Abstract. n engl j med 362;19 nejm.org may 13,

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1 The new england journal of medicine established in 1812 may 13, 2010 vol. 362 no. 19 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Dennis M. Black, Ph.D., Michael P. Kelly, M.D., Harry K. Genant, M.D., Lisa Palermo, M.A., Richard Eastell, M.D., Christina Bucci-Rechtweg, M.D., Jane Cauley, Ph.D., Ping Chung Leung, M.D., Steven Boonen, M.D., Ph.D., Arthur Santora, M.D., Anne de Papp, M.D., and Douglas C. Bauer, M.D., for the Fracture Intervention Trial and HORIZON Pivotal Fracture Trial Steering Committees Abstract Background A number of recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. A populationbased study did not support this association. Such a relationship has not been examined in randomized trials. Methods We performed secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). We reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare (subtrochanteric and diaphyseal femur fractures) and to assess atypical features. We calculated the relative hazards for subtrochanteric and diaphyseal fractures for each study. Results We reviewed 284 records for hip or femur fractures among 14,195 women in these trials. A total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 patient-years. As compared with placebo, the relative hazard was 1.03 (95% confidence interval [CI], 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Although increases in risk were not significant, confidence intervals were wide. From the University of California at San Francisco, San Francisco (D.M.B., M.P.K., H.K.G., L.P., D.C.B.); University of Sheffield, Sheffield, United Kingdom (R.E.); Novartis Pharmaceuticals, East Hanover, NJ (C.B.-R.); University of Pittsburgh, Pittsburgh (J.C.); Chinese University of Hong Kong, Hong Kong (P.C.L.); Katholieke Universiteit Leuven, Leuven, Belgium (S.B.); and Merck Research Laboratories, Rahway, NJ (A.S., A.P.). Address reprint requests to Dr. Black at 185 Berry St., Suite 5700, University of California, San Francisco, San Francisco, CA 94107, or at dblack@psg.ucsf.edu. This article ( /NEJMoa ) was published on March 24, 2010, at NEJM.org. N Engl J Med 2010;362: Copyright 2010 Massachusetts Medical Society. Conclusions The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions. n engl j med 362;19 nejm.org may 13,

2 The new england journal of medicine Several case series have described cases of atypical subtrochanteric and diaphyseal fractures of the femoral shaft and have suggested that the risk may be increased in long-term users of bisphosphonates Descriptions of associated atypical characteristics vary but have been described as a simple transverse or oblique (<30 degrees) fracture with cortical beaking and diffuse cortical thickening. 2 Clinical associations that have been mentioned in some reports include low-level trauma, prodromal pain or evidence of a previous stress fracture, contralateral changes, and the use of specific concomitant drugs (including corticosteroids), 9,10 antiresorptive drugs (including hormone-replacement therapy), 10 and proton-pump inhibitors. 13 However, these case reports and series have not had either a controlled or a prospective design and have not systematically examined risk factors. More recently, a population-based registry evaluated hip and subtrochanteric and diaphyseal femur fractures 14 and compared their incidence in alendronate users with that in nonusers. All three fracture types were more common in alendronate users. Given the known efficacy of alendronate for a reduction in the rate of hip fracture, the higher rates of all three types of fracture among alendronate users were attributed to the increased use of alendronate among high-risk patients rather than an increase in risk associated with alendronate. This confounding by indication is a bias often seen in nonrandomized studies. 15 The authors concluded that there was no evidence of an increased risk of fracture of the subtrochanteric or diaphyseal femur with either short-term or long-term use of a bisphosphonate. However, population-registry studies have limitations, including their observational, nonrandomized nature, a limited ability for covariate adjustment, and incomplete details with respect to fractures (e.g., precise morphologic features and the presence or absence of trauma). Randomized, controlled trials may provide unbiased information about femoral-shaft fractures. We evaluated the effect of bisphosphonates on such fractures by reevaluating femur fractures from three large, controlled, blinded, randomized trials of bisphosphonates with more than 14,000 patients and more than 51,000 patientyears of follow-up for up to 10 years. Methods Study Design We examined the incidence of fracture of the subtrochanteric or diaphyseal femur in three large, randomized trials: two that studied the use of oral alendronate (a placebo-controlled phase 3 trial and a randomized extension to 10 years of follow-up) and a placebo-controlled trial of zoledronic acid (infused annually). The trials used similar protocol-specified procedures for original collection and classification of fractures. We reviewed the fractures, using identical methods for the three studies, to identify and describe femoral-shaft fractures and assess atypical features if possible. Evaluation of Three Trials Fracture Intervention Trial (FIT) In this trial, 6459 women over the age of 65 years with a bone mineral density T score of less than 1.6 were recruited 16 and randomly assigned to receive daily alendronate (at a dose of 5 mg for 2 years and 10 mg thereafter) or placebo and were followed for 3 to 4.5 years Relevant data included demographic characteristics, bone mineral density scores, the use of concomitant medications, previous osteoporosis therapies, adverse events, and levels of biochemical markers of bone turnover. FIT Long-Term Extension (FLEX) Trial After the FIT trial ended, women were offered open-label alendronate for 1 year, after which a randomized extension trial began. 19 A total of 1099 women who were originally assigned to receive alendronate underwent a second randomization to receive alendronate at a daily dose of 5 mg (in 30% of subjects) or 10 mg (in 30% of subjects) or placebo (in 40% of subjects) and were followed for 5 more years. At baseline in the FLEX trial, the mean duration of alendronate therapy was 5 years; by the end of the trial, the mean duration was 10 years for women who were assigned to the continued alendronate group. HORIZON Pivotal Fracture Trial In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT), 7736 women were randomly assigned to receive an annual infusion 1762 n engl j med 362;19 nejm.org may 13, 2010

3 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur 6459 Patients were enrolled in FIT 1099 Patients were enrolled in FLEX 7736 Patients were enrolled in HORIZON-PFT 83 Hip or femur fractures 36 Hip or femur fractures 164 Hip or femur fractures 47 Were excluded from review because of location (femoral neck or subcapital) 5 Were periprosthetic, pathologic, or highenergy 17 Were excluded from review because of location (femoral neck or subcapital) 0 Were periprosthetic, pathologic, or highenergy 71 Were excluded from review because of location (femoral neck or subcapital) 8 Were periprosthetic, pathologic, or highenergy 1 Had insufficient data to classify Review by radiologist Review by radiologist Review by radiologist 29 Were not fractures of interest 15 Were not fractures of interest 78 Were not fractures of interest 2 Were fractures of interest (in 2 patients) 4 Were fractures of interest (in 3 patients) 6 Were fractures of interest (in 5 patients) 12 Were fractures of interest (in 10 patients) Figure 1. Process for Review of Hip and Femur Fractures from Three Clinical Trials. FIT denotes Fracture Intervention Trial, FLEX FIT Long-Term Extension (ClinicalTrials.gov number, NCT ), and HORIZON-PFT Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (NCT ). of 5 mg of zoledronic acid or placebo and were followed for 3 years. 20 Inclusion criteria included an age between 65 and 85 years and a bone mineral density T score of less than 2.5 or less than 1.5 in women with a vertebral fracture. Other information included previous osteoporosis medications and concurrent use of all prescription medications, bone mineral density score, and biochemical markers of bone turnover in approximately 20% of the subjects. Fracture Reporting and Adjudication The procedures for central adjudication of clinical fractures at the University of California, San Francisco (UCSF), were almost identical in the three studies. Subjects were specifically queried about fractures at study visits. With positive reports, investigators at the clinical site obtained documentation of all fractures, including those associated with trauma. The primary adjudication document was usually either a preoperative radiology report or the surgical medical record. Original radiographs were not generally obtained unless documentation was insufficient or inconclusive. In the FIT and FLEX trials, hip fractures were classified as involving the femoral neck, the intertrochanteric region, or miscellaneous hip. In the HORIZON-PFT trial, a fifth category of subtrochanteric fracture was added. Classification was based on the determination of community radiologists, as interpreted by the central adjudi- n engl j med 362;19 nejm.org may 13,

4 The new england journal of medicine Table 1. Review of Fracture Location in Three Randomized Trials of Bisphosphonates.* Variable Alendronate (N = 3236) Fracture Intervention Trial (FIT) Placebo (N = 3223) Relative Hazard (95% CI) no. (%) patient-yr no. (%) patient-yr Fractures reviewed Results of review Intertrochanteric 12 (0.4) (0.4) ( ) 0.99 Intertrochanteric and subtro chanteric 1 (<0.1) (<0.1) ( ) 0.99 Subtrochanteric or diaphyseal femur 1 (<0.1) (<0.1) ( ) 0.98 Distal metaphysis 1 (<0.1) (<0.1) ( ) 0.99 Femoral neck 16 (0.5) (1.0) ( ) 0.03 * High-trauma fractures were excluded according to the original study protocols. CI denotes confidence interval, and NA not applicable. Data regarding fractures of the femoral neck are based on classification during original studies but were not reviewed as part of this analysis. During the HORIZON-PFT study, an additional category of subcapital fractures was used. In the table, such fractures were combined into the category of femoral-neck fractures. P Value cator at UCSF and was not standardized across clinical centers. These procedures were developed to classify types of hip fractures, not to classify femoral-shaft fractures. Review of Fractures Procedures In 2008, after the publication of reports of atypical femoral-shaft fractures, we began a systematic review of fracture documentation. We used available radiographic and surgical reports to review fractures that originally had been classified as occurring in the hip (with the exception of those involving the femoral neck) and all other femur fractures. The review was performed by a radiologist who was not aware of study-group assignments and who specifically evaluated the location and any atypical features of fractures. Location of Fractures In our study, the region of interest was a fracture confined to the area below the lesser trochanter and above the distal metaphyseal flare (hereafter termed subtrochanteric and diaphyseal femur fractures). We excluded all periprosthetic fractures, pathologic fractures (i.e., those occurring in bone weakened by another disease process), and fractures associated with high-energy trauma. Other fracture categories included intertrochanteric only, intertrochanteric to subtrochanteric, and distal metaphysis. Assessment of Atypia For fractures meeting the criteria for location, we used radiographs (which were rarely available) for morphologic evaluation. Morphologic measurements included transverse or oblique versus spiral, abnormal cortical thickening (focal or generalized), cortical beaking, medial spiking, and any contralateral similarities. When radiographs were not available, atypical features in the radiology report were recorded. Study Oversight The original studies were designed by the steering committees in collaboration with the sponsors (Merck for the FIT and FLEX trials and Novartis for the HORIZON-PFT trial). UCSF investigators were responsible for the collection and adjudication of fracture data for all three studies. All other aspects of data collection were the responsibility of UCSF investigators for the FIT trial and of the sponsors for the FLEX and HORIZON trials. In each study, investigators developed publication guidelines that specified full participation of academic investigators together with sponsors in the publication of results. The two lead academic authors designed the study we report here and wrote the initial draft of the manuscript with substantial input from the other authors. Data analyses were performed solely by members of the UCSF group, who had full access to the study data. Representatives of the sponsors reviewed the 1764 n engl j med 362;19 nejm.org may 13, 2010

5 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Zoledronic Acid (N = 3875) no. (%) HORIZON Pivotal Fracture Trial patient-yr no. (%) Placebo (N = 3861) Relative Hazard (95% CI) P Value patient-yr no. (%) Alendronate/Alendronate (N = 662) FIT Long-Term Extension (FLEX) patient-yr no. (%) Alendronate/Placebo (N = 437) patient-yr Relative Hazard (95% CI) P Value 22 (0.6) (1.0) ( ) (1.5) (1.1) ( ) (0.1) (0.1) ( ) NA 0 NA NA NA 3 (0.1) (0.1) ( ) (0.3) (0.2) ( ) (<0.1) (0.1) ( ) NA 0 NA NA NA 21 (0.5) (1.2) ( ) (1.5) (1.6) ( ) 0.91 final drafts of the manuscript. All authors vouch for the completeness and accuracy of the data. Statistical Analysis For each trial, we calculated the risk person-years according to treatment and the relative hazard of fracture of the subtrochanteric or diaphyseal femur for subjects receiving bisphosphonates, as compared with control subjects. We also tabulated selected characteristics for individual subjects, including age, trauma level, and the duration of and adherence to treatment. When available, we compared biochemical-marker values for subjects who were receiving treatment but before the occurrence of a fracture with reference ranges for premenopausal women. 21 Results subtrochanteric and diaphyseal Fractures In all three trials, there were 283 hip or femur fractures (Fig. 1). Excluded from the review were 135 femoral-neck or subcapital fractures and 13 periprosthetic, pathologic, or high-energy fractures and 1 hip fracture with insufficient information to classify the location. Of the remaining 134 fractures, 12 were fractures of the subtrochanteric or diaphyseal femur that occurred in 10 women (for whom only one radiograph was available). With 12 fractures during 51,287 patientyears in the three studies, the combined rate was 2.3 patient-years. FIT Trial In the FIT trial, we reviewed 31 fractures, of which a majority were either intertrochanteric or extended from the intertrochanteric to the subtrochanteric region (Fig. 1). Only two fractures met the criteria for fracture of the subtrochanteric or diaphyseal femur (one in each study group), with an overall rate of 0.8 personyears. The relative hazard among subjects receiving alendronate, as compared with those receiving placebo, was 1.03 (95% confidence interval [CI], 0.06 to 16.46) (Table 1). Details regarding individual patients are shown in Table 2. Neither of the two women reported having received previous antiresorptive therapy. Levels of biochemical markers for serum C-terminal telopeptide of type 1 collagen (CTX) and serum procollagen type 1 N-propeptide (P1NP) for the women who received alendronate were below the lower limit of the premenopausal range, although the level of bone-specific alkaline phosphatase (BSAP) was within the premenopausal range. One woman was 69 years of age, and the other was 75. Neither reported a history or current use of corticosteroids or proton-pump inhibitors or any diseases affecting bone metabolism. HORIZON-PFT Trial For the HORIZON-PFT trial, we reviewed 84 hip or femur fractures in 82 women. Five women had six fractures that met the location criteria for fracture of the subtrochanteric or diaphyseal femur; of these women, three were receiving zoledronic acid (2.8 person-years) and two were receiving placebo (1.9 personyears) (relative hazard for zoledronic acid, 1.50; 95% CI, 0.25 to 9.00) (Table 1). The mean age of the five women was 71 years and 2 years below the study mean of 73 years. In three women re- n engl j med 362;19 nejm.org may 13,

6 The new england journal of medicine Table 2. Characteristics of 10 Patients with 12 Fractures of the Subtrochanteric or Diaphyseal Femur.* Patient No. Study Study Medication Age Days from Randomization to Fracture Compliance 1 FIT Placebo 75 yr 962 >75% 2 FIT Alendronate 69 yr 1682 >75% 3 HORIZON Zoledronic acid 65 yr % 4 HORIZON Placebo 78 yr % 5 HORIZON Zoledronic acid 65 yr % 6 HORIZON Placebo 72 yr % 7 Two fractures HORIZON Zoledronic acid 71 yr % 8 First fracture FLEX Alendronate/alendronate 79 yr 1250 Stopped study medication 3 yr before fracture Second fracture FLEX Alendronate/placebo 80 yr 1257 Stopped study medication 3 yr before fracture 10 FLEX Alendronate/alendronate 83 yr 1006 >75% * NA denotes not available. The level of compliance was assessed on the basis of the pill count in the FIT and FLEX trials; in the HORIZON trial, all five patients had three infusions of zoledronic acid (100% compliance). The level of trauma was recorded as one of the following categories: minimal (fall from standing height or less); fall from a step, stair, or curb; fall from more than standing height ( 20 in.); minimal trauma other than fall; moderate or severe trauma other than fall; and pathologic fracture. Listed are patients most recent measurements of biochemical markers of bone metabolism before fracture. Markers of bone metabolism that were used in the FIT and FLEX trials included serum C-terminal telopeptide of type 1 collagen (CTX), serum procollagen type 1 N-propeptide (P1NP), serum bone-specific alkaline phosphatase (BSAP), and serum N-terminal telopeptide of type 1 collagen (NTX). In the HORIZON trial, markers were assessed only in a sample of subjects. None of the five subjects with subtronchanteric or diaphyseal femur fractures were in this sample. ceiving zoledronic acid, one had simultaneous fractures of both femoral shafts, one had a transverse fracture but no beaking and no focal or generalized cortical thickening on radiography, and one had a spiral fracture on radiography, although the morphologic features were not described as atypical in case reports. For these five fracture events, three events in women receiving zoledronic acid occurred after minimal trauma (a fall from standing height or less), and two events in women receiving placebo occurred after a fall from a stair, step, or curb. Two women (one receiving zoledronic acid and one receiving placebo) reported taking concurrent antiresorptive therapy (raloxifene and injectable calcitonin, respectively), and one woman (who had two simultaneous fractures) reported having previously taken a bisphosphonate (>4 years before baseline) and hormone-replacement therapy. No women reported previous use of corticosteroids. Two women reported having hip pain at some point before the fracture, and the 1766 n engl j med 362;19 nejm.org may 13, 2010

7 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Level of Trauma Fall from step, stair, or curb Associated Medications before or during Study Bone Metabolism Marker (Reference Range) None CTX, ng/ml ( ); P1NP, 43.2 ng/ml ( ); BSAP, 14.5 ng/ml ( ) Unknown None CTX, ng/ml ( ); P1NP, 9.4 ng/ml ( ); BSAP, 7.5 ng/ml ( ) Minimal Fall from step, stair, or curb Raloxifene (before and during study) NA Other Comments Hip pain reported as adverse event at previous visit; transverse fracture on radiography None NA Hip pain reported as adverse event at previous visit Minimal None NA Spiral fracture on radiography Fall from step, stair, Injected calcitonin (before NA or curb and during study) Minimal Bisphosphonate (>4 yr) and HRT (both before study) NA Bone pain reported as adverse event at previous visit; simultaneous fractures of both femurs Minimal Minimal trauma other than fall Minimal 6 yr alendronate (in FIT before FLEX) NTX, 14.0 pmol/μmol ( ); BSAP, 12.0 ng/ml ( ) Minimal 6 yr alendronate (in FIT before FLEX) 5 yr alendronate (in FIT before FLEX) NTX, 54.0 pmol/μmol ( ); BSAP, 9.5 ng/ml ( ) NTX, 11.0 pmol/μmol ( ); BSAP, 5.5 ng/ml ( ) woman with simultaneous fractures had reported bone pain at two previous annual visits. Biochemical markers were not assessed in these patients. FLEX Trial In the FLEX trial, we reviewed 19 hip or femur fractures, and 4 fractures (occurring in 3 women) met the criteria for fracture of the subtrochanteric or diaphyseal femur: 2 of 662 women receiving alendronate (6.3 patient-years) and 1 of 437 women receiving placebo (4.7 per 10,000 patient-years; relative hazard in the alendronate group, 1.33; 95% CI, 0.12 to 14.67). All women had previously taken alendronate in the FIT trial (mean duration at FLEX baseline, 5 years). 19 The two women receiving alendronate had fractures more than 1000 days after randomization but had discontinued therapy 3 years earlier. None of the three women reported previous use of antiresorptive drugs or corticosteroids. One woman receiving alendronate (Subject 8 with two fractures) reported the use of a proton-pump inhibitor. In all three women with fractures in the location of interest, biochemical markers of bone turnover before fracture were substantially above the lower reference value for premenopausal women. The average age of the women (80 years) was about 7 years above the mean in the study. Three fractures occurred after a fall from standing height, while the fourth was due to trauma not associated with a fall. Discussion Data from three large, placebo-controlled, randomized trials indicate that the risk of fracture of the subtrochanteric or diaphyseal femur associated with the use of bisphosphonates was extremely low. Although the point estimates of the n engl j med 362;19 nejm.org may 13,

8 The new england journal of medicine relative risk with bisphosphonate use suggested no association, confidence intervals were wide because of the small number of events. In addition, in the FLEX trial (the largest and longest randomized extension study of long-term bisphosphonate use), despite an average of 10 years of alendronate use, the risk of fracture of the subtrochanteric or diaphyseal femur was low, with no significant increase among women who continued to receive alendronate for 10 years, as compared with those who discontinued the drug, although again confidence intervals were wide. In all three studies, atypical features could not be fully assessed, since radiographs were not generally available. The low risk of femoral-shaft fracture is consistent with recent results from a Danish population-based registry. 14 That study showed low rates overall, and women receiving alendronate had no higher risk than that caused by their underlying osteoporotic fragility. A recent study that was based on national discharge and medical-claims data in the United States reported similarly low rates of femoral-shaft fracture, 22 which made up less than 10% of all hip fractures. In the three studies that we reviewed, even among women with up to 10 years of bisphosphonate exposure, the risk of fracture of the subtrochanteric or diaphyseal femur ranged from one to six cases patient-years. If we had been able to assess atypical characteristics (e.g., cortical thickness and fracture morphology) and limit our consideration to atypical fractures, we probably would have excluded some additional events; this would have further reduced the risk. This assumption is supported by one study showing that only one quarter of subtrochanteric and diaphyseal fractures had atypical features 23 and another study showing that approximately one third of low-energy femoralshaft fractures were transverse or oblique with a small angle. 24 Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals preclude definitive conclusions regarding the relative risk of treatment. In the studies that we analyzed here and in other studies, bisphosphonates have been shown to decrease the rates of both vertebral and nonvertebral (including hip) fractures in women with osteoporosis. 17,18,20,25 Among women with osteoporosis in the FIT 25 and HORIZON-PFT 20 trials, 25 the estimated numbers of women who would need to be treated were 90 to prevent one hip fracture, 35 to prevent one nonvertebral fracture, and 14 to prevent one morphometric vertebral fracture (Table 3). Thus, we estimated that treating 1000 women with osteoporosis for 3 years would prevent about 100 fractures: 71 vertebral fractures and 29 nonvertebral fractures, including 11 hip fractures. On the basis of our studies, we estimated that bisphosphonate treatment would result in an annual rate of 2.3 subtrochanteric or diaphyseal fractures patient-years in untreated women with osteoporosis. This rate is consistent with those of the Danish registry study 14 and a recent population-based study. 22 According to the hypothetical relative risks, the increase in the number of such fractures per 1000 women who are treated for 3 years would be 0.3 events if the relative risk were 1.5, 0.7 events if the relative risk were 2.0, and 1.4 events if the relative risk were 3.0 (Table 3). When balanced against the prevention of 100 fractures, the hypothetical risk is quite small and would be even smaller if the risk were limited to fractures with atypical features. The Danish observational study showed no relationship between the use of bisphosphonates and the risk of femoral-shaft fracture, 14 consistent with our findings. However, these results contrast with those of some case series. For example, one case series 2 identified 20 women who had fractures with atypical features (e.g., transverse morphology, cortical thickening, or a low-level trauma), 19 of which were diagnosed in women receiving bisphosphonates. The lack of a control group (together with an inconsistent definition of atypia across case studies) increases the challenge of interpreting discrepancies among the studies. But results from case series suggest that patients taking bisphosphonates who have persistent thigh pain, evidence of a stress fracture, or a contralateral femur fracture should be carefully evaluated for further testing and possible interventions. It has been suggested that an increased risk of atypical femoral-shaft fracture associated with the use of bisphosphonates may be confined to a small subgroup of patients. 3,9 This hypothesis suggests that future studies should attempt to identify risk factors for subtrochanteric or dia n engl j med 362;19 nejm.org may 13, 2010

9 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Table 3. Comparison of Number of Patients Who Would Need to Be Treated for 3 Years with Bisphosphonates to Prevent One Fracture and the Hypothetical Number Associated with an Increase of One Subtrochanteric or Diaphyseal Fracture. Type of Fracture and Hypothetical Relative Risk Patients Who Would Need to Be Treated* physeal fracture in patients receiving bisphosphonates. Case reports have suggested several risk factors, particularly the concomitant use of corticosteroids. 9,10 Other proposed risk factors include concurrent use of proton-pump inhibitors 13 and markedly suppressed bone turnover, perhaps owing to the use of multiple antiresorptive medications. 8,10 In the HORIZON-PFT trial, one woman in the placebo group who had a femoral-shaft fracture was also receiving injected calcitonin; in the zoledronic-acid group, one woman was also receiving raloxifene, and another had a relevant history of taking multiple antiresorptive medications. In the FIT trial, one woman in the alendronate group had low levels of biochemical markers of bone turnover, but in the FLEX trial, such levels were all well within the premenopausal reference range. Most of the initial case series did not include data on the use of concurrent medications. 5,23 Other characteristics that have been suggested as risk factors include a younger age at the time of bisphosphonate initiation, a low pretreatment level of bone turnover, and normal bone mineral density. 10 However, none of the characteristics that have been postulated to increase the risk of femoralshaft fracture among women receiving bisphosphonates have been systematically or prospectively studied. Our results from the FLEX trial did not show a significant increase in the risk of fracture of the subtrochanteric or diaphyseal femur after 10 years of alendronate use, despite suggestions that a longer duration of use may increase risk. Data regarding duration from the case studies have been mixed. The mean duration in the cases reported by Neviaser et al. 2 was 7 years, but the duration of therapy has varied from 2 to 4 years in other reports, 8,10,12 suggesting that long-term use of bisphosphonates may not be necessary to increase risk. The Danish registry study showed no increase in risk with long-term use (>10 years). It would be important to identify the effect of the duration of bisphosphonate use so that it could be weighed against benefits in clinical decision making regarding continuing therapy. Although most of the reported cases of atypical femoral-shaft fracture among bisphosphonate users have occurred in women receiving alendronate (the most commonly used bisphosphonate), cases of such fractures also have been reported among users of ibandronate and risedronate. 8,10,12 Furthermore, we found cases of femoral-shaft fracture in patients receiving zoledronic acid, as well as in those receiving placebo, so there is no definitive evidence or theoretical reason to believe that any possible increase in risk would be limited to alendronate. Rare conditions such as atypical femoralshaft fractures are difficult to study. The ideal study would be a long, placebo-controlled, randomized trial involving tens of thousands of patients, a study design that is neither feasible nor ethical, given the known efficacy of bisphosphonates to reduce the overall risk of fracture. More rigorous observational studies with the use of a population database with both archived Events per 1000 Patients Treated number Type of fracture Any fracture 100 Any nonvertebral fracture Hip only Vertebral fracture (morphometric) Hypothetical relative risk of subtrochanteric or diaphyseal femur fracture * The estimated numbers of patients who would need to be treated with either zoledronic acid or alendronate in order to prevent one fracture were derived from fracture rates, as compared with placebo, in the HORIZON-PFT trial 20 for zoledronic acid and in the FIT trial 25 (for patients with either a vertebral fracture or a bone mineral density T score of less than 2.5 at the hip) for alendronate. The number of events per 1000 patients treated for 3 years refers to fractures that would be prevented by bisphosphonate treatment (under type of fracture) and fractures associated with bisphosphonate treatment (under hypothetical relative risk). The hypothetical relative risk is the risk of fracture of the subtrochanteric or diaphyseal femur in women receiving a bisphosphonate, as compared with those receiving placebo. On the basis of results from this study, it was estimated that the rate of subtrochanteric or diaphyseal fracture in untreated women with osteoporosis would be 2.3 patient-years, a rate that was consistent with those from a Danish population-registry study 14 and a recent population-based study. 22 n engl j med 362;19 nejm.org may 13,

10 The new england journal of medicine fracture radiographs and medication information might be more feasible. Although our study was based on randomized trials, it has important limitations. First, we did not have access to radiographs and therefore could not evaluate the atypical features of these fractures. Second, although the studies that we evaluated were large, there were insufficient numbers of events to make definitive conclusions. Third, by design, the use of many potentially confounding medications, including corticosteroids, was excluded from all three studies. The use of other antiresorptive medications was allowed in the HORIZON-PFT trial but excluded in the FIT and FLEX trials. Finally, the two placebo-controlled trials lasted only 3 to 4.5 years and thus could not assess whether the risk of fracture increased with treatment duration. Although the FLEX trial included women who were treated up to 10 years, all women had received bisphosphonates for at least 3 years; therefore, the trial could address only the question of bisphosphonate continuation versus discontinuation. We conclude that the risk of fracture of the subtrochanteric or diaphyseal femur associated with bisphosphonate use is very low, even in women with osteoporosis who received bisphosphonates for up to 10 years. Given the limitation of a small number of events and wide confidence intervals, these studies did not show a significant increase in the risk of subtrochanteric or diaphyseal fracture with 3 to 4 years of use of alendronate or zoledronic acid or up to 10 years of alendronate use. Supported by Merck and Novartis. Dr. Black reports receiving grants (to UCSF) from Merck, Novartis, Amgen, and Roche and travel reimbursements from Merck and Novartis; Dr. Genant, receiving consulting and lecture fees and grant support from Merck and Novartis; Ms. Palermo, receiving support from Nycomed for data analysis; Dr. Eastell, serving on advisory boards for Procter & Gamble and the Medical Research Council and receiving consulting fees from Amgen, AstraZeneca, GlaxoSmithKline, Medtronics, Nastech, Nestle, Fonterra Brands, Novartis, Ono Pharma, Osteologix, Pfizer, Lilly, Sanofi-Aventis, Tethys, Unilever, Unipath, Inverness Medical, Ortho Clinical Diagnostics, OSI Prosidion, and Roche, lecture fees from Takeda, Lilly, Amgen, National Osteoporosis Foundation, Procter & Gamble, and GlaxoSmith- Kline Nutrition, and travel expenses from Novartis; Dr. Bucci- Rechwig, being a full-time employee of and having an equity interest in Novartis; Dr. Cauley, receiving consulting fees from Novartis; Drs. Santora and de Papp, being full-time employees of and having equity interests in Merck; and Dr. Bauer, receiving consulting fees from Amgen and lecture fees from Merck. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Lewis Nusgarten for help in compiling the fracture records for review and Thuy Le for assistance in the preparation of the manuscript. References 1. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358: Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 2008; 22: Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 2008;93: Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90: Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007;89: Armamento-Villareal R, Napoli N, Panwar V, Novack D. Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 2006;355: Cheung RK, Leung KK, Lee KC, Chow TC. Sequential non-traumatic femoral shaft fractures in a patient on long-term alendronate. Hong Kong Med J 2007;13: Armamento-Villareal R, Napoli N, Diemer K, et al. Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int 2009;85: Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE. Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res 2009;24: Odvina CV, Levy S, Rao S, Zerwekh JE, Sudhaker Rao D. Unusual mid-shaft fractures during long term bisphosphonate therapy. Clin Endocrinol (Oxf) 2009 March 19 (Epub ahead of print). 11. Capeci CM, Tejwani NC. Bilateral lowenergy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am 2009;91: Kwek EB, Goh SK, Koh JS, Png MA, Howe TS. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 2008;39: Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital. Drug Saf 2009;32: Abrahamsen B, Eiken P, Eastell R. 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11 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur 16. Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. Osteoporos Int 1993;3:Suppl 3:S29-S Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280: Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296: Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356: Glover SJ, Gall M, Schoenborn-Kellenberger O, et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res 2009;24: Nieves JW, Bilezikian JP, Lane JM, et al. Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 2010;21: Lenart BA, Neviaser AS, Lyman S, et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 2009;20: Salminen S, Pihlajamäki H, Avikainen V, Kyrö A, Böstman O. Specific features associated with femoral shaft fractures caused by low-energy trauma. J Trauma 1997;43: Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85: Copyright 2010 Massachusetts Medical Society. f u l l t e x t o f a l l j o u r n a l a r t i c l e s o n t h e w o r l d w i d e w e b Access to the complete contents of the Journal on the Internet is free to all subscribers. To use this Web site, subscribers should go to the Journal s home page (NEJM.org) and register by entering their names and subscriber numbers as they appear on their mailing labels. After this one-time registration, subscribers can use their passwords to log on for electronic access to the entire Journal from any computer that is connected to the Internet. Features include a library of all issues since January 1993 and abstracts since January 1975, a full-text search capacity, and a personal archive for saving articles and search results of interest. All articles can be printed in a format that is virtually identical to that of the typeset pages. Beginning 6 months after publication, the full text of all Original Articles and Special Articles is available free to nonsubscribers. n engl j med 362;19 nejm.org may 13,