The potential of parathyroid hormone as a therapy for osteoporosis

Over the past 10 years, therapeutic optimism in osteoporosis has been fueled by the development of agents that inhibit the resorption of bone. An increase in bone density with the bisphosphonates alendronate and risedronate, for example, is associated with significant reductions in vertebral and hip fracture incidence. Although bone is clearly stronger when these agents are used, there is no conclusive evidence that they improve the microarchitectural defects that characterize the disorder. It has been known for years that parathyroid hormone (PTH) can be an anabolic agent in animals. Recently, it has been confirmed that low-dose, intermittent administration of PTH is associated with selective anabolic effects in human subjects, whereas higher doses administered continuously are associated with catabolic effects. This observation has led to an experimental design in which PTH is administered to human subjects once daily in doses that do not regularly lead to adverse events, such as hypercalcemia. Two-year studies using PTH alone have been directed at postmenopausal osteoporosis (PMO) in women and at men with idiopathic osteoporosis. In both women and men, PTH leads to marked increases in bone density at the lumbar spine and also, significantly, in the hip. In PMO, PTH is associated with significant reductions in vertebral and nonvertebral fractures. When PTH is used in combination with an anti-resorptive agent, like estrogen, the markedly positive effects on bone mass are also seen in PMO and in those with glucocorticoid-induced osteoporosis. After PTH is withdrawn, but estrogen therapy is continued, the gains in bone mass are maintained. It is not known whether gains in bone mass are maintained if PTH is withdrawn without continuing therapy with an anti-resorptive agent; however, preliminary data suggest that the gains in bone mass begin to be lost. Bone biopsy samples in PMO and in men with idiopathic osteoporosis, before and after therapy with PTH, when subjected to histomorphometric analysis show marked increases in cortical thickness and improvements in indices of trabecular connectivity, thus allaying concerns that PTH may cause cortical thinning. It would appear that the increase in cortical wall thickness is due, in part, to stimulation by PTH of periosteal apposition at a rate greater than its effect to cause endocortical resorption. In all studies reported to date, PTH appears to be well tolerated. The era of anabolic therapy for osteoporosis is at hand, with PTH being the first to be tested with sufficient rigor to demonstrate its efficacy.