Unusual Mid-shaft Fractures during Long-term Bisphosphonate Therapy

Clarita V. Odvina; Shiri Levy; Sudhir Rao; Joseph E. Zerwekh; D. S. Rao


Clin Endocrinol. 2010;72(2):161-168. 

In This Article

Abstract and Introduction


Background Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of nonvertebral fractures.
Objective The objective of this study was to report the clinical presentation, selected bone histomorphometry and X-ray images of patients who developed mid-shaft long bone fractures during bisphosphonate therapy, six of whom had bone biopsy for histomorphometery.
Results Of the 13 patients who sustained atraumatic mid-shaft fractures, 10 were on alendronate and three were on risedronate therapy before the fractures. In addition to bisphosphonates, three patients were on oestrogen and two on tamoxifen concomitantly. Four patients with glucocorticoid-induced osteoporosis were on alendronate for 3–11 years along with glucocorticoid therapy. Bone histomorphometry showed severe suppression of bone turnover in five patients and low bone turnover in one patient.
Conclusion Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is probably due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy remains unknown, but appears to be small.


Bisphosphonates are the most commonly used drugs in the prevention and treatment of osteoporosis.[1] Several placebo-controlled randomized trials have established their effectiveness in preventing bone loss and osteoporotic fractures,[2–6] and the recent extension trial with alendronate suggests that the medication is safe and effective for up to 10 years.[7] Another long-term study with risedronate demonstrated that 7 years of continuous therapy in postmenopausal women significantly increased bone mineral density (BMD), and decreased bone turnover marker to within premenopausal range with no indication of loss of antifracture efficacy.[8]

However, because of the long skeletal half-life of bisphosphonates,[9] there is growing concern that long-term treatment with these agents might lead to oversuppression of bone turnover compromising bone quality and bone strength. In 2005, we described nine patients who sustained atraumatic nonvertebral fractures with delayed fracture healing after long-term bisphosphonate therapy.[10] Quantitative bone histomorphometry revealed severely suppressed bone turnover (SSBT) with marked reduction in both bone formation and resorption. Furthermore, we found that more than half of the patients had femoral mid-shaft fractures, an unusual manifestation even in patients with severe osteoporosis. Additional cases of atraumatic long bone and pelvic fractures have since been reported, but the number of cases is relatively small in relation to the large number of patients treated with bisphosphonates worldwide.[11–21]

Although osteoporosis is associated with increased risk of fractures, spontaneous or minimal trauma long bone mid-shaft fractures rarely occur in these patients. In 1991, a study that prospectively recorded all fractures occurring in a large cohort of 9704 women followed for an average period of 2·23 years reported 27 leg fractures, which included tibiae and fibulae as well as femoral shafts.[22] In an expanded analysis with a mean follow up of 10·4 years, the investigators reported 280 fractures of the humerus, 63 lower leg fractures and 43 femoral fractures. None of the fractures resulted from severe trauma such as motor vehicle accidents, being struck by a rapidly moving projectile or assault.[23] However, there was no mention of how many of these fractures occurred during normal activities of daily living or the exact location within the femur. In contrast, in the combined clinical experience in bone and mineral disorders of the senior author (DSR) and his mentor (Dr A. Michael Parfitt) for over 80 years, they never saw a patient with femoral shaft fractures that could be directly attributable to low bone mass (personal observations).

In this report, we describe 13 additional patients, who developed long bone mid-shaft fractures during long-term bisphosphonate therapy. This raises the possibility that such therapy may be associated with unusual spontaneous cortical fracture syndrome.


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