New selective estrogen receptor modulators (SERMs), new combinaton drugs, and more convenient dosing forms are under development for osteoporosis.
People with osteoporosis are benefiting from several new drugs that have reached the market in recent years, but the fight against the bone-thinning disorder is yet to be won. The National Osteoporosis Foundation estimates that one in every two women over the age of 50 will experience an osteoporosis-related fracture in her lifetime. Osteoporosis, a disease characterized by low bone mass and structural deterioration of bone tissue and an increased susceptibility to fractures, is the nation's most common bone disease, affecting more than 10 million people.
Another 34 million Americans are at increased risk for osteoporosis and fractures because of low bone mass. With 1.5 million osteoporotic fractures occurring in the United States every year, the direct medical costs are about $14 billion, which is estimated to swell to $50 billion by 2040.
With an aging population and increasing medical costs, osteoporosis research has experienced renewed attention from the medical community. Scientists are investing countless resources to better understand the disease at the cellular level. There are some 20 agents in all stages of development for the treatment of osteoporosis, according to the Pharmaceutical Research & Manufacturers of America in Washington, D.C.
"Osteoporosis is a silent disease that doesn't get as much attention as other conditions such as heart disease and diabetes. But it's an important women's health issue, and pharmacists can do so much to both prevent and treat it," said Amy Stump, Pharm.D., clinical assistant professor at the University of Wyoming School of Pharmacy.
New forms of existing products as well as novel agents are expected to reach pharmacies this year. Alendronate (Fosamax Plus D, Merck) was recently approved with a higher concentration of vitamin D3 (5,600 IU) for the treatment of osteoporosis in postmenopausal women and to increase bone mass in men with osteoporosis. Several of investigational agents are being studied in clinical trials.
The product closest to market is bazedoxifene (Viviant, Wyeth). The selective estrogen receptor modulator (SERM) was submitted to the Food & Drug Administration last year for the prevention of postmenopausal osteoporosis, and is currently in phase III clinical trials for the prevention of postmenopausal osteoporosis. If approved, bazedoxifene would be the first new SERM in a decade since raloxifene (Evista, Lilly) gained marketing clearance in 1997.
According to Kristi Kelley, Pharm.D., bazedoxifene could be an advancement over raloxifene. The phase III study showed that bazedoxifene was similar to raloxifene in preventing osteoporosis as measured by spinal bone mineral density tests. In addition, bazedoxifene-treated patients experienced fewer endometrium-related events than raloxifene.
"It's a more selective SERM, meaning it is more selective for the bone, so we may not see as many adverse effects such a breast tenderness or vaginal atrophy that you might see with other SERMs," said Kelley, associate clinical professor in the department of pharmacy practice at Auburn University in Auburn, Ala.
Despite the presence of a good endometrial safety profile, some researchers are more enthusiastic about the combination of bazedoxifene with estrogen than about bazedoxifene alone. Pharmaceutical manufacturer Wyeth is currently studying a combination product, called Aprela, for the treatment of vasomotor symptoms, vaginal atrophy, and prevention of osteoporosis.
"I think this combination could be fascinating," said Robert Lindsay, M.D., Ph.D., a professor of medicine at Columbia University, who presented phase II data about the combination product at the Endocrine Society's annual meeting held June 2 to June 5, in Toronto.
While he was unable to provide specific details about the trial results at press time, Lindsay said there could be some unique benefits from the combination of a SERM with estrogen because it could improve bone health while also reducing vasomotor symptoms, and without stimulating breast and uterine tissues.
"The Women's Health Initiative showed us that a lot of the problems with combination hormone therapies were related to progestin, particularly progesterone acetate, and this combination might give us endometrial protection because of the presence of bazedoxifene and eliminate the potentially harmful effects of progesterone acetate," said Lindsay.
Other SERMs in the advanced stages of research include arzoxifene (Lilly), which is being studied in comparison with raloxifene in about 300 postmenopausal women with osteoporosis to determine percentage change in the lumbar spine bone mineral density.
Lasofoxifene (Oporia, Pfizer/Ligand) was also studied in comparison with raloxifene and was originally expected to reach the market by now. In 2005, however, the FDA rejected the drug for approval as a preventive therapy for osteoporosis. Two studies reported in 2004 found that postmenopausal women treated with lasofoxifene had greater gains in spine bone mineral density, but not in hip bone mineral density compared with placebo-treated patients.
Among the promising compounds being tested are several that may be taken only once or twice a year. Pharmacy experts say that less-frequent dosing may help patients adhere to their therapies.
Adherence to osteoporosis treatments is poor, according to numerous studies, and is associated with increased fractures. One study reported that more than 50% of women with osteoporosis did not remain on prescribed bisphosphonate therapy, and another one found one-year adherence rates of less than 25% for all osteoporosis therapies.
"We all thought that the once-weekly and once-monthly bisphosphonates would be great for adherence strategies, but what we have found is that adherence to bisphosphonates is not that great if you do it once a month, once a week, or once a day," said Stump.
The bisphosphonate agent zoledronic acid (Zometa, Novartis), which is approved for the treatment for bone metastases related to cancer, is being tested in a lower-dose version as a once-yearly intravenous infusion for osteoporosis.
At the 2006 annual meeting of the American Society for Bone and Mineral Research, studies showed that a 15-minute, once-yearly infusion over three years with zoledronic acid compared with placebo decreased the frequency of spine fractures by 70% and hip fracture risk by 40%. The overall incidence of fracture was reduced by 24%. "That would put the drug in the same category with other bisphosphonates, but the advantage here is for those patients who have trouble complying with oral bisphosphonates," commented Marjorie Luckey, M.D., associate professor at Mount Sinai School of Medicine in New York and medical director of Saint Barnabas Osteoporosis and Metabolic Bone Disease Center in Livingston, N.J.
The most common side effects seen with zoledronic acid-treated patients were flu-like symptoms that lasted a few days. The symptoms of muscle and joint aches, fever, and headache were mild to moderate. Zoledronic acid is being further studied to determine whether three doses during a patient's lifetime would provide enough protection from fractures. "We don't know yet when the bone loss may start again, so follow-up studies are under way," said Luckey.
"The idea of getting an infusion once a year sounds like a great concept, but there are people with an aversion to needles, not to mention the question of who will administer the therapy and cost issues," explained Stump. "Ultimately, it may be good for a certain group of the population, but it's hard to say that something like that would revolutionize osteoporosis care."
Another agent in development that the pharmacy community is watching closely is denosumab. The agent would be the first in a new class of agents called RANK ligand receptors. Denosumab is a monoclonal antibody that binds to RANKL, a key mediator of the formation, function, and survival of osteoclasts, the cells responsible for resorbing or breaking down bone.
A 412-patient study showed that denosumab was overall more effective in increasing bone mineral density than alendronate. Denosumab was administered to patients as a subcutaneous injection at three- and six-month intervals over a 12-month period.
"The twice-yearly dosing would help bypass some patient compliance issues because it could be administered in a doctor's office," said Luckey.
While administering a drug once or twice a year is a significant development in osteoporosis therapy, Kelley cautioned that patients need to be reminded by doctors and pharmacists that osteoporosis needs year-round care.
"Pharmacists need to help patients have a clear understanding that they still have a condition for which they are receiving treatment and it is something that they have to do other things for than receive an occasional drug," said Kelley.
Osteoporosis drugs in the pipeline
There are currently more than 20 drugs being tested for the treatment of osteoporosis. Here are some therapies in the later stages of development.
|BA058||Human parathyroid hormone-related protein||Phase II||Radius|
|Bazedoxifene (Viviant)||SERM||NDA submitted||Wyeth|
|Bazedoxifene/conjugated estrogens (Aprela)||SERM plus estrogen||Phase III||Wyeth|
|Denosumab||Monoclonal antibody targeting RANK ligand||Phase III||Amgen|
|Lasofoxifene (Oporia)||SERM||NDA submitted||Pfizer/Ligand|
|Ostabolin-C||Parathyroid hormone analog||Phase II||Zelos Therapeutics|
|Preos||Parathyroid hormone analog||Phase III||NPS Pharmaceuticals|
|Zoledronic acid||Bisphosphonate (IV once yearly)||Phase III||Novartis|
THE AUTHOR is a pharmacy writer based in Brooklyn, N.Y.