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

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

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

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

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

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

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

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

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

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.