Short-Term, High-Dose Parathyroid Hormone-Related Protein as a Skeletal Anabolic Agent for the Treatment of Postmenopausal Osteoporosis

Abstract

PTH-related protein (PTHrP) is homologous with PTH. PTH, an effective anabolic agent for treating osteoporosis, has been shown to stimulate both bone resorption by osteoclasts and bone formation by osteoblasts. We examined whether PTHrP might share anabolic properties in osteoporosis. A 3-month double-blind, prospective, placebo-controlled, randomized clinical trial was performed in 16 healthy postmenopausal women with osteoporosis. All received calcium and vitamin D, and all continued their prior hormone replacement therapy. One group also received daily sc PTHrP (6.56 microg/kg x d, or approximately 400 microg/d), and the other group received placebo injections. The PTHrP group displayed a 4.7% increase in lumbar spine bone mineral density (BMD) and also demonstrated an increase in osteoblastic bone formation, as assessed using serum osteocalcin measurements. In contrast, there was no increase in bone-specific alkaline phosphatase and collagen-1 propeptide or either of two markers of osteoclastic bone resorption, N-telopeptide, or deoxypyridinoline. One subject in the placebo group withdrew from the study, but there were no significant adverse events in the PTHrP group. PTHrP administered sc in high doses for only 3 months appears to be a potent anabolic agent, producing a 4.7% increase in lumbar spine BMD. This compares very favorably to available antiresorptive drugs for osteoporosis and is similar to the increases in BMD at this early time point reported for PTH. Despite the high doses, PTHrP was well tolerated. Larger clinical trials are required to confirm these results and fully assess the anabolic potential of PTHrP in osteoporosis.

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

“…These in vivo results thus suggest that PTHrP could act on precursor cells before they are committed to either preosteoblasts or the adipocyte lineage. The present in vitro results in human MSC cultures further support the aforementioned in vivo findings, and provide a new rationale to explain the osteogenic effect of PTHrP in osteoporotic postmenopausal women (Horwitz et al, 2003).…”

“…Some PTHrP (1-36)-treated cultures were also treated with PTHrP (7-34), at 1 μM added 30 min before, from day 6 ((7-34)/6). postmenopausal women with osteoporosis, daily PTHrP (1-36) administration increases trabecular bone mineral density, apparently at the expense of an increase in bone formation without significant changes in bone resorption (Plotkin et al, 1998;Horwitz et al, 2003). However, the true molecular mechanisms associated with the osteogenic action of this PTH-like fragment of PTHrP -in contrast to those of PTH (Goltzman, 2008) -have not been explored much.…”

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…This anabolic response of the skeleton to repeated cycles of systemic PTH elevation is quite distinct from the effect of continuous PTH elevation and results from increased bone formation on the surfaces of cancellous, endocortical and periosteal bone of the appendicular and axial skeleton. Though less studied, intermittent administration of parathyroid hormone related protein (PTHrP) peptide 1-36, an amino-terminal fragment of the other principal ligand of the PTH receptor, is also anabolic [6].…”

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

“…Intermittent administration of parathyroid hormone (PTH) and PTH-related protein (PTHrP) enhances bone mass (11) in part by promoting the differentiation of committed osteoblast precursors (12), decreasing osteoblast apoptosis (13), and decreasing production of sclerostin by osteocytes (14). PTH treatment is also associated with reduced adipocyte generation (15).…”