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 non-vertebral fractures. Objective: 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 3 were on risedronate therapy before the fractures. In addition to bisphosphonates, 3 patients were on estrogen and 2 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 5 patients and low bone turnover in 1 patient. Conclusion: Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is likely 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 is not known, but appears to be small.