The cellular and clinical parameters of anabolic therapy for osteoporosis

Abstract

A new era in the management of osteoporosis began with the recent approval of parathyroid hormone (PTH) for the treatment of postmenopausal osteoporosis. This peptide holds promise as the first in a series of anabolic growth factors that promote bone formation, enhance mineralization,and stimulate periosteal growth, yet exert relatively limited effects on bone resorption. Daily intermittent PTH treatment for postmenopausal women results in a dramatic increase in bone mineral density (BMD) (i.e., 10-15% improvement in spine BMD) and a significant decline (i.e., a risk reduction of nearly 2/3) in the occurrence of fragility fractures. The mechanism of PTH's anabolic action on the skeleton is complex and involves multiple pathways linked to common signaling peptides that affect gene transcription in osteoblasts. One fascinating aspect of PTH, both at the clinical and molecular level, is the relationship between the frequency of PTH treatment and the bone response. Depending on the type of PTH exposure, there can be an anabolic or catabolic skeletal phenotype that can then be recapitulated by certain in vivo and in vitro model systems. Transcriptional events following ligand binding to the PTH/PTHrP1 receptor have been studied, with particular interest in target genes such as IGF-I that can regulate both bone formation and resorption. Novel in vivo strategies, including temporal and conditional mutagenesis, will almost certainly lead to newer therapeutic paradigms for the treatment of postmenopausal osteoporosis.