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, a new study has found.
Bone density is the standard predictor of fracture risk associated with osteoporosis.
Results of the clinical trial, financed by the National Institutes of Health (NIH), are reported in the August 11 issue of the
New England Journal of Medicine (NEJM).
Increases in spine and hip bone density were much larger than those seen with either drug alone, and were 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 (PTH), a bone-building (anabolic) drug, for a year followed by a year on alendronate, marketed as Fosamax, a standard osteoporosis drug that inhibits bone degradation.
The study focused on 238 postmenopausal women with low bone density recruited from four US cities.
The form of PTH used in the study was PTH1-84, currently under consideration for Food and Drug Administration approval and closely related to the only anabolic drug now available for the treatment of osteoposoris, PTH1-34, marketed as Forteo.
Synergistic Action
Bisphosphonates, such as alendronate, are used by millions of women and belong to the class of antiresorptive drugs that act by slowing bone degradation, or resorption. Since PTH1-34 was approved in 2002, clinicians and researchers have been excited about the potential of anabolic drugs for osteoporosis treatment, particularly the potential for synergistic action when combined with antiresorptive drugs. But determining an effective combination has proved difficult in recent trials, said 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 spinal 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, sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the NIH, was carried out in New York, Pittsburgh, Boston and Bangor, Maine, and was coordinated by UCSF.
The study compared the PTH-alendronate sequence with three other regimens: taking PTH for a year followed by a year on a placebo; taking alendronate alone for two years; or taking PTH and alendronate for one year followed by a second year on alendronate.
The sequential PTH-alendronate treatment increased bone mineral density (BMD) significantly more than did the PTH-placebo treatment 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 measurement 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 10 percent of the women, which was usually corrected by reducing the dosage of calcium supplements, Black noted.
Parathyroid hormone's effect on bone has been known for more than 75 years, but development has been slow for a number of reasons, Black said. PTH1-34 is now approved for use for up to two years.
Although PTH is the first truly bone-building drug to be tested against osteoporosis, 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 PTH1-84 treatment followed by a year with the antiresorptive drug alendronate, the one-two approach can provide the largest gains in bone density yet available and at a savings, compared with 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 large trials are not feasible, Black said.
Questions Remain
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 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 antiresorptive 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 (parathyroid hormone and matching placebo), Merck (alendronate and matching placebo) and GlaxoSmithKline (calcium).
Additional funding for the study came from Merck.
Source: Wallace Ravven
