Fractures of the subtrochanteric region or femoral diaphysis

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1 SPECIAL FEATURE Clinical Case Seminar Atypical Femoral Fractures during Prolonged Use of Bisphosphonates: Short-Term Responses to Strontium Ranelate and Teriparatide N. N. C. Carvalho, L. A. Voss, M. O. P. Almeida, C. L. Salgado, and F. Bandeira Division of Endocrinology, Agamenon Magalhães Hospital, University of Pernambuco Medical School, Recife, Brazil Context: Atypical femoral fractures have rarely been reported in women taking bisphosphonates, but this is still a controversial issue. Data are derived mainly from observation studies because a post hoc analysis from a randomized clinical trial did not find any such association. Objective: The aim of this study was to report three cases of what are considered atypical femoral fractures and their responses to the use of strontium ranelate and teriparatide. Patients: We studied three postmenopausal women with a diagnosis of osteoporosis who suffered fractures of the subtrochanteric region and femoral diaphysis with no major trauma while on long-term use of bisphosphonates. Results: All the major features of atypical femoral fractures highlighted in the Task Force Report of the American Society for Bone and Mineral Research were present in the three cases. They had had unconsolidated fractures for approximately 1 yr before being referred to our center. After 3 months on strontium ranelate 2 g/d, serum osteocalcin and serum -carboxyterminal telopeptide had increased in case 1 by 125 and 100%, respectively, and in case 2 by 50 and 22%, respectively, with total closure of the fracture. In case 3, after 1 month on teriparatide 20 g/d, a radiographic closure of the fracture was achieved, and 3 months later serum osteocalcin and serum -carboxyterminal telopeptide had increased by 300 and 22%, respectively. Conclusion: Our finding showed that both teriparatide and strontium ranelate had a rapid bone anabolic effect on unhealed atypical fractures associated with chronic bisphosphonate use. (J Clin Endocrinol Metab 96: , 2011) Fractures of the subtrochanteric region or femoral diaphysis are relatively rare in postmenopausal women, representing about 6% of all osteoporotic hip fractures (1). Currently, the bisphosphonates are the most widely used agents to treat osteoporosis in men and women. They act by inhibiting osteoclast-mediated bone loss, thereby reducing bone turnover (3). There are controversial data showing a possible association of prolonged bisphosphonate use with atypical femoral fractures (3), which are also known as low-energy fractures and occur with low-impact trauma, such as falls from standing height or less, and are usually located in the subtrochanteric region or the proximal femoral diaphysis (4, 5). They have rarely been reported in women taking bisphosphonates, and in large clinical trials a significant increase in risk has not been seen during their use (3). Strontium ranelate (SR) reduces bone resorption and increases bone formation, leading to a rearrangement of remodeling in favor of bone formation (6). By having an anabolic effect, albeit less than teriparatide, it may contribute to fracture healing. In this report, we describe three women with osteoporosis who were postmenopausal for over 10 yr and who suffered fractures of the subtrochanteric region and fem- ISSN Print X ISSN Online Printed in U.S.A. Copyright 2011 by The Endocrine Society doi: /jc Received March 7, Accepted June 22, First Published Online July 13, 2011 Abbreviations: BMD, Bone mineral density; FN, femoral neck; salp, serum alkaline phosphatase; sca, serum calcium; s -CTX, serum -carboxyterminal telopeptide; s25(oh)d, serum 25-hydroxyvitamin-D; spth, serum PTH; SR, strontium ranelate. J Clin Endocrinol Metab, September 2011, 96(9): jcem.endojournals.org 2675

2 2676 Carvalho et al. Atypical Femoral Fractures J Clin Endocrinol Metab, September 2011, 96(9): oral diaphysis with no major trauma while taking bisphosphonates. All the major features of atypical femoral fractures highlighted in the Task Force Report of the American Society for Bone and Mineral Research (7) were present in the three cases. They had had unconsolidated fracture for approximately 1 yr before being referred to our center. After the administration of SR (cases 1 and 2) and teriparatide (case 3), the patients experienced rapid healing with a short-term increase in bone formation markers. Case 1 TABLE 1. Bone marker values before fracture and after treatment with SR or TPD Patient no. On bisphosphonates before fracture After fracture After SR or TPD soc s -CTX soc s -CTX soc s -CTX 1 NA NA NA NA TPD, Teriparatide; soc, serum osteocalcin; NA, not applicable. Normal soc, 3 22 ng/ml; normal s -CTX, pg/ml. FIG. 1. Case 1. Transverse, noncomminuted fracture of the femur diaphysis. A 63-yr-old white woman, postmenopausal for 13 yr, was referred to us because of recurrent femoral subtrochanteric fractures. The first fracture was at the left femur, which she had had for 1 yr and which had not healed; there was also a recent fracture located at the right femur. The patient reported pain at the fracture sites, but no history of trauma. She has been taking alendronate for approximately 5 yr and risedronate 35 mg/wk during the previous 12 months. Laboratory data were as follows: serum alkaline phosphatase (salp), 97 U/liter (normal, 32 92); serum -carboxyterminal telopeptide (s -CTX), 470 pg/ml (normal, ) (Table 1); and serum 25-hydroxyvitamin-D [s25(oh)d], 16.2 ng/ml (normal, 25). While she was still in another hospital after the first fracture had occurred, zolendronate 5 mg/yr and cholecalciferol 600 U/d were started. Closure of the fracture line was achieved after 4 months, with salp, 74 U/liter (normal, up to 306); s -CTX, 209 pg/ml (normal, ); serum osteocalcin, 12.1 ng/ml (normal, 3 22); serum calcium (sca), 8.9 ng/dl (normal, ); s25(oh)d, 56 ng/ml (normal, 25); serum bone alkaline phosphatase, 15 U/liter (normal, ); and serum PTH (spth), 25 pg/ml (normal, 15 65). At the end of the second year, a radiographic callus at the fracture site was seen, with femoral neck (FN) bone mineral density (BMD) (T score, 1.6), lumbar spine BMD (T score, 2.5), and normalization of the s25(oh)d level. After the third dose of 5-mg zolendronate, she suffered the second fracture, this time in the middle one third of the right femur with no history of trauma (Fig. 1). After she was referred for our evaluation, s -CTX was 190 pg/ml (normal, ), serum osteocalcin was 8.2 ng/ml (normal, 3 22), salp was 78 U/liter (normal, 32 92), and SR 2 g/d was started. After 2 months on SR, s -CTX and serum osteocalcin had increased by 100 and 125%, respectively, with total closure of the fracture. Case 2 A 79-yr-old white woman, postmenopausal for 28 yr, had been on alendronate 70 mg/wk for 10 yr, followed by 1 yr off (washout period). Laboratory and BMD results were as follows: s -CTX, 177 pg/ml (normal, ); salp, 71 U/liter (normal, 32 92); sca, 10.3 ng/dl (normal, ); spth, 63 pg/ml (normal, pg/ml); s25(oh)d, 27.4 ng/ml (normal, 25 ng/ml); FN BMD, T score 2.5; and lumbar spine BMD, T score 3.5. After 1 yr, oral ibandronate 150 mg/month was started, and in the third year of its use the patient suffered a subtrochanteric fracture of the left femur with no significant trauma (Fig. 2A). After 10 months, the fracture had still not healed, and the patient was referred to our hospital (Fig. 2B). The laboratory data were as follows: s -CTX, 337 pg/ml (normal, ); serum osteocalcin, 12 ng/ml (normal, 3 22); salp, 325 U/liter (normal, up to 306); and s25(oh)d, 14.7 ng/ml (normal, 25). Cholecalcif-

3 J Clin Endocrinol Metab, September 2011, 96(9): jcem.endojournals.org 2677 A 77-yr-old white woman, postmenopausal for 23 yr, was evaluated for a fracture of the left tibia and a subtrochanteric fracture of the right femur after a fall from standing height. The fracture of the right femur had not healed after 1 yr (Fig. 3), despite the use of risedronate 35 mg/wk, calcium carbonate 1 g/d, and cholecalciferol 800 U/d for 2 yr, when she was referred to our center. The patient had been on alendronate for 4 yr. She presented with FN BMD (T score 2.5); spth, 34.5 pg/ml (normal, 15 65); sca, 9.2 ng/dl (normal, ); salp, 67 U/liter (normal, up to 104); s -CTX, 211 pg/ml (normal, ); serum osteocalcin, 14.6 ng/ml (normal, 3 22); and s25(oh)d, 37.4 ng/ml(normal, 25ng/ml).Teriparatide20 g/d was instituted sc. After 1 month, a radiograph showed closure of the right femur fracture, and after 3 months, s -CTX and serum osteocalcin had increased by 22 and 300%, respectively. FIG. 2. Case 2. A, Transverse subtrochanteric and noncomminuted fracture. B, Postoperative subtrochanteric fracture. C, Fracture callus after 3 months on SR. erol 20,000 U/wk was prescribed, and ibandronate was replaced by SR 2 g/d. After 3 months on SR, there was healing of the fracture line (Fig. 2C), s -CTX and serum osteocalcin increased 22 and 50%, respectively, and s25(oh)d was 32 ng/ml. Case 3 Discussion Bisphosphonates are considered first-line medication for the treatment of osteoporosis, being particularly effective in reducing the risk of vertebral and hip fractures (4). Although there is evidence to support a good safety profile, these agents could result in excessive suppression of bone remodeling, affecting bone quality and strength, and thus increasing the risk of fractures (8). This prolonged suppression of bone remodeling could lead to an accumulation of microdamage and the development of bone hypermineralization. Various case series have identified a subgroup of atypical fractures of the femoral stem that might be related to the prolonged use of bisphosphonates. A secondary analysis using the results of three large randomized, doubleblind, placebo-controlled studies (FIT, FLEX, and HORIZON) showed that the occurrence of subtrochanteric or femoral diaphysis fracture was very rare among all women who had been treated with bisphosphonates, including alendronate, for over 10 yr. In this analysis, no increased risk of fractures associated with the use of bisphosphonates for a period of 3 to 5 yr was observed (3). A typical femoral osteoporotic fracture usually involves the proximal femur, whereas the atypical type usually affects the subtrochanteric region or femoral diaphysis, despite the fact that a typical osteoporotic hip fracture rarely affects this region. A Danish report examined two observational studies (one cross-sectional and one retrospective cohort) and did not find a higher frequency in subtrochanteric or femoral diaphysis fractures during alendronate therapy than what was expected for a typical osteoporotic hip fracture. However, there were some limitations, both in relation to which radiographs were not reviewed to confirm the diagnosis and to the trauma history, which was not carefully reported, and the exclusion of high-impact fractures was not possible (9).

4 2678 Carvalho et al. Atypical Femoral Fractures J Clin Endocrinol Metab, September 2011, 96(9): FIG. 3. Case 3. Oblique fracture of the femoral diaphysis without healing. A case series showed that 10 of 15 patients had a single radiographic pattern, defined as a simple transverse or oblique fracture ( 30 ) with cortical beaking and diffuse cortical thickening (1), which were also found in the study of Kwek etal(10). The Task Force Report of the American Society for Bone and Mineral Research defined major and minor features of complete and incomplete atypical femoral fractures and recommended that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant exposure to drugs, including bisphosphonates, other antiresorptive agents, glucocorticoids, and proton pump inhibitors (7). In all the cases cited, the patients displayed all the major features: transverse fractures were found in cases 1 and 2, and an oblique fracture in case 3; as for location, it was in the subtrochanteric part of the femur in case 2 and in the femoral shaft in cases 1 and 3. A few minor characteristics were also seen, particularly the use of bisphosphonates and the delayed healing of the fractures. Osteoporosis is associated with delay and/or reduction in the healing process of fractures (11). In this report, the three patients also had difficulty with fracture healing for approximately 1 yr while on bisphosphonates. This finding is in agreement with the study of Odvina et al. (5) who, on analyzing bone biopsy data in nine patients who were on alendronate (1 to 8 yr from the start of treatment), found that six of these patients had difficulty in fracture healing. These data are also similar to those of another study by the same group (7) who examined 13 patients, eight of whom had difficulty in fracture healing for approximately 6 months. There are few published data on the effect of SR in fracture healing. Some clinical cases (12, 13) and experimental studies in rats (14 16) have been reported, but none on the use of SR in patients with atypical fractures while on long-term bisphosphonates. Experimental studies using SR at a dose of 450 mg/kg d after fractures in rats with osteoporosis showed an association with better healing in fractures of the middle stem of the tibia than the control group (14). This is in contrast to another study that found no significant differences in callus formation of rat tibia (15). However, in another report, the SR dose of 625 mg/kg d promoted healing of tibial fractures in ovariectomized rats. This dose corresponds to 0.87-fold in the median serum strontium concentrations observed in patients taking the therapeutic dose of 2 g/d and receiving 1500 mg calcium per day (16). SR has been approved in several countries for the treatment of postmenopausal osteoporosis. It increases BMD and reduces vertebral and nonvertebral fractures (17), as demonstrated in major studies (18 22). It seems to have a dual mode of action by increasing the synthesis of collagen and noncollagen protein, increasing preosteoblast differentiation, inhibiting osteoclast differentiation, and reducing osteoclast function. In animal models, the increase in BMD is related to increases in biomechanical bone strength. Histomorphometry showed a reduction in the osteoclast surface with an increase in bone formation (23). Experimental studies in animals show that teriparatide may lead to a significant improvement in bone healing. A randomized, double-blind, placebo-controlled study in postmenopausal women with a distal radius fracture, treated by closed (nonsurgical) reduction, showed a shorter fracture healing time in the teriparatide group, suggesting that repair fractures could be accelerated by use of this drug (24). Teriparatide is an anabolic agent that stimulates the differentiation, proliferation, and activity of osteoblasts, restoring the synthesis of the bone matrix, increasing the life span of osteoblasts and osteocytes, and inhibiting their apoptosis (25). This leads to an increase in bone mass and improved bone architecture, thus reducing the incidence of vertebral and nonvertebral fractures (26, 27). An experimental study in rats was performed to investigate whether teriparatide and SR affect the healing of

5 J Clin Endocrinol Metab, September 2011, 96(9): jcem.endojournals.org 2679 fractures in ovariectomized rats when administered for the first time after the occurrence of an osteoporotic fracture. Sixty ovariectomized rats were divided randomly into four groups (SR, teriparatide, placebo, and control). Only treatment with SR increased callus strength in the torsion test when compared with the controls; however, both SR and teriparatide increased the volume of trabecular bone within the callus. The better results with SR, as compared with teriparatide, in terms of callus strength could be due to a better quality of newly formed bone within the callus (27). Bone turnover markers allow a better evaluation of the anabolic effect of teriparatide, as well as the anabolic and antiresorptive effects of SR. There is substantial evidence indicating that short-term changes in serum levels may play an important role in predicting future changes in BMD or fracture risk (17). In this report, serum osteocalcin increased in all three patients after approximately 3 months on SR (cases 1 and 2) and teriparatide (case 3). As in the study of Sousa et al. (28), the short-term increase in osteocalcin was greater with the use of teriparatide than with SR in patients previously treated with bisphosphonates. Another interesting finding is that, before the fracture had occurred, the available data from two patients (cases 1 and 2) showed normal values for s -CTX. This is at odds with the hypothesis of a very low bone remodeling as a potential risk factor for this type of fracture (5). Acknowledgments Address all correspondence and requests for reprints to: Nara Nóbrega Crispim Carvalho, 17 de Agosto av, 2666, Casa Forte, , Recife, Brazil. naranc@gmail.com. Disclosure Summary: The authors have nothing to disclose. References 1. Lenart BA, Lorich DG, Lane JM 2008 Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. 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