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Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.This Review outlines the pathogenesis of skeletal fragility in patients with type 2 diabetes mellitus, and discusses potential therapeutic approaches to the management of increased fracture risk in these patients. The evidence that skeletal fragility should now be included in the list of well-recognized diabetic complications is also summarized.

Cellular senescence is a fundamental aging mechanism that is currently the focus of considerable interest as a pathway that could be targeted to ameliorate aging across multiple tissues, including the skeleton. There is now substantial evidence that senescent cells accumulate in the bone microenvironment with aging and that targeting these cells prevents age-related bone loss, at least in mice. Cellular senescence also plays important roles in mediating the skeletal fragility associated with diabetes mellitus, radiation, and chemotherapy. As such, there are ongoing efforts to develop \"senolytic\" drugs that kill senescent cells by targeting key survival mechanisms in these cells without affecting normal cells. Because senescent cells accumulate across tissues with aging, senolytics offer the attractive possibility of treating multiple age-related comorbidities simultaneously.

Key Points Both peak bone mass attained during childhood and adolescent growth, and bone loss associated with senescence are major determinants of bone mass and fracture risk late in life Incidence of distal forearm fractures increases markedly around the time of puberty and children who sustain these fractures in the setting of mild, but not moderate, trauma have systemic skeletal deficits that persist into young adult life With ageing, cortical bone at multiple skeletal sites remains fairly stable in both sexes until mid-life, when estrogen deficiency in women and gradual sex steroid deficiency in men begins to drive cortical bone loss By contrast, substantial trabecular bone loss occurs in both sexes during young adult life, in conditions of sex steroid sufficiency Cortical porosity is increasingly recognized as an important component of bone 'quality' that increases markedly with age; changes in cortical porosity are not captured by dual-energy X-ray absorptiometry Assessment of cortical porosity might help identify individuals at increased risk of fracture from the large group of patients with osteopenia, in whom assessment of fracture risk remains most ambiguous In this Review, Joshua Farr and Sundeep Khosla discuss changes in bone architecture during growth, placing an emphasis on skeletal changes at the distal radius, a clinically relevant site of forearm fractures. The implications of these changes for fracture risk in adolescence and later in life, and the architectural changes in bone with ageing that might contribute to increased fracture risk are also discussed. Age-related fragility fractures are an enormous public health problem. Both acquisition of bone mass during growth and bone loss associated with ageing affect fracture risk late in life. The development of high-resolution peripheral quantitative CT (HRpQCT) has enabled in vivo assessment of changes in the microarchitecture of trabecular and cortical bone throughout life. Studies using HRpQCT have demonstrated that the transient increase in distal forearm fractures during adolescent growth is associated with alterations in cortical bone, which include cortical thinning and increased porosity. Children with distal forearm fractures in the setting of mild, but not moderate, trauma also have increased deficits in cortical bone at the distal radius and in bone mass systemically. Moreover, these children transition into young adulthood with reduced peak bone mass. Elderly men, but not elderly women, with a history of childhood forearm fractures have an increased risk of osteoporotic fractures. With ageing, men lose trabecular bone primarily by thinning of trabeculae, whereas the number of trabeculae is reduced in women, which is much more destabilizing from a biomechanical perspective. However, age-related losses of cortical bone and increases in cortical porosity seem to have a much larger role than previously recognized, and increased cortical porosity might characterize patients at increased risk of fragility fractures.

Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs. Identification of senescent cells in vivo remains a challenging task. Here the authors present and validate a senescence gene set called SenMayo enriched in human and murine aged tissues.

Abstract Context With the aging of the population and projected increase in osteoporotic fractures coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (e.g., atherosclerosis, diabetes, frailty) that share aging as the leading risk factor, there is growing interest in the “Geroscience Hypothesis,” which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share aging as the underlying risk factor. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. This mini-review provides an overview on cellular senescence with a focus on its role in mediating age-related bone loss. Methods This summary is based on the authors’ knowledge of the field supplemented by a PubMed search using the terms “senescence,” “aging,” and “bone.” Results There is compelling evidence from preclinical models and supportive human data demonstrating an increase in senescent cells in the bone microenvironment with aging. These cells produce a proinflammatory secretome that leads to increased bone resorption and decreased bone formation, and approaches that either eliminate senescent cells or impair the production of their proinflammatory secretome have been shown to prevent age-related bone loss in mice. Conclusions Targeting cellular senescence represents a novel therapeutic strategy to prevent not only bone loss but potentially multiple age-related diseases simultaneously. Cellular senescence is an aging mechanism that contributes to age-related osteoporosis and other age-associated diseases. Targeting this pathway could simultaneously treat multiple aging morbidities.

A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood.

Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice. Transfer of senescent cells into naive, young mice can induce physical dysfunction, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. What happens to those healthy cells that reside in this harmful environment? Emerging evidence indicates that cells that survive irreparable genomic damage undergo cellular senescence, a crucial intermediate mechanism connecting DNA damage and the immune response. In this review, we hypothesize that sustained Gram-negative bacterial challenge, chronic inflammation itself, and the constant renewal of damaged tissues create a permissive environment for the abnormal accumulation of senescent cells. Based on emerging data we propose a model in which the dysfunctional presence of senescent cells may aggravate the initial immune reaction against pathogens. Further understanding of the role of senescent cells in periodontal disease pathogenesis may have clinical implications by providing more sophisticated therapeutic strategies to combat tissue destruction.

Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1 , and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism. Anti-resorptive bone therapies also inhibit bone formation, as osteoclasts secrete factors that stimulate bone formation by osteoblasts. Here, the authors identify osteoclast-secreted factors that couple bone resorption to bone formation in healthy subjects, and show that osteoclast-derived DPP4 may be a factor coupling bone resorption to energy metabolism.

Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24 high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24 high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics. Technical challenges have previously hindered the detailed study of in vivo senescent cells. Here, the authors deeply characterize senescent skeletal cells across murine aging, establishing CD24 as a marker of osteolineage cells cleared by senolytics.