Denosumab May Offer Better Fracture Protection for Dialysis Patients

Dialysis patients on denosumab (Prolia, Xgeva) had a lower risk for fracture but higher risk for a certain heart event, suggested an observational trial weighted to emulate a clinical trial.

Among 1,032 Japanese patients on dialysis who started treatment for osteoporosis, denosumab use had a 45% lower risk for a composite of all fractures compared with oral bisphosphonates over 3 years (risk ratio [RR] 0.55, 95% CI 0.28-0.93), Koji Kawakami, MD, PhD, of Kyoto University in Japan, and colleagues reported.

This translated to a 5.3-percentage point lower weighted 3-year risk for composite fractures for denosumab users, which was statistically significant, they wrote in Annals of Internal Medicine.

On the other hand, denosumab users trended towards a 36% higher risk for a major adverse cardiovascular event (MACE) within the next 3 years than bisphosphonate users, though this didn’t reach significance (RR 1.36, 95% CI 0.99-1.87). The weighted 3-year risk of MACE was 8.2 percentage points lower for denosumab initiators, which likewise didn’t reach significance.

But denosumab users had a significantly higher risk for acute myocardial infarction when this outcome was separated out. This outcome occurred in 24 of 658 denosumab users and four of 374 bisphosphonate users:

• Weighted RR 3.50 (95% CI 1.44-21.4)
• Weighted risk difference: 3.9 percentage points (95% CI 1.1-7.1)

“Among dialysis patients with osteoporosis, denosumab may be more effective than oral bisphosphonates in reducing fracture risk, but it might also increase the risk of MACE,” lead study author Soichiro Masuda, MD, PhD, of Kyoto City Hospital in Japan, summarized.

Masuda told MedPage Today that he was a bit surprised by the magnitude of denosumab’s fracture prevention benefit, at a 45% relative risk reduction. However, the overall net benefit is unclear, he said, because renal outcomes, which were not assessed, could potentially offset the cardiovascular risks.

“Preliminary data hints that denosumab may have a favorable renal safety profile, possibly impacting total mortality, but this needs further investigation,” Masuda added.

Bisphosphonates are generally considered the first-line treatment to prevent fractures in osteoporosis but have been tied to chronic kidney disease (CKD) progression and should be used with caution in certain patients.

“Because denosumab does not depend on kidney clearance for its excretion and exerts its preventive effect against fracture regardless of the degree of renal impairment, its adoption and importance in the management of osteoporosis in dialysis-dependent patients has increased,” the researchers explained.

But in January 2024, the FDA added a boxed warning to denosumab’s label over the risk of severe hypocalcemia in patients with advanced CKD. This was based on an analysis of Medicare data that found 41.1% of women on denosumab developed severe hypocalcemia compared with 2.0% of those taking oral bisphosphonates within the first 12 weeks of treatment, translating to a 20-fold higher risk for incident severe hypocalcemia. As a result, the agency advised clinicians to carefully select appropriate patients for denosumab and increase monitoring of blood calcium levels.

So far, no clinical trials have compared the safety and fracture prevention effects of denosumab and bisphosphonates in dialysis-dependent patients, Kawakami’s group noted.

To delve further into this topic, they looked at a Japanese commercial administrative database covering claims from April 2014 to October 2022. They identified patients 50 and older undergoing dialysis with an osteoporosis diagnosis, all whom either newly initiated denosumab at the 60-mg subcutaneous dose approved for osteoporosis or one of the following oral bisphosphonates: alendronate (Fosamax, Binosto), risedronate (Actonel, Atelvia), ibandronate (Boniva), or minodronate (not approved in the U.S.). The database was representative of the general Japanese population.

After the cohort was weighted, about 63% of the patients were women, the average age was 75, and duration since first osteoporosis diagnosis was 3.5 years. Nearly all the patients were on hemodialysis, with only a few on peritoneal dialysis. Average duration since first dialysis was 2.5 years. Patients who had less than 90 days of dialysis before the start of follow-up were excluded.

Aside from acute myocardial infarction, no safety outcomes differed between the two treatment groups. This included outcomes of stroke, hospitalization for heart failure, cardiovascular death, total mortality, and osteonecrosis of the jaw.

As for denosumab’s effectiveness, the reduction in composite fracture risk was largely driven by fewer nonvertebral fractures (risk difference -5.8 percentage points; RR 0.38, 95% CI 0.18-0.71), which included fractures of the hip, shoulder, forearm, leg, femur, and ankle. Risk for hip fracture alone and for vertebral fracture didn’t differ between the two treatment groups.

“Although our study adjusted for comorbidities, medication use, and health care use, we did not have clinical information on measures of cardiovascular risk or severity of kidney disease or baseline electrolyte imbalances that may potentially confound the choice between denosumab and bisphosphonates,” the researchers pointed out. “Denosumab may be more likely prescribed for patients with more severe disease or risk factors, which would have biased the findings toward overestimation of cardiovascular event risk with denosumab use.”

Masuda said that “due to the difficulty of conducting large trials in this population, future large-scale prospective studies with comprehensive clinical data are crucial to confirm our findings.”

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