Frequency of Incomplete Atypical Femoral Fractures in Asymptomatic Patients on Long- Term Bisphosphonate Therapy

Musculoskeletal Imaging Original Research La Rocca Vieira et al. Femoral Fractures in Asymptomatic Patients Musculoskeletal Imaging Original Research Renata La Rocca Vieira 1 Zehava Sadka Rosenberg 1 Mary B. Allison 2 Shelly A. Im 2 James Babb 1 Valerie Peck 2 La Rocca Vieira R, Rosenberg ZS, Allison MB, Im SA, Babb J, Peck V Keywords: bisphosphonate, femoral fracture, femur, fracture DOI:10.2214/AJR.11.7442 Received June 29, 2011; accepted after revision August 19, 2011. 1 Department of Radiology, Hospital for Joint Diseases New York University School of Medicine, 301 E 17th St, New York, NY 10003. Address correspondence to R. La Rocca Vieira (relarocca@gmail.com). 2 Osteoporosis and Metabolic Bone Disease Program, Division of Endocrinology, Diabetes, and Metabolism, New York University School of Medicine, New York, NY. AJR 2012; 198:1144 1151 0361 803X/12/1985 1144 American Roentgen Ray Society Frequency of Incomplete Atypical Femoral Fractures in Asymptomatic Patients on Long- Term Bisphosphonate Therapy OBJECTIVE. The purpose of our study was to determine the frequency and imaging features of atypical femoral fractures in a consecutive asymptomatic patient population on longterm bisphosphonate treatment and search for distinguishing clinical and laboratory parameters in the subset of patients with fractures. SUBJECTS AND METHODS. Two hundred femoral radiographs in 100 asymptomatic patients (93 women and seven men; age range, 47 94 years; mean age, 69.3 years) were prospectively reviewed by two radiologists. All patients had received bisphosphonate treatment for at least 3 years and had no history of pain or recent trauma. MRI studies were performed when a fracture was suspected on radiographs. Bone mineral density, serum calcium, albumin, 25-hydroxy vitamin D, intact parathyroid hormone (ipth), serum C-telopeptide, and urine N-telopeptide values were obtained. RESULTS. Two of 100 patients (2%) had three insufficiency fractures. Both patients, 50 and 57 years old, were white, active, and had been receiving bisphosphonate therapy for 8 years. The patient with bilateral atypical femoral fractures showed typical features of bisphosphonate-related incomplete atypical femoral fractures. MRI confirmed the radiographic findings in both patients. The two patients with incomplete atypical femoral fractures were significantly younger than those without atypical femoral fractures. There were no significant differences among the fracture and nonfracture groups in terms of clinical or laboratory results, except for mean ipth, which was significantly decreased in the fracture group. CONCLUSION. The 2% frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy is higher than suggested in the literature. Aside from age and mean ipth, there were no significant differences in clinical or laboratory data between the two groups. B isphosphonates are the most commonly prescribed drugs for the prevention and treatment of osteoporosis and are highly effective in reducing the risk of vertebral and hip fractures [1, 2]. However, in the past few years, studies have linked prolonged bisphosphonate therapy with atypical, subtrochanteric, and diaphyseal femoral fractures [3 25]. This phenomenon is believed to be related to bisphosphonate-induced oversuppression of bone turnover with secondary aging of collagen and accumulation of microdamage that then predisposes to atypical fractures [10, 14, 15, 19, 26]. Most patients with bisphosphonate-related atypical femoral fractures describe minimal to mild hip or thigh pain in the affected limb before the onset of fracture [10, 12, 15]. Not infrequently, however, the pain is noted only in retrospect after a complete fracture has oc- curred. Furthermore, the fractures have been documented in completely asymptomatic patients [12]. They typically originate in the lateral femoral cortex and may remain incomplete for an unknown time period. Thus, early detection and treatment of these incomplete fractures is of great clinical importance and has the potential of sparing the patient a devastating and highly morbid event. To the best of our knowledge, there are no reported prospective studies identifying the frequency of incomplete bisphosphonate-related proximal femoral fractures in asymptomatic individuals nor are there any known distinguishing clinical criteria to help aid in early detection of these patients. The purpose of this prospective study is twofold: First, to determine the frequency and imaging features of incomplete atypical fractures in a consecutive asymptomatic patient 1144 AJR:198, May 2012

Femoral Fractures in Asymptomatic Patients population on long-term bisphosphonate treatment and second, to search for potentially distinguishing clinical and laboratory parameters in the subset of patients with fractures. Subjects and Methods Patient Population Approval was obtained from the institutional review boards, and all research was in compliance with HIPAA protocols. All patients were prospectively seen by one of the investigators, an endocrinologist specializing in the treatment of osteoporosis and metabolic bone diseases, between August 1, 2009, and March 1, 2011. The inclusion criterion was completely asymptomatic patients who have been on bisphosphonate therapy for at least 3 years. All of the patients were carefully questioned by the endocrinologist before being enrolled in the study as to excellent compliance with the medication and the presence of hip and thigh pain. Exclusion criteria included patients with pelvic, hip, or thigh pain; history of recent trauma; previous femoral fracture; hip replacement therapy; malignancy; or any other disease that would predispose to insufficiency fracture. Imaging Studies All studies were interpreted in consensus by two musculoskeletal radiologists with 7 and 25 years of experience. All patients were imaged with anteroposterior, frog leg lateral, and lateral radiography of both femurs. Lack of symptoms was confirmed again, either by telephone or by a visit to the endocrinologist, at the time the radiographs were obtained. MRI of both femurs was performed if incomplete atypical femoral fracture or another finding suggestive of a femoral fracture, such as linear intramedullary sclerosis, was identified on the radiographs. Atypical femoral fracture was defined on the radiographs as focal cortical thickening along the lateral aspect of the femur, with or without a fracture line [23] (Fig. 1A). MRI Technique and Interpretation The patients were imaged on a 3-T magnet (Verio, Siemens Healthcare). The MRI protocol consisted of axial T1-weighted (TR/TE, 811/8.5), axial T2-weighted fat-suppressed (TR/TE, 3960/36), coronal STIR (TR/TE, 4000/34; inversion time, 200 ms), sagittal T1-weighted (TR/TE, 637/6), and sagittal T2-weighted (TR/TE, 4000/66) images of the femurs. All MR sequences were obtained with a slice thickness of 3 6 mm and matrix of 256 256, 256 116, or 384 230. The following MRI features were noted: presence of focal cortical thickening along the lateral cortex of the femur with or without signal abnormality, a fracture line, adjacent periosteal or bone marrow, and edema or other findings suggestive of fracture or stress reaction (Figs. 1B 1D). Laboratory Data All patients underwent the following studies: bone mineral density (BMD) and serum calcium, albumin, 25-hydroxy vitamin D, intact parathyroid hormone, alkaline phosphatase, and serum C-telopeptide and urine N-telopeptide. In 90% of cases, imaging and laboratory studies were performed within a 4-month interval and in 10% of cases within a 5-month to 1-year interval. The BMD measurements of the femoral necks, total hips, and anteroposterior lumbar spine were performed using a dual-energy x-ray absorptiometry (DXA) machine. In accordance with the World Health Organization criteria, normal BMD was defined as a value less than 1 SD below the young adult peak BMD (T-score), osteopenia was defined as a value ranging from 1.0 to 2.5 SD below the young adult peak BMD, and osteoporosis was defined as a value equal to or greater than 2.5 SD below that of the young adult peak BMD [27]. Clinical information such as age, sex, height in inches, weight in pounds, and duration of bisphosphonate treatment was also recorded for all patients. Statistical Analysis Independent sample Student t and Mann-Whitney tests were used to compare patients with and without radiographic evidence of subtrochanteric incomplete femoral fractures in terms of each numeric imaging and laboratory study endpoint. All reported p values are two-sided and are not corrected for multiple comparisons. Statistical significance was defined as p < 0.05. SAS version 9.0 (SAS Institute) was used for all computations. In addition, the 95% CI method was used to compare the nonfractured group and fractured patient number 2 with regard to serum C-telopeptide and urine N-telopeptide mean values. Patient 1 was excluded from this analysis because she had been off the medication for 8 months at the time of the study. Results Two hundred femoral radiographs were obtained in 100 patients (seven men and 93 women; age range, 47 94 years; mean age, 69.3 years). Fifty-six of 100 patients were receiving alendronate therapy, 26 were on risedronate, and 18 had received more than one bisphosphonate (including ibandronate and zoledronic acid). In two of 100 patients or three of 200 femurs, there was radiographic evidence of incomplete femoral fracture. In the other 98 patients, the radiographs were normal. The two patients with abnormal findings on radiographs were subsequently imaged with MRI of both femurs. In each case, the MRI was obtained within 1 month of the initial radiographs. Case Presentations Patient 1 The patient was a 57-year-old active, asymptomatic white woman, who had been receiving alendronate therapy for 8 years, with no history of acute trauma. However, she had discontinued the bisphosphonate therapy 8 months before her visit because of dental implant surgery. The DXA study showed a lumbar spine T-score of 2.5, a total hip T-score of 1.1, and a femoral neck T-score of 1.7. Laboratory data showed calcium, 10.2 mg/ dl (normal range, 8.3 10.3 mg/dl); intact parathyroid hormone, 21 pg/ml (15 75 pg/ ml); 25-hydroxy vitamin D, 42 ng/ml (> 30 ng/ml); alkaline phosphatase, 101 u/l (39 117 u/l); serum C-telopeptide, 377 pg/ml (104 1008 pg/ml); and urine N-telopeptide, 27 nm BCE/mM Cr (26 124 nm BCE/mM Cr). Radiographs showed bilateral incomplete atypical subtrochanteric femoral fractures (Figs. 1A and 1E). There was a left-sided fracture that manifested as focal lateral cortical subtrochanteric thickening, with an incomplete transverse fracture line (Fig. 1A). An incomplete subtrochanteric fracture with focal lateral cortical thickening, without a fracture line, was noted on the right side (Fig. 1E). MRI showed left focal cortical thickening and a simple incomplete transverse fracture line on both the T1-weighted and fluid sensitive images (Fig. 1C). There was focal increased signal in the affected lateral cortex as well as a small amount of adjacent marrow edema (Figs. 1C and 1D). On the right, there was focal cortical thickening along the lateral aspect of the subtrochanteric region, without a fracture line or bone marrow edema (Figs. 1F 1H). Patient 2 The patient was an asymptomatic 50-year-old active white woman on alendronate therapy for 8 years with no history of acute trauma. The DXA study showed a lumbar spine T-score of 1.4, a right femoral neck T-score of 2.7, and a total hip T- score of 1.8. Laboratory data showed calcium, 9.3 mg/ dl (8.3 10.3 mg/dl); intact parathyroid hormone, 26 pg/ml (15 75 pg/ml); 25-hydroxy vitamin D, 22 ng/ml (> 30 ng/ml); alkaline phosphatase, 63 u/l (39 117 u/l); serum C- telopeptide, 42 pg/ml (104 1008 pg/ml); AJR:198, May 2012 1145

La Rocca Vieira et al. A D G B E H Fig. 1 Bilateral incomplete atypical subtrochanteric femoral fractures in 57-year-old asymptomatic woman taking alendronate therapy for 8 years. A, Lateral radiograph of left femur shows focal lateral cortical thickening (solid arrows) with incomplete fracture line (open arrow). B D, Axial T1-weighted (B), axial T2-weighted fat-saturated (C), and coronal STIR (D) images depict focal cortical thickening (solid arrows) with incomplete fracture line (open arrow, D) limited to lateral cortex with cortical edema. E, Anteroposterior radiograph of right femur shows multiple sites of focal lateral cortical thickening of subtrochanteric femur (arrows). F H, Axial T1-weighted (F), axial T2-weighted fat-saturated (G), and coronal STIR (H) images of right femur show focal lateral cortical thickening of subtrochanteric region (solid arrows, E and F; open arrows, H), without fracture line or significant bone marrow edema. C F 1146 AJR:198, May 2012

Femoral Fractures in Asymptomatic Patients Fig. 2 Right incomplete subtrochanteric femoral fracture in asymptomatic 50-year-old active woman taking alendronate therapy for 8 years. A, Anteroposterior radiograph of right femur shows no significant cortical thickening but fine incomplete intramedullary fracture line (arrow). B D, Axial T1-weighted (B), coronal (C), and sagittal (D) fluid-sensitive images depict incomplete fracture line (solid arrow, B; open arrow, C and D). and urine N-telopeptide, 23 nm BCE/mM Cr (26 124 nm BCE/mM Cr). Radiographs showed a linear area of intramedullary sclerosis originating from the lateral aspect of the right subtrochanteric femur, without focal lateral cortical thickening (Fig. 2A). MRI showed right femoral focal anterolateral thickening. There was also a focal 3-mm A C oblique fracture line, with minimal edema of the adjacent bone marrow (Figs. 2B 2D). The left femur was completely normal, with no fracture line or cortical thickening. Statistical Analysis On the basis of the radiographic findings, the patient population was divided in two distinct B D groups: the nonfractured population, consisting of 98 patients with no evidence of subtrochanteric or diaphyseal focal cortical thickening or fracture and the fractured population, consisting of two patients with imaging evidence of incomplete atypical femoral fracture. Comparison of clinical and laboratory data between the two groups revealed that the two patients with fractures were significantly younger (p = 0.0286) than those without a fracture. There were no significant differences between the two groups in terms of clinical or laboratory results (p > 0.15), except for intact parathyroid hormone values, which were significantly decreased in the fractured group (p < 0.0001) (Table 1). However, intact parathyroid hormone values were within normal limits for both the fractured and nonfractured groups. Among the 98 nonfractured patients, there were 16 patients whose age matched the fractured population (age range, 50 60 years). Laboratory data comparison between those 16 patients and the two patients with fractures showed significantly decreased intact parathyroid hormone values in the fractured group (p = 0.027) (Table 2). The BMD in the spine, in the femoral neck, and in the total hip did not show a statistical difference between the two groups. When comparison was made between the fractured population (n = 2) and a nonfractured population (n = 36) who, similarly, had been receiving bisphosphonate treatment for 8 10 years, there was also a significant decrease in the mean intact parathyroid hormone values (p = 0.0002) (Table 3). When the 95% CI method was used to compare the nonfractured group and fractured patient number 2 with regard to serum C-telopeptide and urine N-telopeptide values, the mean urine N-telopeptide value for patient 2 was within the 95% CI. However, the mean serum C-telopeptide value for patient 2 was far below the 95% CI (Table 4). Patient 1 was excluded from this analysis because she had been off the medication for 8 months at the time of the study. Discussion Since their introduction into clinical practice more than 30 years ago, bisphosphonates AJR:198, May 2012 1147

La Rocca Vieira et al. TABLE 1: Mean Clinical and Laboratory Parameters in the Two Groups of Patients Nonfractured Fractured Outcome Mean SD Mean SD p a Age (y) 69.67 10.23 53.50 4.95 0.0286 Duration of treatment (y) 7.95 2.77 8.00 0.00 0.9791 Height (in) 62.90 2.80 62.00 0.00 0.6509 Height (cm) 159.77 7.11 157.48 0.00 Weight (lb) 131.21 21.25 129.00 41.01 0.8863 Weight (kg) 59.52 9.64 58.51 18.6 DXA femoral neck 2.12 0.67 2.20 0.71 0.8727 DXA lumbar spine 1.94 1.28 1.95 0.78 0.9914 DXA total hip 1.71 0.84 1.45 0.50 0.9421 Serum calcium 9.66 0.49 9.75 0.64 0.8414 Alkaline phosphatase 71.31 20.45 82.50 27.58 0.5694 ipth 44.10 20.18 23.50 3.54 < 0.0001 Urine N-telopeptide 31.45 50.63 25.00 2.83 0.2538 25-Hydroxy vitamin D 39.49 12.16 32.00 14.14 0.4594 Serum C-telopeptide 178.93 115.09 209.50 236.88 0.8559 Note Normal values for serum calcium, 8.3 10.3 mg/dl; alkaline phosphatase, 39 117 u/l; 25-hydroxy vitamin D, > 30 ng/ml; intact parathyroid hormone (ipth), 15 75 pg/ml; urine N-telopeptide, 26 124 nm BCE/ mm Cr; serum C-telopeptide, 104 1008 pg/ml. DXA = dual-energy x-ray absorptiometry. a Independent sample Student t test with p < 0.05 defined as statistically significant. have become first-line agents in the management of several skeletal disorders, such as osteoporosis, Paget disease, and bone metastasis [2]. Alendronate and the other thirdgeneration bisphosphonates (risedronate, ibandronate, and zoledronic acid) are potent inhibitors of bone resorption. They inhibit osteoclast function and induce osteoclast apoptosis by interfering with protein prenylation and inhibiting the mevalonate pathway of cholesterol synthesis [28]. Alendronate was the first drug to be approved for use in the prevention of osteoporotic fractures by the U.S. Food and Drug Administration in 1995 [29] and is the most commonly prescribed drug for the prevention and treatment of osteoporosis. Several published trials have established the efficacy of alendronate, risedronate, and zoledronic acid in reducing vertebral and hip fractures and ibandronate in reducing vertebral fractures [1, 30, 31]. Recently, severely suppressed bone turnover has been recognized as a potential complication of long-term bisphosphonate therapy. Studies suggest that, with inhibition of osteoclastic-mediated bone resorption and turnover, there is an imbalance between the accumulation of skeletal microdamage and its repair. Old, highly mineralized bone has increased brittleness. Microdamage accumulates, particularly in areas of physiologic loads, such as the subtrochanteric region, and insufficiency fractures may develop [12]. Indeed, in recent years, several reports have shown an association between prolonged bisphosphonate particularly alendronate therapy and the development, in a small number of patients, of low-energy atypical fractures of the femur. Most reported cases of atypical femoral fractures are in patients on alendronate, but occurrence has been reported in patients taking risedronate, pamidronate, and zoledronic acid. This has been mostly explained by the greater availability and use of alendronate for a longer time because of earlier approval and generic availability [3 23]. Furthermore, it has also been shown that incomplete subtrochanteric and diaphyseal femoral fractures may progress to complete fractures if treated conservatively [12].Therefore, early detection of these incomplete fractures is of paramount importance because it can offer potentially preventive treatment, such as limited weightbearing, bone electric stimulation, careful serial radiographic monitoring of the fracture, and prophylactic intramedullary nailing of the femur. Discontinuing the bisphosphonate therapy and treating the patients with alternative drugs, such as teriparatide, may also be indicated. To the best of our knowledge, our study is the first to study the frequency of subtrochanteric and diaphyseal atypical femoral fractures in asymptomatic patients who are taking longterm oral bisphosphonates. We imaged 200 femurs in 100 asymptomatic patients who had been on alendronate therapy for at least 3 years and noted a frequency of three incomplete fractures in two patients. Although the percentage of patients with incomplete fractures detected in our study was quite small, it nevertheless raises the need for obtaining serial radiographs of the femurs as part of the routine follow-up protocol of patients on long-term bisphosphonate therapy. Future larger prospective studies are required, however, to further assess the prevalence of these TABLE 2: Comparison of Mean Laboratory Parameters in the Fractured and Age-Matched Nonfractured Groups Nonfractured Fractured Outcome Mean SD Mean SD p a Alkaline phosphatase (u/l) 65.35 16.39 82.50 27.58 0.4009 Serum calcium (mg/dl) 9.65 0.41 9.75 0.64 0.8358 Serum C-telopeptide (pg/ml) 187.00 139.45 209.50 236.88 0.8970 DXA femoral neck 1.78 0.95 2.20 0.71 0.4524 DXA lumbar spine 1.99 0.77 1.95 0.78 0.9483 DXA total hip 1.21 0.92 1.45 0.50 0.628 ipth 34.54 13.20 23.50 3.54 0.0271 Urine N-telopeptide (nm BCE/mM Cr) 56.25 119.58 25.00 2.83 0.3125 25-Hydroxy vitamin D (ng/ml) 41.35 11.19 32.00 14.14 0.3793 Note Age range, 50 60 years. DXA = dual-energy x-ray absorptiometry, ipth = intact parathyroid hormone. a Independent sample Student t test with p < 0.05 defined as statistically significant. 1148 AJR:198, May 2012

Femoral Fractures in Asymptomatic Patients TABLE 3: Comparison of Laboratory Parameters in Fractured and Nonfractured Groups Nonfractured Fractured Outcome Mean SD Mean SD p a Alkaline phosphatase (u/l) 74.86 23.31 82.50 27.58 0.7031 Serum calcium (mg/dl) 9.60 0.47 9.75 0.64 0.7399 Serum C-telopeptide (pg/ml) 188.82 131.97 209.50 236.88 0.9034 DXA femoral neck 2.10 0.61 2.20 0.71 0.8499 DXA lumbar spine 1.61 1.43 1.95 0.78 0.5722 DXA total hip 1.58 0.94 1.75 0.07 0.3402 ipth 44.96 23.17 23.50 3.54 0.0002 Urine N-telopeptide (nm BCE/mM Cr) 42.49 83.60 25.00 2.83 0.2424 25-Hydroxy vitamin D (ng/ml) 40.51 12.17 32.00 14.14 0.4100 Note Patients had been on bisphosphonate treatment for 8 10 years. DXA = dual-energy x-ray absorptiometry, ipth = intact parathyroid hormone. a Independent sample t test with p < 0.05 defined as statistically significant. fractures in asymptomatic individuals and to determine the timing and frequency of femoral radiographs. Patients with alendronate fractures tend to be active women, typically in their late 50s and early 60s, who have been taking alendronate therapy for at least 3 years. They provide a typical history of no preexisting or mild ache or pain in the affected limb before the time of presentation [10, 12, 15]. The fractures range from incomplete ones, which show focal subtrochanteric lateral cortical thickening, frequently with a fracture line, to complete fractures, which tend to be transverse or shortly oblique noncomminuted with a medial beak. The inciting event for a complete fracture is usually minor, such as a slip or fall [10]. At times, the fracture is spontaneous, with no inciting event and the patient describes the leg as giving way, causing the patient to fall. Progression of an incomplete fracture to a complete fracture has also been documented in patients who were treated nonsurgically [12]. Our two asymptomatic patients fit the previously listed clinical description of patients with bisphosphonate-related femoral fractures. Similar to a subset of patients described in the literature, our two patients denied preexisting hip or thigh pain. Both patients were taking long-term bisphosphonate therapy (8 years). Both were significantly younger (50 and 57 years old) compared with the rest of the patients (p = 0.0286), and both had led very active lifestyles at the time of presentation. Two of the three fractures showed the typical incomplete subtrochanteric fractures described in the literature. Both depicted focal thickening of the lateral cortex, one with and one without an associated cortical fracture line (Figs. 1A and 1E). In the third case, the fracture was somewhat atypical, with a focal linear intramedullary sclerosis noted on radiographs (Fig. 2A). The focal lateral cortical thickening was better appreciated on MRI (Fig. 2B). We postulated that bone turnover markers, serum C-telopeptide and urine N-telopeptide, would be the most useful parameters for identifying patients with asymptomatic fractures. Interestingly, when the 95% CI method was used to compare the nonfractured group with the fractured patient who continued taking the bisphosphonate at the time of radiography (patient 2), the mean serum C- telopeptide fell far out of the 95% CI and was below normal limits. This suggests that, with a larger patient population, the serum C-telopeptide may have had a statistically significant lower value in the fractured compared with the nonfractured group. We did not find a significant difference between the nonfractured and fractured groups with respect to laboratory results (serum calcium, 25-hydroxy vitamin D, urine N-telopeptide, serum C-telopeptide, and alkaline phosphatase) except for mean intact parathyroid hormone values, which were significantly decreased in the fractured group. When comparison was made between the fractured population and the subgroup of the agematched nonfractured population as well as between the fractured population and the subgroup treated with bisphosphonate for 8 10 years, the mean intact parathyroid hormone was again statistically decreased. We are unsure of the clinical significance of this finding because the mean intact parathyroid hormone values were within normal limits for both the fractured and nonfractured groups. We postulate, however, that because ipth promotes bone turnover, a decreased level may exacerbate the suppressed bone remodeling in the bisphosphonate-treated bones. In Sweden, Schilcher and Aspenberg [20] reported an overall incidence of bisphosphonate atypical fractures of one per 1000 per year. Black et al. [32] reported a secondary analysis of three large clinical trials and concluded that the risk of atypical femoral fractures is not increased even among women who had been treated with bisphosphonates for as long as 10 years. This article has since been questioned in the literature because of its many limitations [33, 34] and is in contradistinction to recent reports in which a significant number of bisphosphonate-associated fractures have been collected in a relatively short time [6, 10, 12, 16, 23, 24, 35, 36]. Our results, although in a small patient population, suggest a much higher incidence than was indicated by Schilcher and Aspenberg because as we noted three fractures in two of 100 asymptomatic patients. We believe that our results differ from those of Schilcher and Aspenberg for the following main reasons: Those authors assessed patients who had been treated with bisphosphonates for a relatively short period of 2 3 years. Furthermore, they identified their patients on the basis of a national drug registry rather than direct assessment. Finally, they only documented the presence of complete subtrochanteric fractures. Conversely, we studied patients who were receiving alendronate therapy for 3 or more years and who were questioned carefully regarding compliance with medication intake. Furthermore, our TABLE 4: Mean and 95% CI for the Mean Values Between Patient 2 and Nonfractured Group Test Mean 95% CI Patient 2 Serum C-telopeptide (pg/ml) 188.82 155.50 202.40 42.0 Urine N-telopeptide (nm BCE/mM Cr) 42.49 21.02 41.88 23.0 Note Normal values are serum C-telopeptide, 104 1008 pg/ml; and urine N-telopeptide, 26 124 nm BCE/mM Cr. AJR:198, May 2012 1149

La Rocca Vieira et al. study had the advantage of having radiographs for all these patients, thus allowing us to detect early fractures before their becoming symptomatic or complete. Regarding the length of bisphosphonate therapy, the optimal duration of treatment is not known. Studies on alendronate and risedronate treatments in osteoporotic patients show antifracture benefit for at least 5 years. Because of current potential concerns with long-term treatment, suggested recommendations by the United States Preventive Services Task Force are to reevaluate patients after 5 years of treatment. For patients without a recent fracture and with a femoral neck T- score greater than 2.5, consideration should be given to a drug holiday from bisphosphonates. There are no data to guide when or whether to restart bisphosphonate therapy after a drug holiday. In moderate- to high-risk patients, it may be appropriate to continue the bisphosphonates after 5 years [34]. Our study had several limitations, including small patient population and lack of correlation with histopathology. Because only two patients were found to have fractures, statistical evaluation of their clinical indexes compared with the rest of the patients was limited. Furthermore, in the one patient with bilateral fractures, the true effect of bisphosphonates on bone turnover markers was not reliable because the patient had already been off the drug for 8 months at the time of presentation. In conclusion, three of 200 femurs or two of 100 asymptomatic patients on long-term bisphosphonate therapy presented imaging evidence of early incomplete atypical fractures of the subtrochanteric femur. Both of the patients were significantly younger with active lifestyles. There were no significant differences among the comparison groups in terms of clinical or laboratory results, with the exception of ipth, which was significantly decreased in the fractured group. 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