Nancy A. Melville

October 19, 2012

MINNEAPOLIS, Minnesota — A combination of the recently approved antiresorptive drug denosumab with the anabolic agent teriparatide is more effective in increasing bone mineral density (BMD) than either drug on its own, researchers reported here at the American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting.

Previous studies evaluating combinations of osteoporosis drugs, such as bisphosphonates and teriparatide, have failed to show any benefit over either drug alone. However, animal studies suggested that the teriparatide-denosumab combination might lead to better results in patients, according to study author Benjamin Leder, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, in Boston, and colleagues.

To investigate the combination in patients, the researchers enrolled 92 postmenopausal women in a 12-month open-label randomized controlled trial. The women, aged 51 to 91 years, were all at high risk for fracture and had gone at least 3 years since their last menstrual period.

Thirty-one women received teriparatide 20 mcg daily; 33 received denosumab 60 mg subcutaneously every 6 months; and 30 received both medications at the same dose and schedule as in the monotherapy arms. All participants also received calcium and vitamin D supplements to provide a total intake of 1200 mg and 400 IU, respectively.

At baseline, there were no significant differences in measurements of hip, spine, and 1/3 radius DXA BMD among the 3 patient groups. However, at 12 months, the researchers saw greater increases in total hip BMD (mean ± SD) in the combination group (4.9% ± 2.9%) than in either the teriparatide (0.7% ± 2.7%, P < .0001) or denosumab (2.5% ± 2.6%, P = .0001) group.

Increases in femoral neck BMD were also greater in the combination group (4.7% ± 4.3%) than in the teriparatide (0.8% ± 4.1%, P < .001) and denosumab (2.1% ± 3.8%, P = .013) groups.

Spine BMD also increased more in the combination group (9.1% ± 3.9%) than in either the teriparatide (6.2% ± 4.6%, P = .0005) or denosumab (5.5% ± 3.3%, P < .0001) group. BMD at the 1/3 radius increased in the denosumab (1.7% ± 3.2%) and combination groups (2.5% ± 2.8%) but decreased in the teriparatide group (-1.8% ± 3.6%, P < .001).

In terms of biochemical markers, the denosumab group showed more inhibition of the bone formation marker P1NP at 3 months than the other groups. However, the denosumab monotherapy and combination groups were similar at 12 months.

CTX, a key marker of bone resorption, was dramatically suppressed by as much as 80% in the denosumab-only and combination groups at 3 months, and the inhibition was maintained throughout the 12 months, with no differences between the 2 groups.

"While bone formation was suppressed in both the denosumab monotherapy and combination groups, the suppression was less in the combination group than denosumab alone, whereas bone resorption was totally and equally suppressed in the denosumab alone and combination groups," Dr. Leder said.

The study's findings show potentially improved treatment from the combination of the 2 drugs, he added.

"From [these findings], we conclude that unlike the combination of teriparatide and bisphosphonates, teriparatide and denosumab appear to have added effects on bone density."

The mechanism by which the 2 drugs work together to improve results remains to be seen, Dr. Leder noted. "The mechanism underlying these observations at this point remains unclear, but it may be related to the ability of denosumab to fully block teriparatide's proresorptive effects while still allowing for continued modeling-based bone formation and perhaps expansion of the anabolic window," he said.

If the results are confirmed in larger studies, "the combination of these 2 agents may eventually prove to be a beneficial treatment in patients who are at a particularly high risk of fracture," Dr. Leder said.

"These are wonderful results and were completely unpredicted by preclinical studies, which showed denosumab and [parathyroid hormone] failed to have adequate effects," said Serge Ferrari, MD, of the Service of Bone Diseases, Geneva University Hospital, in Switzerland.

Dr. Ferrari noted that one issue to consider is whether the effects are limited to any particular period.

"I guess the question is whether all of the effects occur in the very first few weeks, because animal studies have shown that once that window is closed, the effects are so minute that there is no productive activity, so it would be interesting to see whether [the effects occur] only in the first couple of months of combination and then if anything more happens."

Dr. Leder responded that "it would have been interesting to have that hyperacute 1 month time point of markers," but he noted that longer-term studies will also help shed light on the issue.

"We see in animal studies that much of what is going on does occur early, but there appears to be continued separation between months 3 and 12, and I think it will also help us answer whether most of the differences are actually attributable to the first 3 months when we see what goes on between 12 and 24 months."

An optional 12-month extension of the trial is currently underway.

Dr. Leder disclosed relationships with Amgen and Merck. Dr. Ferrari has disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting. Abstract 1097. Presented October 14, 2012.