Teriparatide (Biosynthetic Human Parathyroid Hormone 1–34): A New Paradigm in the Treatment of Osteoporosis

Abstract

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecul...

Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

“…In addition, we identified 19 human genes with druggable domains, which have become pseudogenes in macaques (Supplementary Section 7). For example, the parathyroid hormone 1 receptor (PTH1R) gene, the target of the anti-osteoporosis drug teriparatide (Forteo) 18,19 , contains a premature stop codon in macaques. One of the targets of recombinant human keratinocyte growth factor (Palifermin 20 ), fibroblast growth factor receptor 3, encoded by FGFR3, has also been pseudogenized in macaques owing to the presence of a premature stop codon.…”

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Evidence for Lgr6 as a Novel Marker of Osteoblastic Progenitors in Mice

“…Presently, there are several pharmacological therapies developed and/or in clinical trials, targeted at building bone by indirectly stimulating osteoblasts, such as recombinant parathyroid hormone, parathyroid hormone related peptide, and anti-sclerostin monoclonal antibody. (14)(15)(16) Although effective, these therapies have reported side effects, (17) underscoring a need for additional research focused on molecularly stimulating endogenous mesenchymal stem cells toward osteogenesis. Beyond their role in bone mass maintenance, mesenchymal stem cells have emerged as a substrate for cell-based therapies for fracture and other bone-related disorders.…”