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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

To discover whether orthopaedic surgeons follow the BOA guidelines for secondary prevention of fragility fractures, a retrospective audit on neck of femur fractures treated in our hospital in October/November 2003 was carried out. There were 27 patients. Twenty-six patients (96%) had full blood count measured. LFT and bone-profile were measured in 18 patients (66%). Only nine patients (30%) had treatment for osteoporosis (calcium and vitamin D). Only one patient was referred for DEXA scan. Steps were taken to create better awareness of the BOA guidelines among junior doctors and nurse practitioners. In patients above 80 years of age it was decided to use abbreviated mental score above 7 as a clinical criterion for DEXA referral. A hospital protocol based on BOA guidelines was made. A re-audit was conducted during the period August-October 2004, with 37 patients. All of them had their full blood count and renal profile checked (100%). The bone-profile was measured in 28 (75.7%) and LFT in 34 (91.9%) patients. Twenty-four patients (65%) received treatment in the form of calcium + Vit D (20) and bisphosphonate (4). DEXA scan referral was not indicated in 14 patients as 4 of them were already on bisphosphonates and 10 patients had an abbreviated mental score of less than 7. Among the remaining 23 patients, nine (40%) were referred for DEXA scan. This improvement is statistically significant (p=0.03, chi square test). The re-audit shows that, although there is an improvement in the situation, we are still below the standards of secondary prevention of fragility fractures with 60% of femoral fragility fracture patients not being referred for DEXA scan. A pathway lead by a fracture liaison nurse dedicated to osteoporotic fracture patients should improve the situation

Introduction. The purpose of this study was to establish whether men and women with a fragility hip fracture were equally investigated and treated for osteoporosis. Methods. A retrospective review was carried out including 91 patients (48 females, 43 males) who were admitted with a fragility hip fracture between March 2003 and April 2004. Data about age, sex, investigations and medication were collected from the case notes, GP surgeries and the bone densitometry database. Investigations and treatment were compared with current guideline recommendations (SIGN 2003, NICE 2005). Data were analysed using SPSS Version 13.0. Results. According to the guidelines patients < 75 years of age should be investigated and patients > 75 years should be treated for osteoporosis. In our review 33% of women and only 8% of men < 75 years were investigated with a DEXA scan following their hip fracture (Fishers Exact Test, p = 0.32). In patients > 75 years 25% of women and only 6% of men were treated with bisphosphonates (Chi-square = 4.18, p < 0.05). There was also a statistically significant difference in overall treatment including bisphosphonates and calcium/vitamin D between the sexes (Chi-square = 6.81, p < 0.05). Conclusion. This study shows that there is clearly a need for improvement in secondary prevention of fragility fractures in both sexes, but men are significantly less likely to be investigated and treated than women. It is important to include recommendations for men in future guidelines and increase the awareness of male osteoporosis. This is of particular importance as men have a higher morbidity and mortality following hip fractures than women. Orthopaedic surgeons should therefore take on responsibility for these fracture patients and ensure that the process of secondary prevention is initiated