Context: Since their introduction into clinical medicine bisphosphonates have revolutionized clinical osteoporosis care. Ironically, in rare circumstances, long term, combined antiremodeling therapy may be associated with skeletal harm.

Evidence Acquisition: We report atypical skeletal fragility in three subjects after long term, combined antiremodeling therapy.

Evidence Synthesis: Three subjects experienced spontaneous or minimal trauma "chalk-stick" type metadiaphyseal femoral fractures while on long term bisphosphonate therapy. The fracture location, type, bilaterality, prodromal pain and delayed healing were atypical for uncomplicated postmenopausal osteoporosis. All three subjects had concomitant circumstances (endogenous estrogen) or medications (glucocorticoids, hormone replacement therapy, raloxifene) that likely suppressed bone remodeling beyond the effect of the bisphosphonate alone. Biochemical markers of bone turnover were very low or in the low premenopausal range. Double tetracycline labeled bone biopsy showed very low activation frequency in one subject and limited single tetracycline label in a second consistent with severely suppressed bone turnover (SSBT). These three cases resemble previous descriptions of SSBT.

Conclusion: Atypical skeletal fragility may signify SSBT in the setting of long term, combined antiremodeling therapy. We speculate that osteoclast tolerance for pharmacologic suppression may vary among individual patients and that in some cases combined antiremodeling therapy may result in skeletal harm.