The RANKL inhibitor denosumab (Prolia, Amgen) is more efficacious than the bisphosphonate risedronate in boosting bone mineral density (BMD) at the lumbar spine in patients just starting or continuing steroid therapy, a new international, randomized, double-blind study indicates.
“Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and increases the risk of vertebral and nonvertebral fractures,” Kenneth Saag, MD, University of Alabama at Birmingham, and colleagues write.
“The 12-month results of this 24-month study showed that denosumab was superior to risedronate, a commonly used bisphosphonate for glucocorticoid-induced osteoporosis, in increasing bone mineral density at the lumbar spine, [and] the two treatments groups had similar safety profiles,” investigators add.
The study was published online April 6 in The Lancet Diabetes & Endocrinology.
In an accompanying editorial, Elena Tsourdi, MD, PhD, and Lorenz Hofbauer, MD, PhD, of Technische Universitat Dresden Medical Center, Germany, say these “results are in line with those of previous head-to-head studies.”
The latter have showed the potency of denosumab in increasing BMD compared with alendronate in postmenopausal osteoporosis and delaying skeletal-related events compared with zoledronic acid in patients with bone metastases in advanced cancer, they note.
Yet they caution that 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.”
Denosumab is currently indicated in the United States for use in postmenopausal women with osteoporosis at high risk for fracture (defined as having multiple risk factors for fracture, a history of osteoporotic fracture, or having failed or being intolerant to other available osteoporosis therapy). It is also approved for treatment to increase bone mass in men with osteoporosis at high risk for fracture. It is indicated for the treatment of glucocorticoid-induced osteoporosis in Canada, but not in the United States.
Denosumab: Useful Addition for Steroid-Induced Osteoporosis
In total, 795 patients from 79 centers were randomized in the noninferiority study.
“Patients who had been taking glucocorticoids for at least 3 months were classed as glucocorticoid continuing; those who were taking glucocorticoids for less than 3 months were classed as glucocorticoid initiating,” the authors note.
Some 505 patients made up the glucocorticoid-continuing subpopulation, and the remaining 290 were classed as glucocorticoid initiating.
A similar number of patients were randomized to denosumab (398) or risedronate (397).
Participants younger than age 50 years had to have a history of an osteoporosis-related fracture. Patients age 50 years and older continuing glucocorticoid treatment had to have a T score of -2.0 or less (at the lumbar spine, total hip, or femoral neck) or -1.0 or less (if they had a history of an osteoporosis-related fracture).
Patients randomized to denosumab received 60 mg subcutaneously every 6 months plus oral placebo daily for 24 months. Those assigned to risedronate received 5 mg/day plus subcutaneous placebo every 6 months for 24 months.
All patients took at least 1000 mg/day of calcium and at least 800 IU/day of vitamin D.
“The primary outcome was noninferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months,” the authors note.
At 12 months, investigators found that denosumab was both noninferior and superior to the bisphosphonate in terms of change from baseline in lumbar spine BMD in both the glucocorticoid-continuing and glucocorticoid-initiating subpopulations.
| Group | Lumbar spine BMD: Denosumab | Lumbar spine BMD: Risedronate | P |
|---|---|---|---|
| Glucocorticoid continuing, % | 4.4 | 2.3 | <.0001 |
| Glucocorticoid initiating, % | 3.8 | 0.8 | <.0001 |
Denosumab was similarly superior to risedronate for BMD endpoints at the lumbar spine, total hip, and femoral neck in both the glucocorticoid-continuing and glucocorticoid-initiating groups.
At 12 months, the difference in lumbar spine BMD between denosumab and risedronate in the glucocorticoid-continuing group was 2.2% in favor of denosumab and 1.5% and 1% for the total hip and femoral neck, respectively, again in favor of denosumab.
For the glucocorticoid-initiating group, the difference in lumbar spine BMD between the two groups was 2.9% in favor of denosumab and 1.5% and 1.1% for the difference in total hip and femoral neck BMD, respectively, again in favor of denosumab.
The incidence of adverse events was similar in both treatment groups with no signal of an increased risk of serious infection in high-risk subgroups taking denosumab who also required concomitant biologic or immunosuppressant therapy, investigators point out.
“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,” they state.
“[And we suggest that] denosumab could be a useful addition to the treatment armamentarium for glucocorticoid-induced osteoporosis,” they conclude.
Important Step Towards Improved Therapy, but BMD Not an Ideal Surrogate
In their editorial, Tsourdi and Hofbauer agree that the current study “is an important step towards improved treatment options for glucocorticoid-induced osteoporosis.”
Nevertheless, as well as BMD not being an ideal surrogate for studies of patients with steroid-induced osteoporosis, they note that the current study was not designed to detect differences in fracture rates between participants treated with denosumab or risedronate, even though equal percentages of patients — 6% in both treatment arms — experienced an osteoporosis-related fracture during the 12-month follow-up.
Similar percentages of patients also developed new or worsening vertebral fractures over the same follow-up period.
Tsourdi and Hofbauer also point out that physicians still don’t know how long to continue treatment with denosumab, as investigators were only able to report results out to 12 months.
“Many patients require long-term, if not life-long glucocorticoid therapy…and thus need concomitant long-term bone-protective therapy,” the editorialists write.
And because discontinuation of denosumab has been shown to lead to a rapid decrease in BMD, at least among postmenopausal women, “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,” Tsourdi and Hofbauer suggest.
They also stress that physicians should assess fracture risk in patients who discontinue glucocorticoid therapy, follow patients with glucocorticoid-induced osteoporosis regularly in order to tailor therapy to their fracture risk, and monitor treatment adherence.
“Regular follow-up also allows clinicians to reassure patients that the benefits of long-term antiresorptive therapy by far outweigh the risk,” the editorialists emphasize — a recent challenge in light of continuing fears about the long-term safety of bisphosphonates that is undermining osteoporosis treatment worldwide, they point out.
Studies from Western countries indicate that less than 50% of patients for whom guidelines recommend treatment for glucocorticoid-induced osteoporosis actually receive some form of bone-specific therapy, and that adherence to daily therapy is often poor.
The study was funded by Amgen. Saag declares receiving research grants and consulting fees from Amgen, Merck, and Radius, as well as consulting fees from Lilly. Tsourdi reports receiving honoraria for lectures from Amgen. Hofbauer reports receiving honoraria for lectures from Alexion, Amgen, Merck, Sandoz, Shire, and UCB. Hofbauer’s institution has received grant support from Amgen and Novartis.
Lancet Diabetes Endocrinol. Published online April 6, 2018. Abstract, Editorial
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