“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

• Published in: Journal of bone and mineral research Vol. 27; no. 5; pp. 987 - 994
• Main Authors: Sutton, Roger AL, Mumm, Steven, Coburn, Stephen P, Ericson, Karen L, Whyte, Michael P
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: ALENDRONATE; Alendronate - adverse effects; Alendronate - therapeutic use; Alendronic acid; ALKALINE PHOSPHATASE; ANTIRESORPTIVES; Biological and medical sciences; Biopsy; Bisphosphonates; Bone mineral density; Bone turnover; Children; Dentition; Diphosphonates - adverse effects; Diphosphonates - therapeutic use; Enzymes; Female; Femoral Fractures - chemically induced; Femur; Fractures; Fundamental and applied biological sciences. Psychology; Humans; Hypophosphatasia; Hypophosphatasia - drug therapy; Imidazoles - adverse effects; Imidazoles - therapeutic use; Isoenzymes; Metatarsal; Middle Aged; Mineralization; Mutation; OSTEOMALACIA; OSTEOPOROSIS; PSEUDOFRACTURE; PYRIDOXAL PHOSPHATE; PYROPHOSPHATE; Skeleton and joints; Stress; STRESS FRACTURE; Teeth; Vertebrates: osteoarticular system, musculoskeletal system; VITAMIN B6; Zoledronic acid; ZOLENDRONATE; Phosphates; Alkaline phosphatase; Diseases of the osteoarticular system; PYRIDOXAL; Phosphoric monoester hydrolases; Antiresorptive agent; Diphosphonic acid derivatives; Esterases; Enzymopathy; Bisphosphonates; ANTIRESORPTIVES; Osteoarticular system; Alendronic acid; Osteoporosis; Vitamin D; PYROPHOSPHATE; Adult; Malnutrition; Osteomalacia; Nutritional status; Human; Enzyme; Nutrition disorder; Vitamin deficiency; Metabolic diseases; Stress fracture; Trauma; Hypophosphatasia; ALENDRONATE; Genetic disease; PSEUDOFRACTURE; PHOSPHATE; ZOLENDRONATE; Metabolic disorder; Vertebrata; Mammalia; Hydrolases; Bone; VITAMIN B
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.1565

We report a 55‐year‐old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for “osteoporosis.” Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the “tissue‐nonspecific” isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn‐error‐of‐metabolism. © 2012 American Society for Bone and Mineral Research.