RESUMO
Hypoparathyroidism is a disorder characterized by hypocalcemia, deficient PTH, and abnormal bone remodeling. Standard treatment of hypoparathyroidism consists of oral calcium and vitamin D supplementation. However, maintaining serum calcium levels can be a challenge. In addition, concerns exist regarding hypercalciuria and ectopic calcifications that can be associated with such treatment. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. This review focuses on the use of PTH in the treatment of hypoparathyroidism, in the form of teriparatide [PTH(1-34)] and the full-length molecule, PTH(1-84). Studies in hypoparathyroid subjects demonstrate that PTH(1-34) and PTH(1-84) lower or abolish supplemental calcium and vitamin D requirements as well as increase markers of bone turnover. Densitometric and histomorphometric studies in some subjects treated with PTH(1- 34) and PTH(1-84) show an improvement in bone-remodeling dynamics and return of bone metabolism toward normal levels. Given the chronic nature of hypoparathyroidism, and the expectation that PTH will be used for extended periods of time in hypoparathyroidism, further studies are needed to determine the long-term safety of PTH therapy in this population.
Assuntos
Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/administração & dosagem , Teriparatida/uso terapêutico , Adolescente , Adulto , Idoso , Remodelação Óssea/efeitos dos fármacos , Cálcio/uso terapêutico , Criança , Humanos , Pessoa de Meia-Idade , Vitamina D/uso terapêuticoRESUMO
UNLABELLED: Hypoparathyroidism, a disorder characterized by low parathyroid hormone (PTH), is generally treated with oral calcium and vitamin D supplementation. We investigated the effects of PTH(1-84) treatment in 30 hypoparathyroid subjects for 24 months. PTH(1-84) treatment in hypoparathyroidism significantly reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels. INTRODUCTION: Hypoparathyroidism, a disorder characterized by low PTH, is associated with hypocalcemia, hypercalciuria, and increased bone mineral density (BMD). Conventional therapy with calcium and 1,25-dihydroxyvitamin D can maintain the serum calcium concentration, but doses are high, and control is variable. We investigated the effects of human PTH(1-84) treatment in hypoparathyroidism. METHODS: Thirty subjects with hypoparathyroidism were treated in an open-label study of PTH(1-84) 100 µg every other day by subcutaneous injection for 24 months, with monitoring of calcium and vitamin D supplementation requirements, serum and 24 h urinary calcium excretion, and BMD by dual energy X-ray absorptiometry. RESULTS: Requirements for supplemental calcium decreased significantly (3,030±2,325 to 1,661±1,267 mg/day (mean±SD); p<0.05), as did requirements for supplemental 1,25-dihydroxyvitamin D (0.68±0.5 to 0.40±0.5 µg/day; p<0.05). Serum calcium levels and 24 h urinary calcium excretion were mostly unchanged at 24 months. BMD increased at the lumbar spine by 2.9±4% from baseline (p<0.05), while femoral neck BMD remained unchanged and distal one third radial BMD decreased by 2.4±4% (p<0.05). CONCLUSION: PTH(1-84) treatment in hypoparathyroidism significantly reduces supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.
Assuntos
Terapia de Reposição Hormonal/métodos , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Adulto , Idoso , Densidade Óssea/efeitos dos fármacos , Cálcio/administração & dosagem , Cálcio/sangue , Cálcio/urina , Esquema de Medicação , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Hipoparatireoidismo/metabolismo , Hipoparatireoidismo/fisiopatologia , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/administração & dosagem , Rádio (Anatomia)/fisiopatologia , Vitamina D/administração & dosagem , Vitamina D/análogos & derivadosRESUMO
CONTEXT: The osteoanabolic properties of PTH may be due to increases in the number and maturity of circulating osteogenic cells. Hypoparathyroidism is a useful clinical model because this hypothesis can be tested by administering PTH. OBJECTIVE: The objective of the study was to characterize circulating osteogenic cells in hypoparathyroid subjects during 12 months of PTH (1-84) administration. DESIGN: Osteogenic cells were characterized using flow cytometry and antibodies against osteocalcin, an osteoblast-specific protein product, and stem cell markers CD34 and CD146. Changes in bone formation from biochemical markers and quadruple-labeled transiliac crest bone biopsies (0 and 3 month time points) were correlated with measurements of circulating osteogenic cells. SETTING: The study was conducted at a clinical research center. PATIENTS: Nineteen control and 19 hypoparathyroid patients were included in the study. INTERVENTION: Intervention included the administration of PTH (1-84). RESULTS: Osteocalcin-positive cells were lower in hypoparathyroid subjects than controls (0.7 ± 0.1 vs. 2.0 ± 0.1%; P < 0.0001), with greater coexpression of the early cell markers CD34 and CD146 among the osteocalcin-positive cells in the hypoparathyroid subjects (11.0 ± 1.0 vs. 5.6 ± 0.7%; P < 0.001). With PTH (1-84) administration, the number of osteogenic cells increased 3-fold (P < 0.0001), whereas the coexpression of the early cell markers CD34 and CD146 decreased. Increases in osteogenic cells correlated with circulating and histomorphometric indices of osteoblast function: N-terminal propeptide of type I procollagen (R(2) = 0.4, P ≤ 0.001), bone-specific alkaline phosphatase (R(2) = 0.3, P < 0.001), osteocalcin (R(2) = 0.4, P < 0.001), mineralized perimeter (R(2) = 0.5, P < 0.001), mineral apposition rate (R(2) = 0.4, P = 0.003), and bone formation rate (R(2) = 0.5, P < 0.001). CONCLUSIONS: It is likely that PTH stimulates bone formation by stimulating osteoblast development and maturation. Correlations between circulating osteogenic cells and histomorphometric indices of bone formation establish that osteoblast activity is being identified by this methodology.