Aug. 17, 2005 Postmenopausal women who took a bone-building drug for one year followed by a year on a standard drug that fights bone loss experienced greater increases in bone density than has been reported from any other drug regimen, an NIH-sponsored study has found. Bone density is the standard predictor of fracture risk associated with osteoporosis.
The clinical trial results are reported in the August 11 issue of The New England Journal of Medicine.
Increases in spine and hip bone density were much larger than those seen with either drug alone, and are larger than those seen with any other osteoporosis drug over two years, the scientists reported.
Senior author and lead investigator of the study is Dennis Black, PhD, professor of epidemiology and biostatistics at UCSF.
The randomized, double-blind trial investigated the effectiveness of taking a form of parathyroid hormone, or PTH, a bone-building or anabolic drug, for a year followed by a year on alendronate, a standard osteoporosis drug that inhibits bone degradation, marketed as Fosamax.
Known in the field as the PTH and alendronate (PaTH) trial, the study focused on 238 post-menopausal women with low bone density recruited from four U.S. cities.
The form of PTH used in the study was PTH-1-84, currently under consideration for FDA approval and closely related to the only anabolic drug now available, PTH 1-34 under the name Forteo.
Bisphosphonates, such as alendronate, are used by millions of women and belong to the class of anti-resorptive drugs that act by slowing bone degradation, or resorption. Since the first anabolic drug, PTH 1-34, was approved in 2002 clinicians and researchers have been excited about their potential, particularly the potential for synergistic action when combined with anti-resorptive drugs. But determining an effective combination has proved difficult in recent trials, said UCSF’s Black.
"Our four-city clinical trial shows convincingly that the back-to-back combination of these two classes of drugs is superior to other ways of combining these drugs and provides sustained increases in bone density," he said.
For example, with the use of powerful CT techniques that provide 3-D views of bone density, the researchers found a 31 percent increase in spine bone density in the PTH-alendronate patients compared with only 14 percent in those taking PTH followed by a placebo for a year.
The cooperative study was sponsored by the National Institute of Arthritis, Musculoskeletal and Skin Disorders (NIAMS), part of NIH, and was carried out in New York, Pittsburgh, Boston and Bangor, Maine and coordinated by UCSF.
The study compared the PTH-alendronate sequence against three other regimens: taking PTH for a year followed by a year on a placebo; taking alendronate alone for two years, or one year on PTH and alendronate followed by a second year on alendronate.
The PTH-alendronate treatment increased bone mineral density (BMD) significantly more than PTH-placebo in all bones studied and generally increased BMD more (but not always significantly so) than the other two treatments, the scientists reported.
Key bone density measurements came from the CT technique’s 3-D bone density capability, considered more reliable than two-dimensional information provided by older, dual energy X-ray techniques.
The main notable side effect from the first year on PTH was a slightly elevated calcium serum level in about ten percent of the women, which was usually corrected by reducing calcium supplements, Black noted.
Parathyroid hormone’s effect on bone has been known for over 75 years, but development has been slow for a number of reasons, Black said. PTH 1-34 is now approved for use for up to two years.
Although PTH is the first truly bone-building drug to be tested against osteoporosis, and is approved for up to two years, treatment with it is quite costly: about $7,000 per year. Since the new study shows strong gains in bone density from just one year of PTH 1-84 treatment followed by a year with the anti-bone resorption drug alendronate, the one-two approach can provide the largest gains in bone density yet available and at a savings compared to two years on parathyroid hormone, Black noted.
Very large, costly clinical trials would be required to study the effect of different drug regimens on fracture risk directly, but smaller studies of bone density – particularly with the newer, more refined CT techniques – are widely regarded as a reliable indicator of treatment efficacy when such trials are not feasible, Black said.
Among the remaining questions about treatment to prevent or reduce osteoporosis, Black said, one key study would be to determine if parathyroid hormone is still effective following bisphosphonates, rather than vice versa --since bisphosphonates currently are the standard therapy. A second study in the same issue of NEJM addresses this basic question over an 18-month period, showing that PTH remains effective but that its effect is blunted when used after alendronate.
"While PTH following alendronate or in concurrent combination with alendronate may be less effective than PTH alone, our study clearly shows that alendronate following PTH provides an additive, perhaps synergistic effect," Black concluded. "In this case one plus one may equal three or even four. Use of anti-resorptive drugs following PTH seems to be the most effective way to combine these two classes of drugs." Other principal investigators in the study were John Bilezikian, MD, professor of medicine and pharmacology and director of the Metabolic Bone Disease Program, Columbia University Medical Center; Kristine Ensrud, MD, associate professor of medicine, University of Minnesota; Susan Greenspan, MD, professor of medicine, University of Pittsburgh Medical Center; Cliff Rosen, MD, director, Maine Center for Osteoporosis Research and Education, University of Maine, Orono; and Joan McGowan, PhD, project director, NIAMS. Other co-authors include Thomas F. Lang, PhD, associate professor of radiology at UCSF.
Study medications were provided by NPS Pharmaceuticals (parathryorid hormone and matching placebo), Merck (alendronate and matching placebo), and GlaxoSmithKline (calcium).
Additional funding for the study came from Merck. ###
The study’s authors report having received consulting, lecture or grant support as follows:
Black: Roche, Merck, Novartis and NPS Pharmacueticals. Bilezekian: NPS Pharmaceuticals, Merck, Eli Lilly Aventis, and the Alliance for Better Bone Health. Ensrud: Pfizer, Eli Lilly and NPS Pharamceuticals. Greenspan: Merck, NPS Pharmaceuticals, Novartis and Aventis. Lang: Amgen, Aventis, Kaiser Permanente, NPS Pharmaceuticals and Aventis, and also holds stock in GlaxoSmithKline, Pfizer and Merck. Rosen: Quintiles Canada, Wyeth-Ayerst, Novartis, Merck, Eli Lilly and Aventis.
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