April 19, 2018
By Reuters Staff
NEW YORK (Reuters Health) - The RANKL inhibitor denosumab is superior to the bisphosphonate risedronate in increasing bone-mineral density (BMD) at the lumbar spine in patients just starting or continuing steroid therapy, according to 12-month results of a 24-month randomized controlled study.
"Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and increases the risk of vertebral and nonvertebral fractures," write Dr. Kenneth Saag from the University of Alabama at Birmingham and colleagues in a paper online April 6 in Lancet Diabetes & Endocrinology. "However, treatment rates are low, despite the availability of therapies."
The researchers compared the efficacy and safety of denosumab and risedronate in 759 patients with glucocorticoid-induced osteoporosis at 79 centers in Europe, Latin America, Asia and North America. Of these, 505 patients were on at least 7.5 mg prednisone daily (or equivalent) for at least three months (glucocorticoid-continuing) and 290 were on steroids for less than three months (glucocorticoid-initiating) before screening.
The patients were on glucocorticoid therapy for conditions such as rheumatological diseases (>70%), respiratory disorders and gastrointestinal disorders.
They were randomly allocated to receive either 60 mg subcutaneous denosumab every six months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every six months for 24 months.
At 12 months, denosumab was superior to risedronate in terms of lumbar spine BMD in both glucocorticoid-continuing (4.4% vs. 2.3%, P<0.0001) and glucocorticoid- initiating (3.8% vs. 0.8%, P<0.0001) patients.
Denosumab was also superior to risedronate in terms of total hip BMD in both glucocorticoid-continuing (2.1% vs. 0.6%, P<0.0001) and glucocorticoid-initiating (1.7% vs. 0.2%, P<0.0001) patients.
"These results are in line with those of previous head-to-head studies that showed the potency of denosumab in increasing bone mineral density compared with alendronate in postmenopausal osteoporosis and in delaying skeletal-related events compared with zoledronic acid in patients with bone metastases in advanced cancer," note the authors of a comment published with the study.
"Possible explanations for the superior efficacy of denosumab might include the different mode of actions of these antiresorptive drugs and the subcutaneous administration of denosumab, which bypasses the variability of gastrointestinal absorption," write Dr. Elena Tsourdi and Dr. Lorenz Hofbauer of Technische Universitaet Dresden Medical Center in Germany.
Both drugs had a similar safety profile. The most common adverse events were back pain (18 patients in the denosumab group and 17 in the risedronate group) and arthralgia (17 patients in the denosumab group and 21 in the risedronate group). Serious infection occurred in 17 patients in the denosumab group and 15 in the risedronate group.
"To our knowledge, ours is the first large, randomized controlled trial of denosumab in patients with glucocorticoid-induced osteoporosis who were either prevalent glucocorticoid users or newly initiating glucocorticoid therapy," Dr. Saag and colleagues write. The findings suggest that denosumab "could be a useful addition to the treatment armamentarium for glucocorticoid-induced osteoporosis," they conclude.
Drs. Tsourdi and Hofbauer note that the trial was not powered to detect differences in fracture rates between the denosumab and risedronate group, and BMD is "not the ideal surrogate for trials in patients with glucocorticoid-induced osteoporosis, because it underestimates fracture risk in view of the extraskeletal adverse effects of glucocorticoids on muscle function and falls."
Also, the data are for only the first 12 months of denosumab treatment. The question of how long denosumab should be used for remains unanswered, they say.
"Many patients require long-term, if not life-long glucocorticoid therapy (eg, those with some autoimmune diseases or who have undergone allogeneic transplantation), and thus need concomitant long-term bone-protective therapy," they point out.
They also caution that in postmenopausal osteoporosis, discontinuing denosumab leads to a rapid decrease in BMD. "This rebound effect after denosumab discontinuation, which is accompanied by upregulation of bone turnover markers, should guide clinical judgement against stopping denosumab in patients continuing glucocorticoid treatment," write Dr. Tsourdi and Dr. Hofbauer.
"In patients discontinuing glucocorticoids, assessment of fracture risk should be done. Overall, Saag and colleagues' study is an important step towards improved treatment options for glucocorticoid-induced osteoporosis," they conclude.
The study was funded by Amgen, which markets denosumab as Prolia. Dr. Saag and Drs. Tsourdi and Hofbauer have disclosed financial relationships with the company.
Lancet Diab Endocrinol 2018.
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