Maintaining healthy bone density requires a balance between two natural processes, the breakdown or resorption of old bone and the formation of new bone. When this balance shifts toward breakdown, bones become less dense and more prone to fracture. Although this condition, called osteoporosis, is seen most frequently in postmenopausal women, it also occurs in men, sometimes as a result of medications that interfere with normal hormone production.
Alendronate, one of a type of drugs called bisphosphonates, is FDA approved to treat osteoporosis in men and women and works by slowing bone resorption. Injections of PTH, a treatment initially developed through MGH research, increase bone formation and were approved by the FDA in December 2002 to treat osteoporosis in men and women. Since the two medications work in complementary fashion to increase bone density, a treatment strategy combining both drugs appeared promising.
"While it seemed likely that combining these two medications would increase bone density more than giving either medication alone, animal studies investigating combination therapy gave conflicting results," says Joel Finkelstein, MD, the MGH endocrinologist who led the study. "Still, we did expect that the combination group would do best, so the actual outcome was a surprise."
The MGH researchers began two studies of combination therapy - one in postmenopausal women, which is not yet complete, and the current study in men with osteoporosis. The 83 men were randomly assigned to three groups: one received daily PTH injections, one was treated with alendronate and the third received both therapies. During the 30-month study, four key bone density measurements - lower spine, the neck of the femur (hip bone), the shaft of the radius (forearm bone) and the total body - were taken every 6 months. Spine bone density was also measured by computerized tomography.
Although combination therapy improved bone density in the spine more than alendronate alone, neither improved spine bone density as much as PTH alone. Similar results were seen at the neck of the femur. At the shaft of the radius, alendronate or combination therapy led to a slight increase in bone density while PTH produced a slight decrease. There were no significant differences among the three groups in effects on total body bone density. The identical MGH study in osteoporotic women is still in progress, but its preliminary results reported last year were similar.
The researchers believe that the reduced effectiveness of combination therapy may be because alendronate's suppression of bone resorption interferes with a process required for bone regrowth. "Bone resorption could release growth factors that stimulate bone formation and are necessary to get the full effect of PTH," says Finkelstein, an associate professor of Medicine at Harvard Medical School. "At this time, we are generally recommending that anyone taking PTH use it by itself and that anti-resorptive therapies be stopped before starting PTH therapy."
Robert Neer, M.D., senior author of the study and director of the MGH Osteoporosis Center, notes that alternative explanations are possible, since combining PTH with other agents that suppress bone resorption has been successful in animals.
The authors add that further research is needed to determine the best bone-density-restoring strategies for individual patients and to improve understanding of the long-term effects of PTH treatment. Additional studies are needed to determine if PTH therapy reduces fractures more when given alone, or when given in combination with an anti-resorptive drug.
The study's co-authors are Annmarie Hayes, MSN, RNC, NP; Joy Hunzelman, MSN, NP; and Jason Wyland, of the MGH Endocrine Unit; and Hang Lee, PhD, MGH Biostatistics Unit. The research was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.