Update on osteoporosis drugs

(This article was first printed in the August, 2004 issue of the Harvard Women's Health Watch. For more information or to order, please go to http://health.harvard.edu/women.)

Research is suggesting new ways to prevent the worst consequence of osteoporosis: broken bones.

The loss of bone strength through osteoporosis, as many people know, increases the risk of fractures. In the United States, a 50-year-old woman has a 40%-50% lifetime chance of having a broken bone due to osteoporosis. The most common fracture sites are the spine, hip, and wrist. Men, too, can have such fractures, but women are far more vulnerable because they lose bone at an accelerated rate during the first several years following menopause. Their bones are also less dense to begin with. However, many additional factors influence the development of osteoporosis, including age, genes, race, level of physical activity, and estrogen status.

There are various treatments available for osteoporosis, and those that are preventive are particularly important. Mainstays in reducing osteoporosis and fracture risk include regular weight-bearing exercise, adequate calcium and vitamin D, quitting smoking, good nutrition, and fall prevention. But women who already have osteoporosis or are at high risk for it may need to take medications as well.

Researchers have gained considerable insight into what constitutes bone strength and the biological pathways that affect it. As a result, we can expect to see new and better uses of current drug therapies, most of which reduce fracture risk by curbing bone loss, and the development and approval of new drugs, particularly ones that work by building bone.

Looking beyond bone mass

Clinicians rely on measurements of bone mineral density (BMD) - sometimes referred to as bone quantity or bone mass - to diagnose osteoporosis, determine who should be treated, and monitor therapy. But the main problem with osteoporosis is fracture, not low bone mass.

Studies of postmenopausal women show a relationship between low bone mass and future fracture risk, but BMD isn't the whole story. For one thing, women with similar BMD scores can have very different levels of fracture risk. For example, an 80-year-old with a low BMD score has a greater risk of bone fracture than a 60-year-old with the same score. Also, half of all fractures occur in people who don't have osteoporosis (as defined by BMD measurements). Furthermore, in some osteoporosis drug trials, improvements in BMD haven't always led to reductions in fracture risk.

According to some experts, currently available drugs that reduce fractures may do so not because they improve BMD, but through other effects on bone. Scientists are looking at several such biomechanical contributors to bone strength and fracture resistance. A major focus of their work is bone quality, a term that encompasses the bone's thickness, interior structure (microarchitecture), cumulative damage, mineralization, and rate of turnover. Researchers have also identified genes and gene products, growth factors, and hormones that influence bone quality and may be targets of future therapies.

Slowing bone turnover

Bone loss occurs with age because the normal process of remodeling, or bone turnover (see illustration above), removes more bone than it replaces. (Earlier in life, the reverse is true.) Bone resorption takes less time than bone formation - resorption at a particular bone site takes about two weeks; formation takes three months or more - so there's also a shortfall of bone at what are called remodeling spaces. Normally, this is of little consequence, but if the remodeling cycle is out of balance, bone turnover can result in major bone loss. High bone turnover is believed to increase fracture risk.

Most approved osteoporosis drugs are antiresorptive - that is, they slow the destructive phase of bone turnover (resorption). This slows bone loss and helps fill in the remodeling spaces. All antiresorptive agents reduce the risk of vertebral (spinal) fractures, and they all reduce markers of bone turnover. (These markers are substances in the blood and urine that reflect the activity of the bone cells involved in breakdown and formation.)

Antiresorptive medications include bisphosphonates, estrogen, selective estrogen receptor modulators (SERMs), and calcitonin (se e the medications chart, below). The bisphosphonates alendronate and risedronate are often the first drugs recommended for treating postmenopausal osteoporosis. They reduce nonvertebral fractures (at the hip or wrist, for example) as well as vertebral fractures, and when taken properly have few side effects. Raloxifene, the only SERM currently approved for osteoporosis, reduces spine fractures about as effectively as bisphosphonates. Researchers are investigating its effects on hip and non-spine fractures.

Antiresorptives produce modest increases in bone density. Research on alendronate suggests that such increases may be due, in part, to mineralization of old bone. Mineral content contributes to bone strength, but too much mineralization can make bones brittle. Data suggest that bisphosphonates are safe taken for up to 10 years, but longer-term studies are needed to clarify their cumulative effects on bone.

There's also a need for fracture-reduction trials that compare antiresorptive agents directly with one another - and with exercise, calcium and vitamin D supplementation, and other nondrug interventions. A trial comparing raloxifene to alendronate is under way in postmenopausal women with BMD-defined osteoporosis.

Building better bone: What's new?

Antiresorptives do not build bone beyond what is produced to help fill the remodeling spaces. Bone-building (anabolic) drugs, on the other hand, stimulate bone formation by increasing the activity of the cells known as osteoblasts. The only such medication approved for treating osteoporosis is teriparatide (Forteo), a form of human parathyroid hormone (PTH). The drug comes as a daily injection, which can be self-administered.

PTH produces larger increases in BMD than antiresorptives do. It also improves bone microarchitecture (see photo below). However, it is prescribed for no more than about two years because its long-term safety and efficacy are unknown. Most experts recommend that antiresorptive drugs be stopped during PTH therapy and restarted after the course of PTH is complete.

At a scientific meeting sponsored by the American Society of Bone and Mineral Research, the National Institutes of Health, and several other organizations, researchers and clinicians discussed anabolic drugs and other potential advances in preventing fractures, including the following:

Strontium ranelate. Strontium ranelate is a compound that incorporates the element strontium, which is found in trace amounts throughout the skeleton. Results from Phase III trials conducted by French researchers suggest that strontium ranelate may reduce vertebral fractures about as well as bisphosphonates. The drug is believed to work by decreasing bone breakdown.

Statins. Laboratory, animal, and observational studies have suggested that statins (drugs that lower cholesterol) may be useful in preventing fractures. However, clinical trials have shown no consistent effect on bone mass or fracture rate. Some researchers think that higher doses than those used to lower blood lipids are required. For now, statins are not an appropriate osteoporosis treatment.

More vitamin D. New research indicates that to improve bone strength and reduce hip fractures, we need more vitamin D than the currently recommended level of 400 IU. The experts suggest getting 800-1,000 IU of vitamin D per day.

Oscillating plate. Experiments in animals and humans suggest that standing on a special, gently oscillating mechanical plate for 10-20 minutes per day can reduce bone loss and possibly stimulate bone formation. This could be a boon to people who may be too frail or incapacitated to exercise.