The effect of zoledronic acid on bone ingrowth was examined in an animal model in which porous tantalum implants were placed bilaterally within the ulnae of seven dogs. Zoledronic acid in saline was administered via a single post-operative intravenous injection at a dose of 0.1 mg/kg. The ulnae were harvested six weeks after surgery. Undecalcified transverse histological sections of the implant-bone interfaces were imaged with backscattered scanning electron microscopy and the percentage of available pore space that was filled with new bone was calculated. The mean extent of bone ingrowth was 6.6% for the control implants and 12.2% for the zoledronic acid-treated implants, an absolute difference of 5.6% (95% confidence interval, 1.2 to 10.1) and a relative difference of 85% which was statistically significant. Individual islands of new bone formation within the implant pores were similar in number in both groups but were 69% larger in the zoledronic acid-treated group. The bisphosphonate zoledronic acid should be further investigated for use in accelerating or enhancing the biological fixation of implants to bone

Aim. To study the efficacy of Zoledronic acid in the treatment of benign osteolytic tumours or tumour like conditions of bone as a therapeutic or as an adjuvant agent. Method. 31 patients- 19 female, 12 male, age from 8 yrs to 42 yrs, were treated with intravenous zoledronic acid. In 17 patients (fibrous dysplasia-10, nonossifying fibroma- 4, UBC- 3) zoledronic acid alone was used as a therapeutic agent. In 14 patients (ABC- 3, GCT- 11), it was used as an adjuvant agent after curettage. Four patients presented with pathological fracture. In all patients, 4 mg. zoledronic acid was given at 2 monthly intervals. In 12 adult patients, in addition oral bisphosphonates - alendronate was given weekly for at least 6 months. Results. Patients were evaluated using visual analog pain scale and x-rays. At last follow-up (6-40 months), in 15 patients, treated with zoledronic acid alone, there was thickening of cortices and reduction in the size of the lesion. Pain score decreased from an average of 8 to 2. All four fractures healed. In 2 patients, there was progression in size of the lesion. In 14 patients, where it was used as an adjuvant agent, there was early thickening of bone cortices. There was no local recurrence in this group. There was no adverse reaction to the drug in any of the patient. Conclusion. Zoledronic acid is a third generation bisphosphonates and a proven anti-osteolytic agent. It has proved effective in the treatment of number of osteolytic conditions. Our study also suggests that Zoledronic acid not only help to stabilize these lesions but also resulted in pronounced healing in majority of the patients. It also reduced recurrence rate in aggressive benign bone tumours such as ABC or GCT when used as an adjuvant treatment

Aim: To examine the effect of the bisphosphonate zoledronic acid in doses of 0.1mg/kg on new bone formation and stress shielding in a distraction-osteogenesis model in New Zealand white rabbits. Method: Thirty male rabbits underwent a right tibial osteotomy at eight weeks of age. Distraction of the osteotomy by 0.75mm/day was performed for two weeks followed by four weeks for consolidation. Group I was given saline infusions, Group II zoledronic acid at surgery, and Group III received zoledronic acid at surgery and again at two weeks. DXA scans evaluated BMC and BMD. Quantitative computerised tomography measured the cross-sectional areas. Four-point bend testing of both distracted and non-operated tibiae was performed in a standardised fashion. Results: Bone mineral accretion between two and four weeks was significantly higher in treated versus saline groups, and was better maintained at six weeks (P< 0.01 ANOVA). Stress shielding osteopaenia that was seen in surrounding bone segments in Group I (controls) was abolished in the treated groups. By six weeks there was a 49% and 59% increase in cross sectional area of new bone in Groups II and III respectively (P< 0.01 ANOVA). Group II tibiae were 29% stronger in four-point bending, while Group III were 89% stronger than Group I (P< 0.01 ANOVA). There was little detectable effect on the non-operated tibiae. Conclusions: Zoledronic acid administration significantly increased the rate and amount of new bone formation and its mineralisation. The increases in bone formation and retention translated to a significant, dose-dependent increase in strength. Further research into the role of zoledronic acid in orthopaedic surgery is indicated

Although bone morphogenetic protein 2 (BMP-2) has been FDA-approved for spinal fusion for decades, its disadvantages of promoting osteoclast-based bone resorption and suboptimal carrier (absorbable collagen sponge) leading to premature release of the protein limit its clinical applications. Our recent study showed an excellent effect on bone regeneration when BMP-2 and zoledronic acid (ZA) were co-delivered based on a calcium sulphate/hydroxyapatite (CaS/HA) scaffold in a rat critical-size femoral defect model. Therefore, the aim of this study was to evaluate whether local application of BMP-2 and ZA released from a CaS/HA scaffold is favorable for spinal fusion. We hypothesized that CaS/HA mediated controlled co-delivery of rhBMP-2 and ZA could show an improved effect in spinal fusion over BMP-2 alone. 120, 8-week-old male Wistar rats (protocol no. 25-5131/474/38) were randomly divided into six groups in this study (CaS/HA, CaS/HA + BMP-2, CaS/HA + systemic ZA, CaS/HA + local ZA, CaS/HA + BMP-2 + systemic ZA, CaS/HA + BMP-2 + local ZA). A posterolateral spinal fusion at L4 to L5 was performed bilaterally by implanting group-dependent scaffolds. At 3 weeks and 6 weeks, 10 animals per group were euthanized for µCT, histological staining, or mechanical testing. µCT and histological results showed that the CaS/HA + BMP-2 + local ZA group significantly promoted bone regeneration than other treated groups. Biomechanical testing showed breaking force in CaS/HA + BMP + local ZA group was significantly higher than other groups at 6 weeks. In conclusion, the CaS/HA-based biomaterial functionalized with bioactive molecules rhBMP-2 and ZA enhanced bone formation and concomitant spinal fusion outcome. Acknowledgements: Many thanks to Ulrike Heide, Anna-Maria Placht (assistance with surgeries) as well as Suzanne Manthey & Annett Wenke (histology)

Purpose of the study: Wide en bloc surgical resection is the treatment of choice for cure of chondrosarcoma. Despite local control of this primary bone tumor in 60–80% of patients, mortality remains high. Recent studies suggest that biphosphonates can provide promising perspectives for the treatment of malignant bone tumors, even for primary tumors such as osteosarcoma. We report here the results obtained when using zoledronate for Swarm chondrosarcoma in an in vivo rat model and the effect of this compound on tumor cells in vitro. Material and methods: Swarm chondrosarcoma was implanted in three series of 12 male Sprague Dawley rats. In series A, the animals were treated after implantation to death or sacrifice. In series B and C, the animals were treated a few days before curettage-resection then to death or sacrifice. Tumor growth was assessed by tumor size, presence of metastasis and death. Control series with PBS injections were also studied. Results: Treatment with zoledronate inhibited tumor growth in all series. In series A, tumor size was significantly smaller in the treated animals (p=0.046). Tumor progression from day 19 to day 32 was significantly less for treated animals (p=0.046). Chance of survival was 0.667 for treated animals versus 0.3 for the controls. For series B and C, recurrence developed later in animals given zoledronate. Tumor size was greater in control animals compared with treated animals (p=0.043). Tumor progression from day 39 to day 49 was significantly greater in the control group (p=0.025). Cultures of cells extracted from the Swarm chondrosarcoma tumor also showed significantly inhibited growth in vitro for concentrations of zoledronic acid from 10 to 100 ml/l. Discussion and conclusion: Zoledronic acid appears to inhibit growth of Swarm chondrosarcoma in all in vivo therapeutic schemas studied, confirming in vitro data. A more precise animal model better fitting clinical situations should provide more detailed information for use of this treatment after recurrence or in the event of intralesional surgery

We studied the effects of hyperbaric oxygen (HBO) and zoledronic acid (ZA) on posterior lumbar fusion using a validated animal model. A total of 40 New Zealand white rabbits underwent posterior lumbar fusion at L5–6 with autogenous iliac bone grafting. They were divided randomly into four groups as follows: group 1, control; group 2, HBO (2.4 atm for two hours daily); group 3, local ZA (20 μg of ZA mixed with bone graft); and group 4, combined HBO and local ZA. All the animals were killed six weeks after surgery and the fusion segments were subjected to radiological analysis, manual palpation, biomechanical testing and histological examination. Five rabbits died within two weeks of operation. Thus, 35 rabbits (eight in group 1 and nine in groups 2, 3 and 4) completed the study. The rates of fusion in groups 3 and 4 (p = 0.015) were higher than in group 1 (p < 0.001) in terms of radiological analysis and in group 4 was higher than in group 1 with regard to manual palpation (p = 0.015). We found a statistically significant difference in the biomechanical analysis between groups 1 and 4 (p = 0.024). Histological examination also showed a statistically significant difference between groups 1 and 4 (p = 0.036). Our results suggest that local ZA combined with HBO may improve the success rate in posterior lumbar spinal fusion

Aseptic loosening is the most frequent cause of implant failure in total hip arthroplasty (THA). Additionally, failure rate was still found by some authors to be increased in patients with osteonecrosis of the femoral head (ON-FH). It is well evidenced that low initial fixation and early migration precedes and predicts long-term failure rate of both, the acetabular and femoral component in THA. This independent, double-blind, randomized, controlled study was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid is sufficient to prevent implant migration determined by the EBRA-digital method. Fifty patients were consecutively enrolled between July 2002 and March 2005 to receive either 4 mg zoledronic acid (ZOL) or saline solution (CTR) one day after THA (Zweymüller system, cementless). Plain radiographs were performed postoperatively and all parameters were evaluated at each follow-up meeting interval at 7 weeks, 6 months, 1 year, and yearly thereafter during a median follow-up period of 2.8 years (2 years minimum). In CTR, subsidence increased up to −1.2 mm ± 0.6 SD at 2 years in CTR (P< 0.001). Less, but a near curve-linear shaped migration pattern was found for the ace-tabular component, with an averaged medialization of 0.6 mm ± 1.0 SD and a cranialization of 0.6 mm ± 0.8 SD at 2 years (P< 0.05, Friedman ANOVA) at 2 years. In ZOL, a significant reduction in bone turnover markers was accompanied by a complete prevention of cup migration in both, the transverse and vertical direction (P< 0.05, ANOVA), while there was only a trend to a decreased subsidence in stems. The study provides useful data which are promising and support the suggestions that bisphosphonates may offer significant opportunities to reduce and prevent implant migration of THA, thus increasing long-term durability of THA especially in selected high-risk patients

Background. The doses of local rhBMP-2 in commercially available materials are high with known drawbacks such as inflammation and premature bone resorption. The latter can be prevented by adding bisphosphonates like zoledronic acid (ZA) but systemic ZA has side effects and patient adherence to treatment is low. In a recent study, we have shown that local co-delivery of rhBMP-2 and ZA via a calcium sulphate/hydroxyapatite (CS-HA) biomaterial can be used to regenerate both cortical and trabecular bone in a rat model of metaphyseal bone defect. Even low doses of local ZA in the biomaterial showed promising results and increased bone formation within the defect compared to the controls. A step before clinical translation of the local treatment regimen is to evaluate the in-vivo release kinetics of these additives and thus in this study, we aimed to investigate the in-vivo pharmacokinetics of rhBMP-2 and ZA from the CS-HA biomaterial in a rat abdominal muscle pouch model over a period of 4-weeks. Methods. In-vivo release kinetics of 125I labeled rhBMP-2 and 14C labeled ZA was performed using an abdominal muscle pouch model in rats (n=6). Both rhBMP-2 and ZA were labeled commercially with a radiochemical purity of >95%. The detection of 125I -rhBMP-2 release was performed by implanting pellets of the CS-HA biomaterial containing 125I -rhBMP-2 and ZA and the same animals followed over a period of 4-weeks (day 1, 3, 7, 14, 21& 28) using SPECT imaging. Similarly, the 14C-ZA was detected by implanting CS-HA pellets containing rhBMP-2 and 14C-ZA. Release was detected via scintillation counting and at each time point (Day 1, 7, 14& 28) 6-animals were sacrificed. Results. BMP Release. The CS-HA biomaterial retained 95±11% after 3-days, 88±12% after a week, 66±9% after 2 weeks, 51±5% after 3 weeks and 43±7% of 125I labeled rhBMP-2 after 4-weeks in-vivo (SPECT-CT). ZA Release. The CS-HA biomaterial retained 89±14% after a week, 84±8% after 2 weeks, 83±9% after 3 weeks and 77±3% of 14C labeled ZA after 4 weeks of in-vivo implantation. Discussion. Improved carriers and better knowledge of the release might improve the effect of bone active drugs in orthopedics. Our previous study shows that an off-the-shelf ceramic biomaterial combined with ZA alone or with both rhBMP-2 and ZA can be used to regenerate bone with potential for clinical translational. This study demonstrates long-term co-delivery of both rhBMP-2 and ZA in-vivo via the biomaterial. Constant availability of rhBMP-2 over a long period of time can give osteoinductive properties to the material while presence of local ZA prevents premature bone loss. The pharmacokinetic release pattern differs from what we have reported in vitro with less BMP and more ZA being released in vivo during the first 4 weeks. We speculate that rapid protein passivation of the ceramic material slows the release of BMP and partly preventing the ZA binding to apatite

The development of multidisciplinary therapy for Ewing’s sarcoma (ES) has increased current long-term survival rates to greater than 50%, but only 20% for patients with clinically detectable metastases at diagnosis, or not responding to therapy or with disease relapse. Anti-bone resorption bisphosphonates (BP) may represent promising adjuvant molecules to limit the osteolytic component of bone tumor. The combination of zoledronic acid (ZOL) and ifosfamide (IFOS) or mafosfamide (MAFOS) was studied in ES models and in 8 human cell lines all expressing the EWS-FLI1 fusion gene. Cell proliferation, viability, apoptosis and cell cycle distribution were analysed. The ES models were developed in immuno-deficient mice by inoculating the human tumor cells either intra-muscular (soft tissue tumor development) or intra-osseous (bone tumor development). Mice were then treated with ZOL (100 μg/kg twice or 4 times/week) and/or ifosfamide (IFOS 30 mg/kg, one to 3 sequences of 3 injections). All the cell lines studied were more or less sensitive to ZOL and MAFOS in terms of cell proliferation. Both drugs induced cell cycle arrest respectively in S and G2M phase and final apoptosis associated to caspase 3 activation. In vivo, ZOL had no effect on soft tumor progression although it dramatically inhibits ES development in bone site. When combined with IFOS, ZOL exerts synergistic effects in the soft tissue model leading to a similar quantitative inhibitory effect when associated with 1 sequence IFOS as compared to 3 sequences of IFOS alone. In the bone model, ZOL prevents tumor recurrence observed with a lonely sequence of IFOS. Combination of ZOL with conventional chemotherapy showed promising results in both ES models and could allow the clinicians to diminish the doses of chemotherapy. Moreover, as ZOL and MAFOS induce cell death by different pathways, respective resistance may be circumvented

Osteosarcoma is the most frequent malignant primary bone tumors. Despite recent improvements in multimodal therapy the problem of non-response to mono-chemotherapy remains. Therefore, novel multi-drug combinations targeting various molecular pathways are needed to decrease the emergence of resistance phenomenon and to potentiate the treatment efficacy. In this context, the effects of RAD001, a new orally available mTOR inhibitor was investigated in vitro and in vivo on osteosarcoma proliferation, both alone and in combination with Zoledronic acid (ZOL). The in vitro effects of ZOL and RAD001 were analyzed on human (MG63), rat (OSRGa) and mouse (POS-1 and MOS-J) osteosarcoma cell lines in terms of cell proliferation (XTT assay, manual cell counting, time-lapse microscopy), cell cycle analysis (flow cytometry analysis) and apoptosis (caspase 1, 3 and 8 activity). RAD001 and ZOL inhibit MG63, OSRGA and POS-1 osteosarcoma cell proliferation in a dose- and time-dependent manner without any modification of cell cycle distribution. In contrast, MOS-J cells are resistant to ZOL and RAD001. In all cell lines assessed, combination of RAD001 and ZOL exerts synergistic effect on the inhibition of cell proliferation and induces a significant decrease of P-mTOR, P-4EBP1 and Ras expression with no accumulation of IPP and ApppI. This drug combination has been then investigated in a mouse osteosarcoma model induced by i.m. inoculation of MOS-J cells in C57BL/6J mice. Clinical relevant doses of RAD001 (5 mg/kg) and ZOL (100 μg/kg) alone have no effect on tumor growth in contrast to combination of both drugs which decreases osteosarcoma progression. ZOL (alone or in combination) strongly increases bone formation. The combination of RAD001 with ZOL improves tissue repair as shown by important area of fibrosis into the residual tumor mass. The present work demonstrates the in vitro and in vivo synergistic effect of mTOR (RAD001) and mevalonate (ZOL) pathway inhibitors and suggests that ZOL potentiates RAD001 activity through Ras molecular pathway

Metaphyseal fracture healing is important in joint-adjacent fractures and appears to differ from diaphyseal healing. We recently found that a biomaterial delivering bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) healed the metaphyseal bone in a tibial defect but failed closing the cortical defect. In this study we added a BMP-2 soaked collagen membrane to study cortical healing from the muscle tissue surrounding the bone. We used SD rats and a 4.5 mm metaphyseal circular tibial defect. In group 1 (G1), a porous gelatin-calcium sulphate-hydroxyapatite (GCH) biomaterial containing rhBMP-2 and ZA was used to fill the defect (GCH+5 μg BMP-2+10 μg ZA). In group 2 (G2), we used a collagen membrane (2 μg BMP-2) to cover the GCH filled defect (GCH+3μg BMP+10 μg ZA). Group 3 (G3) was an empty control. Animals were sacrificed after 8-weeks and bone regeneration was evaluated with micro-CT and histology. In both G1 (P<0.001) and G2 (p<0.001) a significantly higher mineralized volume was found in the defect compared to empty G3. In G2 higher mineralized volume was found in the cortical region compared to both G1 (p<0.01) and G3 (p<0.001) as seen via micro-CT. Histologically, G1 and G2 showed islands of trabecular bone in the defect peripherally but only G2 showed cortical healing. G3 was empty in the middle but showed healed cortex. In conclusion, GCH can be used to deliver BMP-2 and ZA to promote metaphyseal bone growth. A membrane (CM) doped with low dose BMP-2 improved cortical regeneration

Fracture prevention has so far been studied in patients included on the basis of low bone density, and not after a fracture. In this study the inclusion criteria was a new hip fracture irrespective of bone density. An international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (HORIZON-RFT) studied whether the bisphosphonate, zoledronic acid (ZOL) 5 mg, reduced subsequent clinical fractures in men and women ≥50 yrs after a hip fracture. Methods: Patients with hip fracture were included. They received daily vitamin D3 and calcium supplements. Of 2127 randomized, 2111 were treated with once-yearly IV infusions of ZOL 5 mg (n=1054) or placebo (PBO; n=1057) and followed until 211 experienced new clinical fractures (the primary efficacy endpoint). Results: Baseline characteristics were similar. Median age was 76 yrs (range, 50–98); 76% were women. Clinical fractures occurred in 92 ZOL and 139 PBO patients. 2-year cumulative event rates were 8.59% and 13.88%, respectively (Kaplan-Meier); relative risk reduction was 35% (HR=0.65; 95% CI: 0.50–0.84; P=.0012). ZOL reduced risk for clinical vertebral and nonvertebral fractures vs. PBO by 46% (HR=0.54; 95% CI: 0.32–0.92; P=.0210) and 27% (HR=0.73; 95% CI: 0.55–0.98; P=.0338), respectively. ZOL reduced risk of hip fractures by 30% vs. PBO (HR=0.70; 95% CI: 0.41–1.19; P=NS). AEs and SAEs were comparable between groups. There were no significant differences in cardiovascular parameters or long-term renal function. No cases of ONJ were reported. Death occurred in 9.58% of ZOL patients vs 13.34% PBO, a 28% lower mortality risk (HR=0.72; 95% CI: 0.56–0.93, P=.0117). Conclusions: Subjects with a new hip fracture treated with annual IV ZOL infusions experienced significantly fewer clinical fractures vs. placebo. ZOL was well tolerated with a favorable safety profile. This is the first trial demonstrating a mortality benefit for an antiresorptive agent

Purpose: Previous studies have shown the utility of the bisphosphonate zoledronic acid (ZA) by systemic administration and local delivery for enhancing local bone formation with porous implants. The purpose of this study was to quantify the long term effect of local delivery of ZA on bone growth within and around porous tantalum implants one year after surgery. Method: Hydroxyapatite coated porous tantalum (Trabecular Metal. ™. , Zimmer Inc) implants measuring 9 mm in diameter and 90 mm in length were used in a canine bilateral femoral intramedullary model. Commercially pure ZA (Novartis Pharma) of either 0.05 mg or 0.20 mg ZA was applied to implants. Bilateral surgery was performed on 10 dogs – all 10 with a control implant on one side and 5 each with either a 0.05 mg or 0.20 mg ZA-dosed implant on the contralateral side. After one year, the femora were harvested and processed for undecalcified thin section histology and backscattered scanning electron microscopy. Statistical analysis was done using the student’s t tests and multiple two-level hierarchical models. Results: The 160 histologic sections revealed that compared with controls, there was more intramedullary bone around implants dosed with both 0.05 mg ZA (+91%, p< 0.001) and 0.20 mg ZA (+115%, p< 0.001). Bone ingrowth was present in all sections and was more abundant within 1.5mm of the implant periphery. The 0.20 mg ZA dose resulted in more net intramedullary bone formation than the 0.05 mg dose (+41%, p< 0.006). The mean extent of bone ingrowth for implants dosed with 0.20 mg ZA was significantly greater than controls (+32%, p< 0.003) and also greater than for implants dosed with 0.05 mg ZA (+47% for the area within 1.5 mm of the periphery, p< 0.002). Conclusion: This study demonstrated that the enhanced net bone formation that occurs due to local elution of ZA from porous implants was sustained out to 1 year after surgery. A notable dose response was also demonstrated. The peri-implant response was confined to within a few millimeters of the implant suggesting that ZA elution remains localized. This study supports the concept of using ZA-dosed implants for enhancing net bone formation within and around noncemented implants

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

Despite great progress in implant design, materials and new implantation techniques aseptic loosening is still the most frequent cause of implant failure in THA, which was found to be increased especially in patients with osteonecrosis of the femoral head (ON-FH). While a direct link between aseptic loosening and periprosthetic bone loss still remains elusive, there is plentiful evidence for a close association with early migration of implant components. Although the beneficial effect of bisphonates on periprosthetic bone mass is well established, little is known to date about their effects on implant migration. This is an important issue, because successful prevention of early implant migration would provide strong evidence of a beneficial effect on the survival rate of THA. Previously, Krismer et al. found that a total migration of the cup of ≥ 1mm and a subsidence of ≥ 1.5mm 2 years after surgery was highly predictive for aseptic implant failure of THA within 8 to 10 years.

Fifty patients with end-stage ON-FH were consecutively enrolled to receive either 4mg of ZOL or saline solution (CTR) in a double-blind fashion. Radiographs standardized for EBRA-digital analysis were performed at each follow-up exam at 7 weeks, 6 months, 1 year, and yearly thereafter. The minimum follow-up period was 2 years (median follow-up: 2.8 years). Migration of the acetabular and femoral components was analyzed with the EBRA-digital software (University of Inns-bruck, Austria) independently by 3 investigators fully blinded to randomization.

Within the placebo group, distal migration of the stem (subsidence) steadily increased up to −1.2mm ± 0.6 SD at 2 years after THA without reaching a plateau phase (P< 0.001, Friedman ANOVA). Less but a nearly curvilinear migration pattern was found for the acetabular components, with a transverse migration of 0.6mm ± 1.0 SD and a vertical migration of 0.6mm ± 0.8 SD at 2 years (P< 0.001, Friedman ANOVA). Treatment with ZOL effectively minimized the migration of cups in both the transverse and vertical direction (0.15 mm ± 0.6 SD and 0.06 mm ± 0.6 SD, respectively, P< 0.05, ANOVA), and a trend to a decreased subsidence was also found for stem migration (−0.91 mm ± 0.51 SD; P=0.11, ANOVA). In addition, total cup migration exceeding 1mm at 2 years was significantly reduced by ZOL in 8 patients (12 vs 4 in CTR vs ZOL, respectively) as was also found in 6 patients for subsidence (≥ 1.5mm in 9 vs 3 patients in CTR vs ZOL, respectively) (P< 0.05, Fisher’s exact).

This is the first clinical trial reporting that a single infusion of ZOL suffices to improve initial implant fixation in THA. Based on best evidence available to date, this new concept shows great promise of improving the long-term outcome in THA and should be given attention in long-term trial.

Objectives. Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis. Methods. We conducted a systematic search in several databases, including PubMed and Embase. A random-effects model was employed and results were assessed by the odds ratio (OR) and corresponding 95% confidence intervals (CI). Furthermore, with respect to each outcome, each intervention was ranked according to the surface under the cumulative ranking curve (SUCRA) value. Results. With respect to preventing new vertebral fractures (NVF), all ten drugs outperformed placebo, and etidronate proved to be the most effective treatment (OR 0.24, 95% CI 0.14 to 0.39). In addition, zoledronic acid and parathyroid hormone ranked higher compared with the other drugs. With respect to preventing clinical vertebral fractures (CVF), zoledronic acid proved to be the most effective drug (OR = 0.25, 95% CI 0.08 to 0.92), with denosumab as a desirable second option (OR = 0.48, 95% CI 0.22 to 0.96), when both were compared with placebo. As for adverse events (AE) and severe adverse events (SAE), no significant difference was observed. According to SUCRA, etidronate ranked first in preventing CVF; parathyroid hormone and zoledronic acid ranked highly in preventing NVF and CVF. Raloxifene was safe with a high rank in preventing AEs and SAEs though performed unsatisfactorily in efficacy. Conclusions. This study suggests that, taking efficacy and safety into account, parathyroid hormone and zoledronic acid had the highest probability of satisfactory performance in preventing osteoporotic fractures. Cite this article: G. Wang, L. Sui, P. Gai, G. Li, X. Qi, X. Jiang. The efficacy and safety of vertebral fracture prevention therapies in post-menopausal osteoporosis treatment: Which therapies work best? a network meta-analysis. Bone Joint Res 2017;6:452–463. DOI: 10.1302/2046-3758.67.BJR-2016-0292.R1

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

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

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality