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

Introduction:. Paley et al has developed a multiplier method for calculating both leg length and total height. In the development of this algorithm, they evaluated the effect of factors including bone age and sex. They established that sex had a significant impact, but adjusting for bone age did not improve accuracy. Bone age and menarche have been shown to improve other height prediction models. Purpose:. We used a large prospective cohort to evaluate if the multiplier is independent of physiological age using menarche as a proxy. Methods:. Using the ALSPAC dataset we determined the accuracy of the Paley multiplier for predicting total height and leg length, and assed weather if the date of first menses increased the accuracy of the multiplier. Female patients over the age of 8, with documented final height and final sub-ishial leg length over the age of 15 and a date of first menses were evaluated. Predicted final height was compared with actual final height at all data points. Results:. There were 28332 data points in 3062 girls prior to skeletal maturity in the total height cohort and 8395 data points in 2300 girls in the leg length cohort. When age was corrected using the difference in age at onset of menarche from average, the accuracy of multiplier decreased for both measurements. When a correction of 50% was used, there was an improvement in the accuracy of multiplier predictions, reducing the average error by up to 24%. Conclusions:. Previous studies have failed to demonstrate that the accuracy of the multiplier is improved when adjusted for bone age. We have used the date of first menses as a proxy for bone age and established that making a 50% correction for physiological age improves the accuracy of this method. Significance:. This will potentially allow more accurate prediction of leg length discrepancy, and total height in girls with early menarche

Our aim in this pilot study was to evaluate the fixation of, the bone remodelling around, and the clinical outcome after surgery of a new, uncemented, fully hydroxyapatite-coated, collared and tapered femoral component, designed specifically for elderly patients with a fracture of the femoral neck. We enrolled 50 patients, of at least 70 years of age, with an acute displaced fracture of the femoral neck in this prospective single-series study. They received a total hip replacement using the new component and were followed up regularly for two years. Fixation was evaluated by radiostereometric analysis and bone remodelling by dual-energy x-ray absorptiometry. Hip function and the health-related quality of life were assessed using the Harris hip score and the EuroQol-5D. Up to six weeks post-operatively there was a mean subsidence of 0.2 mm (−2.1 to +0.5) and a retroversion of a mean of 1.2° (−8.2° to +1.5°). No component migrated after three months. The patients had a continuous loss of peri-prosthetic bone which amounted to a mean of 16% (−49% to +10%) at two years. The mean Harris hip score was 82 (51 to 100) after two years. The two-year results from this pilot study indicate that this new, uncemented femoral component can be used for elderly patients with osteoporotic fractures of the femoral neck

We carried out a retrospective review over ten months of patients who had presented with a low-energy subtrochanteric fracture. We identified 13 women of whom nine were on long-term alendronate therapy and four were not. The patients treated with alendronate were younger, with a mean age of 66.9 years (55 to 82) vs 80.3 years (64 to 92) and were more socially active. The fractures sustained by the patients in the alendronate group were mainly at the femoral metaphyseal-diaphyseal junction and many had occurred after minimal trauma. Five of these patients had prodromal pain in the affected hip in the months preceding the fall, and three demonstrated a stress reaction in the cortex in the contralateral femur. Our study suggests that prolonged suppression of bone remodelling with alendronate may be associated with a new form of insufficiency fracture of the femur. We believe that this finding is important and indicates the need for caution in the long-term use of alendronate in the treatment of osteoporosis

Aims

The aim of this study was to evaluate the outcomes of a salvage procedure using a 95° angled blade plate for failed osteosynthesis of atypical subtrochanteric femoral fractures associated with the long-term use of bisphosphonates. These were compared with those for failed osteosynthesis of subtrochanteric fractures not associated with bisphosphonate treatment.

Objectives

The biomembrane (induced membrane) formed around polymethylmethacrylate (PMMA) spacers has value in clinical applications for bone defect reconstruction. Few studies have evaluated its cellular, molecular or stem cell features. Our objective was to characterise induced membrane morphology, molecular features and osteogenic stem cell characteristics.

Objectives

Deep bone and joint infections (DBJI) are directly intertwined with health, demographic change towards an elderly population, and wellbeing.

The elderly human population is more prone to acquire infections, and the consequences such as pain, reduced quality of life, morbidity, absence from work and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets.

DBJIs are less responsive to systemic antibiotics because of poor vascular perfusion in necrotic bone, large bone defects and persistent biofilm-based infection. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently needed to curb its current trajectory.

Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing.

A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague–Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology.

The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm^-2 (sd 7.63) vs 24.65 Nmm^-2 (sd 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (sd 0.75) vs 4.6 mmAl (sd 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007).

Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing.

Cite this article: Bone Joint J 2013;95-B:1263–8.

Several bisphosphonates are now available for the treatment of osteoporosis. Porous hydroxyapatite/collagen (HA/Col) composite is an osteoconductive bone substitute which is resorbed by osteoclasts. The effects of the bisphosphonate alendronate on the formation of bone in porous HA/Col and its resorption by osteoclasts were evaluated using a rabbit model. Porous HA/Col cylinders measuring 6 mm in diameter and 8 mm in length, with a pore size of 100 μm to 500 μm and 95% porosity, were inserted into a defect produced in the lateral femoral condyles of 72 rabbits. The rabbits were divided into four groups based on the protocol of alendronate administration: the control group did not receive any alendronate, the pre group had alendronate treatment for three weeks prior to the implantation of the HA/Col, the post group had alendronate treatment following implantation until euthanasia, and the pre+post group had continuous alendronate treatment from three weeks prior to surgery until euthanasia. All rabbits were injected intravenously with either saline or alendronate (7.5 μg/kg) once a week. Each group had 18 rabbits, six in each group being killed at three, six and 12 weeks post-operatively. Alendronate administration suppressed the resorption of the implants. Additionally, the mineral densities of newly formed bone in the alendronate-treated groups were lower than those in the control group at 12 weeks post-operatively. Interestingly, the number of osteoclasts attached to the implant correlated with the extent of bone formation at three weeks.

In conclusion, the systemic administration of alendronate in our rabbit model at a dose-for-weight equivalent to the clinical dose used in the treatment of osteoporosis in Japan affected the mineral density and remodelling of bone tissue in implanted porous HA/Col composites.

Objectives

Small animal models of fracture repair primarily investigate indirect fracture healing via external callus formation. We present the first described rat model of direct fracture healing.

This multicentre prospective clinical trial aimed to determine whether early administration of alendronate (ALN) delays fracture healing after surgical treatment of fractures of the distal radius. The study population comprised 80 patients (four men and 76 women) with a mean age of 70 years (52 to 86) with acute fragility fractures of the distal radius requiring open reduction and internal fixation with a volar locking plate and screws. Two groups of 40 patients each were randomly allocated either to receive once weekly oral ALN administration (35 mg) within a few days after surgery and continued for six months, or oral ALN administration delayed until four months after surgery. Postero-anterior and lateral radiographs of the affected wrist were taken monthly for six months after surgery. No differences between groups was observed with regard to gender (p = 1.0), age (p = 0.916), fracture classification (p = 0.274) or bone mineral density measured at the spine (p = 0.714). The radiographs were assessed by three independent assessors. There were no significant differences in the mean time to complete cortical bridging observed between the ALN group (3.5 months (se 0.16)) and the no-ALN group (3.1 months (se 0.15)) (p = 0.068). All the fractures healed in the both groups by the last follow-up. Improvement of the Quick-Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, grip strength, wrist range of movement, and tenderness over the fracture site did not differ between the groups over the six-month period. Based on our results, early administration of ALN after surgery for distal radius fracture did not appear to delay fracture healing times either radiologically or clinically.

Cite this article: Bone Joint J 2013;95-B:1544–50.

We performed a retrospective review of all patients admitted to two large University Hospitals in the United Kingdom over a 24-month period from January 2008 to January 2010 to identify the incidence of atypical subtrochanteric and femoral shaft fractures and their relationship to bisphosphonate treatment. Of the 3515 patients with a fracture of the proximal femur, 156 fractures were in the subtrochanteric region. There were 251 femoral shaft fractures. The atypical fracture pattern was seen in 27 patients (7%) with 29 femoral shaft or subtrochanteric fractures. A total of 22 patients with 24 atypical fractures were receiving bisphosphonate treatment at the time of fracture. Prodromal pain was present in nine patients (11 fractures); 11 (50%) of the patients on bisphosphonates suffered 12 spontaneous fractures, and healing of these fractures was delayed in a number of patients. This large dual-centre review has established the incidence of atypical femoral fractures at 7% of the study population, 81% of whom had been on bisphosphonate treatment for a mean of 4.6 years (0.04 to 12.1).

This study does not advocate any change in the use of bisphosphonates to prevent fragility fractures but attempts to raise awareness of this possible problem so symptomatic patients will be appropriately investigated. However, more work is required to identify the true extent of this new and possibly increasing problem.

In an interdisciplinary project involving electronic engineers and clinicians, a telemetric system was developed to measure the bending load in a titanium internal femoral fixator. As this was a new device, the main question posed was: what clinically relevant information could be drawn from its application? As a first clinical investigation, 27 patients (24 men, three women) with a mean age of 38.4 years (19 to 66) with femoral nonunions were treated using the system. The mean duration of the nonunion was 15.4 months (5 to 69). The elasticity of the plate-callus system was measured telemetrically until union. Conventional radiographs and a CT scan at 12 weeks were performed routinely, and healing was staged according to the CT scans. All nonunions healed at a mean of 21.5 weeks (13 to 37). Well before any radiological signs of healing could be detected, a substantial decrease in elasticity was recorded. The relative elasticity decreased to 50% at a mean of 7.8 weeks (3.5 to 13) and to 10% at a mean of 19.3 weeks (4.5 to 37). At 12 weeks the mean relative elasticity was 28.1% (0% to 56%). The relative elasticity was significantly different between the different healing stages as determined by the CT scans.

Incorporating load measuring electronics into implants is a promising option for the assessment of bone healing. Future application might lead to a reduction in the need for exposure to ionising radiation to monitor fracture healing.

There have been recent reports linking alendronate and a specific pattern of subtrochanteric insufficiency fracture. We performed a retrospective review of all subtrochanteric fractures admitted to our institution between 2001 and 2007. There were 20 patients who met the inclusion criteria, 12 of whom were on long-term alendronate. Alendronate-associated fractures tend to be bilateral (Fisher’s exact test, p = 0.018), have unique radiological features (p < 0.0005), be associated radiologically with a pre-existing ellipsoid thickening of the lateral femoral cortex and are likely to be preceded by prodromal pain. Biomechanical investigations did not suggest overt metabolic bone disease. Only one patient on alendronate had osteoporosis prior to the start of therapy. We used these findings to develop a management protocol to optimise fracture healing. We also advocate careful surveillance in individuals at-risk, and present our experience with screening and prophylactic fixation in selected patients.

The purpose of this study was to describe the anatomical distribution and incidence of fatigue injuries of the femur in physically-active young adults, based upon MRI studies. During a period of 70 months, 1857 patients with exercise-induced pain in the femur underwent MRI of the pelvis, hips, femora, and/or knees.

Of these, 170 patients had a total of 185 fatigue injuries, giving an incidence of 199 per 100 000 person-years. Bilateral injuries occurred in 9% of patients. The three most common sites affected were the femoral neck (50%), the condylar area (24%) and the proximal shaft (18%). A fatigue reaction was seen in 57%, and a fracture line in 22%. There was a statistical correlation between the severity of the fatigue injury and the duration of pain (p = 0.001). The location of the pain was normally at the site of the fatigue injury. Fatigue injuries of the femur appear to be relatively common in physically-active patients.