Parathyroid Hormone Decreases the Risk of Fractures in Postmenopausal Women with Osteoporosis
Current treatments for postmenopausal osteoporosis reduce bone resorption, moderately increase bone density, and some reduce the risk of fracture. Parathyroid hormone (PTH), when given by daily injection, stimulates bone formation and bone mass. Neer, et al (N Engl J Med 344: 1434, 2001) enrolled 1637 postmenopausal women with prior vertebral fractures to assess the effectiveness of human recombinant PTH in preventing fractures.
Participants were randomly assigned to receive daily injections of placebo, or PTH ( 20µg or 40µg per day). Vertebral radiographs were done at baseline and at the end of the study (median duration, 21 months). Bone mineral density of the lumbar spine, proximal femur, and radius and total-body bone mineral were measured at 0, 12 and 18 months using dual-energy x-ray absorptiometry. The mean duration of treatment in the three groups was 18+5, 18+6, and 17+6 months, respectively. Participants in all three groups received equivalent daily doses of calcium and vitamin D. The study was stopped by the sponsor (Eli Lilly and Company) due to reports of osteosarcomas in rats treated with PTH.
PTH at a dose of 20µg and 40µg decreased the risk of one or more new vertebral fractures by 65 and 69%, and increased the bone mineral density in the spine by 9 and 13%, respectively, as compared with placebo. The risk of nonvertebral fractures was reduced by 35% at the 20µg dose and by 40% at the 40µg dose when compared to placebo. Total-body bone mineral increased by 2 to 4 percentage points for both groups receiving PTH compared to the group receiving placebo. More patients in the 40µg group withdrew from the study due to adverse events (11%) compared to the 20µg and placebo groups (6%). Nausea and headache were the most common side effects. No osteosarcomas developed in any of the 3 groups.
These data demonstrate the ability of PTH to reduce the risk of both vertebral and nonvertebral fractures in addition to stimulating bone formation and increasing bone mass.
Editorial Comment: Excessive PTH, such as that seen in chronic hyperparathyroidism, is classically associated with bone resorption. However, daily injections of PTH that do not result in sustained elevations of PTH levels have been shown in animals and humans to prevent bone loss and increase bone mass and bone strength. The current study provides proof of concept that daily PTH is associated with a clinically relevant outcome – that is, significant reduction of osteoporosis-related vertebral and non-vertebral fractures.
There are two issues of potential concern, however. Osteosarcomas have been noted in rats treated with PTH although only with lifetime dosing. Osteosarcomas have not been observed in monkey treated with PTH, nor in humans with chronic hyperparathyroidism. The other potential concern is the observed decrease in density in cortical bone (radial shaft). The long-term significance of this is uncertain but is consistent with PTHs ability to reduce cortical bone mass.
