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

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

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

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

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

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

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.

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

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.

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.

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.

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.

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