Anabolic Agents Show Promise for Building Bone Mass

Family Practice News, August 1, 2000 by Barbara Baker

CHICAGO -- The field of osteoporosis prevention and treatment is being spurred by burgeoning research in the field of anabolic agents, with recombinant parathyroid hormone leading the pack.

Parathyroid hormone is "clearly the most promising bone-building agent on the horizon," but the statins, anabolic steroids, growth hormone axis agents, and fluoride continue to hold some promise, Dr. Felicia Cosman maintained at the World Congress on Osteoporosis.

The osteoporosis treatments now on the market are antiresorptive agents. They do not specifically stimulate bone formation. The strongest of these agents are the bisphosphonates, but they reduce fracture risk by no more than 50%, noted Dr. Cosman, the clinical director of the National Osteoporosis Foundation in Washington.

Anabolic agents directly stimulate bone formation. The hope is that they can have a more potent effect on bone mass and can further reduce fracture risk.

The agent that is the closest to widespread clinical use is recombinant parathyroid hormone (rPTH). By the end of the year, Eli Lilly & Co. plans to submit to the Food and Drug Administration a new drug application for its rPTH formulation, Forteo, for treating postmenopausal osteoporosis.

This is based, in part, on the results of a phase III study sponsored by Lilly The study was presented by Dr. Robert M. Neer of the Massachusetts Institute of Technology, Cambridge, at the annual meeting in Toronto of the Endocrine Society. In a randomized, double-blind trial of more than 1,300 postmenopausal women with a prior spine fracture, rPTH at a dosage of 40 [mu]g/ day reduced the relative risk of new vertebral fractures by 69%, compared with placebo, during 21 months of treatment.

Dr. Cosman of Columbia University, New York, gave her perspective on the anabolic agents now under investigation:

* Recombinant Parathyroid Hormone. The study results presented at the Endocrine Society meeting confirmed those of smaller studies showing that rPTH can stimulate major bone mass accrual and can reduce fractures. The mechanisms of rPTH's anabolic action are unclear but may be related to its ability to increase osteoblast activity, recruitment, and lifespan.

* At the World Congress on Osteoporosis, Dr. Cosman and her associates reported on a randomized trial of 52 postmenopausal women who had been on estrogen replacement therapy for at least a year. During 3 years of study the addition of rPTH significantly increased bone mass and reduced vertebral fractures, compared with estrogen alone.

Recombinant parathyroid hormone is taken as a daily self-administered injection. Three years of treatment "is a burden," Dr. Cosman acknowledged, but studies are now planned to see whether 3-6 months of treatment may be enough to have a significant, longterm impact. Studies also will assess whether the combination of rPTH with a bisphosphonate could have additive effects.

So far, rPTH has not been associated with major complications in humans. Data from rat studies suggest a link with osteogenic sarcoma, but the rats were given very, very high doses for their lifetimes," she said.

* Statins. There is now preliminary evidence that these lipid-lowering agents may be anabolic to bone. In vitro and rat studies suggest that lovastatin and simvastatin can increase bone formation rate and trabecular bone volume. The findings, published late last year by Dr. Gregory Mundy of the University of Texas, San Antonio, "have generated a lot of excitement," Dr. Cosman commented.

In June, three groups of investigators published retrospective studies suggesting that statin use was associated with a 45%-70% reduction in risk of fractures. But there have been no prospective, randomized, placebocontrol trials in humans yet.

The approved statins may not be the ideal statins, because most of them are first metabolized by the liver and have small concentrations in bone, she said.

* Anabolic Steroids. Overall, these agents have shown modest effects on bone. They appear to be no better than the available antiresorptive drugs.

Research on some of the older compounds was hindered by their masculinizing side effects, their association with lipid abnormalities and liver function abnormalities, and concern over their abuse potential. Short-term biochemical studies show that methyltestosterone combined with estrogen can maintain bone formation while inhibiting bone resorption, but so far there is no information on its effects on bone mass.

* Growth Hormone Axis Agents. Growth hormone deficiency reduces bone mass, which is improved with growth hormone administration.

But so far, study results in osteoporosis "have been disappointing," with increases in bone mass generally no greater than those seen with standard antiresorptive agents, Dr. Cosman said.

These agents do, however, increase lean body mass, which may cut the risk of falls among frail osteoporotic elderly patients.

* Fluoride. Observational studies show that fluoride can increase bone mass, but the quality of bone produced is "not totally normal," she noted, and it is unclear whether fluoride can actually reduce fractures.