Context: Type 2 diabetes mellitus is associated with more rapid bone loss in women, but less evidence is available for men or those with prediabetes. Objective: To determine whether bone loss rate is affected by diabetes status in older men, we analyzed data from the Osteoporotic Fractures in Men (MrOS) study. Methods: The multisite MrOS study enrolled 5994 men aged ≥ 65 years. Diabetes status was defined by self-report, diabetes medication use, or elevated fasting serum glucose at baseline. Hip bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA) at baseline and a follow-up visit after 4.6 ± 0.4 years. This analysis included 4095 men, excluding those without follow-up DXA or with unknown diabetes status. Changes in hip BMD in participants with normoglycemia (NG), prediabetes, or type 2 diabetes, excluding thiazolidinedione (TZD) users, were evaluated using generalized linear models (GLM). Diabetes medication use and BMD loss among those with type 2 diabetes were also evaluated with GLM. Results: In adjusted models, hip BMD loss was greater in men with type 2 diabetes (− 2.23%; 95% CI: −2.54 to −1.91; P < .001) but not in men with prediabetes (−1.45%; 95% CI −1.63 to −1.26; P = .33) compared with NG (−1.57%; 95% CI −1.73 to −1.41). Among men with type 2 diabetes, TZD, insulin, and sulfonylurea use were associated with greater hip BMD loss. Conclusion: Men with type 2 diabetes, but not prediabetes, experienced accelerated bone loss compared to participants with normoglycemia. More rapid bone loss predicts increased risk of fractures and mortality in broader populations.

Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Pro-inflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. 505 men (85.0±4.2yrs) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D₃Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP) and a subsample (n=305) with interleukin (IL-6, IL-1β, IL-17A) and tumor necrosis factor-α (TNF-α)) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23-92% of the inverse relationship between inflammatory markers and D₃Cr muscle mass was mediated by KP metabolites (indirect effect p0.05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D₃Cr muscle mass may focus on KP metabolites rather than inflammation per se.

Aging is the results of several complex and multifactorial processes, where several agents contribute to increase intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms, finely regulated and strictly interconnected, initiating or contributing to biological changes anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic affects. Vitamin D (VitD) is known to have positive impact not only on muscle and bone health, but also on several extra-skeletal districts, due to the widespread presence of VDRs (VDR). VitD and VDR could be molecules potentially targeting the hallmark of aging network. To date, evidence about the potential effect of VitD on the hallmark of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seems to confirm the modulatory effect of VitD on some hallmarks aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.