Adult hypophosphatasia treated with teriparatide.

INTRODUCTION: Hypophosphatasia (HPP) features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) due to loss-of-function mutation within TNSALP, the gene that encodes "tissue-nonspecific" ALP (TNSALP). Consequently, inorganic pyrophosphate accumulates extracellularly and impairs skeletal mineralization. Affected adults manifest osteomalacia, often with slowly healing metatarsal stress fractures (MTSFs) and proximal femur pseudofractures. Pharmacotherapy remains elusive. PATIENT AND METHODS: A middle-aged woman sustained a slowly healing MTSF and then two enlarging MTSFs and a spontaneous proximal femur fracture. Pain persisted at all fracture sites. HPP was diagnosed as a result of low ALP activity (10-24 IU/liter; normal, 40-150 IU/liter) and elevated inorganic phosphate and pyridoxal 5'-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1-34), 20 microg, was injected sc daily in an attempt to enhance osteoblast synthesis of TNSALP.
RESULTS: Six weeks later, all fracture pain improved, and it resolved after 4 months. Radiographs of the enlarging MTSFs showed repair after 2-4 months. The femur fracture partially mended after 2 months and then healed. Additionally, hypophosphatasemia and hyperphosphatemia corrected, and biochemical markers of bone remodeling increased as long as TPTD (given for 18 months) was continued. The patient carried a heterozygous TNSALP missense mutation, p.D378V, which is common in the United States.
CONCLUSION: This first HPP patient given TPTD demonstrated fracture repair accompanying correction of hypophosphatasemia and hyperphosphatemia and bone marker responses indicating enhanced skeletal remodeling. Increased TNSALP synthesis in bone together with lowered extracellular concentrations of inorganic phosphate (a competitive inhibitor of ALPs) seemed to improve her skeletal mineralization. Further evaluation of TPTD for HPP is warranted.