Denosumab Protective Against Diabetes?

Continued treatment with the osteoporosis drug denosumab (Prolia) was tied to a lower risk of developing diabetes in a Taiwanese cohort study.

In a propensity score-matched analysis, adherence to denosumab for osteoporosis was associated with a 16% lower risk for incident diabetes compared with cessation after the first dose (HR 0.84, 95% CI 0.78-0.90), Edward Chia-Cheng Lai, PhD, of National Cheng Kung University in Taiwan, and colleagues reported in JAMA Network Open.

Stratification by age, however, showed the findings to be entirely driven by patients 65 and up:

• Age 65 and over: HR 0.80 (95% CI 0.75-0.85)
• Younger than 65 years: HR 1.02 (95% CI 0.83-1.27)

The findings, which had an average follow-up of just under 2 years, suggest a potential dual benefit with denosumab in this population, Lai told MedPage Today, combining the agent’s established role in preventing bone fractures with the potential protection against diabetes.

“This is particularly significant given the increasing prevalence of both osteoporosis and diabetes in the aging population,” Lai said. “Our study suggests that when choosing anti-osteoporosis medication, physicians might also consider the potential benefit of lowering diabetes risk. This could be especially relevant for patients at high risk of diabetes or those with preexisting metabolic conditions.”

While promising, the findings weren’t entirely surprising, he added. “Given the preclinical evidence suggesting that receptor activator of nuclear factor κB ligand (RANKL) signaling inhibition can improve insulin sensitivity and glucose tolerance, we hypothesized that denosumab could have a positive impact on glucose homeostasis,” Lai explained. “It’s rewarding to see clinical data align with preclinical expectations, reinforcing the potential for osteoporosis treatments to have broader metabolic benefits.”

“We hope doctors will recognize the importance of considering the broader health implications of anti-osteoporosis treatments,” said Lai.

Denosumab was first approved back in 2010 for postmenopausal women with osteoporosis at high risk for bone fracture. The RANKL inhibitor later picked up a number of other indications, including osteoporosis in men, glucocorticoid-induced osteoporosis in either sex, bone loss in men receiving androgen-deprivation therapy for prostate cancer, and bone loss for women receiving aromatase inhibitor therapy for breast cancer. But following an FDA safety alert in November 2022, the agency recently added a boxed warning to the label over the risk of severe hypocalcemia in patients with advanced chronic kidney disease.

Denosumab is also approved under the trade name Xgeva to reduce the risk of bone-related events in certain cancer patients.

A total of 68,510 patients were included in the nationwide, propensity score-matched cohort study. Patient data came from Taiwan’s National Health Insurance Research Database on adults who received denosumab for osteoporosis from 2012 to 2019. Most were female (84.3%) and the average age was 78 years.

The treatment group included 34,255 patients who received their second dose per the anticipated administration schedule 180 days after the initial dose, and the comparison group included 34,255 patients who didn’t receive a second dose.

Half of the patients in each group had a history of vertebral fracture, 15% had a history of hip fracture, and 5% had a history of wrist or humerus fracture.

Incident diabetes was defined as need for a new antidiabetic drug. Over a mean 1.9 years of follow-up, a total of 2,016 denosumab-treated adults developed diabetes versus 3,220 of those who stopped treatment (incidence rates of 35.9 vs 43.6 per 1,000 person-years, respectively).

The lower risk of diabetes associated with denosumab was consistent across sexes and seen regardless of comorbidity status: with or without dyslipidemia, with or without hypertension, with or without ischemic heart disease, and with or without kidney failure.

Other factors such as lifestyle, substance use, prediabetes status, weight, and lab results weren’t available for the patients.

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