatment. Some patients also noted relief of pain following treatment. In a few cases, no apparent treatment effect was noted and there was disease progression. Several inoperable large spinal/pelvic GCTBs remained stable in size following treatment. Discussion: Our findings provide preliminary evidence for the use of bisphosphonates to inhibit the progressive osteolysis associated with GCTB. These agents had a beneficial clinical and/or radiological effect in most cases. This study reports results from four European centres and highlights the fact that these centres are all employing different clinical indications and different regimes of bisphosphonate treatment. Bisphosphonates have significant side effects and indications for treatment and standardisation of drug type and dosage regimes (and measurement of agreed outcome measures to determine treatment efficacy) should be established for the use of these agents to control GCTB tumour growth and osteolysis

Background: Traumatic femoral head osteonecrosis in adolescents has a poor prognosis due to collapse and subsequent degenerative change. There are currently no satisfactory treatments available for this condition. Bisphosphonate therapy has improved outcome in animal models of osteonecrosis. We have evaluated bisphosphonate therapy as a novel strategy for adolescent traumatic osteonecrosis. Methods: We established a protocol of identification of adolescents with osteonecrosis utilizing bone scans immediately after surgical treatment for hips at risk of osteonecrosis after trauma. Of a consecutive group of twenty-eight patients with either unstable slipped capital femoral epiphyses (SCFE) (22), femoral neck fracture (4) or hip dislocation (2), seventeen patients with osteonecrosis were identified. These patients (13 boys and 4 girls, mean age 12.6 years) and their families consented for treatment with intravenous bisphosphonates based on animal experimental evidence. Of the patients with osteonecrosis, twelve had presented with unstable SCFE, four with femoral neck fractures and one following traumatic hip dislocation. The average length of bisphosphonate treatment was 20.3 months (range 7 to 39). All patients were followed for at least 2 years. Results: At mean follow-up of 38.7 months, fourteen patients (82%) were pain free. Clinically, all patients had a good to excellent outcome. The mean Harris Hip Score was 91.1, the Iowa Hip Rating was 92.1 and the Global PODCI score was 91.5. On radiographs, nine patients (53%) were rated as Stulberg I–II, six (35%) as Stulberg III, and two (12%) as Stulberg V. Conclusion: Bisphosphonates therapy may play an adjunctive role in the treatment of adolescents with traumatic osteonecrosis

For over a decade, bisphosphonate administration has evolved and become the cornerstone of the prevention and treatment of fragility fractures. Millions of post-menopausal women have relied on, and continue to depend on, the long-acting, bone density-maintaining pharmaceutical drug to prevent low-energy fractures. In return, we have seen the number of fragility fractures decrease, along with associated costs and emotional benefits. However, with any drug, there are often concerns with side effects and complications, and this unique drug class is seeing one such complication in atypical subtrochanteric femoral fracture, counterproductive to that which it was designed to prevent. This has created concern over long-term bisphosphonate administration and its potential link to these atypical fractures. There is controversial evidence surrounding such a definitive link, and no protocol for managing these fractures. . This review offers the latest information regarding this rare but increasingly controversial adverse effect and its potential connection to one of the most successful forms of treatment that is available for the management of fragility fractures

Aim. Giant cell tumour (GCT) of bone is a benign but locally aggressive tumour. Although topical adjuvants have been used in the past, local recurrence following intralesional excision of GCT of bone continues to remain a problem. The use of bisphosphonates as an anti-osteoclastic agent in the management of osteolytic bone metastases is well accepted. Therefore our study aims to retrospectively demonstrate whether the administration of bisphosphonate as an adjuvant can control aggressive local recurrence of GCT and prevent wide resections of bones or amputations. Method. A retrospective study was performed between 2004 and 2010. 6 patients were diagnosed with aggressive local recurrence of appendicular GCT. All patients were treated for the primary tumour by surgical curettage and cryoablation followed by cementation or biological reconstruction. In 5 patients the tumour was located in the distal radius and in one in the first metacarpal bone. All recurrences were in the bone with large soft-tissue extension. After histological diagnosis – by CT core needle biopsy – the patients were treated by intravenous bisphosphonate, followed by clinical & radiological assessments. Results. Average follow-up of 42 months, ranging from 12 to 72 consecutive months. All patients showed good response to bisphosphonate treatment: lesions become calcified gradually as shown in x-rays & CT scans, reduction in size of soft tissue components, patient reported relief of pain & improvement of the affected limb. All treated patients did not report any untoward effects. Conclusion. In the current study bisphosphonate treatment is found to be an effective treatment for local control of aggressive local recurrence of GCT of the extremities and can therefore be a good alternative to wide resections of bone and complicated reconstructions. Functional results are shown to be promising as well. The study results need further investigation & a larger scale of patients

In an attempt to increase the life of cementless prostheses, an hydroxyapatite-coated implant which releases a bisphosphonate has been suggested as a drug-delivery system. Our in vitro study was designed to determine the maximum dose to which osteoblasts could be safely exposed. Our findings demonstrated that zoledronate did not impair the proliferation of human osteoblasts when used at concentrations below 1 μ. m. Murine cells can be exposed to concentrations as high as 10 μ. m. . A concentration of 0.01% of titanium particles did not impair the proliferation of either cell line. Zoledronate affected the alkaline phosphatase activity of murine osteoblasts through a chelation phenomenon. The presence of titanium particles strongly decreased the alkaline phosphatase activity of murine osteoblasts. We did not detect any synergic effect of zoledronate and titanium particles on the behaviour of both human and murine osteoblasts

Background. Distraction Osteogenesis can be complicated by regenerate insufficiency resulting in prolonged implant usage or regenerate failure with malalignment or fracture. Experimental evidence has demonstrated that bisphosphonates may mediate improved local limb BMD and regenerate strength. Methods. A prospective series of 14 patients over 5 years. One cohort (Group A) of these cases presented with established regenerate insufficiency leading to consideration for surgical intervention. Patients received a therapeutic regime of intravenous bisphosphonate A further cohort (Group B) of 7 patients was commenced on bisphosphonate therapy at an earlier stage, prior to the regenerate maturation phase. Results. Mean age at primary surgery was 11.6 years (3-17 yrs) with a minimum follow-up of 12 months after fixator removal. The sites of regenerate insufficiency were tibia (12) and distal femur (3), with 1 patient undergoing both femoral and tibial lengthening. Mean fixator time was 108 days prior to treatment for a mean lengthening of 5.3 cm. At time of treatment measurements demonstrated a reduced BMD in the bone, mean 44% (39-58%) of the normal limb, the primary consolidation index was high at 40.5 (46-68) days/cm, reflecting observed regenerate insufficiency. Significant increase in regenerate bone mass and mineral density was observed after the first dose of intravenous bisphosphonate. No significant systemic complications were encountered. After a mean 130 days (range 103-231 days) of therapy the bone consolidated to unencumbered full weight bearing, final healing index of 82 days/cm (Range 67-108days/cm). Cases demonstrated a rapid and sustained improvement in local BMD (increasing to mean 78% of the normal side). Remodelling was seen radiologically from 12 months post-therapy. However, subsequently, one femoral regenerate fractured and required intramedullary nail stabilisation. Conclusion. This is early clinical evidence that Bisphosphonate therapy has potential therapeutic benefit in managing regenerate insufficiency and counteracting local osteopenia in distraction osteogenesis

Aims. Proximal femur fractures treatment can involve anterograde nailing with a single or double cephalic screw. An undesirable failure for this fixation is screw cut-out. In a single-screw nail, a tip-apex distance (TAD) greater than 25 mm has been associated with an increased risk of cut-out. The aim of the study was to examine the role of TAD as a risk factor in a cephalic double-screw nail. Methods. A retrospective study was conducted on 112 patients treated for intertrochanteric femur fracture with a double proximal screw nail (Endovis BA2; EBA2) from January to September 2021. The analyzed variables were age, sex, BMI, comorbidities, fracture type, side, time of surgery, quality of reduction, pre-existing therapy with bisphosphonate for osteoporosis, screw placement in two different views, and TAD. The last follow-up was at 12 months. Logistic regression was used to study the potential factors of screw cut-out, and receiver operating characteristic curve to identify the threshold value. Results. A total of 98 of the 112 patients met the inclusion criteria. Overall, 65 patients were female (66.3%), the mean age was 83.23 years (SD 7.07), and the mean follow-up was 378 days (SD 36). Cut-out was observed in five patients (5.10%). The variables identified by univariate analysis with p < 0.05 were included in the multivariate logistic regression model were screw placement and TAD. The TAD was significant with an odds ratio (OR) 5.03 (p = 0.012) as the screw placement with an OR 4.35 (p = 0.043) in the anteroposterior view, and OR 10.61 (p = 0.037) in the lateral view. The TAD threshold value identified was 29.50 mm. Conclusion. Our study confirmed the risk factors for cut-out in the double-screw nail are comparable to those in the single screw. We found a TAD value of 29.50 mm to be associated with a risk of cut-out in double-screw nails, when good fracture reduction is granted. This value is higher than the one reported with single-screw nails. Therefore, we suggest the role of TAD should be reconsidered in well-reduced fractures treated with double-screw intramedullary nail. Cite this article: Bone Jt Open 2024;5(6):457–463

Traumatic osteonecrosis of the femoral head in adolescents has a poor prognosis due to collapse and degenerative change. We hypothesised that early bisphosphonate treatment to reduce osteoclast activity could allow revascularisation and repair with maintenance of joint congruity. Nine patients with documented osteonecrosis were treated with intermittent intravenous pamidronate (Aredia, Novartis) commencing within a mean 1 month of diagnosis (range, 5 to 91days). The dosing protocol has evolved over two years with the current dose being 9 mg/kg/year for 18 months. Mean follow up is 19.8 months (range, 13 to 30 months) with all patients followed for more than one year. There were 6 patients, who presented after unstable SCFE. Of these the index procedure had failed in three, requiring multiple early operations. The other three patients had sustained an inter-trochanteric fracture with a pelvic fracture, a traumatic hip dislocation and a femoral neck fracture respectively. Eight of the patients are painfree. Six have been instructed to fully weight bear, while two can partial weight bear and one is non-weight bearing. Seven of 9 patients do not show significant resorption of the femoral heads at the most recent follow up. Of the two patients with significant resorption, one patient began to resorb after his medication was ceased, so it was recommenced. He has subsequently undergone a realignment procedure. The other patient had resorption of a section of the femoral head, which had not re-vascularised by 18 months, and this was elevated and bone grafted. These two hips are considered functional in the short term as they are currently pain free, but their deformity is expected to bring about early osteoarthritis in adult life. This early experience lays the foundation for prospective clinical trials of bisphosphonate therapy in adolescents with osteonecrosis. It appears that bisphosphonate treatment protocols for adolescents will need to be prolonged. Our current practice is for a duration of around 18 months with normalisation of uptake on bone scan as the end point for therapy

Introduction Traumatic osteonecrosis of the femoral head in adolescents has a poor prognosis due to femoral head collapse and degenerative change. We hypothesised that early bisphosphonate treatment to reduce osteoclast activity could allow revascularisation and repair with maintenance of joint congruity. Methods Nine patients with documented osteonecrosis are presented. There were six patients, who presented after unstable SCFE. Of these the index procedure had failed in three, requiring multiple early operations. The other three patients had sustained an inter-trochanteric fracture with a pelvic fracture, a traumatic hip dislocation and a femoral neck fracture respectively. They were treated with intermittent intravenous pamidronate (Aredia, Novartis) commencing within a mean one month of diagnosis (range 5 to 91 days). The dosing protocol has evolved over two years with the current dose being 9 mg/kg/year for 18 months. Mean follow-up is 19.8 months (range 13 to 30 months) with all patients followed for more than one year. Results Eight of the patients are painfree. Six have been instructed to fully weight bear, while two can partial weight bear and one is non-weight bearing. Seven of nine patients do not show significant resorption of the femoral heads at the most recent follow-up. Of the two patients with significant resorption, one patient began to resorb after his medication was ceased, so it was recommenced. He has subsequently undergone a realignment procedure. The other patient had resorption of a section of the femoral head, which had not re-vascularised by 18 months, and this was elevated and bone grafted. These two hips were considered functional in the short term as they were pain free, but their deformity was expected to bring about early osteoarthritis in adult life. Conclusions This early experience lays the foundation for prospective clinical trials of bisphosphonate therapy in adolescents with osteonecrosis. It appears that bisphosphonate treatment protocols for adolescents will need to be prolonged. Our current practice is for a duration of around 18 months with normalisation of uptake on bone scan as the end point for therapy. In relation to the conduct of this study, one or more of the authors is in receipt of a research grant from a non-commercial source

Bone is the preferred site of metastases in women with breast cancer, which can cause skeletal-related events (SRE¡¦s) such as pathologic fractures. Bisphosphonates are the current standard of care for treatment of meta-static bone disease by preventing further bone destruction. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for malignancies. In PDT, light is delivered to a tumour after the administration of a photosensitiser. Earlier pre-clinical studies in a metastatic rat model have shown that PDT reduced the tumour burden in the vertebrae. The goal of this investigation was to study the effect of PDT on bisphosphonate pre-treated cancer in-vitro. Human breast cancer cells, MT-1, were cultured until confluent. The following groups were formed: no treatment; incubation with zoledronic acid (24h; 10 ƒÝmol) only; PDT treatment only and incubation with zoledronic acid and PDT treatment. Prior to light application 1 microg/ml of the photosensitiser BPD-MA was added. PDT was performed with a light dose of 1J and 10 J. The cells were stained with a live/dead stain and analyzed by fluorescence microscope and flowcytometry. Incubation of the MT-1 carcinoma cells with bisphosphonate zoledronic acid resulted in a significantly higher number of dying cells following PDT treatment when compared cells that were not treated by zoledronic acid (p< 0.05). When comparing cell groups that did not undergo PDT treatment the incubation with zoledronic acid alone did not have a statistically significant effect on cell survival twenty-four hours following zoledronic acid administration. In-vitro, breast cancer cells appear more susceptible to PDT after they have been incubated with the zoledronic acid. Zoledronic acid, a potent bisphosphonate, inhibits farsenylpyrophosphate (FPP) which is involved in farsenylation of cell membrane proteins. The inhibition of FPP may cause a reduced effect of PDT on cell rescue. The treatment with bisphosphonates seems to have a synergistic effect with PDT treatment. As such, light dosimetry in PDT treatment may need to take into account potential therapeutic interactions between PDT and current medical therapies in the treatment of skeletal metastatic burden

Introduction. The emergence of a new variant of subtrochanteric stress fractures of the femur affecting patients on oral bisphosphonate therapy has only recently been described. This fracture is often preceded by pain and distinctive radiographic changes, and associated with a characteristic fracture pattern. We undertook a review of this cohort of patients in our service. Method. A retrospective review was carried out looking for patients with subtrochanteric fractures who were taking oral bisphosphonates presenting with a low velocity injury over a two year period. Clinical data and radiographs were assessed. Results. 11 fractures were found in 10 patients matching the inclusion criteria outlined. All were female, and taking bisphosphonates for a mean of 4.3 years. 5 of the 10 patients described prodromal symptoms, for an average of 7.8 months before fracture. Although all fractures were deemed low velocity, 5 of 11 were atraumatic. 3 patients have had bilateral subtrochanteric fractures. Presence of the distinctive radiological ‘bleb’ was common. Surveillance on 2 patients shows lateral cortical blebs on the contralateral femur which merit close follow up. Conclusion. Patients taking oral bisphosphonate therapy may be at risk of a new variant of stress fracture of the proximal femur. Awareness of the symptoms is key to ensure appropriate investigations are undertaken. Following such a fracture surveillance of the contralateral femur is recommended, and the option of discontinuing bisphosphonates should be discussed

Giant cell tumour of bone (GCTB) is an expansile osteolytic tumour of bone which contains numerous osteoclast-like giant cells. GCTB is a locally aggressive tumour which can cause extensive bone destruction that can be difficult to control surgically, up to 35% of cases recurring after simple curettage. Bisphosphonates are anti-resorptive agents that have proved effective in the treatment of a number of osteolytic conditions. In keeping with its known effect on osteoclasts, we found that the aminobisphosphonate zoledronate abolished in vitro lacunar resorption in cultures of osteoclasts isolated from GCTB. The effect of zoledronate and other bisphosphonates on 15 cases of recurrent primary GCTB, four of which had metastasised to the lung, was assessed clinically. Most recurrent tumours did not exhibit progressive enlargement and, in some cases, both primary and metastatic GCTBs showed a degree of radiological improvement following treatment However, tumours did not diminish in size and, in some cases, no apparent treatment effect was noted. Our findings provide in vitro evidence for the use of bisphosphonates to inhibit the progressive osteolysis associated with GCTB. In vivo, these agents produced a degree of clinical and radiological improvement in some cases. This study reports results from three European centres where bisphosphonates are being used to treat recurrent GCTB and highlights the fact that these centres are all employing different clinical indications and different regimes of bisphosphonate treatment. Bisphosphonates have significant side effects and indications for treatment and standardisation of drug type and dosage regimes (and measurement of agreed outcome measures to determine treatment efficacy) should be established before these agents are included as part of a treatment protocol to control GCTB tumour growth and osteolysis

Background: Giant-cell tumour (GCT) of bone is a benign but aggressive tumour, usually treated by radical surgical curettage. Surgical treatment of GCT involving the ischium is associated with a high local recurrence rate. We describe a case in which serial arterial embolisation and bisphosphonate treatment resulted in radiological healing of the tumour. So far we have avoided surgical treatment. Case Report: A 40-year-old lady was referred to the bone tumour unit following a fall. A plain radiograph of the pelvis revealed a lytic lesion in the ischium, extending into the posterior column of the acetabulum and associated with a pathological fracture. Biopsy confirmed a diagnosis of GCT. Given the anatomic location, the tumour was treated with serial arterial embolisation and intravenous zoledronate infusions. Follow up at one-year shows healing of the lesion, with no radiological evidence of recurrence. The patient has so far avoided surgery. Discussion: Serial arterial embolisation has been described in the treatment of giant cell tumours in anatomical regions where surgery is likely to be associated with significant morbidity, such as the sacrum. There is a sound theoretical basis for the use of bisphosphonates in this disease; they have been shown to cause apoptosis of the osteoclast-like giant cells and interfere with osteoclast recruitment. As far as we are aware this is the first case described in which embolisation and bisphosphonate treatment appears to have led to healing and stabilisation of the lesion. The durability of this response remains uncertain

Aims. We aimed to evaluate the utility of . 68. Ga-citrate positron emission tomography (PET)/CT in the differentiation of periprosthetic joint infection (PJI) and aseptic loosening (AL), and compare it with . 99m. Tc-methylene bisphosphonates (. 99m. Tc-MDP) bone scan. Methods. We studied 39 patients with suspected PJI or AL. These patients underwent . 68. Ga-citrate PET/CT, . 99m. Tc-MDP three-phase bone scan and single-photon emission CT (SPECT)/CT. PET/CT was performed at ten minutes and 60 minutes after injection, respectively. Images were evaluated by three nuclear medicine doctors based on: 1) visual analysis of the three methods based on tracer uptake model, and PET images attenuation-corrected with CT and those not attenuation-corrected with CT were analyzed, respectively; and 2) semi-quantitative analysis of PET/CT: maximum standardized uptake value (SUVmax) of lesions, SUVmax of the lesion/SUVmean of the normal bone, and SUVmax of the lesion/SUVmean of the normal muscle. The final diagnosis was based on the clinical and intraoperative findings, and histopathological and microbiological examinations. Results. Overall, 23 and 16 patients were diagnosed with PJI and AL, respectively. The sensitivity and specificity of three-phase bone scan and SPECT/CT were 100% and 62.5%, 82.6%, and 100%, respectively. Attenuation correction (AC) at 60 minutes and non-AC at 60 minutes of PET/CT had the same highest sensitivity and specificity (91.3% and 100%), and AC at 60 minutes combined with SPECT/CT could improve the diagnostic efficiency (sensitivity = 95.7%). Diagnostic efficacy of the SUVmax was low (area under the curve (AUC) of ten minutes and 60 minutes was 0.814 and 0.806, respectively), and SUVmax of the lesion/SUVmean of the normal bone at 60 minutes was the best semi-quantitative parameter (AUC = 0.969). Conclusion. 68. Ga-citrate showed the potential to differentiate PJI from AL, and visual analysis based on uptake pattern of tracer was reliable. The visual analysis method of AC at 60 minutes, combined with . 99m. Tc-MDP SPECT/CT, could improve the sensitivity from 91.3% to 95.7%. In addition, a major limitation of our study was that it had a limited sample size, and more detailed studies with a larger sample size are warranted. Cite this article: Bone Joint Res 2022;11(6):398–408

Osteoporosis is a global health issue with 200 million people suffering worldwide and it is a common condition in the elderly. Bisphosphonates including alendronate and risendronate are considered as the first line treatment for osteoporosis. However, there is increasing evidence that bisphosphonate (BP) therapy is associated with atypical fractures. Animal studies have reported a dose-dependent association between the duration of BP therapy and the accumulation of micro-damage. We tested the hypothesis that hip fracture patients treated with BP exhibited greater micro-damage density than untreated fracture and ‘healthy’ aging non-fracture controls. Trabecular bone cores from patients treated with BP were compared with patients who had not received any treatment for bone metabolic disease (ethics reference: R13004). Non-fractured cadaveric femora from individuals with no history of bone metabolic disease were used as controls. Cores were imaged in high spatial resolution (∼1.3µm) using Synchrotron X-ray tomography (Diamond Light Source Ltd.) A novel classification system was devised to characterise features of micro-damage in the Synchrotron images: micro-cracks, diffuse damage and perforations. Synchrotron micro-CT stacks were visualised and analysed using ImageJ, Avizo and VGStudio MAX. Our findings show that the BP group had the highest micro-damage density across all groups. The BP group (7.7/mm. 3. ) also exhibited greater micro-crack density than the fracture (4.3/mm. 3. ) and non-fracture (4.1/mm. 3. ) controls. Furthermore, the BP group (1.9/mm. 3. ) demonstrated increased diffuse damage when compared to the fracture (0.3/mm. 3. ) and non-fracture (0.8/mm. 3. ) controls. In contrast, the BP group (1.9mm. 3. ) had fewer perforations than fracture (3.0/mm. 3. ) and non-fracture controls (3.9/mm. 3. ). BP inhibits bone remodelling, thereby reducing the number of perforated trabeculae, but over-suppression leads to micro-damage accumulation. Accumulated damage could weaken the trabecular bone in the femoral head and neck, increasing the risk of a fracture during a trip or fall

Introduction. Bisphosphonates (BP) are the first-line therapy for preventing osteoporotic fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate use is associated with over-suppression of remodeling. Animal studies have reported that BP therapy is associated with accumulation of micro-cracks (Fig. 1) and a reduction in bone mechanical properties, but the effect on humans has not been investigated. Therefore, our aim was to quantify the mechanical strength of bone treated with BP, and correlate this with the microarchitecture and density of micro-damage in comparison with untreated osteoporotic hip-fractured and non-fractured elderly controls. Methods. Trabecular bone cores from patients treated with BP were compared with patients who had not received any treatment for bone osteoporotic disease. Non-fractured cadaveric femora from individuals with no history of bone metabolic disease were also used as controls. Cores were imaged in high resolution (∼1.3µm) using Synchrotron X-ray tomography (Diamond Light Source Ltd.) The scans were used for structural and material analysis, then the cores were mechanically tested in compression. A novel classification system was devised to characterise features of micro-damage in the Synchrotron images: micro-cracks, diffuse damage and perforations. Synchrotron micro-CT stacks were visualised and analysed using ImageJ, Avizo and VGStudio MAX. Results. Our findings demonstrated that patients treated with BP (17.2 MPa) had significantly lower tissue strength than untreated fracture (24.0 MPa) and non-fracture controls (28.0 MPa). Yet treated and untreated hip-fracture patient's exhibited comparable bone microarchitecture, volume fraction, apparent and material density. The data also revealed that the BP group had the highest micro-damage density across all groups. The BP group (7.7/mm. 3. ) also exhibited significantly greater micro-crack density than the fracture (4.3/mm. 3. ) and non-fracture (4.1/mm. 3. ) controls. Furthermore, the BP group (1.9/mm. 3. ) demonstrated increased diffuse damage when compared to the fracture (0.3/mm. 3. ) and non-fracture (0.8/mm. 3. ) controls. In contrast, the BP group (1.9. mm. 3. ) had fewer perforations than fracture (3.0/mm. 3. ) and non-fracture controls (3.9/mm. 3. ). Discussion. Despite having comparable microarchitecture apparent and material density, patients taking BP exhibited weaker tissue strength compared to the controls. This weakness is likely to be the the result of the increased accumulation of micro-damage found in BP treated bone. BP inhibits bone remodelling, thereby reducing the number of perforated trabeculae, meanwhile over-suppression leads to the accumulation of micro-cracks and diffuse damage which reduce strength. Conclusion. In our subgroup of hip-fracture patients, BP therapy appeared to offer no mechanical advantage in resisting femoral fractures. BP accumulated micro-damage may have weakened the trabecular bone in the femoral head and neck thereby, therefore increasing the risk of a fracture during a trip or fall

Bone healing especially in elderly patients is a complex process with limited therapeutic options. In recent years the use of BMP2 for fracture healing is investigated extensively. However, for many applications superficial amounts of BMP2 were required for efficacy due to the absence of sustained release carriers and severe side effects have reported thereby limiting the use of BMP2. Here we present an alternative method based on the use of a combination of low molecular weight compounds, testosterone and alendronate, with established safety profiles in men. Moreover, in contrast to BMP2 which activates both osteoblasts and osteoclasts, this combination of drugs enhances osteoblast activity but simultaneously inhibits osteoclast activity resulting in a net effect of bone growth. Human primary osteoblasts were obtained from bone of patients requiring knee prostheses and cultured in the presence of various concentrations testosterone with and without alendronate. Optimal concentrations were selected and used to stimulate 5×8 mm porcine bone biopsies for 4 weeks. Medium was exchanged regularly and ALP activity was determined. At endpoint biopsies were analyzed in a MicroCT (Bruker Skyscan 1076) to analyze bone volume (BV), trabecular thickness (Tb.Th) and tissue volume (TV). Bone strength was measured using Hounsfield (H10KT) test equipment. The data obtained showed a significant and dose dependent increase in ALP activity of primary osteoblasts (day 7–10) indicating robust activation of osteoblast activity. Optimal and synergistic ALP activation was observed when treating cells with 15–375 nM testosterone in combination with 2 μM alendronate. Significant inhibition (75%) of osteoclast activity was observed by alendronate (2–10 μM) which was further enhanced by high testosterone levels. This concept was further tested in bovine bone biopsies cultured for 4 weeks in the presence of 75 nM testosterone and 2 μM alendronate. MicroCT analysis of the biopsies revealed a ± 40% increase in both bone volume (trabecular and cortical bone) and bone strength. Moreover bone mineral density was increased by 20% indicating increased mineralization of bone tissue. Treatment of human primary osteoblasts or human or bovine bone explants with a combination of an androgen (testosterone) and a bisphosphonate (alendronate) significantly enhance bone growth and bone mineral density. Moreover, bone strength was increased indicating the formation of high quality bone tissue. These findings are the basis for the development of sustained release materials to be applied locally at the bone fracture site, which would allow for low amounts of the drugs and no systemic exposure. By encapsulating testosterone and alendronate in a biodegradable polymer coating, a sustained release up to 5 weeks can be achieved, and the loaded coating can be applied in combination with collagen membranes to improve bone healing or as a coating onto implants to improve osseo-integration

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1. +/−. ) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection. When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1. +/−. mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07). These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1

Objective: To evaluate the effects of a new potent bisphosphonate on the formation, mineralisation, density, and mechanical properties of bone in distraction osteogenesis. Methods: Thirty immature New Zealand White rabbits had a 10.5 millimetre lengthening of their tibia performed over 2 weeks using an Orthofix M-100 fixator. Ten control rabbits received saline only; 10 received the new bisphosphonate at the time of surgery, and 10 received a second dose at the end of distraction. Bone mineral content (BMC) and density (BMD) measurements were made at two, four and six weeks. Quantitative CT analysis of regenerate, proximal and distal bone, and corresponding segments in the non-operated limb was performed after culling. Mechanical testing was by 4-point bending. Results: Bone mineral accrual was significantly faster in both treatment groups (ANOVA p< 0.01). BMD increased in all treated animals (ANOVA p< 0.01). Cross sectional area of regenerate at six weeks was increased by 49% in the single dosed group versus controls and by 59% in the re-dosed group. (ANOVA p< 0.01). BMC of the regenerate was increased by 92% in the single dose group and by 111% in the re-dosed group (ANOVA p< 0.01). Moment of inertia of the regenerate was significantly increased in both treated groups (ANOVA p< 0.05). The difference between single dose and controls was significant (p< 0.05), the difference between re-dosed and single dosed was not (p=0.5). Conclusion: Bisphosphonate therapy significantly increased new bone formation, bone mineralisation and mechanical properties. Osteoporotic effects were reversed. This effect could have wide ranging implications for many orthopaedic practices

Children with osteogenesis imperfecta(OI) have multiple long bone fractures with subsequent deformities. The mainstay of treatment is correction with multiple osteotomies and intramedullary fixation. The Shefffield intramedullary telescoping rod system has been successful in the treament of long bone fractures and deformities (Wilkinson et al ,JBJS-B,1998) Bisphosphonates (Pamidronate -1- 1.5mg/kg/day)have been used as adjuvant therapy in the treatment of OI since the last five years. The perceived benefits include reduction in fracture frequency, improvement in bone density and a general feeling of well being. We present our experience of five cases of OI who developed infections around thier Sheffield telescoping rods while on Pamidronate therapy. There was only one case of sepsis over a ten year period(over eighty patients)in a previously reported series from our centre. The time interval between the start of Pamidronate therapy and the diagnosis of infection varied between 12–36 months ie. between 4–12 cycles of Pamidronate (parenteral administration over a three day period at three month intervals). All patients had their intramedullary rods in situ from anywhere between 2–7 years. The infections were low grade with a 2–3 month period of dull ache prior to actual presentation. Intrestigly though all patients had multiple rods in situ, only one of their femoral rods was affected and they did not have any other infective focus at the time of diagnosis. Three patients presented with thigh abcesses while the other two presented with ipsilateral knee pain and effusion. All had raised inflammatory markers, radiological signs of sepsis with Staph Aureus the commonest infecting organism. Those cases presenting with abcesses were treated by drainage and rod removal, however only antibiotics were sufficient in the rest. The relationship between Pamidronate therapy and these infections is not absolutely clear and has not been reported previously. The possible links are discussed and a high degree of suspicion is recommended for those cases of OI on bisphosphonate

This study examined the inhibitory effects of anti-TNF-a antibody (anti-TNF) and a new bisphosphonate (TRK-530) on peri-implant oseteolysis in a rat model with continuous infusion of polyethylene particles. TRK-530 is a novel synthetic bisphophonate to have a direct effect on osteoclastic bone resorption as well as suppressive effects on bone resorbing cytokines from macrophages. Materials and methods: Sixty Wister rats were randomized to three groups (n=20 each). In each rat, a Kirshner wire (K-wire) was inserted into the femur and polyethylene particles (HDPE, mean size; 2 microns) were continuously infused into the knee joint using an osmotic pump. The animals were subcutaneously injected with saline (control group) or 1 mg/kg of TRK (TRK group) or intraperitoneally injected with 100 mg of anti-TNF (anti-TNF group) every second day after surgery until 8 weeks. At 4 weeks or 8 weeks after surgery, rats were sacrificed. Rdiographs were evaluated for the presence of osteolysis, thereafter, garnulation tissues were stored for PCR analysis for IL-1 mRNA as well as TNF-a mRNA. Then, femurs were prepared for the histology. Results: Radiographic peri-implant osteolysis was seen more frequently in TRK group compared to other two groups (p< 0.01). The interfacial membrane was significantly thinner in TRK and anti-TNF group compared to the control group (p< 0.01). The average number of osteoclasts around K-wire was significantly fewer in the TRK group compared to the other groups (p< 0.01). The expression of IL-1 mRNA and TNF-a mRNA was significantly suppressed in the TRK group at 8 weeks after surgery. Discussion: The present study demonstrates that cumulative effects of TRK such as the suppression of bone resorbing cytokines as well as direct suppression of osteoclasts reduce the polyethylene induced peri-implant osteolysis. In addition, single anti-cytokine therapy appears not to be enough to inhibit peri-implant osteolysis in our model

Purpose: The bisphosphonate Zoledronic acid (ZA) is effective for increasing net bone formation within and around implants when directly eluted from implants. The extent to which this occurs or whether ZA is more widely distributed through diffusion into the circulation is unknown. The purpose of this study was to utilize 14C-labeled ZA to quantify the localization and skeletal distribution of ZA in a canine intramedullary implant model. Method: A solution of 100μg 14C-labeled ZA was evenly distributed onto each implant surface of three hydroxyapatite coated porous tantalum (Trabecular Metal. ™. , Zimmer Inc) implants measuring 5 mm in diameter and 50 mm in length. The implants were inserted within the left femoral intramedullary canal of an adult mongrel dog and left in situ for 6 weeks. The 3 femora with implants and all the other long bones were harvested, dried, pulverized into a fine powder and disolved in HCl. This solution was then placed in a scintillation cocktail (Ultima Gold AB, Perkin Elmer USA) and analyzed with a Packard Tri-Carb 2100TR liquid scintillator spectrometer. Data were analyzed with student’s t tests and nested analyses of variance with p=0.05. Results: Very high amounts of ZA were present within the bone samples immediately adjacent to the implants – range 243 – 1487 ng ZA/g of bone, mean of 800 ng ZA/g. By 1 cm proximal or distal to the implant, the values diminished by up to an order of magnitude. All other bone samples contained very low amounts of 14C, (range, 0.8 – 22.6 ng ZA/g; mean 6.5 ng ZA/g), indicating diffusion of ZA into the circulation and a level of systemic distribution. This is about 11-fold less in magnitude (p< 0.0001). Conclusion: Local elution of ZA directly from an implant results in half of the ZA being distributed locally in the femur with the rest being distributed throughout the skeleton, at levels that are much less than the therapeutic dose required to appreciably affect bone remodeling or cause complications. postoperative time periods

The April 2023 Research Roundup³⁶⁰ looks at: Ear protection for orthopaedic surgeons?; Has arthroscopic meniscectomy use changed in response to the evidence?; Time to positivity of cultures obtained for periprosthetic joint infection; Bisphosphonates for post-COVID-19 osteonecrosis of the femoral head; Missing missed fractures: is AI the answer?; Congenital insensitivity to pain and correction of the knee; YouTube and paediatric elbow injuries.

Management of bisphosphonate-associated subtrochanteric fractures remains opinion- or consensus-based. There are limited data regarding the outcomes of this fracture.

We retrospectively reviewed 33 consecutive female patients with a mean age of 67.5 years (47 to 91) who were treated surgically between May 2004 and October 2009. The mean follow-up was 21.7 months (0 to 53). Medical records and radiographs were reviewed to determine the post-operative ambulatory status, time to clinical and radiological union and post-fixation complications such as implant failure and need for second surgery.

The predominant fixation method was with an extramedullary device in 23 patients. 25 (75%) patients were placed on wheelchair mobilisation or no weight-bearing initially. The mean time to full weight-bearing was 7.1 months (2.2 to 29.7). The mean time for fracture site pain to cease was 6.2 months (1.2 to 17.1). The mean time to radiological union was 10.0 months (2.2 to 27.5). Implant failure was seen in seven patients (23%, 95 confidence interval (CI) 11.8 to 40.9). Revision surgery was required in ten patients (33%, 95 CI 19.2 to 51.2).

A large proportion of the patients required revision surgery and suffered implant failure. This fracture is associated with slow healing and prolonged post-operative immobility.

Cite this article: Bone Joint J 2014;96-B:658–64.

Aims

Current levels of hip fracture morbidity contribute greatly to the overall burden on health and social care services. Given the anticipated ageing of the population over the coming decade, there is potential for this burden to increase further, although the exact scale of impact has not been identified in contemporary literature. We therefore set out to predict the future incidence of hip fracture and help inform appropriate service provision to maintain an adequate standard of care.

Background: Aseptic loosening of implants is commonly associated with periprosthetic bone loss, and several authors aimed to preserve periprosthetic bone mass by treatment with bisphosphonates (BPs) in THA. While local application of BPs was argued to provide higher concentrations of bioactive drug at the component-bone interface, we hypothesized that a systemically administration of BPs will be sufficient for sustained effects on local bone metabolism due to local accumulation of the drug in freshly exposed bone mineral early after reaming during implantation. The high antiresorptive potential of zoldronic acid (ZOL) on osteoclasts will be sustained locally by re-attachment after release by osteoclast resorption during the remodelling cycle. While we were able to demonstrate beneficial effects of ZOL on early implant fixation, its local effects on bone metabolism is best reflected by monitoring the relative changes of biochemical markers during follow-up after THA. This is an important issue to be addressed, since there are no reliable data available but essential for a prove-of-concept. Methods: Fifty patients with ON-FH were consecutively enrolled to receive randomly either 4mg of ZOL or saline solution (CTR) in a double-blind fashion one day after THA. The biochemical bone turnover markers C-terminal teleopeptides of collagen type I (ICTP), CrossLaps (CL), osteocalcin (OC), osteoprotegerin (OPG), soluble RANKL, as well as 25-hydroxyvitamin D (25OHD3) were measured from fasting blood samples before surgery and at 7 weeks, 6 months, 1 year, and yearly thereafter. One patient was lost and after excluding three patients with deficiency in renal function 22 and 24 patients were analyzed in ZOL and CTR, respectively, during a median follow-up of 2.8 yrs. Results: Within the placebo group, the bone resorption markers ICTP and CL peaked at 7 wks, but continuously decreased thereafter beyond baseline levels. The bone formation marker OC also increased, but peaked at 6 months and stayed increased during the follow-up. Although there was only a transient effect of ZOL found in ICTP, CL rapidly decreased within 7 wks and remained depressed during the whole follow-up period (~ − 65% at 2 yrs, P< 0.0001). Similarly, OC was also depressed in ZOL but never reached significance compared to baseline levels (~ − 19%, NS). No differences or changes were apparent in 25OHD3 levels. Discussion and Conclusion: The findings strongly support a predominant local effect of systemically infused ZOL over a whole-body effect. Furthermore, the data demonstrate the sufficiency of a single infusion of a single infusion of ZOL for a pronounced and sustained antiresorptive effect after THA, which is essential to preserve periprosthetic bone mass in an effort to prevent aseptic loosening

Aims

We wanted to evaluate the effects of a bone anabolic agent (bone morphogenetic protein 2 (BMP-2)) on an anti-catabolic background (systemic or local zoledronate) on fixation of allografted revision implants.

Purpose

Maintenance of vertebral mechanical stability is of paramount importance to prevent pathologic fractures and resultant neurologic compromise in individuals with spinal metastases. Current non-surgical treatments for vertebral metastases (i.e. chemotherapy, bisphophonates (BP) and radiation) yield variable responses in the tumour and surrounding bone. Photodynamic therapy (PDT) is a novel, minimally-invasive technology that utilizes a drug activated by light at a specific non-thermal wavelength to locally destroy tumour cells. Previously, we observed that PDT can ablate cancer cells within bone and yield short-term (1-week) improvements in vertebral architecture and biomechanical strength, particularly when combined with BP therapy. This study aims to evaluate the effects of PDT in vertebral bone over a longer (6-week) time period, alone and combined with previous BP treatment, to determine if improvements in skeletal architecture and strength are maintained.

Osteoporosis is a mineral bone disease arising from the predominance of osteoclastic bone resorption. Bisphosphonates which inhibit osteoclasts are commonly used in osteoporosis treatment, but are not without severe adverse effects like osteonecrosis of the jaw. The mechanisms behind the development of such phenomena is not well understood. Bone homeostasis is achieved through an intimate cross-talk between osteoclasts and osteoblasts. Thus, it is important to visualise activities of these cells simultaneously in situ. Currently, there are means to visualise osteoclast shape and numbers with tartrate-resistant alkaline phosphatase (TRAP) staining but no practical and accurate methods to quantify osteoclast activity in situ.

This investigation aims to establish the use of ELF97, a substrate of TRAP, to visualise and quantify osteoclast activity. This provides vital clues to mechanisms of various bone disorders. TRAP dephosphorylation of ELF97 results in a detectable fluorescent product at areas of osteoclast activity.

Osteoclastic activity was initiated in zebrafish by inducing crush injuries in tail fin rays. Colocalisation of ELF97 fluorescence with osteoclast-specific DsRed in transgenic zebrafish, visualised under confocal microscopy, is used to further establish the specificity of ELF97 to sites of osteoclastic activity. Quantification is established by comparing fluorescence between wild type, osteoclast-deficient mutants and bisphosphonate-treated zebrafish. The utility of ELF97 will also be investigated in terms of the stability of the florescent product.

The investigation revealed that ELF97 and DsRed fluorescence were found commonly at crush sites with osteoclastic activity. Wild type zebrafish had greater fluorescence compared to osteoclast-deficient (p<0.0001) and bisphosphonate-treated zebrafish (p<0.0001) after 7 and 14 days post-crush, revealing that fluorescence from ELF97 corresponds to expected osteoclastic activity. Fluorescence of tail fins treated with ELF97 did not diminish over a period of 21 days of storage, demonstrating its stability. ELF97 is thus a useful means to visualise osteoclast activity, potentially crucial in more advanced investigations to understand bone disorders. It could be used in combination with other cellular markers in whole biological samples to study and experimentally manipulate bone remodelling.

Osteosarcoma is the most frequent bone tumor in adolescents and young adults. Already, the bisphophonates were introduced as the first line therapy for metastatic disease as well as the maintenance therapy, but new drugs are still in researchers interest.

Between 2005 and 2008, we have been treated 17 osteosarcoma patients, from 4 till 18 years of age. All patients have been followed up for 11 months average (range 4–18). At the time of diagnosis 15 of them had local disease, and 2 had metastatic disease. They were treated according to EURAMOS protocol. There were two groups of patients; the high risk patients who has received the pamidronat disodium (pamidronat) after the standard postoperative chemotherapy, and the other group who hadn’t received pamidronat. One patient, who had bone and pulmonary metastasis at the diagnosis, received the pamidronat as the first line therapy. We have introduced the 2 mg/kg mothly of pamidronat to 7 patients, median age of 13. Patients have received 8 cycles average of pamidronat (range 4–12). Two patients had to be excluded from therapy due to nephrotoxycity and pregnancy. The patient with metastatic disease, bone and lung metastasis, at the diagnosis, had died, and two patients who had pulmonary metastasis, afer the surgery and second line chemotherapy, showed no disease progression during the pamidronat therapy. In the other group of patients, who hadn’t received the pamidronat, one patient with metastatic disease had died, 2 of them had local reccurence, and 2 died due to disease progession.

Introducing the pamidronat has been a big step forward for osteosarcoma patients, because, according to our results, during the pamidronat therapy they haven’t developed local recurrence and/or disease progression.

Majority of osteoporosis related fractures are treated surgically using metallic fixation devices. Anchorage of fixation devices is sometimes challenging due to poor osteoporotic bone quality that can lead to failure of the fracture fixation. Using a rat osteoporosis model, we employed neutron tomography and histology to study the biological effects of implant augmentation using an isothermally setting calcium sulphate/hydroxyapatite (CaS/HA) biomaterial with synthetic HA particles as recruiting moiety for systemically administered bisphosphonates. Using an osteoporotic sawbones model, we then provide a standardized method for the delivery of the CaS/HA biomaterial at the bone-implant interface for improved mechanical anchorage of a lag-screw commonly used for hip fracture fixation. As a proof-of-concept, the method was then verified in donated femoral heads and in patients with osteoporosis undergoing hip fracture fixation. We show that placing HA particles around a stainless-steel screw in-vivo, systemically administered bisphosphonates could be targeted towards the implant, yielding significantly higher peri-implant bone formation compared to un-augmented controls. In the sawbones model, CaS/HA based lag-screw augmentation led to significant increase (up to 4 times) in peak extraction force with CaS/HA performing at par with PMMA. Micro-CT imaging of the CaS/HA augmented lag-screws in cadaver femoral heads verified that the entire length of the lag-screw threads and the surrounding bone was covered with the CaS/HA material. X-ray images from fracture fixation surgery indicated that the CaS/HA material could be applied at the lag-screw-bone interface without exerting any additional pressure or risk of venous vascular leakage.: We present a new method for augmentation of lag-screws in fragile bone. It is envisaged that this methodcould potentially reduce the risk of fracture fixation failure especially when HA seeking “bone active” drugs are used systemically

A painful “dreaded black line” (DBL) has been associated with progression to complete fractures in atypical femur fractures (AFF). Adjacent sclerosis, an unrecognized radiological finding, has been observed in relation to the DBL. We document its incidence, associated features, demographics and clinical progression. We reviewed plain radiographs of 109 incomplete AFFs between November 2006 and June 2021 for the presence of sclerosis adjacent to a DBL. Radiographs were reviewed for location of lesions, and presence of focal endosteal or periosteal thickening. We collected demographical data, type and duration of bisphosphonate therapy, and progression to fracture or need for prophylactic stabilization, with a 100% follow up of 72 months (8 – 184 months). 109 femurs in 86 patients were reviewed. Seventeen sclerotic DBLs were observed in 14 patients (3 bilateral), involving 15.6% of all femora and 29.8% of femora with DBLs. Location was mainly subtrochanteric (41.2%), proximal diaphyseal (35.3%) and mid-diaphyseal (23.5%), and were associated with endosteal or periosteal thickening. All patients were female, mostly Chinese (92.9%), with a mean age of 69 years. 12 patients (85.7%) had a history of alendronate therapy, and the remaining 2 patients had zoledronate and denosumab therapy respectively. Mean duration of bisphosphonate therapy was 62 months. 4 femora (23.5%) progressed to complete fractures that were surgically managed, whilst 6 femora (35.3%) required prophylactic fixation. Peri-lesional sclerosis in DBL is a new radiological finding in AFFs, predominantly found in the proximal half of the femur, at times bilateral, and are always associated with endosteal or periosteal thickening. As a high proportion of patients required surgical intervention, these lesions could suggest non-union of AFFs, similar to the sclerotic margins commonly seen in fractures with non-union. The recognition of and further research into this new feature could shed more light on the pathophysiological progression of AFFs

Lung cancer is the most common cancer diagnosed, the leading cause of cancer-related deaths, and bone metastases occurs in 20–40% of lung cancer patients. They often present symptomatically with pain or skeletal related events (SREs), which are independently associated with decreased survival. Bone modifying agents (BMAs) such as Denosumab or bisphosphonates are routinely used, however no specific guidelines exist from the National Comprehensive Cancer Center or the European Society of Medical Oncologists. Perhaps preventing the formation of guidelines is the lack of a high-quality quantitative synthesis of randomized controlled trial (RCT) data to determine the optimal treatment for the patient important outcomes of 1) Overall survival (OS), 2) Time to SRE, 3) SRE incidence, and 4) Pain Resolution. The objective of this study was to perform the first systematic review and network meta-analysis (NMA) to assess the best BMA for treatment of metastatic lung cancer to bone. We conducted our study in accordance to the PRISMA protocol. We performed a librarian assisted search of MEDLINE, PubMed, EMBASE, and Cochrane Library and Chinese databases including CNKI and Wanfang Data. We included studies that are RCTs reporting outcomes specifically for lung cancer patients treated with a bisphosphonate or Denosumab. Screening, data extraction, risk of bias and GRADE were performed in duplicate. The NMA was performed using a Bayesian probability model with R. Results are reported as relative risks, odds ratios or mean differences, and the I2 value is reported for heterogeneity. We assessed all included articles for risk of bias and applied the novel GRADE framework for NMAs to rate the quality of evidence supporting each outcome. We included 132 RCTs comprising 11,161 patients with skeletal metastases from lung cancer. For OS, denosumab was ranked above zoledronic acid (ZA) and estimated to confer an average of 3.7 months (95%CI: −0.5 – 7.6) increased survival compared to untreated patients. For time to SRE, denosumab was ranked first with an average of 9.1 additional SRE-free months (95%CI: 4.0 – 14.0) compared to untreated patients, while ZA conferred an additional 4.8 SRE-free months (2.4 – 7.0). Patients treated with the combination of Ibandronate and systemic therapy were 2.3 times (95%CI: 1.7 – 3.2) more likely to obtain successful pain resolution, compared to untreated. Meta-regression showed no effect of heterogeneity length of follow-up or pain scales on the observed treatment effects. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for SRE incidence, and low for pain resolution. While a generally high risk of bias was observed across studies, whether they were from Western or Chinese databases. The overall GRADE for the evidence underlying our results is High for Pain control and SRE incidence, and Moderate for OS and time to SRE. This study represents the most comprehensive synthesis of the best available evidence guiding pharmacological treatment of bone metastases from lung cancer. Denosumab is ranked above ZA for both overall survival and time to SRE, but both treatments are superior to no treatment. ZA was first among all bisphosphonates assessed for odds of reducing SRE incidence, while the combination of Ibandronate and radionuclide therapy was most effective at significantly reducing pain from metastases. Clinicians and policy makers may use this synthesis of all available RCT data as support for the use of a BMA in MBD for lung cancer

Objectives. There remains conflicting evidence regarding cortical bone strength following bisphosphonate therapy. As part of a study to assess the effects of bisphosphonate treatment on the healing of rat tibial fractures, the mechanical properties and radiological density of the uninjured contralateral tibia was assessed. Methods. Skeletally mature aged rats were used. A total of 14 rats received 1µg/kg ibandronate (iban) daily and 17 rats received 1 ml 0.9% sodium chloride (control) daily. Stress at failure and toughness of the tibial diaphysis were calculated following four-point bending tests. Results. Uninjured cortical bone in the iban group had a significantly greater mean (standard deviation (. sd. )), p < 0.001, stress at failure of 219.2 MPa (. sd. 45.99) compared with the control group (169.46 MPa (. sd. 43.32)) following only nine weeks of therapy. Despite this, the cortical bone toughness and work to failure was similar. There was no significant difference in radiological density or physical dimensions of the cortical bone. Conclusions. Iban therapy increases the stress at failure of uninjured cortical bone. This has relevance when normalising the strength of repair in a limb when comparing it with the unfractured limb. However, the 20% increase in stress at failure with iban therapy needs to be interpreted with caution as there was no corresponding increase in toughness or work to failure. Further research is required in this area, especially with the increasing clinical burden of low-energy diaphyseal femoral fractures following prolonged use of bisphosphonates. Cite this article: Bone Joint Res 2015;4:99–104

Objectives. Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs. Methods. We present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use. Results. Six broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed. Conclusions. This article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes. Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144–153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1

The purpose of this study was to determine whether there have been changes in the complexity of femoral fragility fractures presenting to our Dunedin Orthopaedic Department, New Zealand, over a period of ten years. Patients over the age of 60 presenting with femoral fragility fractures to Dunedin Hospital in 2009 −10 (335 fractures) were compared with respect to demographic data, incidence rates, fracture classification and treatment details to the period 2018-19 (311 fractures). Pathological and high velocity fractures were excluded. The gender proportion and average age (83.1 vs 83.0 years) was unchanged. The overall incidence of femoral fractures in people over 60 years in our region fell by 27% (p<0.001). Intracapsular fractures (31 B1 and B2) fell by 29% (p=0.03) and stable trochanteric fractures by 56% (p<0.001). The incidence of unstable trochanteric fractures (31A2 and 31A3) increased by 84.5% from 3.5 to 6.4/10,000 over 60 years (p = 0.04). The proportion of trochanteric fractures treated with an intramedullary (IM) nail increased from 8% to 37% (p <0.001). Fewer intracapsular fractures were treated by internal fixation (p<0.001) and the rate of acute total hip joint replacements increased from 13 to 21% (p=0.07). The incidence of femoral shaft fractures did not change significantly with periprosthetic fractures comprising 70% in both cohorts. While there has been little difference in the numbers there has been a decrease in the incidence of femoral fragility fractures likely due to the increasing use of bisphosphonates. However, the incidence of unstable trochanteric fractures is increasing. This has led to the increased use of IM nails which are increasingly used for stable fractures as well. The increasing complexity of femoral fragility fractures is likely to have an impact on implant use, theatre time and cost

A number of techniques have been developed to improve the immediate mechanical anchorage of implants for enhancing implant longevity. This issue becomes even more relevant in patients with osteoporosis who have fragile bone. We have previously shown that a dynamic hip screw (DHS) can be augmented with a calcium sulphate/hydroxyapatite (CaS/HA) based injectable biomaterial to increase the immediate mechanical anchorage of the DHS system to saw bones with a 400% increase in peak extraction force compared to un-augmented DHS. The results were also at par with bone cement (PMMA). The aim of this study was to investigate the effect of CaS/HA augmentation on the integration of a different fracture fixation device (gamma nail lag-screw) with osteoporotic saw bones. Osteoporotic saw bones (bone volume fraction = 15%) were instrumented with a gamma nail without augmentation (n=8) or augmented (n=8) with a CaS/HA biomaterial (Cerament BVF, Bonesupport AB, Sweden) using a newly developed augmentation method described earlier. The lag-screws from both groups were then pulled out at a displacement rate of 0.5 mm/s until failure. Peak extraction force was recorded for each specimen along with photographs of the screws post-extraction. A non-parametric t-test was used to compare the two groups. CaS/HA augmentation of the lag-screw led to a 650% increase in the peak extraction force compared with the controls (p<0.01). Photographs of the augmented samples shows failure of the saw-bones further away from the implant-bone interface indicating a protective effect of the CaS/HA material. We present a novel method to enhance the immediate mechanical anchorage of a lag-screw to osteoporotic bone and it is also envisaged that CaS/HA augmentation combined with systemic bisphosphonate treatment can lead to new bone formation and aid in the reduction of implant failures and re-operations

Our knowledge of primary bone marrow edema (BME) of the knee is still limited. A major contributing factor is that it shares several radiological findings with a number of vascular, traumatic, and inflammatory conditions having different histopathological features and etiologies. BME can be primary or secondary. The most commonly associated conditions are osteonecrosis, osteochondritis dissecans, complex regional pain syndrome, mechanical strain such as bone contusion/bruising, micro-fracture, stress fracture, osteoarthritis, and tumor. The etiology and pathogenesis of primary BME are unclear. Conservative treatment includes analgesics, non-steroidal anti-inflammatory drugs, weight-bearing limitations, physiotherapy, pulsed electromagnetic fields, prostacyclin, and bisphosphonates. Surgical treatment, with simple perforation, fragment stabilization, combined scraping and perforation, and eventually osteochondral or chondrocyte transplant, is reserved for the late stages. This retrospective study of a cohort of patients with primary BME of the knee was undertaken to describe their clinical and demographic characteristics, identify possible risk factors, and assess treatment outcomes. We reviewed the records of 48 patients with primary BME of the knee diagnosed on MRI by two radiologists and two orthopedists. History, medications, pain type, leisure activities, smoking habits, allergies, and environmental factors were examined. Analysis of patients’ characteristics highlighted that slightly overweight middle-aged female smokers with a sedentary lifestyle are the typical patients with primary BME of the knee. In all patients, the chief symptom was intractable day and night pain (mean value, 8.5/10 on the numerical rating scale) with active as well as passive movement, regardless of BME extent. Half of the patients suffered from thyroid disorders; indeed, the probability of having a thyroid disorder was higher in our patients than in two unselected groups of patients, one referred to our orthopedic center (odds ratio, 18.5) and another suffering from no knee conditions (odds ratio, 9.8). Before pain onset, 56.3% of our cohort had experienced a stressful event (mourning, dismissal from work, concern related to the COVID-19 pandemic). After conservative treatment, despite the clinical improvement and edema resolution on MRI, 93.8% of patients described two new symptoms: a burning sensation in the region of the former edema and a reduced ipsilateral patellar reflex. These data suggest that even though the primary BME did resolve on MRI, the knee did not achieve full healing

Aims. Bone health assessment and the prescription of medication for secondary fracture prevention have become an integral part of the acute management of patients with hip fracture. However, there is little evidence regarding compliance with prescription guidelines and subsequent adherence to medication in this patient group. Patients and Methods. The World Hip Trauma Evaluation (WHiTE) is a multicentre, prospective cohort of hip fracture patients in NHS hospitals in England and Wales. Patients aged 60 years and older who received operative treatment for a hip fracture were eligible for inclusion in WHiTE. The prescription of bone protection medications was recorded from participants’ discharge summaries, and participant-reported use of bone protection medications was recorded at 120 days following surgery. Results. Of 5456 recruited patients with baseline data, 2853 patients (52%) were prescribed bone protection medication at discharge, of which oral bisphosphonates were the most common, 4109 patients (75%) were prescribed vitamin D or calcium, and 606 patients (11%) were not prescribed anything. Of those prescribed a bone protection medication, only 932 patients (33%) reported still taking their medication 120 days later. Conclusion. These data provide a reference for current prescription and adherence rates. Adherence with oral medication remains poor in patients with hip fracture. Cite this article: Bone Joint J 2019;101-B:1402–1407

Total knee arthroplasty (TKA) is known to lead to a reduction in periprosthetic bone mineral density (BMD). In theory, this may lead to migration, instability and aseptic loosening of the prosthetic components. Bisphosphonates inhibit bone resorption and may reduce this loss in BMD. We hypothesised that treatment with bisphosphonates and calcium would lead to improved BMD and clinical outcomes compared with treatment with calcium supplementation alone following TKA. A total of 26 patients, (nine male and 17 female, mean age 67 years) were prospectively randomised into two study groups: alendronate and calcium (bisphosphonate group, n = 14) or calcium only (control group, n = 12). Dual energy X-ray absorptiometry (DEXA) measurements were performed post-operatively, and at three months, six months, one, two, four, and seven years post-operatively. . Mean femoral metaphyseal BMD was significantly higher in the bisphosphonate group compared with controls, up to four years following surgery in some areas of the femur (p = 0.045). BMD was observed to increase in the lateral tibial metaphysis in the bisphosphonate group until seven years (p = 0.002), and was significantly higher than that observed in the control group throughout (p = 0.024). There were no significant differences between the groups in the central femoral metaphyseal, tibial medial metaphyseal or diaphyseal regions of interest (ROI) of either the femur or tibia. Bisphosphonate treatment after TKA may be of benefit for patients with poor bone quality. However, further studies with a larger number of patients are necessary to assess whether this is clinically beneficial. Cite this article: Bone Joint J 2015;97-B:337–45

Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that they may be associated with rare atypical femoral fractures. 1480 patients of proximal femur and shaft fractures over a period of 2 years from Jan 2014 to Jan 2016 were retrospectively reviewed in Gloucestershire Hospitals NHS trust. Hospital trauma database was used.195 patients had fractures in subtrochancteric and femoral shaft area. 11 patients had atypical femur fractures as defined by American society for bone and mineral research (ASBMR) task force 2013, revised criteria. Ten were female, one was male. Patients were aged from 68 to 97. In 6 patients, fractures were in the shaft, 5 in subtrochancteric area and 4 patients out of these had bilateral fractures. 10 out of 11 patients were on bisphosphonates. 4 patients had delayed diagnosis. 5 out of 11 patients did not have contralateral femoral x-rays. Treatment, 9 patients had intramedullary nail, one blade plate, and one treated conservatively. One patient in the IM group, had bilateral nailing. Average follow up was 7.6 months (range 1 to 16 months). At the end of the study, only 4 had united, 6 had not united and one not followed up. 4 out of 7 had low Vitamin D levels, 3 out of 7 had their bisphosphonate treatment stopped and 2 had histology which showed necrotic bone with trabeculae surrounded by fibrosis. Increasing number of patients are on bisphosphonates for osteoporosis. Atypical femur fractures from bisphosphonates are often occult, often bilateral, with delayed healing. Patients on bisphosphonatetreatment should be advised to report any thigh or groin pain. Painful incomplete fractures need treatment with cephalomedullary nailing. Bone biology needs correcting by stopping bisphosphonatesand administering calcium & vitamin D supplements. Implications: We need to raise awareness amongst treating clinicians and have national guidelines

Abstract. Background. Atypical femur fracture (AFF) is a well known complication of Bisphosphonate therapy. Due to prolonged suppression of bone re-modelling in these fractures, surgical complications are difficult to manage. The aim of this study was to analyze the causes of surgical complications in AFF fixations and provide algorithm for management. Method. In this retrospective 10-year study (2010–2020), we identified patients surgically treated for AFF. We included patients who underwent revision surgery for any cause. Data collection included demographics, surgical complications, details of revision surgery and time to union. Result. Out of 57 patients who were operated for AFF, 17 underwent revision fixation. The average age was 69 with only 2 males. Around two-third (64%) were sub-trochanteric fractures and method of fixation in 64% cases was intra-medullary nail. The most common complication was non-union (12), followed by stress fracture and infection in 3 and 2 cases respectively. In most cases inadequate reduction and sub-optimal fixation was perceived as cause of failure except two cases which got infected. Revision fixation in all cases included improved bone contact (non-union site osteotomy), use of bone morphogenic proteins and improved fixation with augmentation device (either nail or plate). Follow up at 1 year showed fracture union in 12 cases, remaining 5 revision fixations failed, 3 of which were managed with proximal femur replacement. Conclusion. High rate of non-union after fixation in AFF. Optimizing the fixation construct results in union in most cases. However, arthroplasty should be considered in elderly patients with poor bone quality

There is strong evidence to support the use of bisphosphonates in the prevention of osteoporotic fractures. There has, however, been growing concern that prolonged use of bisphosphonates can lead to the development of atypical femoral fractures and can protract healing time. We conducted a retrospective study looking at all femoral fractures between 2011–2013. Of 109 patients, 12 were diagnosed with atypical femoral fractures. The mean age of presentation was 69 (52–92). Five patients held no history of falls and presented with hip pain. The remaining seven sustained minor falls. Seven patients were on bisphosphonates on presentation. Bisphosphonates were discontinued in five cases and continued in two. Bisphosphonates commenced in one patient who subsequently developed second fracture. All fractures were managed with intramedullary nailing. Healing time was prolonged in all cases (mean healing time 7.3 months). Three patients needed further surgeries to achieve union. Overall, we observed that patients with prolonged bisphosphonate intake were more susceptible to atypical fractures with a delayed recovery time. Increasing awareness amongst medical professionals may aid timely diagnoses and subsequent referrals to orthopaedics. Recognition of these fractures may also permit early discontinuation of bisphosphonates, which may prevent future fractures and reduced healing times

Introduction and Objective. Some periprosthetic femoral fractures (PFFs) present history and radiographic aspect consistent with an atypical femoral fracture (AFF), fulfilling the criteria for AFF except that PFFs by themselves are excluded from the diagnosis of AFFs. The aim of this study was to evaluate in a single Institution series of PFFs if any of them could be considered a periprosthetic atypical femoral fracture (PAFF), and their prevalence. Materials and Methods. Surgical records were searched for PFFs around a primary hip stem from January 2013 to December 2019. Cases were classified according to Vancouver classification. Demographic and medical history were extracted. Fisher's exact test was used for statistical analysis. Results. One-hundred-fifteen PFFs were identified, 59 of them were type B1 and 16 were type C. Radiographs and medical records were available for all patients. Twenty-four patients (32%) have been treated with bisphosphonates (BPs) for longer than 4 years. Four patients presented a fracture with characteristics of PAFF. When enlarged to all PFFs of the series, no other PAFF was found: prevalence of PAFFs was 5.3% for type B1 and C cases and 3.5% for all surgically treated PFFs. Statistical significative difference between PAFFs and PFFs was found for prolonged BPs assumption and for the level of fracture clear of the stem. Conclusions. Fracture with characteristics of AFFs can also happen over a prosthetic stem, configuring themselves as PAFFs, and they are related to prolonged BPs use. As a correct diagnosis is mandatory for proper treatment, a revision of criteria for AFFs should be considered, accepting that PAFFs exist

This prospective multicentre study was undertaken to determine whether the timing of the post-operative administration of bisphosphonate affects fracture healing and the rate of complication following an intertrochanteric fracture. Between August 2008 and December 2009, 90 patients with an intertrochanteric fracture who underwent internal fixation were randomised to three groups according to the timing of the commencement of risedronate treatment after surgery: Group A (from one week after surgery), Group B (from one month after surgery), and Group C (from three months after surgery). The radiological time to fracture healing was assessed as the primary endpoint, and the incidence of complications, including excessive displacement or any complication requiring revision surgery, as the secondary endpoint. The mean time to fracture healing post-operatively in groups A, B and C was 10.7 weeks (. sd. 4.4), 12.9 weeks (. sd. 6.2) and 12.3 weeks (. sd. 7.1), respectively (p = 0.420). At 24 weeks after surgery, all fractures had united, except six that had a loss of fixation. Functional outcomes at one year after surgery according to the Koval classification (p = 0.948) and the incidence of complications (p = 0.386) were similar in the three groups. This study demonstrates that the timing of the post-operative administration of bisphosphonates does not appear to affect the rate of healing of an intertrochanteric fracture or the incidence of complications

Aims. The Fassier Duval (FD) rod is a third-generation telescopic implant for children with osteogenesis imperfecta (OI). Threaded fixation enables proximal insertion without opening the knee or ankle joint. We have reviewed our combined two-centre experience with this implant. Methods. In total, 34 children with a mean age of five years (1 to 14) with severe OI have undergone rodding of 72 lower limb long bones (27 tibial, 45 femoral) for recurrent fractures with progressive deformity despite optimized bone health and bisphosphonate therapy. Data were collected prospectively, with 1.5 to 11 years follow-up. Results. A total of 24 patients (33%) required exchange of implants (14 femora and ten tibiae) including 11 rods bending with refracture. Four (5%) required reoperation with implant retention. Loss of proximal fixation in the femur and distal fixation in the tibia were common. Four patients developed coxa vara requiring surgical correction. In total, 13 patients experienced further fractures without rod bending; eight required implant revision. There was one deep infection. The five-year survival rate, with rod revision as the endpoint, was 63% (95% confidence interval (CI) 44% to 77%) for femoral rods, with a mean age at implantation of 4.8 years (1.3 to 14.8), and 64% (95% CI 36% to 82%) for tibial rods, with a mean age at implantation of 5.2 years (2.0 to 13.8). Conclusion. FD rods are easier to implant but do not improve on the revision rates reported for second generation T-piece rods. Proximal femoral fixation is problematic in younger children with a partially ossified greater trochanter. Distal tibial fixation typically fails after two years. Future generation implants should address proximal femoral and distal tibial fixation to avoid the majority of complications in this series. Cite this article: Bone Joint J 2020;102-B(8):1048–1055

Several bisphosphonates are now available for the treatment of osteoporosis. Porous hydroxyapatite/collagen (HA/Col) composite is an osteoconductive bone substitute which is resorbed by osteoclasts. The effects of the bisphosphonate alendronate on the formation of bone in porous HA/Col and its resorption by osteoclasts were evaluated using a rabbit model. Porous HA/Col cylinders measuring 6 mm in diameter and 8 mm in length, with a pore size of 100 μm to 500 μm and 95% porosity, were inserted into a defect produced in the lateral femoral condyles of 72 rabbits. The rabbits were divided into four groups based on the protocol of alendronate administration: the control group did not receive any alendronate, the pre group had alendronate treatment for three weeks prior to the implantation of the HA/Col, the post group had alendronate treatment following implantation until euthanasia, and the pre+post group had continuous alendronate treatment from three weeks prior to surgery until euthanasia. All rabbits were injected intravenously with either saline or alendronate (7.5 μg/kg) once a week. Each group had 18 rabbits, six in each group being killed at three, six and 12 weeks post-operatively. Alendronate administration suppressed the resorption of the implants. Additionally, the mineral densities of newly formed bone in the alendronate-treated groups were lower than those in the control group at 12 weeks post-operatively. Interestingly, the number of osteoclasts attached to the implant correlated with the extent of bone formation at three weeks. In conclusion, the systemic administration of alendronate in our rabbit model at a dose-for-weight equivalent to the clinical dose used in the treatment of osteoporosis in Japan affected the mineral density and remodelling of bone tissue in implanted porous HA/Col composites

Introduction and Objective. Aneurysmal bone cyst (ABC) of the spine is a locally aggressive benign lesion which can be treated by en bloc resection with wide margin to reduce the risk of local recurrence. To avoid morbidity associated with surgery, selective arterial embolization (SAE) can be considered the first-line treatment for ABCs of the spine. Other emerging treatments for ABCs include bisphosphonates, percutaneous doxycycline, sclerotherapy and Denosumab. In addition, we previously introduced the use of autologous bone marrow concentrate (BMC) injection therapy to stimulate bone healing and regeneration in ABC of the spine. One of the potential advantages of such a method is that surgical treatments are not necessary, thus allowing for both a minimally invasive approach and the treatment of poorly accessible lesions. In this prospective study we described the clinical and radiological outcomes of percutaneous injection of autologous BMC in a series of patients affected by ABCs of the spine and followed for at least one year. Materials and Methods. Fourteen patients (6 male, 8 female) were treated between June 2014 to December 2019 with BMC injection for ABC of the spine. The mean age was 17.85 years. The mean follow up was 37.4 months (range 12– 60 months). The dimension of the cyst and the degree of ossification were measured by Computed Tomography (CT) scans before the treatment and during follow-up visits. Results. Six patients received a single dose of BMC, five patients received two doses and in three patients three doses of BMC were administered. The mean ossification of the cyst (expressed in Hounsfield units) increased statistically from 43.48±2.36 HU to 161.71±23.48 HU during follow-up time and the ossification was associated to an improvement of the clinical outcomes. The mean ossification over time was significantly higher in patients treated with a single injection compared to patients treated with multiple injections. No significant difference in ossification was found between cervical and non-cervical localization of the cyst. Moreover, the initial size of the cyst was not statistically associated with the degree of ossification during follow-up. We also observed that five out of six female patients (83.3%) were less than sixteen years old and four of these (66.7%) were managed with a single dose of BMC injection, while a higher percentage of male patients (6/8, 75%) were more than sixteen years old and more than one injection was administered to them. Conclusions. The results of this study reinforce our previous evidence on the use of BMC as a valid alternative for spinal ABC management when SAE is contraindicated or ineffective. The initial size of the cyst and its localization does not influence the efficacy of the treatment. However, BMC injection could be indicated as treatment of choice for spinal ABC in young adolescent women

We have examined the deterioration of implant fixation after withdrawal of parathyroid hormone (PTH) in rats. First, the pull-out force for stainless-steel screws in the proximal tibia was measured at different times after withdrawal. The stimulatory effect of PTH on fixation was lost after 16 days. We then studied whether bisphosphonates could block this withdrawal effect. Mechanical and histomorphometric measurements were conducted for five weeks after implantation. Subcutaneous injections were given daily. Specimens treated with either PTH or saline during the first two weeks showed no difference in the mechanical or histological results (pull-out force 76 N vs 81 N; bone volume density 19% vs 20%). Treatment with PTH for two weeks followed by pamidronate almost doubled the pull-out force (152 N; p < 0.001) and the bone volume density (37%; ANOVA, p < 0.001). Pamidronate alone did not have this effect (89 N and 25%, respectively). Thus, the deterioration can be blocked by bisphosphonates. The clinical implications are discussed

Over 200,000 osteoporotic fractures occur in the UK annually. Patients with fragility fractures are at highest risk of further fracture, though preventative treatment has been shown to reduce subsequent fracture incidence. In 2005, the National Institute for Health & Clinical Excellence (NICE) recommended bisphosphonates as a treatment option in women over 75 years without the need for prior DEXA scanning (Technology Appraisal Guidance 87). We prospectively reviewed the medication of such patients who were admitted to our Trauma Unit to identify if the NICE guidance was being followed. Over a three month period between May and July 2007, 54 women over 75 years old were discharged from our Trauma Unit having sustained an osteoporotic fracture. We prospectively reviewed their medication to identify if a bisphosphonate had been commenced by the General Practitioner and their discharge letters to their General Practitioners to see if it had been suggested to start one. 7 of the 54 women (13%) were already on a bisphosphonate and were therefore excluded. Only one (2%) of the discharge letters (written by the Orthopaedic doctor to the General Practitioner) recommended commencing a bisphosphonate. 6 of the 47 patients (13%) had been started on a bisphosphonate by the General Practitioner. Nice guidance from 2005 is clearly not being implemented in our area. A minority of patients will have contraindications or allergies to bisphosphonates (up to 1 in 4 patients as highlighted recently by the National Osteoporosis Society). Important deficiencies in local services have been identified, particularly with respect to communication between secondary and primary care. This study lead to an education initiative to ensure the Trauma department and our local General Practitioners were aware of the NICE guidance. A second prospective audit is currently being undertaken to assess the effect on our service

Introduction. We have previously published limb lengthening using external fixation in pathological bone diseases. We would like to report a case series of femoral lengthening using the PRECICE system in a similar pathological group especially looking at it's feasibility and complications. Materials and Methods. This is a case series of four patients, two patients with osteogenesis imperfecta and two with Ollier's disease, who underwent femoral lengthening via distraction osteogenesis using the PRECICE intramedullary nail system. It was a retrospective study from a prospective database from clinical records and radiographs. Results. The mean age at the time of surgery was 15.5 years, the mean preoperative leg length discrepancy was 30mm, and the mean distraction distance achieved was 28.75mm. Since these patients were of shorter heigh, limb lengthening was considered. All 4 patients had successful insertion of the nail. The outcomes noted from the 4 patients are collated, with several complications occurring including delayed femoral union, fixed flexion deformity of the hip, persisting pain and quadriceps weakness. Those with Ollier's disease underwent an increased rate of distraction to prevent premature healing. The implications of long-term bisphosphonate therapy in OI are discussed with regards to the risk of delayed femoral union and intra-operative fracture. Conclusions. Intramedullary femoral lengthening in pathological bone disease is possible, but the surgeon needs to give attention to certain details. The regenerate formation is based on the background pathology irrespective of the hardware used. There is much more compliance with the nail technique

Introduction: Over 200,000 osteoporotic fractures occur in the UK annually. Patients with fragility fractures are at highest risk of further fracture, though preventative treatment has been shown to reduce subsequent fracture incidence. In 2005, the National Institute for Health & Clinical Excellence (NICE) recommended bisphosphonates as a treatment option in women over 75 years without the need for prior DEXA scanning (Technology Appraisal Guidance 87). We prospectively reviewed the medication of such patients who were discharged from our Trauma Unit to identify if the NICE guidance was being followed. Method: Over a three month period between May and July 2007, 54 women over 75 years old were discharged from our Trauma Unit having sustained an osteoporotic fracture. We prospectively reviewed their medication to identify if a bisphosphonate had been commenced by the General Practitioner and their discharge letters to their General Practitioners to see if it had been suggested to start one. Results: 7 of the 54 women (13%) were already on a bisphosphonate and were therefore excluded. Only one (2%) of the discharge letters (written by the Orthopaedic doctor to the General Practitioner) recommended commencing a bisphosphonate. 6 of the 47 patients (13%) had been started on a bisphosphonate by the General Practitioner. Conclusions: Nice guidance from 2005 is clearly not being implemented in our area. Some patients will have contraindications or allergies to bisphosphonates, however, they will be a minority (up to 1 in 4 patients as highlighted recently by the National Osteoporosis Society). We believe the results demonstrate a lack of health promotion opportunities to prevent future fracture. Although there is clear focus and impetus for developing falls prevention services nationwide, this enthusiasm has not been translated across to bone health, despite the potential savings in terms of morbidity, mortality and healthcare costs. Important deficiencies in local services have been identified, particularly with respect to communication between secondary and primary care. This study lead to an education initiative to ensure the Trauma department and our local General Practitioners were aware of the NICE guidance. A second prospective audit is currently being undertaken to assess the effect on our service

Bone marrow lesions (BMLs), identified by MRI, are defined as a region of cancellous bone with high T2 and low T1 signal intensity. They are associated with various knee pathologies including spontaneous osteonecrosis of the knee (SPONK), AVN, trauma (fracture and bone contusion), following arthroscopy and secondary to overuse (i.e., after completing a marathon). They also are commonly recognised in patients with knee OA (referred to as OA-BMLs) and their substantial importance in knee OA pathogenesis has been recently identified. Depending upon the etiology (i.e., bone contusion, overuse, etc.) of the BML, these lesions can be “acute” in nature and spontaneously resolve over time. However, OA-BMLs generally are considered to be a “chronic” condition and overtime they have been shown to often persist and increase in size. Retrieval studies following THA and TKA, in patients with a preoperatively identified BML, have greatly expanded our understanding of OA – BMLs and these investigations consistently identify the critical role subchondral bone plays in OA disease progression. Histologic, histochemical and mechanical studies of OA-BMLs demonstrate significant alternations from healthy subchondral bone. The effected bone contains regions where fibrous tissue has replaced cancellous bone, microfractures are present and vascularity is increased. There is an increased concentration of inflammatory mediators and the bone structural integrity is compromised. Standard radiographs of the knee correlate only modestly with patient symptoms, but conversely, the presence of an OA-BML is an extremely strong predictor of pain and knee joint dysfunction. Felson et al. reported this relationship. In a large group of patients with painful knee OA, 77.5% of these patients had a BML. Both the presence and size of the BML, following multiregression analysis, were significant predictors of knee pain severity. Additionally, likely secondary to inadequate subchondral bone plate support, the presence of an OA-BML is associated with subchondral bone attrition (SBA). SBA leads to collapse of the subchondral bone plate and progressive joint deformity. Based on the association of an OA-BML with pain, joint dysfunction and deformity, it is not surprising that these lesions are prognostic for patients seeking knee arthroplasty. Several studies have demonstrated that the odds of knee arthroplasty performance are substantially higher in patents with an OA-BML. This enhanced understanding of knee OA pathogenesis and the critical role of subchondral bone in this process creates an opportunity for development of novel prevention and treatment strategies. Prevention of OA-BML formation has been considered and pharmacologic interventions proposed. Recent studies have reported positive results for treatment with bisphosphonates in patients with knee OA. One study reported significant pain and OA-BML size reduction in patients receiving a bisphosphonate for 4 months. A strategy aimed at repairing and/or enhancing subchondral bone compromised by an OA-BML has also been proposed. Early results reported with this intervention are encouraging, but preliminary

Over the last 10 years atypical femoral fractures (AFFs) have become recognised as a complication of standard-dose bisphosphonate use. In 2014 the American Society for Bone and Mineral Research published updated diagnostic criteria for AFF. We undertook a 5-year retrospective analysis of the trauma admission database at a major trauma centre to establish the incidence of this problem in our patient population. Initial screening was performed using keyword-matching methodology to produce a shortlist of patients with low-energy femoral fractures. These patients’ case notes, radiographs, and electronic discharge summaries were reviewed to discriminate AFF from typical femoral fractures. Initial filtering identified a total of 112 low energy femoral fractures. Of these, 12 were confirmed as AFFs. 58% (7/12) of the AFF group were on bisphosphonates compared to 15% (15/100) of the typical femoral fracture group. This finding was statistically significant (p = 0.0004). These data show that there is a link between bisphosphonate use and AFF. However, a causal relationship cannot be inferred. The incidence of AFF in our study is broadly in line with the published data

Background: In a previous randomized studiy using Röntgen Stereometric Analysis (RSA), we showed that oral bisphosphonates reduce the mean migration distance during the first 6 months. In a similar randomized study, bisphosphonates applied locally at the operation had a similar effect. These studies showed a 0.1 mm difference in mean value between groups. Does such a small difference matter? We addressed this question by use of frequency analysis. Methods: The 2 previous studies were combined for analysis, and designated as bisphosphonate (n=44) or control treated (n=49). We analysed the migration vector (for the center of the rigid body) by use of a set of algoritms for frequency distribution analysis called Rmix. The migration vector lengths were assumed to be a compound of log-normal distributions. The frequency analysis determined if the observed frequency distributions were best described as a single, or a sum of 2 or more lognormally distributed subgroups. Results: After 6 months, the control patients had formed 2 subgroups, one comprising 85% of the patients. The dichotomy was significant (p=0.016). After 2 years, the dichotomy persisted (p=0.027). In the bisphosphonate-treated patients, no dichotomies could be found. The distribution of the migration vector length appeared similar to the larger and less migrating subgroup among the controls. Discussion: The risk of aseptic loosening for cemented knees is extremely small. However, the migrating subgroup among our control patients may be at risk of loosening, and would have run a high risk if they were young and active. This subgroup did not appear with bisphosphonate treatment. Summary: In previous comparisons we found a slight decrease in mean value with bisphosphonates. The present analysis shows that this reflects the disappearance of a small subgroup with large migration

Targeted delivery of drugs is a major challenge in diseases such as infections and tumors. The aim of this study was to demonstrate that hydroxyapatite (HA) particles can act as a recruiting moiety for various bioactive molecules and as a proof-of-concept demonstrate that the affinity of drugs to hydroxyapatite can exert a biological effect. A bisphosphonate, zoledronic acid (ZA), was used as a model drug. Experiment 1 (ZA seeks HA): Calcium sulphate (CaS)/hydroxyapatite (HA) biomaterial pellets (diameter¸=5 mm, height=2 mm) were implanted in the abdominal muscle pouch of rats. After 2-weeks of implantation, a sub-cutaneous injection of 14C-ZA (0.1 mg/kg) was given. 24 h later, the animals were sacrificed and the uptake of ZA determined in the pellets using scintillation counting. Experiment 2 (Systemically administered ZA seeks HA and exerts a biological effect): A fenestrated implant was filled with the CaS/HA biomaterial and inserted in the proximal tibia of rats. 2-weeks post-op, a subcutaneous injection of ZA (0.1 mg/kg) was given. Animals were sacrificed at 6-weeks post-op. Empty implant was used as a control. Peri-implant bone formation was evaluated using different techniques such as micro-CT, mechanical testing and histology. Welch's t-test was used for mechanical testing and Mann-Whitney U test for micro-CT data analysis. Experiment 1: Uptake of radioactive ZA in the CaS/HA biomaterial was confirmed. Almost no ZA was present in the surrounding muscle. These results show high specific binding between systemically administered ZA and synthetic particulate HA. Experiment 2: Significantly higher peri-implant bone was measured using micro-CT in the group wherein the implant contained the CaS/HA biomaterial and ZA was administered systemically (This study presents a method for biomodulating HA in situ by different bioactive molecules. The approach of implanting a biomaterial capable of recruiting systemically given drugs and thereby activate the material is novel and may present a possibility to treat bone infections or tumors

Aims. Treatment guidelines for atypical femoral fractures associated with bisphosphonates have not been established. We conducted a systematic review of the treatment of atypical femoral fractures first, to evaluate the outcomes of surgical fixation of complete atypical fractures and secondly, to assess whether prophylactic surgery is necessary for incomplete atypical fractures. Materials and Methods. Case reports and series were identified from the PubMed database and were included if they described the treatment of atypical femoral fractures. In total, 77 publications met our inclusion criteria and 733 patients with 834 atypical complete or incomplete femoral fractures were identified. Results. For complete fractures, internal fixation was predominantly achieved by intramedullary nailing. The mean time to healing post-operatively was 7.3 months (2 to 31). Revision surgery for nonunion or implant failure was needed in 77 fractures (12.6%). A greater percentage of fractures treated with plate fixation (31.3%) required revision surgery than those treated with intramedullary nailing (12.9%) (p < 0.01). Non-operative treatment of incomplete fractures failed and surgery was eventually needed in nearly half of the patients (47%), whereas prophylactic surgery was successful and achieved a 97% rate of healing. Conclusion. Intramedullary nailing is the first-line treatment for a complete fracture, although the risk of delayed healing and revision surgery seems to be higher than with a typical femoral fracture. Non-operative treatment does not appear to be a reliable way of treating an incomplete fracture: prophylactic intramedullary nailing should be considered if the patient is in intractable pain. Radiographs of the opposite side should be obtained routinely looking for an asymptomatic fracture. Bisphosphonates must be discontinued but ongoing metabolic management in the form of calcium and/or vitamin D supplements is advisable. Teriparatide therapy can be considered as an alternative treatment. Cite this article: Bone Joint J 2017;99-B:295–302

There is a paradox surrounding the use of bisphosphonates and bone biology. On one hand, it has been used to treat osteoporosis, osteogenesis imperfecta, Pagets disease, osteonecrosis, and other disorders associated with low bone mass. On the other hand, there have been a number of cases reported suggesting an association between treatment with bisphosphonates and osteonecrosis of the jaw. Answers to why this paradox exists lies in a better understanding of the pathogenesis of osteonecrosis and the mechanism of action of bisphosphonates. This seminar was created to explore the perspectives of three different medical disciplines concerning the use of bisphosphonates

Bone metastases are the most common cause of cancer-related pain and often lead to other complications such as pathological fractures and spinal cord compression. Bisphosphonates (BP) are a class of potent anti-resorptive agents commonly prescribed to retard osteoporosis progression. Interestingly, BP may have indirect anti-tumour properties through negative effects on macrophages, osteoclasts, endothelial cells and their ability to suppress matrix metalloproteinase (MMP) activity. Currently, the use of bisphosphonates for cancer therapy is generally restricted to high dose systemic delivery. The purpose of this study was to investigate the effects of direct local delivery of Zoledronate at the metastatic site in a mouse model of breast cancer metastasis to bone. Seven days following intra-tibial inoculation with MDA-MB-231 (N = 1× 105) breast cancer cells in athymic mice, the experimental group (N = 11) was treated by direct infusion of 2µg of Zoledronate into the tibial lesion (three times/week for three weeks) and compared to vehicle-treated mice (N = 5). The formation of bone metastases and growth of the lesions were followed up by weekly bioluminescence imaging. In a subsequent experiment, a comparison of the effects of local versus systemic delivery of Zoledronate on the formation of osteolytic bone metastases was carried in athymic mice (N = 15). Seven days following intra-tibial inoculation with MDA-MB-231 breast cancer cells, the systemic group (N = 5) was treated with Zoledronate (0.025mg/kg) once per week for four weeks and compared to systemic delivery of vehicle (N = 4). Following treatment, the mice were sacrificed, and micro-CT images of the right tibia were obtained. Bone volume to tissue volume ratio (BV/TV%) was determined using µ-CT biomarkers. The first experiment showed a statistically significant increase in mean bone volume/tissue volume ratio% (BV/TV%) in the treated group (7.0±1.54%) as compared to the control group (3.8±0.48%) (P <0.001, 95%CI=1.9–4.3). This corresponded to a net increase of 84.21% in response to Zoledronate treatment. Comparison between the local and systemic effects of Zoledronate also revealed a significant increase in the BV/TV% in the locally treated group (6.69±0.62%) when compared to the cohort administered systemic bisphosphonate treatment (4.03±0.44%) (P<0.001, 95%CI=1.24–3.20), corresponding to a net increase of 66.0%. These preliminary results suggest that high dose sustained release of Zoledronate can lead to a significant inhibition of tumor-induced osteolysis. Moreover, comparison between local and systemic delivery revealed that the effect of local bisphosphonate administration exceeds the benefits of systemic delivery in terms of osteolysis inhibition. Lastly, the noted effects of Zoledronate local delivery triggers the need for further assessment of its anti-tumour activity

Osteoporosis affects over 350,000 New Zealanders including 30% of women aged over 60 years and more than half aged over 80. Osteoporotic fractures are a significant cause of morbidity and mortality. From July 1999 to 30 June 2000, 3131 people aged over 65 sustained a fractured neck of femur. 27% died in the subsequent 12 months, equating to 17% of all cause mortality. Fractures are also a significant economic burden. In the period, July 2005 to June 2006, over $18 million was spent on hip fractures in those aged over 65 years. Bisphosphonates improve Bone Mineral Density and consequently reduce the incidence of fracture; however oral bisphosphonates are contraindicated in some patients. Zoledronate is an intravenous bisphosphonate that has recently been licensed for osteoporosis treatment. We undertook a retrospective chart review and General Practitioner consultation of CMDHB patients who received zoledronate from June 2006 to June 2008. Assessment of clinician compliance with current safety protocols, patient outcomes and side effects were assessed. 78 patients received 101 doses of zoledronate, approximately double the preceding 2 year period (37 patients and 60 administrations). The most commonly indication was osteoporosis. 19% (19/101) administrations were organised through the geriatric clinic and 81% (82/101) were inpatients. Bone Mineral Densities within 2 years were available for 59% (48/82) of administrations. 80% (51/64) had previous osteoporotic fractures. 84% (54/64) of osteoporotic patients were utilising additional calcium and vitamin D therapy. Oral bisphosphonates were contraindicated in 94% (60/64) because of gastrointestinal upset, 3% (2/64) for headaches and 3% (2/64) for worsened BMD despite oral bisphosphonates. Following treatment 13% (8/64) of patients sustained further fractures. In inpatient administration 83% (21/82) pre-creatinine and 80% (66/82) post-creatinine measurements were appropriately assessed in comparison to 58% (11/19) and 79% (15/19) respectively for clinic patients. In inpatients administration 59% (48/82) pre-calcium and 63% (52/82) post-calcium measurements were appropriately assessed in comparison to 37% (7/19) and 68% (13/19) respectively for clinic patients. For GP follow-up of creatinine and calcium measurements, 90% had creatinine and 80% had calcium correctly assessed. Zoledronate was well tolerated with no jaw osteonecrosis in this cohort. Zoledronate is a well tolerated treatment for osteoporosis in those patients intolerant of oral bisphosphonates. The use of zoledronate has more than doubled in the last 2 years. Stricter adherence to current guidelines is needed to prevent incipient adverse effects

Introduction. Long-term use of bisphosphonates has been known to induce femoral insufficiency fracture in osteoporotic patients. We followed patients who had femoral insufficiency fractures after a long-term use of bisphosphonates. Methods. Eleven patients (14 hips) were diagnosed as having an insufficiency fracture of the femur after long-term (> 4 years) use of bisphosphonate to treat osteoporosis between January 2002 and December 2008. All patients were women who had a mean age of 68 years (range, 57 to 82 years). The fracture site was located in the subtrochanteric area in 6 hips and the femoral shaft in 8 hips. Three patients had bilateral involvement. These patients were followed-up for a mean of 27 months (range, 12 to 60 months). Results. Five hips in five patients displaced during the follow-up period. The mean period from the diagnosis of insufficiency fracture to the displacement was 10 months (range, 1 to 19 months). Five hips (five patients) underwent internal fixation due to persistent pain. Thus, during the follow-up of 27 months, operation was necessary in 71% (10 hips) of 14 insufficiency fractures. Four hips (four patients) that did not undergo any operation had persistent pain at the latest follow-up. Conclusion. The insufficiency fractures after prolonged bisphosphonate therapy seldom healed spontaneously and most of them required operation due to fracture displacement or persistent pain. We recommend preventive surgery to prevent further fracture displacement and persistent pain

Introduction: Conflicting opinions exist as to whether bone healing is affected by the administration of bisphosphonates for osteoporosis. In an animal model, we assessed the effect of bisphosphonates on osteoporotic fracture healing and whether the timing of administration made a difference. Methods: 36 female Wistar rats underwent a mid-diaphyseal femoral osteotomy six weeks after ovariectomy. They were then divided into 3 groups:. no treatment (control);. administration of alendronate (ALN) from 14 days after osteotomy;. ALN from the time of osteotomy. Fracture repair was assessed weekly with the use of standardised radiography, DEXA scan and in vitro peripheral quantative computed tomography (pQCT). The rats were sacrificed 42 days post-osteotomy and the femora underwent mechanical testing. Results: Of the 36 rats, 8 were unable to complete the study. Group 3 differed from control in three respects: higher bone mineral content (BMC) and density (BMD); larger callus; lower torsional stiffness. Group 2 did not differ significantly from control. There was a significant positive correlation between stiffness and change in BMC in group 1 (r=0.85, p< 0.001) but not so for group 2 (r=0.2, p> 0.05) and group 3 (r=0.04, p> 0.05). A similar trend existed for all radiographic parameters in the three groups. Conclusion: The results suggest that, with early bisphosphonate treatment, although there is an increase in the size of the callus, that callus is biomechanically inferior. Furthermore, administration of bisphosphonates at either stage destroys the relationship between radiographic and mechanical parameters used to assess fracture healing

The common factor in all (mechanical) prosthetic failure mechanisms is the induction of osteolysis around the endoprosthesis with subsequent prosthetic migration and finally loosening of the prosthesis. Both initial prosthesis-bone fixation and long-term prosthesis survival depend on the quality of the peri-prosthetic bone mass. The effects of treatment of RA patients with prednison are inhibition of osteoblastic activity and inhibition of calcium resorption from the intestines. The bone mass loss during the first six months of prednison treatment is substantial and will seldom be regained. Bisphosphonates are known to decrease osteoclastic activity and may therefore stop osteolysis at the bone-prosthesis interface. The aim of the study was to evaluate a possible association of bisphosphonates with reduced migration of total knee prostheses (Interax, Howmedica Osteonics, Rutherfort, USA) in a high-risk group. Roentgen Stereophotogrammetric Analysis (RSA-CMS, Medis, The Netherlands) was used to measure the micromotion. Retrospectively a group of nine RA patients treated with prednison (non-bisphosphonates group) and a group of fourteen RA patients (bisphosphonates group) treated with prednison in combination with bisphosphonates (Etidronate) were included from a prospective randomized study of 82 patients (. Nelissen et al., 1998. ). At the two-year follow-up evaluation, functional scores and knee scores did not differ significantly among the two groups. At the two-year follow-up evaluation, the non-bisphosphonates group subsided −0.47 ± 0.8 mm, and the bisphosphonates components subsided 0.07 ± 2.9 mm. In the analysis of variance with repeated measurements, with correction for follow-up time, sedimentation rate, and prosthesis fixation type, the bisphosphonates group migrated 1.20 mm less in the total migration (95% c.i.: 1.07–1.30 mm) compared to the non-bisphosphonates group. In this study, bisphosphonates medication in addition to corticosteroid medication was associated with reduced migration of knee prostheses compared to corticosteroid medication alone

Aims: Secondary prevention in patients suffering neck of femur fractures is an effective but under utilised strategy in reducing subsequent fragility fractures. Published BOA guidelines recommend patients aged 75 or over with fragility fractures should receive bisphosphonates, falls risk assessment, and vitamin D supplements if there are concerns regarding deficiency. This audit aimed to determine the effectiveness of implementing secondary prevention strategies in patients admitted with neck of femur fractures. Methods: Patients aged 75 or above admitted to a local trauma unit with neck of femur fractures were identified over a two-year period. In-hospital mortality was recorded. Discharge letters for the remaining patients were obtained. Data was collected on whether patients were commenced on bisphosphonates and vitamin D supplements in hospital, or whether advice was given for these therapies to be initiated in the community. Patients undergoing falls risk assessment prior to discharge were also noted. Results: Overall 549 patients met the inclusion criteria. Eighty patients died during admission giving an in-hospital mortality rate of 14.6% per year. A further 238 patients were excluded due to missing data leaving 231 patients in the final study population. Mean age was 84.4 yr (range 75–97 yr) and 77.9% (n=180) were female. Bisphosphonate therapy was commenced or recommended in 22.9% (n=53), vitamin D supplements in 46.3% (n=107), and 16.5% (n=38) underwent falls risk assessment. Only 4.3% (n=10) were commenced on bisphosphonates and underwent falls risk assessment. Conclusions: Despite evidence that secondary prevention is effective in reducing subsequent fragility fractures our findings demonstrate these strategies are poorly implemented with less than one in twenty patients receiving the recommended falls assessment and antiresorptive therapy. A standardised discharge letter for patients with neck of femur fractures would provide more effective communication between hospitals and primary care thereby assisting the implementation of secondary prevention strategies

The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. . We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage. . Take home message: Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease. Cite this article: Bone Joint J 2016;98-B:160–5

The bisphosphonate, pamidronate, has been used successfully in our hospital for the management of osteogenesis imperfecta with an excellent safety profile in growing children. We have performed several research studies on distraction osteogenesis in New Zealand white rabbits showing significant increases in new bone formation and the abolition of stress shielding osteopaenia using both pamidronate and zoledronic acid. Recent studies have shown that bisphosphonates positively effect osteoblasts as well as inhibiting osteoclastic bone resorption. We present a series of early cases where this research has been used in humans. Two cases of pamidronate assisted distraction osteogenesis are presented, one of which also had congenital pseudarthrosis of the tibia, which united after pamidronate administration. Two cases of post-traumatic avascular necrosis have been successfully treated such that osteolysis and collapse of the necrotic femoral head did not occur. Bisphosphonates may act to slow bone resorption while simultaneously increasing new bone formation, such that the mechanical integrity of the necrotic segment can be maintained during revascularisation. A randomised controlled trial of bisphosphonates in distraction osteogenesis at our hospital has now received ethical approval. Newer bisphosphonates have proven their clinical value in osteogenesis imperfecta and adult osteoporosis, but other potential roles are emerging for these compounds, which have extremely potent effects on bone

Clinical use of glucocorticoids engenders deleterious changes in bone fragility and initiates apoptosis in osteoblasts and osteocytes. The pathways leading to corticosteroid-induced death in bone remain unclear. Similarly little is known about the effects of ‘bone sparing’ bisphosphonates on osteocytes in vivo. We investigated the effects of bisphosphonates (BPs) on dexamethasone (Dex)-induced apoptosis in the murine osteocyte cell line, MLO-Y4 and studied the putative pathways involved by intervention with inhibitors of signalling molecules, such as p42/44 MAPK and protein kinase A (PKA). Cells were preincubated with N- & non N-containing BPs and/or inhibitors before insult with Dex or H. 2. O. 2. for 5 hrs. Apoptotic morphology was revealed by acridine orange staining. Activation of p42/44 was identified using Western blotting and in situ immunocytochemistry in the presence or absence of serum. Both N- & non N-containing BPs were shown to protect against cell death. The addition of inhibitors of p42/44 and PKA blocked the action of Dex. H. 2. O. 2. -induced apoptosis was not blocked by BPs or by any of the inhibitors. Dex appeared to activate p42/44 only in serum supplemented cultures. These data suggest that glucocorticoid but not oxidant-induced osteocyte apoptosis involves activation of p42/44 and that bisphosphonate engendered cell rescue is brought about by inhibition of these MAPK’s. Studies using truncated BPs that lack anti-resorptive activity, and therefore do not interrupt bone remodelling showed that these BPs were also able to protect osteocytes from glucocorticoid-induced death. The ability of bisphosphonates to influence MAPK activation and cell death in the osteocyte opens up exciting possibilities for pharmaceutical intervention during age and steroid hormone related osteocyte loss

Summary Statement. Atypical femoral fractures consist of a thin fracture line extending through the lateral cortex. The adjacent bone is undergoing resorption and mechanical abrasion and is often replaced with woven bone. The mechanical environment seems to inhibit healing. Background. The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself might provide important clues. So far only one case describing the histological appearance of the fracture has been published. Methods. Between 2008 and 2013, bone biopsies comprising the fracture site were collected from 8 patients with 4 displaced and 4 undisplaced atypical femoral fractures. Seven female patients reported continuous bisphosphonate use for an average of 9.5 years. One patient was a man, not using bisphosphonates. The bone biopsies were evaluated histologically, with Fourier transformed infrared imaging (FTIR) and micro-computed tomography. Results. The 4 undisplaced fractures engaged the whole cortical thickness and comprised a 150 to 200 µm wide, meandering fracture gap filled with amorphous necrotic material. Von Kossa staining showed occasional mineralised elements with bony structure within the amorphic material. Active resorption and remodeling was common in the close vicinity of the fracture, but seldom reached into the fracture gap. In some areas, the bone adjacent to the gap appeared to undergo fragmentation and disintegration, possibly due to abrasion. Woven bone was common adjacent to the fracture gap, and appeared to have been formed in defects caused by abrasion or where resorption cavities had reached into the fracture gap. Periosteal and endosteal callus was found in all cases. Far away from the fracture, large areas of osteonal bone with only empty osteocyte lacunae were found in some samples. In one patient, the remodeling process bridged the fracture gap at some points. The fracture was otherwise similar to the other undisplaced fractures. This patient had suffered from thigh pain since her bisphosphonate treatment was discontinued 18 months earlier, when the atypical fracture was diagnosed. Discussion. Atypical femoral fractures show signs of increased remodeling in the vicinity of the fracture gap. The narrow width of the gap and its necrotic contents suggest that micromotion leads to strains between the fracture fragments that precludes survival of ingrowing cells. Moreover, there seemed to be continuous mechanical fragmentation of the bone at the crack, and replacement of fragmented areas with woven bone. Thus, it appears that the fracture line is not static, but moves in the bone over time, like the changes in the course of a meandering river

An atypical femoral fracture (AFF), with a transverse fracture radiologically through the lateral cortex is a rare but serious condition. In order to improve our ability to identify patients with this condition, we retrospectively surveyed all subtrochanteric, peri-implant and diaphyseal femoral fractures in patients aged ≥ 65 years who underwent surgical treatment at our hospital between 2004 and 2011. We describe the incidence of atypical fractures and their characteristics, with observational data including a review of the hospital and general practitioner records. Clinical outcomes were evaluated using the Harris hip score (HHS) and the timed up-and-go (TUG) test. Atypical fractures only occurred in women with an incidence of 9.8 per 100 000 person-years. The incidence in those who were treated with bisphosphonates was 79.0 per 100 000 person-years; eight of 17 fractures occurred around metal implants. There was a high incidence of delayed union and revision surgery. A total of nine patients (ten AFFs) were available for review at a mean follow-up of 36.5 months (10 to 104). The clinical outcome was poor with a mean HHS of 58.9 (95% CI 47.4 to 70.4) and a mean TUG test of 25.7 s (95% CI 12.7 to 38.8). The delay in diagnosis and treatment of AFF may result from a lack of knowledge of this condition. Cite this article: Bone Joint J 2014; 96-B:1035–40

The August 2013 Research Roundup. 360 . looks at: passive smoking and bone substitutes; platelet-rich plasma and osteogenesis; plantar fasciitis and platelet-rich plasma: a match made in heaven?; MRSA decolonisation decreases infection rates; gums, bisphosphonates and orthopaedics; PRAISE and partner violence; blunt impact and post-traumatic OA; and IDEAL research and implants

The February 2014 Hip & Pelvis Roundup. 360 . looks at: length of stay; cementless metaphyseal fixation; mortality trends in over 400,000 total hip replacements; antibiotics in hip fracture surgery; blood supply to the femoral head after dislocation; resurfacing and THR in metal-on-metal replacement; diabetes and hip replacement; bone remodelling over two decades following hip replacement; and whether bisphosphonates affect acetabular fixation

The effect of bisphosphonates on the mechanical properties of the uninjured contra-lateral cortical bone during fracture healing is poorly reported. There remains conflicting evidence with regards the effect of bisphosphonate therapy on cortical bone strength. We assessed the effect of nine weeks of Ibandronate therapy, in a dose known to preserve cancellous bone BMD and strength, on the mechanical properties of the uninjured rat tibial diaphyses using a standardised model of tibial osteotomy and plate fixation. Skeletally mature ex-breeder rats were used. Stress at failure of the tibial diaphyses was measured by a four-point bending test using a custom made jig for rat tibiae. The mechanical strength was compared with radiographic measurements of bone density. Animals received daily subcutaneous injections. 11 rats received 1μg/kg Ibandronate (IBAN) daily and 17 rats received 1ml 0.9% Sodium Chloride (CONTROL) daily. The IBAN group had a statistically significant, p=0.024, higher stress at failure 212.7 (±42.04) MPa compared to the CONTROL group 171.7 (±46.13)MPa. There was a positive correlation between the mechanical strength of bone and the radiological measure of bone density. Osteopenia is known to occur following a fracture even in the contra-lateral limb. This study demonstrates that ibandronate therapy has no detrimental effect and may even increase the strength of uninjured cortical bone during the fracture healing process. The longer term effect of ibandronate on cortical bone especially in relation to the accumulation of mico-damage requires further study. Bisphosphonate effect on the uninjured limb needs to be considered when reporting proportional strength of fracture repair compared to the uninjured limb

The senior author has treated a series of patients with subtrochanteric and diaphyseal femoral stress fractures associated with long-term alendronate or other bisphosphonate usage. Several patients completely fractured their femurs prior to referral. Most patients had consulted other physicians and were referred for presumed neoplasms. All patients had been diagnosed with osteoporosis and had been treated with bisphosphonates. Their plane radiographs revealed abnormalities that are pathognomonic of bisphosphonate-associated stress fractures. However, due to the subtle nature of these new unfamiliar abnormalities, most were unrecognized as such by clinicians (including experienced ISTA member hip surgeons) and radiologists. This series is presented to illustrate this pattern of impending fracture. The authors have reviewed and will present a series (n=17) of femoral stress fractures in bisphosphonate-treated patients to illustrate the clinical and radiographic pattern of these stress fractures, and review their treatment. The most common lesion is a subtrochanteric lateral cortical thickening that in actuality is a horizontal plane “dreaded black line” of a stress fracture with surrounding proximal and distal cortical thickening of the endosteal and periosteal bone. The stress fracture line is obscured unless a near-perfect radiographic projection is obtained. The lesion is best seen with CT scans. MRI scans reveal the stress fracture lines with surrounding edema (Fig 1), which may be misinterpreted as a tumor. Without treatment, a low-impact completed fracture will likely occur. Many bisphosphonate-associated impending subtrochanteric femoral stress fractures are misdiagnosed as trochanteric bursitis, leading to subsequent displaced subtrochanteric fractures [Fig. 2 - Note subtle impending fracture lesion on right, completed fracture on left]. The clinical and subtle radiographic findings must be recognized by orthopaedic surgeons, particularly hip surgeons, to prevent these complete fractures. These fractures are preventable with internal fixation. Long-term administration of bisphosphonates can have adverse effects, and alternatives to long-term continuous dosing must be investigated to determine optimal administration regimens

The June 2013 Hip & Pelvis Roundup. 360 . looks at: failure in metal-on-metal arthroplasty; minimal hip approaches; whether bisphosphonates improve femoral bone stock following arthroplasty; whether more fat means more operative time; surgical infection; vascularised fibular graft for osteonecrosis; subclinical SUFE; and dentists, hips and antibiotics

Fractures repair by two mechanisms; direct fracture healing and indirect fracture healing via callus formation. Research concerning the effects of bisphosphonate on fracture repair has solely assessed indirect fracture healing. Patients with osteoporosis on bisphosphonates continue to sustain fragility fractures. A proportion of osteoporotic fractures require plate fixation. Bisphosphonates impair osteoclast activity and therefore, may adversely affect direct fracture healing that predominates with plate fixation. Five skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1mg/kg Ibandronate (IBAN). Similarly, five control rats received saline (CONTROL). Three weeks following commencement of injections a tibial osteotomy was rigidly fixed with compression plating similar to that seen in routine clinical practice. Fracture healing was monitored with radiographs. Six weeks post plate fixation, animals were sacrificed. Radiographs were performed of the extricated tibiae following plate removal. The visibility of the osteotomy site was scored as totally visible, partially visible or absent as previously described. Mechanical testing was conducted on the healing osteotomies via 4-point bending. Fractures healed without visible external callus. In the IBAN group three animals had totally visible osteotomy lines and two had partially visible osteotomy lines. The CONTROL group had three animals with absent osteotomy lines and two with partially visible osteotomy lines. The mean (±SD) stress at failure for the healing tibial osteotomies at 6 weeks was 28.8 (±23.97)MPa in the IBAN group and 37.4(±29.20) MPa in the CONTROL group (p=0.62). Our results indicate that Ibandronate adversely affected direct fracture repair as demonstrated by the radiographic density of the fracture line. The strength of the repair was reduced but this did not reach statistical significance. Our results suggest that a sample size of 220 animals is required to detect a 15% difference (alpha 0.05, beta 0.2) which suggests the effect of bisphosphonates on direct fracture repair may be small

The October 2013 Children’s orthopaedics Roundup. 360. looks at: Half a century of Pavlik treatment; Step away from the child!: trends in fracture management; Posterolateral rotatory elbow instability in children; Osteochondral lesions undiagnosed in patellar dislocations; Oral bisphosphonates in osteogenesis imperfecta; Crossed or parallel pins in supracondylar fractures?; Not too late nor too early: getting epiphysiodesis right; Fixation of supramalleolar osteotomies

A Ruys, School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney. The effects of bone anabolics can be maximised by systemic co-treatment with an anti-catabolic. Local treatment may reduce the total drug required and produce superior outcomes, although high dose local bisphosphonate has been reported to impair bone formation. We have explored local co-delivery of anabolic/anti- catabolic bone drugs at different doses. We manufactured biodegradable poly-D,L-lactic acid (PDLLA) polymer pellets containing 25g BMP-7 as an anabolic with or without 0.002mg-2mg Pamidronate (PAM) as an anti-catabolic. Polymer pellets were surgically implanted into the hind limb muscle of female C57BL6 mice. Animals were sacrificed at three weeks post- implantation and bone formation was assessed by radiography, microcomputed tomography (microCT) and histology. Histological staining on five Âm paraffin sections included haematoxylin/eosin, alcian blue/picrosirius red, and tartrate- resistant acid phosphatase (TRAP). Radiographic and microCT data confirmed that 0.02mg and 0.2mg local PAM doses significantly augmented BMP-7 induced bone formation. In contrast, 2mg local PAM dramatically reduced the amount of bone present. This dose was comparable to that used by Choi et al who also reported impaired bone formation in a skull defect model.2 three-dimensional microCT and histological analyses of the ectopic bone and surrounding muscle showed a cortical shell covering the polymer pellet, which had not completely resorbed. Histological analysis at the pellet/bone interface showed tissue granulation and no inflammation, suggesting a high biocompatibility of the PDLLA polymer. The presence of bisphosphonate also decreased the amount of fatty marrow tissue seen within between the cortical shell and the unresorbed polymer. For the first time we can demonstrate synergy with local BMP/bisphosphonate. This study confirms that high local PAM doses can have negative effects, indicating a need to avoid overdosing. The lack of implant degradation suggests a need to optimise polymer degradation for bone tissue engineering application

Neurogenic heterotopic ossification (NHO) is a disorder of aberrant bone formation affecting one in five patients sustaining a spinal cord injury or traumatic brain injury. Ectopic bone forms around joints in characteristic patterns, causing pain and limiting movement especially around the hip and elbow. Clinical sequelae of neurogenic heterotopic ossification include urinary tract infection, pressure injuries, pneumonia and poor hygiene, making early diagnosis and treatment clinically compelling. However, diagnosis remains difficult with more investigation needed. Our pathophysiological understanding stems from mechanisms of basic bone formation enhanced by evidence of systemic influences from circulating humor factors and perhaps neurological ones. This increasing understanding guides our implementation of current prophylaxis and treatment including the use of non-steroidal anti-inflammatory drugs, bisphosphonates, radiation therapy and surgery and, importantly, should direct future, more effective ones

There has been evidence of association between femoral shaft fractures and prolonged bisphosphonate therapy. We present a case series of bisphosphonate-associated fractures and invaluable lessons we have learnt. Over the last three years at our unit we have collected a case series of eight patients who have had atypical femoral fractures whilst on bisphosphonate therapy. We present illustrative cases, a summary of key findings, and invaluable lessons we have learnt. There was a long period of prodromal pain for two years before incomplete fractures developed. We speculate this is a warning sign of impending fracture. This may have been prevented with screening. Between incomplete fracture and complete fracture there was a short window of one month. Five patients presented with complete fracture, and three with thigh pain +/- evidence of incomplete fracture. Of the latter group all but one went on to develop complete fractures. The one patient who did not progress died six years after diagnosis. Of those five patients who presented with initial complete fracture, three patients recall thigh pain before fracture on further questioning. Despite being diaphyseal femoral fractures, there is a higher risk of neck of femur fractures in this patient cohort (both patients with initial interlocked nails subsequently developed neck of femur fractures soon after and were revised to cephalomedullary nails). Excluding one death from unrelated cause, only one patient has signs of complete fracture healing. All other patients are still receiving follow-up (mean 490 days). Three patients reported bilateral symptoms (pain). Two had had bilateral symptoms for one year. Both had visible incomplete fractures on further radiographic scrutiny; one underwent prophylactic cephalomedullary nailing, one was managed with active surveillance. We suggest that improved pain and radiographic changes of cortical healing may be misleading and should not be relied upon. Cephalomedullary nailing is the treatment of choice in these fractures due to higher risk of neck of femur fractures in this cohort. We suggest prompt prophylactic cephalomedullary nailing when radiographic incomplete fractures are identified due to a short window before progression to complete fracture, and the need to consider contralateral prophylactic nailing in patients describing bilateral symptoms. We speculate that thigh pain is a warning sign of impending fracture and fracture-progression can be prevented with appropriate screening

Introduction: Distraction osteogenesis is a widely utilised orthopaedic procedure; however prolonged treatment time and considerable disuse osteoporosis remain problematic, with decreases of 44% to 61% in bone mineral density reported in adjacent bone. Refracture rates of 10–20% are reported after frame removal. We set out to examine the role of bisphosphonates in protecting the bone against stress-shielding related osteopaenia during distraction osteogenesis. We used a NZW rabbit model with 2 weeks distraction to 10.5 mm then 4 weeks consolidation. We achieved positive results in the initial trial using the bisphosphonate pamidronate (Novartis). Not only were we able to abolish the decrease in BMD in the surrounding bone, we noted an increase in the mineral properties and strength of the new bone. Moving on to zoledronic acid (Novartis), a third generation bisphosphonate designed for use in malignant hypercalcaemia and bone metastases, we achieved even more promising results. In a study of thirty rabbits, we gave saline to 10 controls, 0.1 mg/kg zoledronic acid to 10 rabbits at surgery and 10 further rabbits received 0.1 mg/kg zoledronic acid at surgery and at two weeks. The animals were scanned by DXA at 2, 4 and 6 weeks, and by QCT after culling. Mechanical testing was performed by destructive 4-point bend tests. Second-weekly DXA scans documented faster mineral accrual after distraction between 2 and 4 weeks in both treatment groups (ANOVA p< 0.01). In the control group, the BMD in the segments around the lengthening fell by 0.16 g/cm2 between the 2nd and 6th week. The BMD showed a net increase over the same time period in all treated animals (ANOVA p< 0.01). The cross sectional area of the regenerate at six weeks as measured by QCT was increased by 49% in the zoledronate group versus controls and by 59% in the re-dosed zoledronate group. (ANOVA p< 0.01). The final (6 week) BMC of the regenerate was increased by 92% in the zoledronate group versus controls and by 111% in the re-dosed zoledronate group (ANOVA p< 0.01). Bone mineral density was increased by a lesser but significant degree to normal values (28% and 34% respectively, ANOVA p< 0.01). Four point bend testing revealed increases in peak load of 29% in the single dose and 89% in the re-dosed group (ANOVA p< 0.01). Two patients are presented, one with congenital pseudarthrosis of the tibia, and one who had not united a distraction gap of 5 cm at six months, who were treated with pamidronate. Both showed successful responses in line with our research findings. A clinical trial is being set up to establish a scientific case for bisphosphonate use in patients undergoing distraction osteogenesis with the aim of possible earlier frame removal and less refractures. Further research in other areas of bone healing is also planned

The superior analgesic effects of minodronate compared with other bisphosphonates has been previously reported. However, to our knowledge, there are no studies analyzing the analgesic effects of bisphosphonates on chronic pain. The purpose of the present study was to evaluate the analgesic effects of minodronate (MIN), alendronate (ALN), and pregabalin (PRG) on chronic pain caused by chronic constriction injury (CCI) of the sciatic nerve. Four-week-old female Wister rats underwent ovariectomy. At 8 weeks old, the left sciatic nerve was ligated to induce the chronic pain model (CCI side), and sham surgery was performed on the right posterior limb as a CCI control (control side). The rats were divided into the following four groups: 1) MIN group, administered with minodronate (0.15 mg/kg/week) (n = 10); 2) ALN group, administered with alendronate (0.15 mg/kg/week) (n = 10); 3) PRG group, administered with pregabalin (10 mg/kg) (n = 9); and 4) Control group, administered with vehicle (n = 10). Treatments were administered subcutaneously every week for 2 weeks immediately after CCI. To quantify the sensitivity to a tactile stimulus, paw withdrawal in response to a tactile stimulus was measured using von Frey filaments at 0, 1, and 2 weeks after CCI. Von Frey filaments were applied to the plantar surface of the hindpaws for 3 s, and this was repeated three times. Paw withdrawal in response to the stimulus was evaluated by scoring as follows: 0, no response; 1, a slow and/ or slight response to the stimulus; 2, a quick withdrawal response; 3, an intense withdrawal response away from the stimulus. The mean value of the score was adopted as the pain score. After evaluating the response, bilateral femurs were harvested for bone mineral density (BMD) measurements. The pain score of the CCI side was significantly higher than that of the sham side in all groups (p < 0.05) at each time point. The pain score for the MIN group, but not the ALN group, of the CCI side was significantly lower (p = 0.05) at 0 and 1 week after CCI. Total femoral BMD of the CCI side was significantly lower in the PRG and Control groups than those of the MIN and ALN groups (p < 0.05). No significant difference was identified for BMD between the MIN and ALN groups. Minodronate showed a significant analgesic effect on chronic pain and suppressed osteoporotic changes caused by CCI

Objectives. To assess the sensitivity and specificity of self-reported osteoporosis compared with dual energy X-ray absorptiometry (DXA) defined osteoporosis, and to describe medication use among participants with the condition. Methods. Data were obtained from a population-based longitudinal study and assessed for the prevalence of osteoporosis, falls, fractures and medication use. DXA scans were also undertaken. Results. Overall 3.8% (95% confidence interval (CI) 3.2 to 4.5) of respondents and 8.8% (95% CI 7.5 to 10.3) of those aged ≥ 50 years reported that they had been diagnosed with osteoporosis by a doctor. The sensitivity (those self-reporting osteoporosis and having low bone mineral density (BMD) on DXA) was low (22.7%), although the specificity was high (94.4%). Only 16.1% of those aged ≥ 50 years and with DXA-defined osteoporosis were taking bisphosphonates. Conclusions. The sensitivity of self-reporting to identify osteoporosis is low. Anti-osteoporotic medications are an important part of osteoporosis treatment but opportunities to use appropriate medications were missed and inappropriate medications were used

Cancer-induced bone diseases are often associated with increased bone resorption and pathological fractures. In recent years, osteoprotective agents such as bisphosphonates have been studied extensively and have been shown to inhibit cancer-related bone resorption in experimental and clinical studies. The third-generation bisphosphonate, ibandronate (BM 21.0955), is a potent compound for controlling tumour osteolysis and hypercalcaemia in rats bearing Walker 256 carcinosarcoma. We have studied the effect of ibandronate given as an interventional treatment on bone strength and bone loss after the onset of tumour growth in bone. Our results suggest that it is capable of preserving bone quality in rats bearing Walker 256 carcinosarcoma cells. Since other bisphosphonates have produced comparable results in man after their success in the Walker 256 animal models our findings suggest that ibandronate may be a powerful treatment for maintaining skeletal integrity in patients with metastatic bone disease