PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.
“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in.
“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”
However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”
The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.
Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).
“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also showed signs of remodeling,” she said. “So, there was no more erosive progression.”
The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.
By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.
Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.
The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.
In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.
“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”
In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.
The second year of the open-label extension study should clarify the pain outcomes, she said.
In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.
The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”
To clarify the pain outcomes, he said, “They’re going to have to work on the data.”
Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.