Advances in Target-Specific Therapy for Osteoporosis

Abstract

Bone is constantly being remodeled, with resorption preceding formation. In the individual who is not losing bone mass, bone remodeling is balanced, with the osteoblast forming the same amount of bone that has been resorbed by the osteoclast. Remodeling in the aging skeleton, aided and abetted by estrogen deficiency after the menopause, is not balanced, with bone resorption exceeding bone formation; as a result, bone loss ensues. The earliest therapeutic attempts to correct this imbalance were focused on inhibiting bone resorption, thus bringing the bone remodeling unit into better balance. When alendronate, an amino-containing bisphosphonate, was approved by the US Food and Drug Administration in 1995 (1–3), it was known that it reduced bone resorption, but the molecular mechanism of action (inhibition of a key enzyme in the mevalonate pathway, farnesyl pyrophosphate synthase) was not understood until later (4, 5). Subsequently, other bisphosphonates (risedronate, ibandronate, and zoledronic acid) joined the family of approved bisphosphonates for the treatment of osteoporosis. Along with estrogen, raloxifene (an estrogen analog), and calcitonin, these agents together are called “antiresorptive” drugs. Although it is true that their initial mechanistic effect is to reduce bone resorption, these drugs also reduce bone formation. Their therapeutic effect depends on the inhibition of resorption being greater than inhibition of formation. Although the classification of these drugs as antiresorptives is not correct because they are general antiremodeling agents, it is unlikely that other more accurate terms such as “anticatabolic” or “antiremodeling” will replace the common classification that is universally used. These antiresorptive agents appear to be generally safe and well tolerated and, with specific reference to alendronate, risedronate, and zoledronic acid, are associated with significant increases in bone mineral density (BMD) and reductions in the incidence of vertebral, hip, and nonvertebral fractures. Despite their safety and efficacy, these drugs maintain skeletal microstructure but do not rebuild it. In 2002, the therapeutic landscape for osteoporosis changed with the approval of teriparatide as a therapy for osteoporosis (6). Teriparatide is the amino-terminal sequence of human PTH [rhPTH (1–34)]. Although chronically elevated levels of PTH cause bone loss by increasing bone resorption, intermittent use of teriparatide or the full-length molecule, PTH (1–84), is associated with a distinct osteoanabolic effect. The pharmacokinetics of this effect are described by an early increase in bone formation, rather exclusively, followed soon thereafter by an increase in bone resorption. Thus, an “anabolic window” is created, helping to explain the osteoanabolic properties of this drug. As with the bisphosphonates, the use of teriparatide for the treatment of osteoporosis was based on empiric observations, with the molecular mechanisms of action worked out only later. As noted for the antiresorptive agents, the terminology for teriparatide is a bit garbled because teriparatide’s actions are not exclusively osteoanabolic. Its effects are also associated in time with an increase in bone resorption. The osteoanabolic effect due to the anabolic window is relatively short-lived. The true osteoanabolic effect, namely when teriparatide is exclusively stimulating bone formation, is likely to be an increase in bone modeling, that is bone formation on quiescent bone surfaces. Similar in principle, however, to the antiresorptives (inhibition of bone resorption is chronically greater than inhibition of bone formation), the efficacy of teriparatide is prolonged beyond the modeling period because bone formation exceeds bone resorption