Denosumab and incidence of type 2 diabetes among adults with osteoporosis: population based cohort study

Abstract

Objective To estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis. Design Population based study involving emulation of a randomized target trial using electronic health records. Setting IQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021. Participants Adults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis. Main outcome measures The primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach. Results 4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06). Conclusions In this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.

Denosumab and the Risk of Diabetes in Patients Treated for Osteoporosis

“…A post hoc analysis of the FREEDOM trial indicated no significant effect of denosumab on reducing diabetes risk (relative risk, 0.85; 95% CI, 0.61-1.17), with potential underpowering hindering conclusive findings. In contrast, a recent retrospective cohort study in the UK suggested reduced risk of diabetes associated with denosumab use compared with bisphosphonate use (HR, 0.68; 95% CI, 0.52-0.89) . However, confounding by indication may not have been completely eliminated in that study because factors such as kidney function and upper gastrointestinal tract diseases may be associated with the selection of denosumab or bisphosphonates.…”

“…However, while some clinical evidence suggests denosumab may be positively associated with glycemic parameters, such as fasting plasma glucose and homeostatic model assessment for insulin resistance, its effect on reducing diabetes risk remains unclear . A previous post hoc analysis of the FREEDOM trial indicated no statistically significant effect of denosumab in lowering diabetes risk, but limitations due to potential issues of being underpowered and having a small number of diabetes cases make the findings of the trial inconclusive . In contrast, a recent retrospective cohort study in the UK suggested lower diabetes risk associated with denosumab use compared with bisphosphonate use, despite potential confounding bias by indication .…”

Association of Bone Mineral Density and Bone Turnover Markers with the Risk of Diabetes: Hong Kong Osteoporosis Study and Mendelian Randomization

“…[ 37,38 ] For example, bone morphogenic proteins derived from the bone matrix and osteoprotegerin secreted by osteoblasts have been shown to regulate insulin secretion. [ 39,40 ] Observational studies examining the effect of denosumab on glucose parameter improvement [ 41 ] and T2DM risk reduction [ 42 ] also support osteoprotegerin may play a role in mediating the relationship, but there has not been a clinical trial on denosumab with glycemic traits as the intended outcome in those with diabetes. Considering the intricate interplay between bone and glucose metabolism, depicting a complete picture of the crosstalk between these two systems is challenging and requires further research.…”

Weight Loss Induced by Antiobesity Medications and All‐Cause Mortality Among Patients With Knee or Hip Osteoarthritis

“…The death date recorded in the IMRD is linked to the NHS; thus, a change in vital status to “dead” is immediately updated in the person's electronic health record. The secondary outcomes were incident hypertension, 25 T2DM, 26 VTE (pulmonary embolism and deep vein thrombosis), CVD (myocardial infarction [MI] and stroke), 27 and any cancer (lung, breast, colorectal, prostate, head and neck, and other cancers) 28 identified by Read codes during the five‐year follow‐up period. VTE was defined as a recorded Read code of VTE with a prescription of anticoagulant medication.…”