Long-term bisphosphonate use has often been associated with atypical femoral fractures. These fractures evolve from incomplete femoral fractures. A previous study demonstrated that the presence of a radiolucent line in an incomplete fracture can indicate a high risk of progression to complete fracture.
The aim of this study is to present a management strategy for symptomatic bisphosphonate-associated incomplete atypical femoral fractures. Specific study questions include the following: (1) Is there a difference in the prognosis of these fractures based on the presence or absence of a radiolucent fracture line? (2) Can treatment with teriparatide assist in clinical/radiographic healing of these incomplete fractures? (3) Is there a characteristic biochemical profile in these patients?
Patients and Methods
We retrospectively examined all femur radiographs ordered by the metabolic bone disease service at our hospital between July 1, 2006 and July 1, 2011 and identified 10 patients with a total of 14 incomplete fractures. Nine patients received bisphosphonates for a mean duration of 10 ± 5 years (range, 4–17). The mean follow-up since the time of diagnosis was 20 ± 11 months (range, 6–36 months).
Five fractures did not have a radiolucent fracture line and were treated conservatively with partial weight-bearing restrictions and pharmacologic therapy. All five of these fractures healed with conservative management. Nine fractures had a radiolucent fracture line, and only two of these were treated successfully with conservative management including teriparatide. Six of the eight patients with a radiolucent line elected for surgical prophylaxis after 3 months of conservative management, whereas one patient underwent surgical prophylaxis without a trial of conservative management. Regarding the biochemical profiles, bone turnover markers for our patient cohort were in the lower quartile.
Fractures without a radiolucent line appear to respond to conservative management and not require surgical prophylaxis. Teriparatide treatment may hold promise in promoting healing of these fractures.
bisphosphonates; atypical femoral fractures; incomplete fractures; teriparatide; radiolucent fracture line
Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with 'atypical femoral fractures' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.
To evaluate the association between bisphosphonate use and the risk of atypical femoral fractures among women aged 65 or older.
Nested case–control study.
General practice research database in Spain.
Use of oral bisphosphonates before the occurrence of atypical fractures among cases or the corresponding index date among controls. Bisphosphonate use was categorised as ever versus never users. Ever users were divided according to the total time since first prescription.
Main outcome measures
Cases were defined as women aged 65 years or older with a first diagnosis of subtrochanteric or diaphyseal fracture, recorded in the BIFAP database between 1 January 2005 and 31 December 2008, and with at least 1 year of follow-up before the index date. For each case, five age-matched and calendar-year-matched controls without a history of hip or atypical fracture were randomly selected from the database.
OR of atypical femoral fracture by bisphosphonate use was determined using conditional logistic regression. Models were adjusted for comorbidities and use of other medications.
The analysis included 44 cases and 220 matched controls (mean age, 82 years). Ever use of bisphosphonates was more frequent in cases than controls (29.6% vs 10.5%). In multivariate analyses, OR (95% CI) of atypical femoral fracture was 4.30 (1.55 to 11.9) in ever versus never users of bisphosphonates. The risk increased with long-term use, with an OR of 9.46 (2.17 to 41.3) comparing those using bisphosphonates over 3 years versus no users (p for trend=0.01).
Bisphosphonate use was associated with an increased risk of subtrochanteric or diaphyseal fractures in elderly women in a low fracture risk population, with a higher risk among long-term bisphosphonate users.
Clinical Pharmacology; Epidemiology; Primary Care
Bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis. Extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk. However, concerns have been raised about potential over-suppression of bone turnover during long-term use of bisphosphonates, resulting in increased susceptibility to and delayed healing of non-spinal fractures. We report a patient who sustained non-traumatic stress fractures in bilateral femoral shafts with delayed healing after long-term bisphosphonate therapy. She underwent open reduction and surgical internal fixation. Although bisphosphonates effectively prevent vertebral fractures, and their safety has been tested in randomized trials, we must emphasize the need for awareness of the possibility that long-term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue-induced damage and adverse skeletal effects such as delayed fracture healing.
Bisphosphonates; Fractures, stress; Fracture healing
Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-naïve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies—12 SSBT patients (SSBT; aged 49–77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)—were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.
Bisphosphonate; Atypical fracture; Severely suppressed bone turnover; Nanoindentation; Mechanical properties; Mineral density
Bisphosphonates are widely used for prevention of fractures in patients at risk, mainly in the presence of osteoporosis and bone metastases. A number of adverse effects of prolonged bisphosphonate treatment have emerged. We would like to highlight the skeletal complications from which a radiologist may be the first healthcare professional to recognise the association with bisphosphonate therapy. We illustrate these complications (namely osteonecrosis of the jaw and less well-known atypical femoral shaft fractures), presenting radiological findings in our patients. Recommendations for safer use of bisphosphonates are included in the conclusion of our review.
Bisphosphonate-associated femur fractures have been well described but the preoperative patient factors, treatment modalities, and complications of treatment are unclear.
We asked whether a diagnosis of osteoporosis, the characteristic radiographic features of bisphosphonate-related femur fractures, and complication rates differed in patients with operatively treated femoral shaft fractures receiving bisphosphonates and in patients not receiving bisphosphonates.
We retrospectively reviewed 43 patients with bisphosphonate-associated femoral shaft fractures (including subtrochanteric) from 2002 to 2008 and 20 patients with similar fractures but not treated with bisphosphonates. Similar implants were used in both groups, but a greater number of adjuvants were used in the bisphosphonate cohort. We recorded preoperative osteoporosis and radiographic findings of the characteristic bisphosphonate femur fracture and early complications. The minimum followup was 5 months (mean, 29 months; range 5–60 months).
Preoperatively a greater percentage of patients treated with bisphosphonates had confirmed osteoporosis than those not treated with bisphosphonates (24% versus 5%, respectively), a greater percentage had a proximal fracture location (48% versus 40%, respectively), and their mean cortex to shaft diameter ratio was greater (24% versus 15%, respectively). The bisphosphonate cohort had a higher rate of intraoperative fractures (21% versus 0%) and postoperative plate failures (30% versus 0%).
Despite low rates of other risk factors and ample use of biologic adjuvants, patients treated with bisphosphonates having femur fractures have more complications.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Antiresorptive bisphosphonate agents are the mainstay of treatment for osteoporosis in both men and postmenopausal women. However, recent studies have raised concerns about the oversuppression of bone turnover related to the long-term use of bisphosphonates. Cases of atypical femoral diaphyseal and subtrochanteric fracture were reported recently in patients on long-term alendronate, and oversuppression of bone turnover was postulated to be the cause. We retrospectively reviewed all patients with femoral diaphyseal and subtrochanteric fracture presented between July 2003 and June 2008, and identified 10 patients who reported prior bisphosphonate use. Bone formation markers of all these patients were in the low range. Although the incidence of bisphosphonate-related atypical fracture accounts for an extremely low percentage of the total number of femoral diaphyseal and subtrochanteric fractures, we observed a steady increase from 0% in 2003 to 2004 to 25% in 2007 to 2008.
Introduction. Recent reports have described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term bisphosphonate use. Although information regarding the surgical treatment of these atypical femoral fractures is increasing, it is unclear if the preventive operation is useful in incomplete fractures. This study examined the results of preventive intramedullary nailing for incomplete atypical femoral fractures. Material and Methods. A retrospective search was conducted for patients older than 50 years receiving bisphosphonate therapy, with incomplete, nondisplaced fractures in either the subtrochanteric or diaphyseal area of the femur. Seventeen patients with a total of 20 incomplete, non-displaced lesions were included. The mean duration of bisphosphonate use was 50.5 months. Eleven of the 17 (64.7%) patients had complete or incomplete fractures on the contralateral femur. All were treated with prophylactic fixation of an intramedullary (IM) nail. The minimum followup was 12 months. Results. All cases healed with a mean period of 14.3 weeks. Nineteen of the 20 cases healed with the dissolution of incomplete fractures of the lateral aspect. A complete fracture developed at the time of nailing in one patient, but it healed with callus bridging. Conclusion. IM nailing appears to be a reliable way of preventing the progress of incomplete atypical femoral fractures.
The relationship between high adherence to oral bisphosphonates and the risk of different types of fractures has not been well studied among adults of different ages.
Using claims data from a large U.S. health care organization, we quantified adherence after initiating bisphosphonate therapy using the Medication Possession Ratio (MPR) and identified fractures. Cox proportional hazards models were used to evaluate the rate of fracture among non-adherent persons (MPR < 50%) compared to highly adherent persons (MPR ≥ 80%) across several age strata and a variety of types of clinical fractures. In conjunction with fracture incidence rates among the non-adherent, these estimates were used to compute the number needed to treat with high adherence in order to prevent one fracture, by age and fracture type.
Among 101,038 new bisphosphonate users, the proportion of persons with high adherence at 1, 2, and 3 years was 44, 39, and 35%, respectively. Among 65–78 year old persons with a physician diagnosis of osteoporosis, the crude and adjusted rate of hip fracture among the non-adherent was 1.96 (95% CI 1.48–2.60) and 1.74 (95% CI 1.30–2.31), resulting in a number needed to treat with high adherence to prevent one hip fracture of 107. The impact of high adherence was substantially less for other types of fractures and for younger persons. Analysis of adherence in a non-time dependent fashion artifactually magnified differences in fracture rates between adherent and non-adherent persons.
The anti-fracture effectiveness associated with high adherence to oral bisphosphonates varied substantially by age and fracture type. These results provide estimates of absolute fracture effectiveness across age subgroups and fracture types that have been minimally evaluated in clinical trials and may be useful for future cost-effectiveness studies.
bisphosphonate; adherence; compliance; fracture; osteoporosis
There are differences in the risk profile of patients prescribed alendronate, risedronate, or ibandronate. Observed reductions in fracture incidence over time suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.
Observational studies of bisphosphonate effectiveness for fracture prevention are subject to bias from unknown characteristics of baseline fracture risk at the start of therapy. The fracture incidence during the short period after starting a bisphosphonate and before any expected clinical benefit likely reflects baseline fracture risk. Bisphosphonate effectiveness may then be estimated by measuring the change in fracture incidence over time on therapy.
Administrative billing data were used to follow three cohorts of women aged 65 and older (total n = 210,144) after starting therapy either on alendronate, risedronate, or ibandronate in the USA between market introduction and 2006. Within each cohort, the baseline incidence of clinical fractures at the hip, vertebral, and nonvertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baselines, we then compared the fracture incidence during the subsequent 12 months on therapy.
At the start of therapy, the ibandronate cohort was younger and had fewer prior fractures than either the risedronate or alendronate cohorts. Accordingly, the baseline incidence of hip fractures was higher in the risedronate cohort (0.90 per 100 person-years) and in the alendronate cohort (0.77) than in the ibandronate cohort (0.64). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (18% lower at hip, 28% at nonvertebral sites, and 57% at vertebral sites) and risedronate (27% lower at hip, 21% at nonvertebral sites, and 54% at vertebral sites). In the ibandronate cohort, the fracture incidence was lower (31%) only at vertebral sites.
Differences in the baseline fracture incidence among the cohorts may reflect differences in the risk profile of patients prescribed each bisphosphonate. The reductions observed in fracture incidence over time within each cohort suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.
Bisphosphonates; Clinical fractures; Effectiveness; Epidemiology; Osteoporosis
Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined.
Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005.
Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200).
Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial (Black et al. 1996).
Several case series have suggested an association exists between atypical femoral subtrochanteric fractures and long-term use of bisphosphonates. It is thought that prolonged use of bisphosphonates may lead to adynamic, fragile bone. The radiologic features of atypical fractures include diffuse cortical thickening, transverse fracture, and beaking at the lateral subtrochanteric area. Atypical subtrochanteric femur fractures have been reported after use of alendronate, but there have been rare reports of atypical femur fractures occurring after administration of zoledronic acid. A 56-year-old female with metastatic breast cancer treated with zoledronic acid presented with pain in the right hip. X-rays showed a right subtrochanteric fracture, and she underwent operation. Four months later after having undergone an operation, the patient struggled with walking and X-ray showed delayed union of the fracture site.
Bisphophonate; Breast neoplasms; Femoral neck fracture
Recent studies have described unique clinical and radiographic characteristics of femoral stress fractures or low-energy fractures associated with long-term bisphosphonate therapy. However, it is unclear whether these fractures require subsequent surgery after the initial treatment.
We performed a cohort analysis of bisphosphonate-associated femoral stress fractures to (1) confirm the unique clinical and radiographic findings compared with existing literature, (2) determine whether any patients with completed fractures had no preexisting transverse stress fracture lines, (3) assess the need for additional surgical procedures, and (4) determine whether the hospital length of stay (LOS) differed for patients with prophylactic fixation of stress fractures versus fixation of completed fractures.
We retrospectively reviewed 16 patients with 24 diaphyseal and subtrochanteric femoral stress fractures (14) or low-energy fractures (10) who had been on bisphosphonates for 3 to 10 years. Data included demographics, symptoms, medication history, radiographic characteristics, treatment parameters, LOS, and outcome. Minimum followup was 9 months (average, 44.0 months; median, 31 months; range, 9–112 months).
All patients had clinical and radiographic findings similar to those reported in the literature. Two of four patients sustained completed fractures after radiographs failed to reveal transverse lateral fracture lines. None of the 14 prophylactically treated impending fractures progressed or required additional surgery; however, in five of 10 femurs treated after fracture completion, six additional surgeries were performed. The average hospital LOS was shorter in patients who underwent prophylactic fixation (3.8 days) than in patients treated for completed fractures (5.6 days).
Bisphosphonate-associated stress fractures and completed fractures are unique, possessing subtle characteristic radiographic features. Completed fractures may occur through the thickened bone in the absence of an appreciable transverse stress fracture line. Our observations suggest prophylactic reconstruction nail fixation may avoid fracture completion and may be associated with a shorter hospital LOS and less morbidity than treatment of completed fractures.
Level of Evidence
Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-011-2194-2) contains supplementary material, which is available to authorized users.
This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case–control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven.
A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians.
A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed.
Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these ‘atypical’ fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case–control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks.
Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk–benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.
Atypical; Bisphosphonate; Femur; Low trauma; Osteoporosis; Subtrochanteric
Bisphosphonates are widely prescribed and highly effective at limiting the bone loss that occurs in many disorders characterized by increased osteoclast-mediated bone resorption, including senile osteoporosis in both men and women, glucocorticoid-associated osteoporosis, and malignancies metastatic to bone. Although they are generally well tolerated, potential adverse effects may limit bisphosphonate use in some patients. Optimal use of bisphosphonates for osteoporosis requires adequate calcium and vitamin D intake before and during therapy. The World Health Organization fracture risk assessment algorithm is currently available to determine absolute fracture risk in patients with low bone mass and is a useful tool for clinicians in identifying patients most likely to benefit from pharmacological intervention to limit fracture risk. This fracture risk estimate may facilitate shared decision making, especially when patients are wary of the rare but serious adverse effects that have recently been described for this class of drugs.
Bisphosphonates are potent inhibitors of bone resorption and considered as a gold standard and are generally recommended as first-line therapy in patients with osteoporosis. Though bisphosphonates are shown to significantly reduce the risk of vertebral, non-vertebral and hip fractures, recent reports suggest a possible correlation between long-term bisphosphonate therapy and the occurrence of insufficiency fractures owing to prolonged bone turnover suppression. We report a patient with non-traumatic stress fractures of bilateral femoral shafts related to long-term bisphosphonate therapy indicating the need for a critical evaluation of patients with long-term bisphosphonate therapy.
Osteoporosis; Bisphosphonates; Stress fracture
Whilst bisphosphonates are an established modality in the treatment of osteoporosis, there have been increasing concerns regarding the risk of an unusual form of femur fracture amongst patients receiving bisphosphonates for prolonged periods. These fractures, referred to as ‘atypical’, have been characterized by a number of clinical and radiographic features that distinguish them from ‘typical’ osteoporotic fractures. The evidence base is currently split between a large number of case series demonstrating an association between the occurrence of atypical fractures and bisphosphonate use and several population-based studies that do not confirm such an association. Hence, a degree of uncertainty surrounds this important issue. In this review, we examine the emerging evidence on atypical femur fractures, assess hypotheses on their biomechanical evolution and discuss the wider clinical implications of this phenomenon.
Atypical femur fractures; osteoporosis; bisphosphonates; adverse drug reactions
Oral bisphosphonates comprise the most widely prescribed class of antiosteoporotic drugs. Recent reports, however, suggest a link between prolonged bisphosphonate use and atypical low-energy, subtrochanteric fractures. We describe the clinical course of two patient treated for a long term with different bisphosphonates who developed subtrochanteric atypical fractures. They were treated initially with intramedullary rodding without pain disappearance or healing of the fracture. Strontium ranelate, a new orally administered agent for the treatment of osteoporosis, was given to these patients with complete closure of the fracture and pain disappearance after a few months. We conclude that based on the chronology of fracture healing and pain disappearance of our patients and published evidence that strontium ranelate can accelerate fracture healing in a rat model, that strontium ranelate had a positive anabolic effect that contributed to fracture healing that produced the secondary disappearance of pain.
bisphosphonate; atypical fractures; delayed healing; strontium ranelate
Bisphosphonates (BPs) represent the most widely used therapy for osteoporosis. Recently, a relationship between long-term treatment with BPs and a subset of atypical femoral fractures (AFFs) from below the lesser trochanter to the sovracondilar line has been described. Many etiopathogenetic theories have been invoked to explain AFFs: reduced bone turnover and increased osteoblast bone apposition with accumulation of microdamage and decreased bone toughness with subsequent increased risk of micro-cracks and duration fractures, collagen fiber cross-linking and vascularization impairment.
Based on published studies, a task force of the American Society for Bone and Mineral Research has redacted the diagnostic criteria of AFFs by classifying them according to their major and minor criteria.
The treatment for displaced AFFs is osteosynthesis, but there is a lack of evidence for undisplaced AFFs and the duration of fracture treatment. BPs have a proven efficacy in osteoporotic fracture reduction as well as in the treatment of other bone diseases caused by the downregulation of osteoclast activity. BPs have an excellent benefit-to-risk ratio; however, minor adverse events, such as AFFs, occur in a variable percentage of patients treated over a long period of time.
atypical femoral fractures; bisphosphonates; surgical treatment
Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6–24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men and women were included. Of the qualifying hip fractures, 5.2% were subtrochanteric, 54.8% femoral neck, 33.0% intertrochanteric, and 7.1% other (generally complex fractures of mixed type). Significant baseline (pre-hip fracture) differences were seen between index hip-fracture types, with the percentage of patients with extreme mobility problems being twofold higher in patients with index subtrochanteric fracture (9.9%) compared to other patients. The distribution of hip-fracture types was similar between the treatment groups at baseline. No patients with index subtrochanteric fractures and six patients with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may be a unique risk factor predisposing to development of incident subtrochanteric fractures rather than other types of hip fracture. In patients with recent hip fracture who received zoledronic acid therapy, the incidence of new subtrochanteric fractures was too small to draw any meaningful conclusions.
Bisphosphonate; Hip fracture; Osteoporosis; Subtrochanteric; Zoledronic acid
Background and purpose
The risk of atypical fracture of the femur is associated with bisphosphonate use. While characterizing atypical fractures from a previous nationwide study in radiographic detail, we had the impression that the fractures were located either in the subtrochanteric region or in the shaft. We determined whether there is a dichotomy in this respect.
Patients and methods
The distance between the atypical fractures and the lesser trochanter was measured on plain radiographs from 129 of 160 patients with atypical fractures, taken from 2008 through 2010. Analysis of the distances measured showed 2 clusters, which were then analyzed with regard to bisphosphonate use and age.
The distribution of the distances would be best described as 2 clusters, with a dichotomy at 8 cm. The proximal (subtrochanteric) cluster comprised 25 patients who were generally younger (median 71 years) than the 104 patients in the cluster with shaft fractures (median 80 years). The 95% CI for the difference between medians was 4–11 years. Of the patients with subtrochanteric fractures, 18 of 25 used bisphosphonates as compared to 89 of 104 with shaft fractures.
The younger age and possibly smaller proportion of bisphosphonate users in the subtrochanteric cluster may be compatible with a greater influence of mechanical stress in the underlying pathophysiology of proximal fractures.
Osteogenesis imperfecta (OI) has been treated with bisphosphonates for many years, with some clear clinical benefits. In adults, there are reports of a new pattern of atraumatic subtrochanteric fractures with bisphosphonate treatment. This study assesses if bisphosphonate treatment leads to an altered pattern of femoral fractures.
Retrospective review of imaging for a cohort of 176 bisphosphonate-treated OI patients to identify the locations of femoral fractures over a two-year period, as compared to a historical control group managed pre-bisphosphonates.
Sixteen femoral fractures were identified in this time period in the bisphosphonate-treated group. All but two were within the subtrochanteric region. In comparison, the historical group—composed of 26 femoral fractures—had a more widespread fracture pattern, with the most frequent location being the mid-diaphysis. Many of the subtrochanteric fractures in the treatment group occurred with minimal trauma.
It appears that concerns over the treatment of the adult osteoporotic population with bisphosphonates are amplified and mirrored in OI. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs increase the risk of this type of injury, which warrants further modification of surgical management of the femur.
Osteogenesis imperfecta; Bisphosphonates
It is estimated that osteoporosis is responsible for about 300 000 hip fractures per year in the United States. Effective prevention of these fractures has been demonstrated using bisphosphonates. However, their mechanism of action has not been elucidated. Furthermore, the precise effect of bisphosphonates on the femoral neck and surrounding areas has never been studied. We are interested in establishing a protocol to analyze the bone quality of proximal femurs from patients treated with bisphosphonates. Following hip replacement surgery, the aim is to determine whether imaging and compression testing of cancellous bone from the discarded femoral necks can accurately assess the bone’s microarchitectural and biomechanical properties, respectively. To validate the technique, it was first tested on an untreated population. A bone biopsy trephine was used to extract cylindrical cores of trabecular bone from the centre of femoral necks. Densitometry, microcomputed tomography, and compression testing were used to assess the quality of bone in these samples. The compressive strength was found to be directly proportional to the modulus (i.e. stiffness) of the samples, thus reproducing previous findings. The relative porosity and, to a lesser extent, the bone mineral density were capable of predicting the quality of cancellous bone. In conclusion, a protocol to analyze the bone quality in human femoral necks using μCT and biomechanical compression testing was successfully established. It will be applied in a clinical setting to analyze bones from bisphosphonate-treated patients following total hip replacement.
microcomputed tomography; biomechanics; bisphosphonates; femoral neck; cancellous; osteoporosis; hip fracture
Osteoporotic fractures remain a major public health problem for their correlated morbidity and mortality. The primary aim of therapy must be the prevention of the first fragility fracture and avoiding subsequent fractures in patients who already have an existing fracture. There are evidences from randomized controlled trials (RCTs) about the efficacy of antiresorptives, such as bisphosphonates in reducing the risk of fracture, but none of these agents completely abolish the fracture risk.
The reduction of RRR by different therapies in RCTs is relatively constant but it is important to note that the proportion of inadequate-responders (i.e.: patients fracturing despite adequate pharmacological treatment) is increasing with the severity of the disease: the higher the risk of fracture the higher the proportion of inadequate-responders. Thus, the proportion of non responders across different trials is directly related to the fracture incidence observed in the control group of RCTs which is the most proximate indicator of osteoporosis severity.
Teriparatide (TPTD) demonstrate a real increases of both trabecular and cortical bone volume, which are associated with a true reduction of fracture risk, as many RCTs confirm.
The beneficial effect of introducing a treatment with antiresorptives after the treatment course with TPTD has been clearly demonstrated with the prevention of the reabsorption of the new bone tissue built during TPTD therapy and rapidly lowers cortical porosity, which leads to further increases in BMD. For these results, the introduction of an anti-resorptive after the treatment course with TPTD is strongly recommended and taken into account.
In Italy TPTD is fully reimbursed in patients incurring in a new vertebral or hip fracture while on chronic treatment with antiresorptive or in naive patients with 3 or more vertebral or hip fractures. In conclusion, since patients with severe osteoporosis are at very high risk of new fractures with worsening of quality of life and life expectancy, antiresorptives represent a sub-optimal treatment in these patients, werehas, since TPTD demonstrated real and substantial improvements in bone mass and reduction of fracture risk independently of initial risk, TPTD represents the only therapeutic option able to reverse at least in part this disabling disease.
severe osteoporosis, antiresorptives, teriparatide, fractures, cost effectiveness.