Romosozumab Safe in Osteoporosis With Mild-Moderate Renal Disease

Nancy A. Melville

October 07, 2019

ORLANDO, Florida — The monoclonal antibody romosozumab (Evenity, Amgen) shows no significant differences in efficacy and safety in the treatment of osteoporosis across different stages of kidney disease.

However, there were not enough people in the study to draw any conclusions on use of the agent in those with severe renal impairment, said Paul D. Miller, MD, medical director of the Colorado Center for Bone Research, Lakewood, when reporting the findings here at the American Society for Bone and Mineral Research (ASBMR) 2019 Annual Meeting.

"The key message from these findings is romosozumab is safe and effective down to an estimated glomerular filtration rate (eGFR) of 30 mL/min, considered the low end of moderate chronic kidney disease (CKD)," Miller told Medscape Medical News.

"At least down to (that level), it seems effective in reducing fractures across the board and also had no effect on kidney function, and I think that's reassuring," he added.

Romosozumab was approved in the United States in April for the treatment of osteoporosis in postmenopausal women with a history of osteoporotic fracture or multiple risk factors for fracture, or for those who have failed or are intolerant to other osteoporosis therapies.

Asked for comment, Thomas L. Nickolas, MD, a nephrologist and associate professor of medicine at Columbia University Medical Center, New York City, noted that the drug does have a warning label about risk for cardiovascular events, required as part of the approval.

For this reason, and the fact that "cardiovascular events are in fact the number one cause of mortality in renal patients, I would be very uncomfortable giving patients with severe CKD this drug," he told Medscape Medical News.

Post-Hoc Analysis of FRAME Study by Renal Status

Although CKD is very common in postmenopausal women with osteoporosis, a clinical challenge is that bisphosphonate drugs often used as first-line treatment are generally contraindicated in patients with compromised kidney function, specifically those with eGFR < 35 mL/min.

However, unlike bisphosphonates, romosozumab, an antisclerostin antibody that increases bone formation, is not cleared through the kidneys and could therefore be a potentially useful alternative treatment option.

To evaluate the drug's effects in people with varying degrees of CKD, Miller and colleagues conducted a post-hoc analysis of the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME) study, which included 7180 postmenopausal women with T-scores of –2.5 to –3.5 at the total hip or femoral neck.

Participants were randomized to 12 months of treatment with monthly injections of romosozumab 210 mg or placebo. FRAME was first reported in 2016.

For the current analysis, patients were categorized according to CKD stage: normal renal function (eGFR ≥ 90 mL/min; n = 848), mild renal failure (eGFR 60–89 mL/min, CKD stage 2; n = 4939), moderate renal failure (eGFR 30–59 mL/min, CKD stage 3; n = 1360); or severe renal failure (eGFR 15–29 mL/min, CKD stage 4; n = 18).

Most patients (88%) had mild or moderate renal insufficiency at baseline, while just 0.3% had severe renal insufficiency.

Overall, the improvements in bone mineral density (BMD) in patients treated with romosozumab after 12 months were significantly higher for the lumbar spine, total hip, and femoral neck compared with placebo.

There were no significant changes to the improvements in any of the BMD measures associated with baseline eGFR ranges.

Likewise, the incidence of new vertebral fractures were similar across levels of CKD for those in the romosozumab vs placebo groups, including those with normal renal function (0.5% vs 3.0%), CKD stage 2 (0.4% vs 1.5%), and CKD stage 3 (0.6% vs 2.1%).

Importantly, there were also no significant differences in rates of adverse events, serious adverse events, or incidence of positively adjudicated cardiovascular events between the treatment groups for all eGFR categories.

There was one case of hypocalcemia in a patient in the romosozumab group with CKD stage 2 at baseline, and there were mild-to-moderate calcium decreases among four patients in the placebo group and 13 patients in the romosozumab group.  

Approximately 80% of patients in each group had no significant changes from baseline in eGFR over the 12 months, and any changes that did occur were similar between the romosozumab and placebo groups, Miller noted.

If Renal Decline Is Not Age-Related, Questions Remain

Miller reiterated that just 18 participants had severe CKD, and so the verdict is still out on those patients.

He also explained that most participants had reduced kidney function that was age-related, and so "a remaining question" is when patients don't have age-related declines in eGFR.

"For instance, in patients with kidney disease and diabetes, I think we still have to be cautious [in making recommendations for those patients] because we don't have enough data and those groups need to be further studied," he said.

Kristina Akesson, MD, PhD, Lund University, Malmo, Sweden, who comoderated the session, said: "I think the presented study is valuable. What I would also have liked to see was splitting CKD stage 3 into 3a (eGFR 45-60 mL/min) and 3b (30-45 mL/min)."

"Other studies are indicating that change in kidney function related to age begins to play a role in this interval," she observed.

The FRAME study was sponsored by Amgen and UCB Pharma. Miller has received research grants from Alexion, Amgen, Radius, Regeneron, UCB Pharma, and Ultragenyx. Nickolas has served on an advisory board for Amgen and is currently involved in two investigator-sponsored studies of Amgen drugs. Akesson has disclosed lecture fees or participation in advisory boards for Amgen, UCB Pharma, Renapharma, Astellas Pharma, Luzan 5, and Sanofi.

ASBMR 2019 Annual Meeting. Presented September 21, 2019. Abstract 1047.

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