Twice in 2008, letters to the editor of the New England Journal of Medicine discussed atypical fractures of the femoral shaft in postmenopausal women with osteoporosis after they took alendronate.(1,2) The unusual subtrochanteric location and distinctive appearance of these breaks suggested that they were a complication of treatment with this bisphosphonate. Eight additional recent publications associate such fractures with antiresorptive therapies, primarily alendronate.(3–10) Typically, this problem begins as a “stress” or “insufficiency” fracture in the lateral diaphysis, appears bilaterally, completes during low-energy trauma, and heals slowly if at all unless there is surgical intervention.(2,3,5,7,8,10) The pathogenesis could involve microdamage accumulation from severely suppressed bone turnover(1,2) noted on iliac crest specimens,(3,8,10) with some patients perhaps having inherently vulnerable osteoclasts.(8,11) However, nondecalcified histology of these acute fractures has not been reported.(1–10)
Actually, similar femoral fractures have been known for at least 30 years to be a hallmark of the adult form of hypophosphatasia.(12,13) Hypophosphatasia is the rare inborn-error-of-metabolism characterized by low serum alkaline phosphatase activity caused by loss-of-function mutation(s) within the gene that encodes the “tissue nonspecific” isoenzyme of alkaline phosphatase (TNSALP).(14,15) Consequently, inorganic pyrophosphate, a natural substrate for this ectoenzyme and an inhibitor of hydroxyapatite crystal growth and dissolution, accumulates extracellularly and blocks skeletal mineralization causing osteomalacia.(14,15) Hypophosphatasia presenting in adult life typically manifests with bilateral femoral pseudofractures (Looser's zones)(12,13,16,17) that are chronic and painful and usually occur laterally in the subtrochanteric diaphysis (Fig. 1)(18,19) rather than within the medial cortex of the femoral neck typical of pseudofractures in more common forms of osteomalacia.(20) Because there is no established medical treatment for hypophosphatasia,(15,17) such pseudofractures are known to remain unchanged for years or to progress, but will not mend unless they go on to completion (often with low trauma) or receive intramedullary fixation.(18) We reported 20 yr ago that similar femoral subtrochanteric pseudofractures occur in adults with X-linked hypophosphatemia (XLH) (Fig. 2), although in XLH they are more often located medially than laterally.(21) This region of the femoral shaft seems to sustain the maximum bending moment.(22)
Bisphosphonates are synthetic analogs of inorganic pyrophosphate that resist hydrolysis by alkaline phosphatase and then suppress skeletal turnover by blocking bone resorption while permitting some bone apposition.(23) Unmasking of hypophosphatasia in a carrier of a TNSALP gene defect or inadvertently treating XLH is probably not the explanation for the atypical femoral fractures that occur during alendronate therapy for postmenopausal osteoporosis. Experience with hypophosphatasia and XLH bolsters the hypothesis that such fractures result from the pharmacological action of this bisphosphonate to suppress bone turnover.