Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use

By Maria S. Goddard, MD; Kristoff R. Reid, MD; James C. Johnston, MD; Harpal S. Khanuja, MD
ORTHOPEDICS 2009; 32:607

Abstract

Postmenopausal women with osteoporosis are commonly treated with the bisphosphonate class of medications, one of the most frequently prescribed medications in the United States. In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures.

This article presents a case of a 67-year-old woman who presented with an atraumatic right femur fracture. She had a medical history notable for use of the bisphosphonate alendronate for 16 years before being switched to ibandronate for 1 year before presentation. She had sustained a similar fracture on the contralateral side 3 years previously.

This case report, in addition to a review of the literature, shows that use of the bisphosphonate class of medications for an extended period of time may result in an increased susceptibility to atraumatic femoral diaphyseal fractures. Some studies have suggested that the reason may be the mechanism of action of bisphosphonates, resulting in decreased bone turnover and remodeling. Studies have not shown if the entire class of medications produce a similar result, but patients who have been treated with any bisphosphonate for an extended period of time should be considered at risk. In patients who have already sustained a femoral diaphyseal fracture, imaging of the contralateral side should be performed to identify cortical thickening as an early sign of fracture risk. Patients should also be questioned about thigh pain.

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Postmenopausal women with osteoporosis are commonly treated with the bisphosphonate class of medications. In 2006, approximately 22 million prescriptions for this medication were written in the United States (National Prescription Audit Plus 2006; IMS Health, Norwalk, Connecticut). However, since 2005, reports have been published indicating that long-term bisphosphonate therapy could be linked to atraumatic low-energy femoral shaft fractures.^1-7 This article presents a case of a 67-year-old woman with a history of sequential bilateral atraumatic femur fractures after long-term use of bisphosphonates.

Case Report

A 67-year-old woman presented to the emergency department with a spontaneous right femoral diaphyseal fracture. There was no history of trauma and she denied antecedent pain. A review of her medical history revealed that she had sustained a left femoral diaphyseal fracture under similar circumstances 3 years previously, which had been treated with intramedullary nailing. In that earlier injury, she reported a feeling of “giving way” before falling. She had no risk factors for pathologic fractures. She was a nonsmoker and did not take corticosteroids. She had a distant history of hormone replacement therapy before 1985 to prevent osteoporosis. She began taking alendronate 70 mg per week in 1991 for osteopenia and was switched to ibandronate 150 mg monthly in 2007 for a more convenient dosing regimen. In addition, her past medical history included degenerative thoracolumbar scoliosis.

Radiographs of the pelvis, right hip, and right femur revealed a displaced diaphyseal fracture at the proximal and middle one-third right femoral junction. There was evidence of osteopenia in the metaphyseal regions (Figure 1). Given her previous history of fracture on the contralateral side and a lack of risk factors for spontaneous fractures, a magnetic resonance imaging scan without contrast was obtained to exclude a pathologic fracture. It showed no evidence of a bone lesion or other abnormality. A review of the records from her previous fracture showed no radiographic evidence of an underlying malignancy to explain that injury.

On the day of admission, she underwent cephalomedullary rod fixation. There were no postoperative complications, and she was discharged after 5 days. Pathologic analysis of bone fragments removed during the procedure showed bony trabeculae and hyaline cartilage with no evidence of granulomas or tumors.

At 6-month follow-up, the patient reported minimal pain at the fracture site. She was ambulating with a cane and maintained full range of motion. Radiographs showed the intramedullary rod in place with evidence of callus formation and a visible fracture line (Figure 2). Because of signs of delayed union, dynamization was performed by removing the distal interlocking screw. She has elected to discontinue use of any type of bisphosphonate medication since her second fall. Conventional radiographs at 1-year follow-up showed that the fracture had healed completely (Figure 3).

Figure 1: Preoperative conventional AP radiograph showing the characteristic fracture pattern of cortical thickening and a unicortical beak. Figure 2: Postoperative conventional AP (A) and lateral (B) radiographs taken 4 months after injury, showing callus formation and visible fracture line. Figure 3: Postoperative radiograph at 1-year follow-up visit showing a completely healed fracture.

Discussion

Some studies have suggested that long-standing bisphosphonate use may be a risk factor for atraumatic femoral shaft fractures.^1-8 It is believed that bisphosphonates inhibit the normal bone remodeling cycle, thus limiting native repair and leading to the accumulation of microfractures, which places a patient at an increased risk for long-bone fractures.^8,9 In a dual-center study, Odvina et al⁸ examined the bone biopsy results from 9 patients treated with alendronate for 3 to 8 years for osteoporosis or osteopenia; those authors proposed that the mechanism behind this paradoxical increased incidence of femoral shaft fractures is severe suppression of bone turnover by bisphosphonates. They confirmed this theory histologically as a decrease in the osteoclastic and osteoblastic surfaces and identified a reduction or lack of tetracycline labeling, indicating diminished mineralized bone.⁸ All patients, including those who were given estrogen therapy, had decreased bone formation and no double-tetracycline labeling.

Because bisphosphonates bind to bone and are slowly released during bone resorption,¹⁰ it may take several years for any detrimental effect to become evident. For example, alendronate has a half-life of 10.9 years,¹¹ and therefore could be present in the body long after therapy is stopped. One study has shown that, after taking alendronate for 5 years, the biochemical markers of bone turnover remained suppressed for at least 3 years after its discontinuation.¹² Using a pharmacokinetic model with a dose of 10 mg per day, Rodan et al¹³ found that the amount of alendronate retained in bone after 10 years of treatment was approximately 75 mg per 2 kg of mineral.

Our patient, who sustained sequential bilateral femoral diaphyseal fractures within a 3-year period, had been treated with bisphosphonates (alendronate and ibandronate) for osteopenia for more than 16 years. Given similar mechanisms without substantial trauma and no other risk factors for these fractures, the long-term use of bisphosphonates is implicated.

Alendronate has been the bisphosphonate most commonly used and has been implicated in most of the reported cases of atraumatic femur fractures. It is likely a class effect, that is, an effect related to bisphosphonates in general rather than to a specific medication. It is likely that other bisphosphonates will result in more complications as their use increases. Using a rat model, Yang et al¹⁴ showed that high levels of the bisphosphonate pamidronate lowered the bone mineral density and mechanical strength of the femur. In addition, they also found that there was reduced healing and callus formation after fracture in femurs with a high intraosseous concentration of pamidronate. They suggested that severe suppression of bone turnover also occurs with bisphosphonates other than alendronate, in high concentrations and over time.

Ott¹⁵ recommended that treatment with bisphosphonates be stopped after 5 years and that patients that require additional fracture protection be given parathyroid hormone. The rationale for this timeframe is to allow adequate time for fracture prevention while minimizing the risks of severe suppression bone turnover. A more recent study by Sebba¹⁶ suggested a medication holiday of 1 year to reduce the fracture risk from long-term uninterrupted use because there is no reduction of the protective benefit during that time. Some studies have shown that discontinuation of alendronate after this time period does not diminish the protective effect for vertebral fractures.¹⁰ It is important to define the minimal duration of treatment needed for osteoporosis to reduce the side effects of these medications.

One study has shown that treatment with estrogen replacement in combination with bisphosphonates resulted in greater levels of suppression of bone turnover than use of the latter alone.¹⁷ Although our patient had a distant history of estrogen use, it was not concomitant with her bisphosphonate therapy.

Atraumatic femoral diaphyseal fractures occurring in long-term bisphosphonate use have similar characteristics: a simple transverse pattern, unicortical beak, and cortical hypertrophy.^3-6 The fracture pattern in our patient was similar to that described in other studies^3-6; it appears to be pathognomonic for a femoral fracture in long-term bisphosphonate use. In a case series of 17 patients on alendronate therapy with subtrochanteric insufficiency fractures, Kwek et al³ found that all patients experienced prodromal pain and that all had similar radiographic fracture patterns. These patterns included a transverse fracture with lateral pattern, which they described as simple with thick cortices. In a 5-year retrospective review of 70 patients with low-energy femoral fractures, Neviaser et al⁵ found that of 25 patients being treated with alendronate, 19 (76%) had a simple, transverse fracture with a unicortical beak in an area of cortical hypertrophy. Only 1 patient of the remaining 45 who were not treated with alendronate in this study had these radiographic findings.

To our knowledge, a bilateral fracture in association with bisphosphonate use over an extended period of time has been reported in only 1 other case.¹ In that study, Cheung et al¹ showed suppressed bone turnover in their patient by using a double-tetracycline-labeled bone biopsy of the anterior superior iliac spine. Goh et al² examined 9 patients who sustained subtrochanteric insufficiency fractures while on alendronate and found hypertrophy of the cortex on the contralateral side in 3 patients, implying a risk for bilateral fracture development.

Since our patient’s follow-up, we have identified 2 other patients with atraumatic fractures after bisphosphonate therapy for several years, 1 of whom had evidence of a cortical stress reaction on the opposite side. For patients presenting with a low-energy subtrochanteric or diaphyseal femur fracture and a history of long-term bisphosphonate treatment, we recommend that such medications be considered a part of the underlying abnormality. Attention should also be paid to patients who have been treated with bisphosphonates for a long time who report thigh pain because this symptom might be an early indication of an impending fracture. We also recommend that patients on bisphosphonate therapy who have already had a femoral fracture should undergo one-time imaging of the contralateral side to identify any cortical thickening. If thickening is identified, consideration should be given to a medication holiday or termination of the bisphosphonate therapy. This decision should be made in conjunction with the physician who prescribed the medication.

It seems clear that in certain patients, chronic use of bisphosphonates predisposes them to low-energy or atraumatic long bone fractures. Undoubtedly, these medications are beneficial for the prevention of vertebral compression and other osteoporotic fractures,^18,19 and the discontinuation of bisphosphonates should be discussed with the patient’s primary physician. Additional pathophysiology studies are needed to identify patients who are at risk for this major complication.

References

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Authors

Drs Goddard, Reid, Johnston, and Khanuja are from the Department of Orthopedic Surgery, The Johns Hopkins University, Baltimore, Maryland.

Drs Goddard, Reid, Johnston, and Khanuja have no relevant financial relationships to disclose.

Correspondence should be addressed to: Harpal S. Khanuja, MD, c/o Elaine P. Henze, BJ, ELS, Medical Editor and Director, Editorial Services, Department of Orthopedic Surgery, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, #A6765, Baltimore, MD 21224-2780.

DOI: 10.3928/01477447-20090624-27