Parathyroid hormone (PTH) is an 84-amino acid polypeptide secreted by the parathyroid glands in response to relatively small changes in serum calcium (figure 1). Like all peptide hormones it has an N-terminal and C-terminal region. The first two amino acids in the N-terminal region of the molecule are obligatory for activation of the PTH 1 receptor (PTH1r), a membrane surface receptor expressed in multiple tissues including cartilage, bone, breast and kidney. While circulating, the intact 1-84 PTH peptide can be cleaved to several fragments at various tissues, although it is unclear if these fragments have intrinsic biologic activity. On the other hand, recombinant PTH 1-31 and 1-34 retain all of the biologic activity of the intact peptide (1-84) .
PTH is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-dihydroxyvitamin D). With respect to calcium, PTH is most responsible for maintaining serum ionized calcium concentrations within a narrow range, through its actions to stimulate renal tubular calcium reabsorption and bone resorption. Chronic exposure to high serum PTH concentrations (as seen with primary or secondary hyperparathyroidism) results in bone resorption. Given this observation, exogenous PTH would seem to be an unlikely candidate for the treatment of osteoporosis. However, intermittent administration of recombinant human PTH (both full-length 1-84 or fragment 1-34) has been shown to stimulate bone formation more than resorption, at least over the first 12 months of treatment.
This topic review will discuss the use of recombinant PTH as a therapy for osteoporosis. PTH physiology and other treatments for osteoporosis are reviewed in detail elsewhere. (See "Parathyroid hormone secretion and action" and "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
MECHANISMS OF ACTION
Anabolic therapy for bone — PTH 1-34 (teriparatide, Forteo) and PTH 1-84 (PreOs) belong to a class of anti-osteoporosis drugs, the so-called "anabolic" agents . These drugs, in contrast to antiresorptive agents, stimulate bone formation, activate bone remodeling and are administered subcutaneously as daily injections . Other agents in this class include growth hormone (GH), insulin-like growth factor-I (IGF-I) and parathyroid hormone (PTH)-related peptide (PTHrp). PTH 1-34, teriparatide, at a dose of 20 mcg/day is available in the United States and Europe for the treatment of severe osteoporosis in both men and women, while PTH 1-84 is approved in Europe but not in the United States. A PTH 1-31 preparation has been studied in a small phase two trial.
None of the other anabolic hormones are approved for the treatment of osteoporosis, although GH has been approved for the treatment of adults with GH deficiency and low bone mineral density (BMD). (See "Growth hormone deficiency in adults", section on 'GH therapy'.)