• pseudofractures;
  • osteomalacia;
  • hypophosphatasia;
  • hypophosphatemia


  1. Top of page
  2. Abstract
  3. Acknowledgements

Lateral subtrochanteric femoral pseudofractures occurring in adults with osteomalacia from hypophosphatasia and X-linked hypophosphatemia support the hypothesis that atypical femoral fractures in osteoporosis treated with bisphosphonates also result from low bone turnover.

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)

thumbnail image

Figure Figure 1. Symmetrical, subtrochanteric pseudofractures involving the lateral femoral diaphysis (arrows) are a hallmark of the adult form of hypophosphatasia and are exemplified here in an affected 48-yr-old woman.(19)

Download figure to PowerPoint

thumbnail image

Figure Figure 2. A femoral subtrochanteric pseudofracture (arrow) is present in a 27-yr-old man with XLH not receiving medical treatment. It has occurred laterally, although such fractures usually develop medially in this form of osteomalacia.(21) The medial cortex is thickened.

Download figure to PowerPoint

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.


  1. Top of page
  2. Abstract
  3. Acknowledgements

This work was supported by the Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, Barnes-Jewish Hospital Foundation, Washington University School of Medicine, St. Louis, MO, USA, and Shriners Hospitals for Children, St. Louis, MO, USA.


  1. Top of page
  2. Abstract
  3. Acknowledgements
  • 1
    Lenart BA, Lorich DG, Lane JM 2008 Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358: 13041306.
  • 2
    Kwek EBK, Koh JSB, Howe TS 2008 More on atypical fractures of the femoral diaphysis. N Engl J Med 359: 316318.
  • 3
    Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY 2005 Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 90: 12941301.
  • 4
    Armamento-Villareal R, Napoli N, Panwar V, Novack D 2006 Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 355: 20482050.
  • 5
    Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, Chua DT, Howe TS 2007 Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 89: 349353.
  • 6
    Lee P, van der Wall H, Seibel MJ 2007 Looking beyond low bone mineral density: Multiple insufficiency fractures in a woman with post-menopausal osteoporosis on alendronate therapy. J Endocrinol Invest 30: 590597.
  • 7
    Sayed-Noor AS, Sjödén GO 2008 Subtrochanteric displaced insufficiency fracture after long-term alendronate therapy–a case report. Acta Orthop 79: 565567.
  • 8
    Visekruna M, Wilson D, McKiernan FE 2008 Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 93: 29482952.
  • 9
    Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorigch DG 2008 Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 22: 346350.
  • 10
    Scheider JP 2006 Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics 61: 3133.
  • 11
    Aspenberg P 2008 Bisphosphonate-induced fractures: Nature strikes back ? Acta Orthop 79: 459460.
  • 12
    Whyte MP, Teitelbaum SL, Murphy WA, Bergfeld MA, Avioli LV 1979 Adult hypophosphatasia: Clinical, laboratory, and genetic investigation of a large kindred with review of the literature. Medicine 58: 329347.
  • 13
    Whyte MP, Murphy WA, Fallon MD 1982 Adult hypophosphatasia with chondrocalcinosis and arthropathy. Am J Med 72: 631641.
  • 14
    Whyte MP 2001 Hypophosphatasia. In: ScriverCR, BeaudetAL, SlyWS, ValleD (eds.) The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, New York, NY, USA 53135329.
  • 15
    Whyte MP 2008 Hypophosphatasia: Nature's window on alkaline phosphatase function in humans. In: BilezkikianJP, RaiszLG, MartinTJ, eds. Principles of Bone Biology, 3rd ed. Academic Press, San Diego, CA, USA 15731598.
  • 16
    Khandwala HM, Mumm S, Whyte MP 2006 Low serum alkaline phosphatase activity and pathologic fracture: Case report and brief review of hypophosphatasia diagnosed in adulthood. Endocr Pract 12: 676681.
  • 17
    Whyte MP, Mumm S, Deal C 2007 Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab 92: 12031208.
  • 18
    Coe JD, Murphy WA, Whyte MP 1986 Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am 68: 981990.
  • 19
    Whyte MP, Wenkert D, McAlister WH, Mughal Z, Freemont AJ, Whitehouse R, Baildam E, Mumm S 2008 Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia. J Bone Miner Res (in press).
  • 20
    Steinbach HL, Noetzli M 1964 Roentgen appearance of the skeleton in osteomalacia and rickets. Am J Roentgenol Radium Ther Nucl Med 91: 955972.
  • 21
    Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP 1989 X-linked hypophosphatemia in adults: Prevalence of skeletal radiographic and scintigraphic features. Radiology 171: 403414.
  • 22
    Pauwels F 1950 Die bedeutung der bauprinzipien des stutz — und bewegungsapparates fur die beanspruchung der Röhrenknochen. Z Anat EntwicklGesch 114: 129166.
  • 23
    Drake MT, Clarke BL, Khosla S 2008 Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc 83: 10321045.