Denosumab for osteoporosis shows potential for lowering diabetes risk

Treatment with denosumab in people with osteoporosis confers a protective effect against the risk of developing diabetes, according to the results of a propensity score–matched cohort study from Taiwan.

Data from a large number of patients treated for osteoporosis showed that the risk of incident diabetes was 16-percent lower among those who continued denosumab than among those who discontinued the medication (hazard ratio [HR], 0.84, 95 percent confidence interval [CI], 0.78–0.90). [JAMA Netw Open 2024;7:e2354734]

“These results were supported by several sensitivity analyses, confirming the robustness of the findings,” the investigators noted.

In stratified analyses, the protective association between denosumab and diabetes was pronounced among participants 65 years of age or older (HR, 0.80) but was not observed among those younger than 65 years (HR, 1.027).

“Given that the prevalence and incidence of diabetes are higher in older adults than in younger ones, a finding of an association between denosumab treatment and lower diabetes risk in older adults but no such association in younger adults was reasonable. This result suggests that our findings should be particularly considered in this vulnerable population,” the investigators said. [Diabetes Care 2012;35:2650-2664]

Other than age, the benefit was consistent across subgroups defined by sex (men: HR, 0.85; women: HR, 0.81) and comorbidities including dyslipidaemia (with: HR, 0.82; without: HR, 0.81), hypertension (with: HR, 0.79; without: HR, 0.86), ischaemic heart disease (with: HR, 0.82; without: HR, 0.81), and kidney failure (with: HR, 0.85; without: HR, 0.81).

The analysis included 68,510 patients with osteoporosis who received denosumab (mean age 77.7 years, 84.3 percent women). Of these patients, 34,255 continued using denosumab and 34,255 discontinued it after the initial dose. Over a mean follow-up of 1.9 years, diabetes was diagnosed in 2,016 of those who continued denosumab and in 3,220 of those who discontinued treatment (incidence rate, 35.9 vs 43.6 per 1,000 person-years).

While the science linking denosumab to lower diabetes risk is far from established, the investigators postulated several possible mechanisms.

One possibility is that denosumab fights inflammation through the inhibition of the receptor activator of nuclear factor κB ligand (RANKL), with chronic inflammation contributing to insulin resistance and in turn diabetes, they explained. [Nat Med 2013;19:358-363; Nat Med 2005;11:183-190]

Another possibility involves the insulin-producing beta-cells in the pancreas, the investigators pointed out. RANKL has been reported to hinder the growth of beta-cells, and by targeting the RANKL/RANK pathway, denosumab may help increase the production of beta-cells. [Cell Metab 2015;22:77-85; Nat Rev Endocrinol 2020;16:349-362]

Although additional studies are needed to validate the findings, the present study “may help physicians choose an appropriate antiosteoporosis medication for patients with osteoporosis while also considering a medication associated with lowering diabetes risk,” according to the investigators.