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

PURPOSE OF THE STUDY. To assess if prolonged use of Bisphosphonates in Osteogenesis Imperfecta alters the pattern of femoral fractures. Osteogenesis Imperfecta (OI) has been treated with Bisphosphonates for many years with some clear clinical benefits. In adult cohorts there are reports of a new pattern of atraumatic subtrochanteric fractures seen with Bisphosphonate treatment. SUMMARY OF METHODS. This study assesses the location of femoral fractures in a cohort of 176 OI patients treated with Bisphosphonates over a two year period and compares it to a historical control group of 45 managed prior to the advent of this specific treatment. SUMMARY OF RESULTS. review of the radiological digital archive identified 16 femoral fractures in this time period in the Bisphosphonate treated group. All but 2 were within 5cm of the lesser trochanter, and 50% within 3cm. In comparison, the historical group, composed of 26 femoral fractures had a more widespread fracture pattern with the most frequent location being the mid-diaphysis. Many of the sub-trochanteric fractures in the treatment group occurred with minimal trauma, and in some cases without any injury. CONCLUSION. It appears that concerns in the adult osteoporotic population treated with Bisphosphonates are mirrored in Osteogenesis Imperfecta. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs, mediated by abnormal osteoclast and osteoblast function, increase the risk of this type of injury and warrants further investigation

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

Introduction and Aims: Periprosthetic bone loss is responsible for the majority of cases of implant failure after total joint arthroplasty. Bisphosphonates are effective in reducing bone loss in many conditions associated with accelerated bone turnover. Our aim was to determine the effect of bisphosphonates on periprosthetic bone mineral density (BMD, g/cm2) after total joint arthroplasty. Method: We conducted computerised searches for randomised controlled trials, evaluating the effects of bisphosphonates on periprosthetic bone mineral density in patients undergoing primary total joint arthroplasty. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews and the United Kingdom National Research Register Web-site to November 2003. Computerised searches of the archives of AAOS Annual Meetings 1989–2003 were also conducted. Additional strategies to identify articles included a hand search of the bibliographies of relevant articles and direct contact with the authors. Results: Of 386 citations initially identified, nine citations met our eligibility criteria. The total number of randomised controlled trials was six (five published and one abstract). Four trials evaluated total hip arthroplasty and two examined total knee arthroplasty. Five trials used alendronate and one used pamidronate. Quality scores ranged from 65 to 75. The pooled sample size was 290 patients. Less periprosthetic bone loss occurred in the intervention group compared to the control group at the following follow-up intervals: three months (n=128, Weighted Mean Difference (WMD): 3.3%, 95% Confidence Interval (CI): 1.9–4.7, p< 0.01); six months (n=224, WMD: 4.5%, CI: 1.6–7.4, p< 0.001); and 12 months (n=173, WMD: 4.2%, CI: 1.5–6.9, p=0.03). Tests of heterogeneity revealed greater maintenance of BMD in cemented arthroplasty than in uncemented arthroplasty (WMD: 7.5%, CI: 4.3–10.7 versus WMD: 2.1%, CI: 0.61–3.6, respectively, p< 0.001) at 12 months follow-up. Conclusion: Bisphosphonates have a beneficial effect on maintaining periprosthetic bone stock compared to control after total joint arthroplasty. The effect seems greater in cemented arthroplasty and total knee arthroplasty. Whether this increase in BMD results in improved fixation and longevity of prosthetic components remains unanswered. Larger trials evaluating the effect of bisphosphonates on rates of implant loosening and functional outcomes are needed

Background/Aims. Bisphosphonates play an important role in the treatment of catabolic bone diseases such as osteoporosis. In addition to their anti-resorptive activity exerted by their proapoptotic effect on osteoclasts, recent data suggest that nitrogen-containing bisphosphonates (N-BP) may also promote osteogenic differentiation by an unknown mechanism. Similar bone-anabolic effects have been attributed to cholesterol-lowering statins, which represent another class of mevalonate pathway inhibitors besides N-BP, suggesting a common mode of action. In vascular endothelial cells statins were recently shown to activate the Mek5/Erk5 mitogen-activated protein kinase cascade, which plays an important role in cellular differentiation, apoptosis or inflammatory processes. Here we evaluated whether N-BPs may also target the Mek5/Erk5 pathway and analysed the consequence of Erk5 activation on bone-relevant gene expression, calcification and osteoblast differentiation. Methods and Results. We show that N-BP dose-dependently activate Erk5 in primary human endothelial cells and osteoblasts. The mechanism likely involves farnesyldiphosphate synthase (FDPS) inhibition and subsequent inactivation of the small GTPase Cdc42 since siRNA-mediated knockdown of both genes could reproduce N-BP-induced ERK5 activation. ERK5 activation resulted in regulation of several bone-relevant genes and was required for calcification and osteoblastic differentiation of mesenchymal stems cells as evident by the lack of alkaline phosphatase induction and alizarin-red staining observed upon Erk5 knockdown or upon differentiation initiation in presence of a pharmacological Erk5 inhibitor. Conclusion. Our data provide first evidence that N-BP activate the Mek5/Erk5 cascade and reveal an essential role of Erk5 in the regulation of bone homeostasis by influencing bone mineralization and osteoblast differentiation

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

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

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

Introduction. Bisphosphonates are among the most commonly prescribed drugs in Osteoporotic Patients. Their mode of action is anti-resorptive. Since remodeling is a key step in fracture healing, there has been concern regarding the effect of bisphosphonates on fracture healing. Objectives. To assess the effect of alendronate on fracture healing in the rabbit ulna osteotomy model. Materials and methods. 16 New Zealand white rabbits were divided into 2 equal groups. Bilateral ulnar osteotomies were performed in the first week. Group 1 was the control group and group 2 was gavaged with alendronate solution (human equivalent dose). 2 rabbits were euthanised at 3 and 6 weeks and the remaining 4 rabbits were euthanised at 8 weeks. Fracture healing was assessed radiologically, with mechanical testing using the Instron 4302 materials testing machine and histologically, in that order. Results. The fractures healed satisfactorily in all the control group animals. However, in the alendronate treated group, there was an abundance of woven bone and little lamellar bone in the callus. However there was no significant difference in mechanical testing. In addition we did not find any evidence of Osteonecrosis in the Bisphosphonate treated group. Conclusion. Bone remodelling in the alendronate treated group is slower but a larger amount of bone callus is formed around the fracture, thus giving the fracture callus a higher ultimate load to failure at an earlier stage

Purpose: Bony metastases in vertebrae secondary to breast cancer can result in osteolysis and an increase in skeletal related events. Bisphosphonates (BP) are the current standard of care for breast cancer patients with skeletal disease. Photodynamic therapy (PDT) is a non-radiative treatment, which has been successfully applied to various malignancies and shown to successfully ablate vertebral human breast cancer (MT1) metastases in a murine model. Previous in-vitro study has shown that pre-treatment of MT-1 cells with the BP zoledronic acid (Zometa. ®. ) renders them more susceptible to PDT. The aim of this study was to evaluate the influence of pre-treatment with BPs on the effect of PDT treatment on tumour ablation in metastatically involved vertebrae in vivo. Method: Metastases were induced in fourteen 5–6 weeks old female athymic rats (Hsd:RH-Foxn1rnu) by intra-cardiac injection of 2x10^6 MT-1 cells. Four groups were formed:. control, no treatment;. BP only;. PDT only;. BP and PDT combined. Seven days after MT-1 injection 60 μg/kg of zoledronic acid was injected. PDT treatment was administered on day 14 using the photosensitizer BPD-MA (1.0 mg/kg; Visudyne). Fifteen minutes later, laser-light (690nm; 75J) was administered to the lumbar vertebrae. The rats were euthanized 7 days after PDT treatment. A total of 45 vertebrae were evaluated using a histomorphometric program (GENIE™, Aperio) to assess tumour burden. Statistical analyses were performed using a one-way ANOVA with a Tukey post hoc test. A p-value p< .05 was considered to be statistically significant. Results: The total The total tumour burden within vertebrae of rats pre-treated with BP and/or PDT was significantly lower compared to the control rats (p< .001). In addition, the PDT alone treated group demonstrated significantly less tumour burden than the combined BP+PDT group. In the control and BP-only groups, large tumours were found to include regions of necrosis. The PDT treatment groups (PDT and BP+PDT) exhibited areas of necrosis throughout the entire vertebral bodies with adjacent formation of granulation tissue. Conclusion: BP, PDT and combined BP+PDT treatments resulted in a lower overall tumour burden at day 21 post MT-1 cell injection compared to control rats. A surprising increased level of tumour burden was found in comparing the combined treatment group to the PDT-only group. These findings are in contrast to previous in-vitro results, where the pre-treatment with BPs made the cells more susceptible to PDT. Pre-treatment with BP affects both the bone and tumour cells, and as such may induce different cellular pathways in response to PDT treatment. However, the ability of PDT applied at day 14 to cause a similar reduction in tumour burden compared to BP treatment at day 7, suggests its ability to rapidly and effectively ablate the tumour within the bone, even in the presence of BP

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

The aim was to analyze the efficacy of zoledronic acid (ZA) versus denosumab in the prevention of pathological fractures in patients with bone metastases from advanced cancers by evaluating all available randomized controlled trials (RCTs) on this subject.

A systematic search of electronic databases (PubMed and MEDLINE) was performed to identify all published RCTs comparing zoledronic acid with denosumab in prevention of pathological fractures in bone metastases. Risk of bias of the studies was assessed. The primary outcomes evaluated were pathological fractures.

Four RCTs (7320 patients) were included. Denosumab was superior to ZA in reducing the likelihood of pathological fractures, when all tumour types were combined (OR 0.86, 95% CI [0.74, 0.99], p = 0.04). Denosumab was not significantly favoured over ZA in endodermal origin (breast and prostate) (OR 0.85, 95% CI [0.68, 1.05], p = 0.13) and mesodermal origin tumours (solid tumours and MM) (OR 0.87, 95% CI [0.71, 1.06], p = 0.16).

Denosumab significantly reduces the likelihood of pathological fractures in comparison to ZA in patients with bone metastases. When pathological fractures were grouped by tumour origin (endodermal or mesodermal), there was no significant difference between denosumab and ZA. Further long-term studies are needed to confirm the effectiveness of these treatment regimens.

Background: In a previous randomized studiy using Röntgen Stereometric Analysis (RSA), we showed that oral bisphosphonates reduce the mean migration distance during the first 6 months. In a similar randomized study, bisphosphonates applied locally at the operation had a similar effect. These studies showed a 0.1 mm difference in mean value between groups. Does such a small difference matter? We addressed this question by use of frequency analysis.

Methods: The 2 previous studies were combined for analysis, and designated as bisphosphonate (n=44) or control treated (n=49). We analysed the migration vector (for the center of the rigid body) by use of a set of algoritms for frequency distribution analysis called Rmix. The migration vector lengths were assumed to be a compound of log-normal distributions. The frequency analysis determined if the observed frequency distributions were best described as a single, or a sum of 2 or more lognormally distributed subgroups.

Results: After 6 months, the control patients had formed 2 subgroups, one comprising 85% of the patients. The dichotomy was significant (p=0.016).

After 2 years, the dichotomy persisted (p=0.027). In the bisphosphonate-treated patients, no dichotomies could be found. The distribution of the migration vector length appeared similar to the larger and less migrating subgroup among the controls.

Discussion: The risk of aseptic loosening for cemented knees is extremely small. However, the migrating subgroup among our control patients may be at risk of loosening, and would have run a high risk if they were young and active. This subgroup did not appear with bisphosphonate treatment

Summary: In previous comparisons we found a slight decrease in mean value with bisphosphonates. The present analysis shows that this reflects the disappearance of a small subgroup with large migration.

Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that they may be associated with rare atypical femoral fractures.

1480 patients of proximal femur and shaft fractures over a period of 2 years from Jan 2014 to Jan 2016 were retrospectively reviewed in Gloucestershire Hospitals NHS trust. Hospital trauma database was used.195 patients had fractures in subtrochancteric and femoral shaft area.

11 patients had atypical femur fractures as defined by American society for bone and mineral research (ASBMR) task force 2013, revised criteria. Ten were female, one was male. Patients were aged from 68 to 97. In 6 patients, fractures were in the shaft, 5 in subtrochancteric area and 4 patients out of these had bilateral fractures. 10 out of 11 patients were on bisphosphonates. 4 patients had delayed diagnosis. 5 out of 11 patients did not have contralateral femoral x-rays. Treatment, 9 patients had intramedullary nail, one blade plate, and one treated conservatively. One patient in the IM group, had bilateral nailing. Average follow up was 7.6 months (range 1 to 16 months). At the end of the study, only 4 had united, 6 had not united and one not followed up. 4 out of 7 had low Vitamin D levels, 3 out of 7 had their bisphosphonate treatment stopped and 2 had histology which showed necrotic bone with trabeculae surrounded by fibrosis.

Increasing number of patients are on bisphosphonates for osteoporosis. Atypical femur fractures from bisphosphonates are often occult, often bilateral, with delayed healing. Patients on bisphosphonatetreatment should be advised to report any thigh or groin pain. Painful incomplete fractures need treatment with cephalomedullary nailing. Bone biology needs correcting by stopping bisphosphonatesand administering calcium & vitamin D supplements.

Implications: We need to raise awareness amongst treating clinicians and have national guidelines.

Osteogenesis imperfecta (OI) is characterised by decreased bone density and increased bone fragility.

We studied the effect of bisphosphonates on clinical features and bone mass, enrolling to the study 22 children with OI treated with these drugs. Sixteen of them received continuous oral alendronate and six received cyclical IV pamidronate. Evaluation included mobility score, fracture rate, chemistry of skeletal remodelling, iliac crest biopsy and DEXA assessment of bone mass.

After 18 months of bisphosphonate therapy, 10 patients were fully assessed. There was a definite clinical improvement, with significantly improved mobility (p =0.04), a reduction in the annualised fracture rate from 1.27 to 0.44, and significant improvement in bone mass density (p =0.01).

Clinical use of glucocorticoids engenders deleterious changes in bone fragility and initiates apoptosis in osteoblasts and osteocytes. The pathways leading to corticosteroid-induced death in bone remain unclear. Similarly little is known about the effects of ‘bone sparing’ bisphosphonates on osteocytes in vivo. We investigated the effects of bisphosphonates (BPs) on dexamethasone (Dex)-induced apoptosis in the murine osteocyte cell line, MLO-Y4 and studied the putative pathways involved by intervention with inhibitors of signalling molecules, such as p42/44 MAPK and protein kinase A (PKA). Cells were preincubated with N- & non N-containing BPs and/or inhibitors before insult with Dex or H₂O₂ for 5 hrs. Apoptotic morphology was revealed by acridine orange staining. Activation of p42/44 was identified using Western blotting and in situ immunocytochemistry in the presence or absence of serum.

Both N- & non N-containing BPs were shown to protect against cell death. The addition of inhibitors of p42/44 and PKA blocked the action of Dex. H₂O₂-induced apoptosis was not blocked by BPs or by any of the inhibitors. Dex appeared to activate p42/44 only in serum supplemented cultures. These data suggest that glucocorticoid but not oxidant-induced osteocyte apoptosis involves activation of p42/44 and that bisphosphonate engendered cell rescue is brought about by inhibition of these MAPK’s. Studies using truncated BPs that lack anti-resorptive activity, and therefore do not interrupt bone remodelling showed that these BPs were also able to protect osteocytes from glucocorticoid-induced death. The ability of bisphosphonates to influence MAPK activation and cell death in the osteocyte opens up exciting possibilities for pharmaceutical intervention during age and steroid hormone related osteocyte loss.

Nitrogen-containing bisphosphonates such as Zoledronic Acid (ZA) are used clinically for the treatment of skeletal diseases related with increased bone resorption. The gold standard is to administrate the drug through a systemic pathway, however this is often associated with high dosages, risk of side-effects, reduced site-specific drug delivery and hence, limited drug-effectiveness. A controlled local drug delivery, via a biomimetic bone graft, could be beneficial by direct and time-regulated application of significantly lower drug dosage at the site of interest. Thus, higher efficacy and reduced side-effects could be expected. In this experimental in vivo study, we examined the effect of ZA when used together with a Calcium Sulphate/Hydroxyapatite biomaterial in a femoral condyle bone defect in rats and compared local to systemic administration. The following groups were used: group1: empty defect (no biomaterial & no treatment), group2: biomaterial alone, group3: biomaterial + systemic ZA (0.1mg ZA/kg – single subcutaneous injection), group4–6: biomaterial conjugated with ZA at different concentrations, (0.07 to 0.70 mg ZA/mL of paste, corresponding to 0.0024 to 0.024 mg ZA/kg). The animals were sacrificed at 6 weeks and toxicological examination was performed. Bone regeneration was evaluated using qualitative and quantitative micro-CT analysis and Histomorphometry. The results showed a significant difference between the groups, suggesting that ZA has an overall effect on bone healing. The most pronounced effect was seen with the local application of approximately 10 times less ZA-dosage when compared to systemic use (p<0.001). This study demonstrates the importance of local ZA administration in bone regeneration.

Introduction

Long-term use of bisphosphonates has been known to induce femoral insufficiency fracture in osteoporotic patients. We followed patients who had femoral insufficiency fractures after a long-term use of bisphosphonates.

Introduction: Distraction osteogenesis is a widely utilised orthopaedic procedure; however prolonged treatment time and considerable disuse osteoporosis remain problematic, with decreases of 44% to 61% in bone mineral density reported in adjacent bone. Refracture rates of 10–20% are reported after frame removal.

We set out to examine the role of bisphosphonates in protecting the bone against stress-shielding related osteopaenia during distraction osteogenesis. We used a NZW rabbit model with 2 weeks distraction to 10.5 mm then 4 weeks consolidation. We achieved positive results in the initial trial using the bisphosphonate pamidronate (Novartis). Not only were we able to abolish the decrease in BMD in the surrounding bone, we noted an increase in the mineral properties and strength of the new bone.

Moving on to zoledronic acid (Novartis), a third generation bisphosphonate designed for use in malignant hypercalcaemia and bone metastases, we achieved even more promising results. In a study of thirty rabbits, we gave saline to 10 controls, 0.1 mg/kg zoledronic acid to 10 rabbits at surgery and 10 further rabbits received 0.1 mg/kg zoledronic acid at surgery and at two weeks. The animals were scanned by DXA at 2, 4 and 6 weeks, and by QCT after culling. Mechanical testing was performed by destructive 4-point bend tests.

Second-weekly DXA scans documented faster mineral accrual after distraction between 2 and 4 weeks in both treatment groups (ANOVA p< 0.01). In the control group, the BMD in the segments around the lengthening fell by 0.16 g/cm2 between the 2nd and 6th week. The BMD showed a net increase over the same time period in all treated animals (ANOVA p< 0.01).

The cross sectional area of the regenerate at six weeks as measured by QCT was increased by 49% in the zoledronate group versus controls and by 59% in the re-dosed zoledronate group. (ANOVA p< 0.01). The final (6 week) BMC of the regenerate was increased by 92% in the zoledronate group versus controls and by 111% in the re-dosed zoledronate group (ANOVA p< 0.01). Bone mineral density was increased by a lesser but significant degree to normal values (28% and 34% respectively, ANOVA p< 0.01).

Four point bend testing revealed increases in peak load of 29% in the single dose and 89% in the re-dosed group (ANOVA p< 0.01).

Two patients are presented, one with congenital pseudarthrosis of the tibia, and one who had not united a distraction gap of 5 cm at six months, who were treated with pamidronate. Both showed successful responses in line with our research findings.

A clinical trial is being set up to establish a scientific case for bisphosphonate use in patients undergoing distraction osteogenesis with the aim of possible earlier frame removal and less refractures. Further research in other areas of bone healing is also planned.

Methods: To participate in this study with a follow-up of 2 years the children with osteogenesis imperfecta (OI) had at least a restricted level of ambulation according to the criteria of Bleck and no history of prior bisphospho-nate use. Primary outcome measurements were BMD (L1-L4 and calcaneus), functional outcome (Bleck, Pediatric Disability Inventory (PEDI) and muscle strength) and quality of life (self-perception profile for children by Harter (CBSK)). Additional outcomes were sitting height, vertebral height (mean L1-L4) and fracture rate. Thirty-four children were included. Half of the children were treated with Olpadronate (dimethyl-APD, 10mg/m2/day), the others received placebo tablets. All children were supplied with calcium (500mg/m2/day) and vitamin D (400 I.U./day).

Results: Thirty-two children completed the two-year follow-up period of the study, 15 of them in the Olpadro-nate and 17 in the placebo group. The mean ages were 10.4 (SD 2.8) and 10.6 (SD 4.0) years, respectively, in both groups. In the complete study group, spinal BMD increased significantly during the two years of follow-up (p< 0.005), but the level of BMD accretion per year in the Olpadronate group was higher than in the placebo group (p< 0.0155). Increase of BMD at the os calcis was also seen in both groups (p< 0.05) with a borderline sig-nificant difference between the groups in favour of the Olpadronate group (p=0.085). Sitting height, vertebral height and muscle strength increased in both groups without a significant difference between the groups. No differences in changes in functional outcome (Bleck, PEDI) or self-perception (CBSK, Harter) were observed. Fracture rate and the percentage of children with 3 or more fractures during the 2 years follow-up were lower in the Olpadronate group compared to the placebo group. No side effects of the medication were noted during this study.

Conclusion: In this first double-blind randomized placebo-controlled study on the effects of bisphosphonates in children with OI, Olpadronate proved to be effective as demonstrated by a greater annual increase in BMD, independent from the effects of increase of age and calcium and vitamin D supplementation. Fracture risk seemed to decrease, however, given the interindividual variation in fracture rate within both groups, care must be taken in the wording of conclusions. The relationship between an increase in BMD and items such as functional outcome and quality of life remains unclear.