Low Serum Alkaline Phosphatase Activity and Pathologic Fracture: Case Report and Brief Review of Hypophosphatasia Diagnosed in Adulthood
Division of Endocrinology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Endocrine Practice
(Impact Factor: 2.81).
11/2006; 12(6):676-81. DOI: 10.4158/EP.12.6.676
To describe an elderly patient with low serum alkaline phosphatase (ALP) activity detected after a pathologic fracture and to characterize hypophosphatasia in adult patients.
We present a case report of a 64-year-old woman, who was referred after sustaining an atraumatic femoral fracture treated successfully with intramedullary nailing. Clinical, biochemical, radiologic, and molecular studies explore the differential diagnosis of her hypophosphatasemia, and the features, diagnosis, and management of the adult form of hypophosphatasia are reviewed.
Physical examination of our patient was revealing only for short stature. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal calcium, elevated inorganic phosphate, and low ALP levels in serum. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5'-phosphate concentration was measured and found to be considerably elevated, a substantiation of the diagnosis of hypophosphatasia. Analysis of the gene encoding the "tissue-nonspecific" isoenzyme of ALP (TNSALP) demonstrated a novel, heterozygous, missense mutation causing her disorder.
Hypophosphatasia is a rare inborn error of metabolism due to a deactivating mutation (or mutations) of the gene encoding TNSALP, in turn leading to global deficiency of TNSALP activity and inadequate skeletal mineralization and fractures. Our patient illustrates the importance of low serum ALP activity in the assessment of patients with fractures. No established treatment exists for hypophosphatasia, but the correct diagnosis should help to avoid the use of traditional therapies for osteoporosis or osteomalacia, which would be ineffective or potentially harmful.
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ABSTRACT: Biomaterials are widely used in medical practice to help maintain, improve or restore diseased tissues or organs. The successful integration of biomaterials with host tissue depends on substratum surface properties, as well as host tissue quality and its regulatory environment. The overall goal of this dissertation is to incorporate these three factors to achieve better biomaterial-host tissue interactions. Important surface properties include surface topography, surface energy, chemical composition and surface charge. We designed a new titanium (Ti) substratum with modified surface chemical composition by preventing the contamination when in contact with the atmosphere. The new Ti surface has lower carbon contamination and promotes osteoblast differentiation phenotype. The osteogenic effect is synergistic with micrometer and sub-micrometer scale surface structures. To further investigate the effects of bone quality on peri-implant bone formation, we developed a novel mouse femoral medullary bone formation model. This new model will facilitate research evaluating the effects of biomaterial surface treatments in host animals with deficient bone development, including genetically engineered mice. Finally, we studied sexual dimorphism in the response of osteoblasts to systemic regulatory hormones 1¦Á,25-dihydroxyvitamin D3 and 17¦Â-estradiol. The results showed intrinsic differences in male and female osteoblasts with respect to their differentiation and their responses to hormones, suggesting that host chromosomal sex should be considered in biomaterial research. Taken together, this research provides fundamental information on biomaterial surface properties and the regulation of host tissue response, which are important in guiding biomaterial design and evaluation. Ph.D. Committee Chair: Barbara Boyan; Committee Co-Chair: Zvi Schwartz; Committee Member: Andres Garcia; Committee Member: Carson Meredith; Committee Member: Robert Baier
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ABSTRACT: 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.
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.
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.
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.
Available from: benthamscience.com
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ABSTRACT: Cole DEC. Hypophosphatasia update: recent advances in diagnosis and treatment.Clin Genet 2008: 73: 232–235. © Blackwell Munksgaard, 2008
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