Denosumab and the Risk of Diabetes in Patients Treated for Osteoporosis

Huang, Huei-Kai; Chuang, Albert Tzu-Ming; Liao, Tzu-Chi; Shao, Shih-Chieh; Liu, Peter Pin-Sung; Tu, Yu-Kang; Lai, Edward Chia-Cheng

doi:10.1001/jamanetworkopen.2023.54734

Cited by 3 publications

(1 citation statement)

References 43 publications

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“…Notably, drugs targeting the IL-18/IL-18R signaling axis, such as IL-18R antagonist or components resembling naturally occurring IL-18 binding protein (IL-18BP) and anti-IL-18 antibodies, are in development and testing for diabetes related conditions, including hypertension and chronic kidney diseases [ 83 – 85 ], as well as HIV infection [ 41 ]. Similarly, drugs like Denosumab targeting the RANKL/RANK/OPG pathway have been proposed as potential novel options for diabetes treatment and glycemic control [ 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Luo,

Peters,

Moon

et al. 2024

Genome Med

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Background Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. Methods We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained by altered metabolites and proteins. Results Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera–diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. Conclusion Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera–diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

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Section: Discussionmentioning

confidence: 99%

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Luo,

Peters,

Moon

et al. 2024

Genome Med

View full text Add to dashboard Cite

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Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all‐cause mortality in adults, compared with bisphosphonates: An analysis of real‐world, cohort data, with a systematic review and meta‐analysis

Henney,

Riley,

O'Connor

et al. 2024

Diabetes Obesity Metabolism

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AimTo evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long‐term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all‐cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta‐analysis.MethodsA retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long‐term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random‐effects meta‐analysis. Risk of bias and evidence quality were assessed using Cochrane‐endorsed tools.ResultsDenosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78‐0.88]). Secondary analysis showed significant risk reduction in all‐cause mortality (0.79 [0.72‐0.87]) and foot ulceration (0.67 [0.53‐0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta‐analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79‐0.87]) (I2 = 10.76%).ConclusionsThis is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all‐cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D.

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RANK–RANKL–OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives

Monti,

Perazza,

Leoni

et al. 2024

IJMS

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Metabolic dysfunction-associated steatotic liver disease (MASLD)—and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage—corresponds to the liver’s involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

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Denosumab and the Risk of Diabetes in Patients Treated for Osteoporosis

Cited by 3 publications

References 43 publications

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all‐cause mortality in adults, compared with bisphosphonates: An analysis of real‐world, cohort data, with a systematic review and meta‐analysis

RANK–RANKL–OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives

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