Treatment with Parathyroid Hormone (PTH) for Osteoporosis: Novel Methods and Benefits

Introduction

Choices for the pharmacological therapy of osteoporosis have been widening since the advent of alendronate, the first bisphosphonate to be approved worldwide for this disease in the mid-1990s. The choices have been increasing ever since. We have now a number of bisphosphonates both as oral (alendronate, risedronate, ibandronate) and intravenous (ibandronate, zoledronic acid) agents. Additionally, the selective estrogen receptor modulator (SERM), raloxifene, became available in the late 1990s. Strontium ranelate became available thereafter in Europe and many other countries (but not in the United States). Most recently, in 2010, denosumab that represents yet another therapeutic class became available. All these agents, with the possible exception of strontium ranelate, represent antiresorptive drugs in which the primary action is to reduce osteoclast-mediated bone resorption. The osteoanabolic era of therapeutics for osteoporosis was inaugurated in 2002 giving us, for the first time, agents in which the primary mechanism is related to processes that stimulate bone formation and not that inhibit bone resorption. Thus, teriparatide, [PTH(1-34)], the foreshortened variant of the full-length PTH molecule and, later, the full-length molecule itself, PTH(1-84), defined yet another era in our quest to treat this disease. The osteoanabolic drugs teriparatide and PTH(1-84) reduce fracture risk by mechanisms completely different from the antiresorptives. While they increase overall bone turnover for most of the period in which they are prescribed, they stimulate bone formation directly and before bone resorption is stimulated. As one might expect, teriparatide and PTH(1-84) not only improve bone mineral density (BMD) but also improve other properties of bone such as microarchitecture and perhaps also bone size. Since the osteoanabolic and antiresorptive classes work by completely different mechanisms, there have been a number of attempts to use combination therapy. Recent studies are providing new insights into the possibility that PTH and antiresorptive agents could be used successfully either sequentially or along with antiresorptive drugs.

Abstract

The osteoanabolic era for the treatment of osteoporosis was ushered in by the advent of teriparatide [hPTH(1-34)] and then the full-length molecule, PTH(1–84). The mechanism of anabolic skeletal therapy differs fundamentally from the antiresorptives in that they directly stimulate processes associated with bone formation. The improvements in skeletal microstructure and other bone qualities distinguish these drugs from other available ones. They effectively increase bone density, bone turnover markers, and reduce fracture incidence. Their safety profile is excellent. Over the past decade, the use of anabolic therapy has been studied both as monotherapy and in various combinations. While combination therapy with an antiresorptive has theoretical attractiveness, no approach has clearly shown advantages over therapy with PTH alone. Following treatment for the recommended 18–24 months, it is necessary to follow osteoanabolic therapy with an antiresorptive to maintain the gains achieved during the treatment period. On the horizon are new forms of PTH and delivery systems that may prove to have utility.

Keywords

Osteoporosis, antiresorptive agents, parathyroid hormone, teriparatide, bone quality, bone density, anabolic window