Introduction

A new drug has been approved for the treatment of osteoporosis - this time one that improves bone formation, as opposed to the action of available drugs that is usually the prevention or slowing bone resorption. It is teriparatide, a 34-amino-acid polypeptide produced by a recombinant DNA technique, which represents the biologically active part of human parathyroid hormone. It has to be given once daily by subcutaneous injection.

In previous studies teriparatide has been shown to increase spinal and femoral bone mineral density (BMD) and total bone mineral content in women with osteoporosis, and to reduce the risk of vertebral and non-vertebral osteoporotic fractures by 65% and 53%, respectively. The analysis summarized here was done to explore whether these apparent benefits were confined to a particular patient population, or were broad ranging.

Method

A total of 1,637 postmenopausal women who had at least either one moderate or two mild atraumatic vertebral fractures were enrolled. They all received daily calcium supplements (1000 mg) and vitamin D (400-1200 IU) throughout the study, and daily placebo injections for 2 weeks before randomization. They were then allocated to one of 3 treatment groups: placebo injections, teriparatide 20 µg, or teriparatide 40 µg, for a mean of 19 months (range up to 25 months). The women self-administered their injections; they attended for spinal radiography at the start and the end of the study period, as well as lumbar spine BMD assessments, periodically. The results analyzed were changes from baseline to study endpoints.

Results

The three treatment groups were evenly matched for age (mean 69-70 +/- 7 years), time since menopause (mean 21 years), previous osteoporosis therapy (13% -16%), spinal BMD (mean BMD T-score -2.6), and prevalent vertebral fractures (2 or more: 58%-62%).

Statistically significant increases in vertebral BMD with teriparatide, compared to placebo, were seen after 3 months across the board, so that by the end of the study they were increased by 10% and 14% for the 20 µg and 40 µg dose levels, respectively.

Age did not have a marked influence on the effect on BMD. The percentage increase was greater in the older age groups selected for analysis, but this was also the case for the placebo-treated subjects. It is possible older subjects may been relatively more deficient in calcium and vitamin D at enrollment.

The participants were divided into tertiles based on their baseline BMD. Dose-dependent percentage increases in vertebral BMD with teriparatide were inversely proportional to the baseline BMD; however, absolute increases (in gm/cm²) were independent of baseline BMD, although again showing dose dependence.

The risk for developing new fractures in the placebo subjects was inversely related to their baseline BMD; thus new fractures occurred in 22%, 11%, and 8% of women in the low, medium, and high tertiles, respectively. However, for both doses of teriparatide, the relative risk of new fractures did not differ significantly with baseline BMDs.

Further analyses showed that neither prevalent vertebral fractures nor body weight had a relevant effect on the increases in BMD offered by teriparatide.

Comment

The study report summarized here doesn't contain any mention of side effects of teriparatide. Other publications, however, refer to a slight increase in nausea, dizziness, and leg cramps, compared with those produced by placebo. Mild hypercalcemia is also reported, in up to 11% of women given 20 µg daily doses.

Slight pain and induration at the injection site have been reported in other studies, but it seems that this is due to the vehicle (placebo) rather than the peptide itself.

During the later stages of development of teriparatide, carcinogenicity studies in rats revealed a dose- and duration-related increase in the occurrence of osteosarcoma. For this reason, people at risk for osteosarcoma - Paget's disease, unexplained raised alkaline phosphatase levels, open epiphyses, those having prior radiation of the skeleton, or those with metabolic bone disease or a history of skeletal malignancy - should not receive teriparatide. And it should not be given for longer than 2 years, at the present time.

In spite of these warnings, teriparatide is a potent agent for increasing BMD and decreasing the risk of vertebral and other fractures. It is also effective in men with osteoporosis. In a clinical study, teriparatide (40 µg daily) increased lumbar spine BMD by 12.5%at 3 months, compared to 5.6% for alendronate (10 mg daily). In view of the need for daily injections and the limits on the duration of treatment, teriparatide should probably be reserved, in the first place, for people with severe osteoporosis.