Both trabecular and cortical bone undergo changes at multiple scales. We previously demonstrated the multi-scale changes in trabecular bone quality that contribute to bone fragility in type 2 diabetes (T2D). The link between increased fragility in T2D and multi-scale changes in cortical bone and their interaction with glycation remains unclear. This study presents, first-ever, multi-scale cortical bone quality parameters in T2D patients after their first hip fracture. The study objective was to determine the association between cortical porosity (Ct.Po.), mechanical, material, and bone compositional properties in T2D. Inferomedial femoral neck (FN) bone tissue specimens were collected from patients (n = 10 with T2D, n = 25 age- and sex-matched non-diabetes controls) who underwent hip replacement surgery following the first hip fragility fracture. Bone mineral density at FN was found to be similar between groups. In T2D, Ct.Po was higher (p = 0.038), while ultimate stress (p = 0.021), ultimate strain (p = 0.040), post-yield strain (p = 0.011), toughness (p = 0.005), yield energy (p = 0.003), and post-yield energy (p = 0.004) were notably lower. Tissue compositional differences included lower gravimetric mineral/matrix (p = 0.017), higher non-enzymatic collagen cross-link ratio (NE-xLR) (p = 0.049) and higher sugar/matrix ratio (p = 0.042) in T2D. Fluorescent advanced glycation end-products (fAGEs) content was higher in T2D bone (p = 0.043). At the mesoscale, the fAGEs in the bone matrix are inversely related to the yield- and ultimate strain of T2D bone, and NE-xLR is negatively correlated with yield- and ultimate- stress in the T2D group. In conclusion, study findings demonstrate that elevated glycation weakens the mechanical integrity of cortical bone by reducing its ability to absorb energy and resist deformation, thereby contributing to bone fragility in T2D. The strong association of fAGEs with lower yield strain, along with the association of NE-xLR with lower yield- and ultimate stress, establishes a causal link between AGEs and the deterioration of cortical bone mechanical properties. These findings underscore the need for strategies targeting glycation and collagen quality to mitigate fracture risk in T2D patients.

The purpose of this review is to investigate the impacts of blood glucose fluctuations on diabetic osteoporosis, a complication of Type 2 diabetes mellitus (T2DM) that remains poorly understood. We reviewed the current evidence of the relationship between blood glucose fluctuations and diabetic osteoporosis in patients with T2DM. The findings indicate that blood glucose fluctuations may contribute to inhibiting the processes of bone formation and resorption, promoting diabetic osteoporosis and fractures in T2DM. Mechanistic studies, both in vitro and in vivo, reveal that these effects are largely mediated by oxidative stress, advanced glycation end products, inflammatory mediators, and multiple pathways inducing cell apoptosis or autophagy. Thus, maintaining the long-term stability of blood glucose levels emerges as a target to be pursued in clinical practice in order to safely reduce mean blood glucose and for its direct effects on osteoporosis and fractures in T2DM.

Impact microindentation (IMI) measures bone material strength index (BMSi) in vivo. However, its ability to predict fractures is still uncertain. This study aimed to determine the association between BMSi and 10 year fracture probability, as calculated by the FRAX algorithm.

BMSi was measured using the OsteoProbe in 388 men (ages 40-90 yr) from the Geelong Osteoporosis Study. The probabilities for a major osteoporotic fracture (MOF) and hip fracture (HF) were calculated using the Australian FRAX tool. Hip (HF) and major osteoporotic (MOF) fracture probabilities were computed with and without the inclusion of femoral neck bone mineral density (BMD). For each participant, four 10 year probability scores were therefore generated: (i) HF-FRAXnoBMD; (ii) HF-FRAXBMD; (iii) MOF-FRAXnoBMD; (iv) MOF-FRAXBMD.

BMSi was negatively correlated with age (r = - 0.114, p = 0.025), no associations were detected between BMSi and femoral neck BMD (r = + 0.035, p = 0.507). BMSi was negatively correlated with HF-FRAXnoBMD (r = - 0.135, p = 0.008) and MOF-FRAXnoBMD (r = - 0.153, p = 0.003). These trends held true for HF-FRAXBMD (r = - 0.087, p = 0.094) and MOF-FRAXBMD (r = - 0.111, p = 0.034), but only the latter reached significance.

BMSi captures the cumulative effect of clinical risk factors in the FRAX algorithm, suggesting that it could provide additional information that may be useful in predicting risk of fractures. Further studies are warranted to establish its efficacy in predicting fracture risk.

Fracture is an under-recognized but common complication of diabetes mellitus, with an incidence approaching twofold in type 2 diabetes mellitus (T2DM) and up to sevenfold in type 1 diabetes mellitus (T1DM) compared with that in the general population. Both T1DM and T2DM induce chronic hyperglycaemia, leading to the accumulation of advanced glycosylation end products that affect osteoblast function, increased collagen crosslinking and a senescence phenotype promoting inflammation. Together with an increased incidence of microvascular disease and an increased risk of vitamin D deficiency, these factors reduce bone quality, thereby increasing bone fragility. In T1DM, reduced anabolic stimuli as well as the presence of autoimmune conditions might also contribute to reduced bone mass and increased fragility. Diabetes mellitus is the most common cause of kidney failure, and fracture risk is exacerbated when chronic kidney disease (CKD)-related mineral and bone disorders are superimposed on diabetic changes. Microvascular pathology, cortical thinning and trabecular deterioration are particularly prominent in patients with T1DM and CKD, who suffer more fragility fractures than do other patients with CKD. This Review explores the pathophysiology of bone fragility in patients with diabetes mellitus and CKD and discusses techniques to predict fracture and pharmacotherapy that might reduce fracture risk.

Humans are biological units that host numerous microbial symbionts and their genomes, which together form a superorganism or holobiont. Changes in the balance of the oral ecosystem can have consequences for both general and oral health, such as cavities, gingivitis, and periodontitis. Periodontitis is initiated by a synergistic and dysbiotic microbial community that causes local inflammation and destruction of the tooth's supporting tissues, potentially leading to systemic inflammation. This inflammation caused by periodontal disease has been associated with various systemic alterations, and the immune system is largely responsible for the body's exacerbated response, which can induce and exacerbate chronic conditions. Studies indicate that subgingival microorganisms found in periodontitis reach the bloodstream and are distributed throughout the body and, therefore, can be found in distant tissues and organs. Among all diseases associated with periodontal disease, diabetes mellitus presents the strongest and most elucidated link, and its bidirectional relationship has already been demonstrated. Chronic hyperglycemia favors the worsening of periodontal parameters, while the aggravation of periodontal parameters can promote an increase in glycemic indexes. Other systemic diseases have been related to periodontitis, such as Alzheimer's, chronic kidney disease, atherosclerosis, and respiratory diseases. The importance of periodontal control may suggest a reduction in the chances of developing chronic inflammatory diseases because these two alterations often share inflammatory pathways and, for this reason, may influence each other.

Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end-products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 yr; n = 20) and age- and sex-matched nondiabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification [total fluorescent AGEs, pentosidine, carboxymethyl lysine (CML)], and matrix composition via Raman spectroscopy. Cortical bone from older adults with T1D had diminished postyield toughness to fracture (-30%, p = .036), elevated levels of AGEs (pentosidine, +17%, p = .039), lower mineral crystallinity (-1.4%, p = .010), greater proline hydroxylation (+1.9%, p = .009), and reduced glycosaminoglycan (GAG) content (-1.3%, p < .03) compared to nondiabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density, CML, and Raman spectroscopic measures of enzymatic collagen crosslinks and GAG content remained highly significant predictors of toughness, while diabetic status was no longer significant (adjusted R2 > 0.60, p < .001). Thus, the impairment of cortical bone to absorb energy following long-duration T1D is well explained by AGE accumulation and modifications to the bone matrix. These results provide novel insight into the pathogenesis of skeletal fragility in individuals with T1D.

Sclerostin, a protein synthesized by bone cells, is a product of the SOST gene. Sclerostin is a potent soluble inhibitor of the WNT signaling pathway, and is known to inhibit bone formation by inhibiting osteocyte differentiation and function. Currently, sclerostin has been the subject of numerous animal experiments and clinical investigations. By conducting a literature review, we have gained insights into the most recent advancements in research. Patients with both type 1 diabetes and type 2 diabetes have high levels of serum sclerostin. Patients with type 1 diabetes and type 2 diabetes are both more likely to suffer from osteoporosis, and serum sclerostin levels are elevated in osteoporosis. Many studies have confirmed that sclerostin has been implicated in the pathogenesis of osteoporosis, so we speculate that sclerostin plays an important role in osteoporosis through the glucose metabolism pathway, which may promote the osteoporosis of morbidity in type 1 diabetes and type 2 diabetes. Based on this, we propose whether serum sclerostin can predict type 1 diabetes and type 2 diabetes-induced osteoporosis, and whether it can be a new target for the prevention and treatment of type 1 diabetes and type 2 diabetes-induced osteoporosis, providing new ideas for clinicians and researchers.

Patients with diabetes often experience reduced bone strength, resulting in a higher fracture risk. This decline and increased susceptibility stem from intricate interactions within the bone microstructure. However, current gold standard methods for assessing bone strength, such as bone mineral density, and widely-used fracture risk assessment tools do not accurately predict fracture risk in diabetic patients. Therefore, it is crucial to incorporate additional indicators that evaluate bone quality and specific markers relevant to diabetes to enhance the accuracy of predictive models. Moreover, the selection of appropriate algorithms for model construction is essential. This review aims to introduce indicators from both imaging examinations and laboratory indicators that hold significant value for inclusion in fracture risk prediction models for diabetic patients. Additionally, this study provides an overview of the research progress in fracture risk prediction models for diabetic patients, serving as a valuable reference for clinical practice.

Ferroptosis, a recently recognized form of regulated cell death (RCD) characterized by iron-dependent lipid peroxide accumulation, has emerged as a noteworthy regulator in various bone-related diseases, including osteoporosis (OP), osteoarthritis (OA), and osteosarcoma (OS). OS primarily afflicts the elderly, rendering them susceptible to fractures due to increased bone fragility. OA represents the most prevalent arthritis in the world, often observed in the aging population. OS predominantly manifests during adolescence, exhibiting an aggressive nature and bearing a significantly unfavorable prognosis. In this review article, we present an overview of the characteristics and mechanism of ferroptosis and its involvement in bone-related diseases, with a particular focus on OP, OA, and OS. Furthermore, we summarize chemical compounds or biological factors that impact bone-related diseases by regulating ferroptosis. Through an in-depth exploration of ferroptosis based on current research findings, this review provides promising insights for potential therapeutic approaches to effectively manage and mitigate the impact of these bone-related pathological conditions.

Insulin and exenatide are two hypoglycaemic agents that exhibit different osteogenic effects. This study compared the differences between exenatide and insulin in osseointegration in a rat model of Type 2 diabetes (T2D) and explored the mechanisms promoting osteogenesis in this model of T2D.

In vivo, micro-CT was used to detect differences in the peri-implant bone microstructure in vivo. Histology, dual-fluorescent labelling, immunofluorescence and immunohistochemistry were used to detect differences in tissue, cell and protein expression around the implants. In vitro, RT-PCR and western blotting were used to measure the expression of osteogenesis- and Wnt signalling-related genes and proteins in bone marrow mesenchymal stromal cells (BMSCs) from rats with T2D (TBMSCs) after PBS, insulin and exenatide treatment. RT-PCR was used to detect the expression of Wnt bypass cascade reactions under Wnt inactivation.

Micro-CT and section staining showed exenatide extensively promoted peri-implant osseointegration. Both in vivo and in vitro experiments showed exenatide substantially increased the expression of osteogenesis-related and activated the LRP5/6/GSK-3β/β-catenin-related Wnt pathway. Furthermore, exenatide suppressed expression of Bmpr1a to inhibit lipogenesis and promoted expression of Btrc to suppress inflammation.

Compared to insulin, exenatide significantly improved osteogenesis in T2D rats and TBMSCs. In addition to its dependence on LRP5/6/GSK-3β/β-catenin signalling for osteogenic differentiation, exenatide-mediated osteomodulation also involves inhibition of inflammation and adipogenesis by BMPR1A and β-TrCP, respectively.

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q -4.1% (-13.2, 2.6), control -7.7% (-20.1, 14.3); P = 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%, P = 0.020) and 4 weeks (+16%, P = 0.024), but was not different from control at 20 weeks (-9%, P = 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 (also known as CDKN2A) mRNA levels) in which D + Q concomitantly increased P1NP (+34%, P = 0.035) and reduced CTx (-11%, P = 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%, P = 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier: NCT04313634 .

The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.

Hyperglycemia is associated with impaired bone health in patients with diabetes mellitus. Although a direct detrimental effect of hyperglycemia on the bone has been previously reported, the specific molecular mediator(s) responsible for the inhibitory effect of high glucose levels on the bone remains unclear. We hypothesized that thioredoxin-interacting protein (Txnip), an essential mediator of oxidative stress, is such a mediator.

We cultured MG-63 cells (immortalized human osteoblasts) with normal or high glucose concentrations and transfected them with scrambled or Txnip-specific small interfering RNA (siRNA).

High glucose levels increased Txnip expression and reduced MG-63 cell proliferation. The high-glucose level mediated reduction in cell proliferation was prevented in Txnip siRNA-transfected cells. In addition, we demonstrated that silencing Txnip mRNA expression in osteoblasts reduced the expression of the osteocalcin gene. Our results suggest that high glucose levels or silencing of Txnip mRNA expression may induce apoptosis in osteoblasts.

Our findings indicate that Txnip is an intracellular mediator of the anti-proliferative effects of extracellular high glucose levels on osteoblasts.

The reasons for the increased fracture risk in type 2 diabetes (T2D) are not fully understood.

To determine if poorer skeletal characteristics or worse physical function explain the increased fracture risk in T2D.

This prospective observational study is based on the population-based Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures study cohort of older women, performed in the Gothenburg area between March 2013 and May 2016. Follow-up of incident fracture data was completed in March 2023. Data analysis was performed between June and December 2023.

Data were collected from questionnaires and through examination of anthropometrics, physical function, and bone measurements using bone densitometry (dual-energy x-ray absorptiometry), and high-resolution peripheral computed tomography. A subsample underwent bone microindentation to assess bone material strength index (BMSi).

Baseline assessment of bone characteristics and physical function and radiograph verified incident fractures.

Of 3008 women aged 75 to 80 years, 294 women with T2D (mean [SD] age, 77.8 [1.7] years) were compared with 2714 women without diabetes (mean [SD] age, 77.8 [1.6] years). Women with T2D had higher bone mineral density (BMD) at all sites (total hip, 4.4% higher; femoral neck (FN), 4.9% higher; and lumbar spine, 5.2% higher) than women without. At the tibia, women with T2D had 7.4% greater cortical area and 1.3% greater density, as well as 8.7% higher trabecular bone volume fraction. There was no difference in BMSi (T2D mean [SD], 78.0 [8.3] vs controls, 78.1 [7.3]). Women with T2D had lower performance on all physical function tests. The study found 9.7% lower grip strength, 9.9% slower gait speed, and 13.9% slower timed up-and-go time than women without diabetes. During a median (IQR) follow-up of 7.3 (4.4-8.4) years, 1071 incident fractures, 853 major osteoporotic fractures (MOF), and 232 hip fractures occurred. In adjusted (for age, body mass index, clinical risk factors, and FN BMD) Cox regression models, T2D was associated with an increased risk of any fracture (HR, 1.26; 95% CI, 1.04-1.54) and MOF (HR, 1.25; 95% CI, 1.00-1.56).

In this cohort study of older women, T2D was associated with higher BMD, better bone microarchitecture, and no different BMSi but poorer physical function, suggesting that poor physical function is the main reason for the increased fracture risk in T2D women.

Osteoporosis is a common diabetic consequence that negatively affects patients' health and quality of life. Nevertheless, there is mutual interference between clinical drugs intended to regulate blood glucose and bone metabolism. Therefore, it is crucial to look for new treatment targets that effectively control blood glucose and safely protect the bone health of patients with diabetes. In this study, mice given a high-fat diet were shown to be resistant to osteoporosis and diabetes when protein phosphatase 5 (PP5) knockout (KO) mice were used. Serum markers of bone remodeling show that PP5 KO mice are resistant to decreased bone formation and increased bone resorption brought on by diabetes. The absence of PP5 resists the reduction of osteoblast differentiation and the enhancement of osteoclast differentiation in diabetic mice, according to the in vitro osteoblast differentiation of bone mesenchymal stem cells and osteoclast differentiation of bone marrow-derived macrophages. Subsequent investigation revealed that PP5 deficiency increases the expression of the key regulator of osteoblast differentiation, runt-related transcription factor 2, and decreases the activity of the receptor activator of the nuclear factor-κB ligand/osteoprotegerin pathway, a crucial regulatory signaling pathway for osteoclast differentiation. In conclusion, we discovered that PP5 deficiency protects diabetic mice against osteoporosis for the first time.

Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking.

To investigate the association between T2DM and HR-pQCT parameters in older men.

HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men (MrOS) study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, BMI, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status.

Among 1777 men, 290 had T2DM (mean age 84.4 years). T2DM men had smaller total cross-sectional area (Tt.AR) at the distal tibia (p=0.028) and diaphyseal tibia (p=0.025), and smaller cortical area at the distal (p= 0.009) and diaphyseal tibia (p= 0.023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all three scan sites. Lower cortical area, cortical thickness, total BMD, cortical BMD, and failure load of the distal sites were associated with increased risk of incident non-vertebral fracture in T2DM.

Older men with T2DM have smaller bone size compared to non-T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

Postmenopausal osteoporosis (PMO) and type 2 diabetes mellitus (T2DM) frequently coexist in postmenopausal women. The study aimed to explore metabolic variations linked to these circumstances and their simultaneous presence through proton nuclear magnetic resonance metabolomics (1H NMR).

Serum samples from 80 postmenopausal women, including 20 PMO individuals, 20 T2DM, 20 T2DM + PMO, and 20 healthy postmenopausal women, were analyzed using 1H NMR spectroscopy.

Our study revealed significant metabolic profile differences among the four groups. Notably, the T2DM + PMO group showed elevated levels of alanine, pyruvate, glutamate, lactate, and aspartate, indicating their involvement in lipid metabolism, energy, and amino acids. Importantly, our multivariate statistical analysis identified a metabolite set that accurately distinguished the groups, suggesting its potential as an early diagnostic marker.

The 1H NMR metabolomics approach uncovered metabolic biomarkers intricately linked to postmenopausal osteoporosis (PMO), type 2 diabetes mellitus (T2DM), and their concurrent presence. Among these biomarkers, alanine emerged as a pivotal player, showing its significant role in the metabolic landscape associated with PMO and T2DM. These findings shed light on the pathophysiological mechanisms underlying these conditions and underscore alanine's potential as a diagnostic biomarker.

Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/Ay mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156-0.366]) vs non-diabetic subjects 0.352% [0.269-0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46-30.10] vs non-diabetic subjects 76.24 MPa [26.81-132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=-0.7500, p=0.0255; r=-0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young's modulus was negatively correlated with SOST (r=-0.5675, p=0.0011), AXIN2 (r=-0.5523, p=0.0042), and SFRP5 (r=-0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.

Impact microindentation (IMI) is a minimally invasive technique that allows the assessment of bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. In this study, we aimed to assess the practicality of its application in 99 women aged 42-84 yr from the Geelong Osteoporosis Study. Impact microindentation was performed in the mid-shaft of the right tibia using the OsteoProbe. Immediately following measurement, each participant was requested to rate on a Visual Analogue Scale [0-10] the level of discomfort anticipated and experienced, any initial reluctance towards the measurement and whether they were willing to repeat the measurement. Of 99 potential participants who attended this assessment phase, 55 underwent IMI measurement. Reasons for non-measurement in 44 women were existing skin conditions (n = 8, 18.2 %) and excessive soft tissue around mid-tibial region (n = 32, 72.2 %). An additional four (9.1 %) participants did not provide any reasons for declining. For 55 participants who had underwent IMI, the expectation for pain when briefed about the procedure was low (2.28 ± 2.39), as was pain experienced during the measurement (0.72 ± 1.58). Participants were not reluctant to undergo the measurement (0.83 ± 1.67), and all indicated a willingness to repeat the measurement. Results of this study showed that the IMI technique is well tolerated and accepted by women participating in the Geelong Osteoporosis Study, suggesting that the technique shows promise in a research or clinical setting.

Fracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters.

The study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable.

MVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 μm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 μm, p = 0.017) and by 8.73 μm (4.8 %, CI: 0.79, 16.7 μm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by -43.6 mg/cm3 (2.6 %, CI: -77.4, -9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 μm (2.9 %, CI: 0.42, 30.4 μm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm-3 (17.8 %, CI: 0.01, 0.21 mm-3, p = 0.033) and vessel volume and diameter were significantly lower by -0.02 mm3 (13.7 %, CI: -0.04, -0.004 mm3, p = 0.015) and - 14.6 μm (2.8 %, CI: -29.1, -0.11 μm, p = 0.048), respectively.

The presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

Bone strength is determined not only by bone quantity [bone mineral density (BMD)] but also by bone quality, including matrix composition, collagen fiber arrangement, microarchitecture, geometry, mineralization, and bone turnover, among others. These aspects influence elasticity, the load-bearing and repair capacity of bone, and microcrack propagation and are thus key to fractures and their avoidance. In chronic kidney disease (CKD)-associated osteoporosis, factors traditionally associated with a lower bone mass (advanced age or hypogonadism) often coexist with non-traditional factors specific to CKD (uremic toxins or renal osteodystrophy, among others), which will have an impact on bone quality. The gold standard for measuring BMD is dual-energy X-ray absorptiometry, which is widely accepted in the general population and is also capable of predicting fracture risk in CKD. Nevertheless, a significant number of fractures occur in the absence of densitometric World Health Organization (WHO) criteria for osteoporosis, suggesting that methods that also evaluate bone quality need to be considered in order to achieve a comprehensive assessment of fracture risk. The techniques for measuring bone quality are limited by their high cost or invasive nature, which has prevented their implementation in clinical practice. A bone biopsy, high-resolution peripheral quantitative computed tomography, and impact microindentation are some of the methods established to assess bone quality. Herein, we review the current evidence in the literature with the aim of exploring the factors that affect both bone quality and bone quantity in CKD and describing available techniques to assess them.

The fracture behavior of bone is critically important for evaluating its mechanical competence and ability to resist fractures. Fracture toughness is an intrinsic material property that quantifies a material's ability to withstand crack propagation under controlled conditions. However, properly conducting fracture toughness testing requires the access to calibrated mechanical load frames and the destructive testing of bone samples, and therefore fracture toughness tests are clinically impractical. Impact microindentation mimicks certain aspects of fracture toughness measurements, but its relationship with fracture toughness remains unknown. In this study, we aimed to compare measurements of notched fracture toughness and impact microindentation in fresh and boiled bovine bone. Skeletally mature bovine bone specimens (n = 48) were prepared, and half of them were boiled to denature the organic matrix, while the other half remained preserved in frozen conditions. All samples underwent a notched fracture toughness test to determine their resistance to crack initiation (KIC) and an impact microindentation test using the OsteoProbe to obtain the Bone Material Strength index (BMSi). Boiling the bone samples increased the denatured collagen content, while mineral density and porosity remained unaffected. The boiled bones also showed significant reduction in both KIC (P < .0001) and the average BMSi (P < .0001), leading to impaired resistance of bone to crack propagation. Remarkably, the average BMSi exhibited a high correlation with KIC (r = 0.86; P < .001). A ranked order difference analysis confirmed the excellent agreement between the 2 measures. This study provides the first evidence that impact microindentation could serve as a surrogate measure for bone fracture behavior. The potential of impact microindentation to assess bone fracture resistance with minimal sample disruption could offer valuable insights into bone health without the need for cumbersome testing equipment and sample destruction.

Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines noninvasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. Although traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography, peripheral quantitative computed tomography, high-resolution quantitative computed tomography, and MRI provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.

Skeletal fracture has recently emerged as a complication of obesity. Given the normal or better than normal bone mineral density (BMD), the skeletal fragility of these patients appears to be a problem of bone quality rather than quantity. Type 2 diabetes mellitus (T2DM), the incidence of which increases with increasing body mass index, is also associated with an increased risk for fractures despite a normal or high BMD. With the additional bone pathology from diabetes itself, patients with both obesity and T2DM could have a worse skeletal profile. Clinically, however, there are no available methods for identifying those who are at higher risk for fractures or preventing fractures in this subgroup of patients. Weight loss, which is the cornerstone in the management of obesity (with or without T2DM), is also associated with an increased risk of bone loss. This review of the literature will focus on the skeletal manifestations associated with obesity, its interrelationship with the bone defects associated with T2DM, and the available approach to the bone health of patients suffering from obesity.

Previous research has confirmed that patients with type 2 diabetes mellitus tend to have higher bone mineral density (BMD), but it is unknown whether this pattern holds true for individuals without diabetes. This Mendelian randomization (MR) study aims to investigate the potential causal relationship between various glycemic trait (including fasting glucose, fasting insulin, 2-h postprandial glucose, and glycated hemoglobin) and BMD in non-diabetic individuals. The investigation focuses on different age groups (15-30, 30-45, 45-60, and 60 + years) and various skeletal sites (forearm, lumbar spine, and hip).

We utilized genome-wide association study data from large population-based cohorts to identify robust instrumental variables for each glycemic traits parameter. Our primary analysis employed the inverse-variance weighted method, with sensitivity analyses conducted using MR-Egger, weighted median, MR-PRESSO, and multivariable MR methods to assess the robustness and potential horizontal pleiotropy of the study results.

Fasting insulin showed a negative modulating relationship on both lumbar spine and forearm. However, these associations were only nominally significant. No significant causal association was observed between blood glucose traits and BMD across the different age groups. The direction of fasting insulin's causal effects on BMD showed inconsistency between genders, with potentially decreased BMD in women with high fasting insulin levels and an increasing trend in BMD in men.

In the non-diabetic population, currently available evidence does not support a causal relationship between glycemic traits and BMD. However, further investigation is warranted considering the observed gender differences.

Bone fragility is an emerging complication of diabetes. People with diabetes are at a significantly higher risk of fractures compared to the general population. Bone fragility occurs in diabetes as a result of complex and poorly understood mechanisms occurring at the cellular level contributed by vascular, inflammatory and mechanical derangements. Bone mineral density (BMD) as assessed by DEXA is low in type 1 diabetes. Type 2 diabetes has a high risk of fracture despite a normal to raised BMD. DEXA thus underestimates the fracture risk in diabetes. Data are scare regarding the efficacy of the available therapies in this low bone turnover state.

Diabetes mellitus (DM) is correlated with poor clinical outcomes in spinal surgery. However, the effect of it on screw stabilization has not been investigated. The aim of this study was to evaluate the screw loosening rate and postoperative outcomes in diabetic patients and to identify potential risk factors associated with loosening.

This was a retrospective study. Two hundred and forty-three patients who received cervical or lumbar internal fixation between 2015 and 2019 were enrolled. Screw loosening was assessed on radiography, and clinical outcomes were evaluated by the improvement of visual analogue scale (VAS), Oswestry disability index (ODI) or Japanese Orthopaedic Association (JOA) scores. The relationship of DM, screw loosening and clinical outcomes were analyzed with chi-square tests and regression analyses.

One hundred and twenty-two patients (50.2%) with diabetes were included in this study. Diabetes led to the increase of the rate of screw loosening in the lumbar spine, while the loosening rate did not vary significantly in the cervical spine. The occurrence of screw loosening in the lumbar spine was more likely to be associated with clinical outcomes for motor performance including walking and sitting. However, no significant effect on JOA and VAS scores in the cervical spine of screw loosening was found. Moreover, the history of DM affected the outcomes of the patients who underwent spinal surgery.

DM had an adverse effect on screw stabilization. The impaired improvement of clinical outcomes in diabetics after spinal surgery was related to screw loosening. In addition to the direct effects on operative wounds and neural function, the impact on the screws due to DM was also worth noting.

A substantial amount of evidence suggests a close relationship between osteoporosis (OP) and Type 2 Diabetes Mellitus (T2DM), but the mechanisms involved remain unknown. Therefore, we conducted this study with the aim of screening for hub genes common to both diseases and conducting a preliminary exploration of common regulatory mechanisms. In the present study, we first screened genes significantly associated with OP and T2DM by the univariate logistic regression algorithm. And then, based on cross-analysis and random forest algorithm, we obtained three hub genes (ACAA2, GATAD2A, and VPS35) and validated the critical roles and predictive performance of the three genes in both diseases by differential expression analysis, receiver operating characteristic (ROC) curves, and genome wide association study (GWAS) analysis. Finally, based on gene set enrichment analysis (GSEA) and the construction of the miRNA-mRNA regulatory network, we conducted a preliminary exploration of the co-regulatory mechanisms of three hub genes in two diseases. In conclusion, this study provides promising biomarkers for predicting and treating both diseases and offers novel directions for exploring the common regulatory mechanisms of both diseases.

Lobeglitazone is a newer oral hypoglycemic agent that has been tested in type 2 diabetes mellitus (T2DM). We aim to conduct a narrative review to find out the therapeutic benefits of lobeglitazone in patients with T2DM. We scientifically searched the electronic database of PubMed from inception until September 12, 2023, using Medical Subject Heading (MeSH) keywords. Additionally, we searched for pre-clinical trials related to lobeglitazone. We retrieved all available results of phase 1 to phase 3 studies of lobeglitazone in T2DM. Subsequently, we reviewed the results narratively. Three double-blind, randomized, placebo-controlled studies and a phase 3 trial of lobeglitazone showed that 0.5 mg daily dose exhibits effective therapeutic activity in glycemic, lipid, and hepatic control, and is also used as a secondary treatment in non-alcoholic fatty liver disease. Lobeglitazone exhibits as much antidiabetic activity as other thiazolidinediones such as pioglitazone and rosiglitazone. Side effects of lobeglitazone included peripheral edema, weight gain, and bone mineral density, which did not require hospitalization for these effects. This article highlights the pharmacological, pre-clinical, clinical, and safety pharmacology of novel thiazolidinedione lobeglitazone.

Type 2 diabetes mellitus (T2DM) increases risk of fractures due to bone microstructural and material deficits, though the mechanisms remain unclear. Preclinical models mimicking diabetic bone disease are required to further understand its pathogenesis. The TALLYHO/JngJ (TH) mouse is a polygenic model recapitulating adolescent-onset T2DM in humans. Due to incomplete penetrance of the phenotype ~25% of male TH mice never develop hyperglycemia, providing a strain-matched nondiabetic control. We performed a comprehensive characterization of the metabolic and skeletal phenotype of diabetic TH mice and compared them to either their nondiabetic TH controls or the recommended SWR/J controls to evaluate their suitability to study diabetic bone disease in humans. Compared to both controls, male TH mice with T2DM exhibited higher blood glucose levels, weight along with impaired glucose tolerance and insulin sensitivity. TH mice with/without T2DM displayed higher cortical bone parameters and lower trabecular bone parameters in the femurs and vertebrae compared to SWR/J. The mechanical properties remained unchanged for all three groups except for a low-energy failure in TH mice with T2DM only compared to SWR/J. Histomorphometry analyses only revealed higher number of osteoclasts and osteocytes for SWR/J compared to both groups of TH. Bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and tartrate-resistant acid phosphatase (TRAP) were low for both groups of TH mice compared to SWR/J. Silver nitrate staining of the femurs revealed low number of osteocyte lacunar and dendrites in TH mice with T2DM. Three-dimensional assessment showed reduced lacunar parameters in trabecular and cortical bone. Notably, osteocyte morphology changed in TH mice with T2DM compared to SWR/J. In summary, our study highlights the utility of the TH mouse to study T2DM, but not necessarily T2DM-induced bone disease, as there were no differences in bone strength and bone cell parameters between diabetic and non-diabetic TH mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Hyperglycemia and oxidative stress, enhanced in diabetes and aging, result in excessive accumulation of advanced glycation and glycoxidation end products (AGEs/AGOEs) in bone. AGEs/AGOES are considered to be "the missing link" in explaining increased skeletal fragility with diabetes, aging, and osteoporosis where increased fracture risk cannot be solely explained by bone mass and/or fall incidences. AGEs/AGOEs disrupt bone turnover and deteriorate bone quality through alterations of organic matrix (collagen and non-collagenous proteins), mineral, and water content. AGEs and AGOEs are also associated with bone fragility in other conditions such as Alzheimer's disease, circadian rhythm disruption, and cancer. This review explains how AGEs and AGOEs accumulate in bone and impact bone quality and bone fracture, and how AGES/AGOEs are being targeted in preclinical and clinical investigations for inhibition or removal, and for prediction and management of diabetic, osteoporotic and insufficiency fractures.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

It remains unclear whether the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) reflects causality in East Asian populations. Herein, a Mendelian randomization study conducted in East Asian population enhances the current clinical cognition that T2DM is not associated with reduction in BMD.

A Mendelian randomization (MR) approach was utilized to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in East Asian populations.

Genome-wide association study summary data from BioBank Japan were used to identify genetic variants strongly related to T2DM risk (36,614 cases and 155,150 controls) and osteoporosis (7788 cases and 204,665 controls). Heel BMD GWAS data of 1260 East Asian people from ieu open gwas project was considered as a second outcome. Inverse variance-weighted (IVW) analysis was mainly applied; MR-Egger and the weighted median were also used to obtain robust estimates. A series of sensitivity analyses including Cochran's Q test, MR-Egger regression, and leave-one-out analysis were used to detect pleiotropy or heterogeneity.

In the main analysis, IVW estimates indicated that T2DM significantly associated with the risk of osteoporosis (odds ratio = 0.92, 95% CI: 0.86-0.99, p = 0.016) and with higher BMD (OR: 1.25, 95% CI: 1.06-1.46, p = 6.49 × 10-3). Results of comprehensive sensitivity analysis were consistent with the main causality estimate. Horizontal pleiotropy and heterogeneity were absent in our MR study.

T2DM is not associated with reduction in BMD in terms of genetic polymorphism in East Asian populations.

The fracture behavior of bone is critically important for assessing its mechanical competence and ability to resist fractures. Fracture toughness, which quantifies a material's resistance to crack propagation under controlled geometry, is regarded as the gold standard for evaluating a material's resistance to fracture. However properly conducting this test requires access to calibrated mechanical load frames the destruction of the bone samples, making it impractical for obtaining clinical measurement of bone fracture. Impact microindentation offers a potential alternative by mimicking certain aspects of fracture toughness measurements, but its relationship with mechanistic fracture toughness remains unknown. In this study, we aimed to compare measurements of notched fracture toughness and impact microindentation in fresh and boiled bovine bone. Skeletally mature bovine bone specimens (n=48) were prepared, and half of them were boiled to denature the organic matrix, while the other half remained preserved in frozen conditions. Notched fracture toughness tests were conducted on all samples to determine Initiation toughness (KIC), and an impact microindentation test using the OsteoProbe was performed to obtain the Bone Material Strength index. Boiling the bone samples resulted increased the denatured collagen without affecting mineral density or porosity. The boiled bones also showed significant reduction in both KIC (p < 0.0001) and the average Bone Material Strength index (p < 0.0001), leading to impaired resistance of bone to crack propagation. Remarkably, the average Bone Material Strength index exhibited a high correlation with KIC (r = 0.86; p < 0.001). The ranked order difference analysis confirmed excellent agreement between the two measures. This study provides the first evidence that impact microindentation could serve as a surrogate measure for bone fracture behavior. The potential of impact microindentation to non-destructively assess bone fracture resistance could offer valuable insights into bone health without the need for elaborate testing equipment and sample destruction.

No previous studies have investigated the association between the bone material strength index (BMSi; an indicator of bone material properties obtained by microindentation) and the risk of incident fracture. The primary purpose of this prospective cohort study was to evaluate if BMSi is associated with incident osteoporotic fracture in older women and, secondarily, with prevalent fractures, anthropometric traits, or measurements of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). In a population-based cohort, 647 women aged 75 to 80 years underwent bone microindentation using the OsteoProbe device. Data on clinical risk factors (CRFs), prevalent fractures, and incident fractures were collected using questionnaires, medical records, and a regional X-ray archive. BMD and vertebral fracture assessment (VFA) were assessed by DXA (Hologic, Discovery A). Associations between BMSi, anthropometrics, BMD, and prevalent fractures were investigated using correlation and linear and logistic regression. Cox proportional hazards and competing risks analysis by Fine and Gray were used to study the association between BMSi and the risk of fracture and mortality. BMSi was weakly associated with age (r = -0.13, p < 0.001) and BMI (r = -0.21, p < 0.001) and with BMD of lumbar spine (β = 0.09, p = 0.02) and total hip (β = 0.08, p = 0.05), but only after adjustments. No significant associations were found between BMSi and prevalent fractures (self-reported and/or VFA identified, n = 332). During a median follow-up time of 6.0 years, 121 major osteoporotic fractures (MOF), 151 any fractures, and 50 deaths occurred. Increasing BMSi (per SD) was associated with increased risk of MOF (hazard ratio [HR] = 1.29, 95% confidence interval [CI] 1.07-1.56), any fracture (HR = 1.29, 95% CI 1.09-1.53), and mortality (HR = 1.44, 95% CI 1.07-1.93). The risk of fracture did not materially change with adjustment for confounders, CRFs, femoral neck BMD, or when considering the competing risk of death. In conclusion, unexpectedly increasing BMSi was associated with greater fracture risk. The clinical relevance and potential mechanisms of this finding require further study. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).