Osteoporosis seems to be featured in the news almost daily. What are some of the future treatments? Are there any new drugs that are being evaluated in clinical trials for the treatment of osteoporosis?

Osteoporosis and bone health are receiving much more notice in the news. Studies of the bones of certain animal species are spurring newer studies to see if those results are applicable to humans. There are several examples. The majority of growth in the bones of lambs takes place during the night when the lambs are sleeping, presumably when there is less pressure on their bones. This might account for children's complaints of growing pains at night. Purring is believed to be one of the factors responsible for the fast healing experienced by cats. Sound treatment in the same sound range as a cat's purr is being investigated to improve bone growth in older adults.

The role of fluoride in building good bone has been evaluated in large scale studies, but with discouraging results. Sodium fluoride as a supplement in baby vitamins and in drinking water has been around for years, and is responsible for helping to prevent tooth cavities. It is not clear from the studies if fluoridated drinking water affects bone mineral density. In one study of postmenopausal women in the Midwest, hip and vertebral fractures were decreased but wrist fractures were increased. A certain amount of fluoride is important for strong bone development, but excessive amounts are believed to cause the bones to become brittle because fluoride increases bone density but produces bone of very poor quality. Fluoride supplements are not currently recommended for the treatment of osteoporosis.

Livial (tibolone) is a synthetic steroid compound that has estrogen-, testosterone-, and progestin-like activity but does not contain any of these hormones. Although prescribed in 70 other countries, the FDA has not approved it, so it is not available in the United States. Studies have shown that tibolone used by postmenopausal women can increase bone mineral density and decrease bone turnover. Tibolone also significantly reduces hot flashes in postmenopausal women and is being studied as a medication to treat sexual dysfunction because of its androgenic effects. In a study of older women, tibolone was shown to reduce fracture risk at rates comparable to those of bisphosphonates, raloxifene, and hormone therapy. In this same study, tibolone was also shown to reduce the risk of invasive breast cancer and colon cancer. Since many women are seeking an alternative to estrogen therapy, it was hoped that tibolone would be approved in the United States; however, the FDA voted against its approval. Like all drugs, tibolone has some risk—it has been shown to increase the risk for stroke.

Osteoprotegerin is a substance known to decrease bone breakdown by preventing osteoclast formation (the cells that break down bone). Some research shows that human estrogen (17-|3 estradiol) and dietary phytoestrogens (see Question 54) can increase levels of osteoprotegerin and therefore reduce bone breakdown. Further research is needed before increased phytoestrogen intake can be recommended. A synthetic isoflavone (one of the phytoestrogens) called ipriflavone is still being studied for its long-term effects, because while there is evidence that it increases bone density, other evidence shows that ipriflavone may cause abnormally low white blood cell counts.

AMG-162, now known as denosumab, recently completed phase III clinical trials and was reviewed in October of 2009 by the FDA for approval for post-menopausal osteoporosis treatment and for treatment of bone loss from hormonal ablation therapy for breast or prostate cancer. It is also being investigated for treatment of rheumatoid arthritis, bone metastases, and multiple myeloma. Denosumab is a monoclonal antibody that acts like osteoprotegerin and interferes with the effects of a protein (RANK ligand). The RANK ligand protein causes bone loss. By interfering with this protein, denosumab inhibits the cells that cause bone breakdown (osteoclasts) and thus allows greater bone formation. Denosumab is administered by injection into the fat tissue (subcutaneous tissue) like Forteo. Unlike Forteo, which is given daily over a period of several months and only to those who do not respond to first-line treatment, denosumab is a first-line treatment agent and only needs to be given once every 6 months. The medication showed a significant increase in bone density and was well tolerated in phase III clinical trials. It also compared favorably with alendronate for both efficacy (bone density, serum markers, and urinary markers) and side effects in research studies. The FDA requested additional information for denosumab, which has a proposed trade name of Prolia. This information will be provided by the pharmaceutical manufacturer (Amgen) and approval is anticipated in 2010. Prolia will provide an important alternative for osteoporosis treatment. The subcutaneous injection is almost painless and can be self-administered at home or given at your clinician's office. It may be easier to remember than a daily or monthly pill and does not need the complex regimen required for taking oral bisphosphonates.

Another human monoclonal antibody, AMG 785, has shown promise in increasing the rate of bone formation. This works by interfering with the usual processes that limit bone formation in the body. A phase II clinical trial is expected for further evaluation of this possible therapy.

Preos, another parathyroid hormone in development, is being investigated for its effects on building bone. It is being evaluated for use in a cyclic dose (once-a-week injection after 3 months of daily injections) and also for its effects when used in combination with other therapies such as bisphosphonates.

Pamidronate, another bisphosphonate, is currently used in the treatment of high calcium levels and bone problems associated with some cancers. It is being studied as a treatment for osteoporosis, particularly in the population undergoing dialysis. Men and women who have chronic kidney disease have significant problems with calcium regulation and bone loss. Pamidronate has been effective in increasing bone density in healthy postmenopausal women when it was administered every 3 months, and studies have shown that a small protective effect on bone density persists after the medication is stopped. Pamidronate is usually given intravenously.

Although not yet approved by the FDA for use in the United States, Strontium ranelate, (Protelos, developed by Servier), a radionuclide, has been studied in Europe and Australia. Research shows that oral strontium ranelate not only increases BMD but also decreases both vertebral and nonvertebral fractures. This new medication represents an alternative for postmenopausal women who cannot tolerate other treatments for osteoporosis. It works by both increasing bone formation (increasing osteoblast activity) and reducing bone resorption (decreasing osteoclast activity). Strontium ranelate is taken orally and is already approved for use in several other countries, including Europe. Other forms of strontium— strontium malonate, strontium carbonate, and strontium citrate—are also being studied for use.

Arzoxifene, a new SERM or estrogen agonist/antagonist being developed by Eli Lilly and Co., completed phase III clinical trials in 2009 with promising results. In this study (called "FOUNDATION") women received 20 mg of the medication each day, plus calcium 500 mg. After 2 years, results indicated that bone mineral density had a statistically significant increase of 2.9% at the spine and 2.2% at the hip over placebo. In another study (called "NEXT"), arzoxifene was compared to Evista (another Lilly product) and demonstrated higher increases in BMD in the hip, spine, and femoral neck area. Arzoxifene was initially developed as a possible breast cancer medication, but tamoxifene proved better at reducing recurrence and women on tamoxifene were disease free longer. An ongoing study (called "GENERATIONS"), is further evaluating the effects of arzoxidene on bone, breast tissue, heart disease, and the uterus. Results from GENERATIONS are expected late in 2009.

Another new possibility is a combination of medications manufactured in one tablet. One such combination currently under investigation combines estrogen and a new estrogen agonist/antagonist. While taking Evista (raloxifene) and estrogen together is contraindicated because the medications compete for the same receptor sites, new estrogen agonists/antagonists that do not carry this contraindication are under investigation. A new estrogen agonist/antagonist that is more selective is being evaluated for combination with estrogen (in the same pill) for the treatment of postmenopausal osteoporosis in women who are also experiencing menopausal symptoms.

One of the new, more selective estrogen agonist/antagonists has shown success in reducing fractures. Bazedoxifene (BZA) is being evaluated by the FDA for osteoporosis prevention and treatment. Research has shown beneficial reductions in fractures (40% fewer fractures at the spine and 46% fewer on nonspine bones) without increasing risks for breast or endometrial cancers. BZA has also been studied in combination with conjugated equine estrogens as a tissue-selective estrogen complex (TSEC). So far results look promising, as this combination reduces symptoms associated with menopause, effectively preserves and strengthens bone, and does not increase risks for breast or endometrial cancer. This combination has also been shown to improve vaginal symptoms as well as sexual function and enjoyment in postmenopausal women.

Lasofoxifene is another new EAA that has been shown to slow bone turnover and increase bone density. Lasofoxifene reduced fractures in the spine and other areas and did not increase the risk for stroke, heart disease, or endometrial cancer. It somewhat increased the risk for blood clots, however it also reduced the risk for breast cancer. While still under investigation, this agent may become available in the future for osteoporosis management.

Therapies aimed at interrupting the bone resorption process in new ways are also being developed. One such compound, an integrin antagonist, currently called L-000845704, works by interfering with how osteoclasts attach to the bone surface. When osteoclasts cannot effectively attach to bone, the process of resorption is slowed. This compound increased bone density and decreased bone markers in a study done with postmenopausal women. Another compound, called odanacatib, is a selective inhibitor of cathepsin K. Cathepsin K is produced by osteoclasts to break down bone. Odanacatib inhibits bone resorption by interfering with the action of cathepsin K.

Other developments in osteoporosis treatment have to do with new ways to give established medications. For example, an oral form of salmon calcitonin is being evaluated. Salmon calcitonin is already available in nasal spray and injectable forms. Additionally, a transdermal form of human parathyroid hormone (PTH 134, Forteo) has shown some promise in increasing bone density. PTH 1-34 is also being evaluated for administration by mouth, nasal spray, and inhalation.

It's also important to keep your eyes and ears open for health care developments that are not specifically related to osteoporosis. For example, the statin drugs long used as treatment for high cholesterol levels may still prove to increase bone density, an indirect and positive result of drugs intended to lower unhealthy levels of cholesterol. And there is news in the nutrition world almost daily. For example, a recent study on rats showed less bone loss in the rats fed a particular substance (GPCS) found in white onions. Also, people who have gluten intolerance (celiac disease) have high rates of osteoporosis because they cannot effectively absorb calcium and vitamin D through their intestines. The gluten intolerance causes diarrhea, making it difficult for nutrients to be absorbed from the intestines because foods move through too quickly. When placed on gluten-free diets, the diarrhea stops and normal amounts of calcium and vitamin D can be absorbed, thereby improving bone density.

There is more osteoporosis news for men, too, particularly for those over the age of 65 who are trying to lose weight. Men in this age range should be wary about weight loss because it is associated with bone loss in the hip. Their clinicians should be monitoring both weight loss and bone loss. Although further study is needed, the potential for bone loss and the increased risk of fracture should be a topic of discussion between you and your clinician when weight loss is being recommended.

Bones will still require, at the very least, calcium, vitamin D, and exercise to stay strong.

It is quite common for an aging spine to look like the one featured in Figure 18, but it's more difficult to imagine that this spine can eventually look like the one in Figure 19. There is no instant cure for a disease that can cause such a deformity. Even future treatments will not be a cure. Bones will still require, at the very least, calcium, vitamin D, and exercise to

Many women have this degree of kyphosis. It can progress to a severe form in which organs are com¬pressed and disability can be significant, as shown in Figure 19. Photo courtesy of Janet Wise.

Figure 18 Many women have this degree of kyphosis. It can progress to a severe form in which organs are compressed and disability can be significant, as shown in Figure 19. Photo courtesy of Janet Wise.

Woman with severe kyphosis (also known as

Figure 19 Woman with severe kyphosis (also known as "dowager's hump"). © Bill Aron/PhotoEdit, Inc.

stay strong. As addressed in Part 3, there are lifestyle changes and various therapies that can improve your bones now without waiting for researchers to develop future treatments.

Where can I go for more information?

While many of your questions have been answered in this book, you likely will want to look for additional information on osteoporosis, osteopenia, and other health-related topics. Refer to Appendix B and the bibliography for a listing of research and resources that may be helpful as you continue to improve your overall health as well as that of your bones.

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