The incidence of type 2 diabetes mellitus (T2DM) complicated with osteoporosis (OP) (T2DM-OP) is growing. Dapagliflozin and metformin are commonly prescribed to manage glycemic levels in T2DM patients. We investigated the clinical efficacy of combining dapagliflozin with metformin in elderly patients with T2DM-OP. Totally 144 T2DM-OP patients were prospectively enrolled and allocated into two groups: the Metformin and Dapagliflozin + Metformin groups. Each group received treatment for 12 months. Fasting peripheral blood samples were collected before and after 12 months of treatment. Glycemic parameters and bone metabolic parameters were measured using oral glucose tolerance test, automatic biochemical analyzers, or liquid chromatography. Bone mineral density (BMD) changes at lumbar vertebrae (L1-4), femoral neck (FN) and total hip (TH) were assessed using dual-energy X-ray bone mineral densitometry. Pain severity was evaluated using the visual analog scale (VAS). The total effective rate, fracture incidence, and adverse reaction rate were also evaluated. After 12 months, both groups showed improvements in glycemic parameters, bone metabolic parameters, and BMD at L1-4, FN, and TH, and reductions in VAS scores. The Dapagliflozin + Metformin group exhibited more significant improvements. The overall effective rate was higher and fracture incidence, was lower in Dapagliflozin + Metformin group, with comparable rates of adverse reactions and safety profiles between the two groups. Taken together, treatment with a combination of dapagliflozin and metformin led to improvements in blood glucose levels, bone metabolism, and BMD in elderly patients with T2DM-OP, demonstrating superior efficacy and safety compared to metformin monotherapy.

This meta-analysis aims to examine differences in biochemical markers of bone metabolism between individuals with type 2 diabetes (T2DM) and non-T2DM control groups.

Two independent evaluators searched five databases: PubMed, EMBASE, EBSCOhost, Web of Science, and the Cochrane Library. We aimed to identify observational studies investigating the impact of T2DM on biochemical markers of bone metabolism. Literature retrieval covered the period from the establishment of the databases up to November 2022. Studies were included if they assessed differences in biochemical markers of bone metabolism between T2DM patients and non-T2DM control groups using cross-sectional, cohort, or case-control study designs.

Fourteen studies were included in the analysis, comprising 12 cross-sectional studies and 2 cohort studies. Compared to the non-T2DM control group, T2DM patients showed reduced levels of Osteocalcin and P1NP, which are markers of bone formation. Conversely, levels of Alkaline phosphatase and Bone-specific alkaline phosphatase, other bone formation markers, increased. The bone resorption marker CTX showed decreased levels, while TRACP showed no significant difference.

In individuals with T2DM, most bone turnover markers indicated a reduced rate of bone turnover. This reduction can lead to increased bone fragility despite higher bone mineral density, potentially increasing the risk of osteoporosis.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php? identifier CRD42022366430.

With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

The growing evidence shows that parathyroid hormone (PTH) may affect glucose metabolism. However, the relationship between them is still controversial among diabetic patients. The current study aimed to investigate the relationship between PTH and glucose metabolism in the patients with newly diagnosed type 2 diabetes (T2D).

A total of 532 participants, including 387 patients with newly diagnosed T2D and 145 healthy controls, were recruited in the present study. PTH and metabolic parameters were measured in all participants.

The PTH levels were significantly lower in the newly diagnosed T2D patients compared with the control group (35.10 (25.90, 47.20) vs. 47.15 (35.83, 58.65) pg/ml, P < 0.001). The T2D patients with a higher glycated hemoglobin (HbA1c) tertile had lower PTH levels than the patients with a lower HbA1c tertile (32.90 (24.85, 41.40) vs. 37.50 (26.10, 54.55) pg/ml, P < 0.001). Spearman correlation analysis showed that PTH was positively correlated with the body mass index (BMI), fasting insulin (FINS), homeostasis model assessment of β-cell function (HOMA-β), and homeostasis model assessment of insulin resistance (HOMA-IR) and negatively correlated with HbA1c, blood calcium (Ca), blood phosphorus (P), and 25-hydroxyvitamin D3 (25-OH-D3). Multiple linear regression analysis demonstrated that PTH was significantly associated with HbA1c (β = -1.475, P=0.003) and HOMA-β (β = 0.090, P=0.001) after adjusting for age, sex, BMI, season, 25-OH-D3, Ca, and P.

PTH was negatively correlated with HbA1c in the newly diagnosed T2D patients. Our results suggested that the PTH level within the reference range is related to islet β-cell function and hyperglycemia.

This study aimed to evaluate the characteristics of bone metabolism and fracture risk in the type 2 diabetes mellitus (T2DM) patients with distal symmetric polyneuropathy (DSPN).

A total of 198 T2DM individuals were recruited from January 2017 to December 2020. Patients with DSPN were evaluated by strict clinical and sensory thresholds. Biochemical parameters and bone mineral density (BMD) were measured. The BMD, bone turnover markers, and probability of fracture were compared between two groups, and the factors related to BMD and probability of hip fracture in 10 years were further explored.

Compared with type 2 diabetes mellitus without distal symmetric polyneuropathy (T2DN-) patients, type 2 diabetes mellitus with distal symmetric polyneuropathy (T2DN+) patients had lower level of cross-linked C-telopeptide (CTX) (0.32 ± 0.19 vs 0.38 ± 0.21 ng/mL, p = 0.038) and higher level of bone-specific alkaline phosphatase (BALP) (15.28 ± 5.56 vs 12.58 ± 4.41 μg/mL, p = 0.003). T2DN+ patients had higher BMD of lumbar L1-L4 (1.05 ± 0.19 vs 0.95 ± 0.37, p = 0.027) and higher probability of hip fracture (0.98 ± 0.88 vs 0.68 ± 0.63, p = 0.009) as compared to T2DN- individuals. Univariate correlation analysis showed that BALP level (coefficient (coef) = -0.054, p = 0.038), CTX level (coef = -2.28, p = 0.001), and hip fracture risk (coef = -1.02, p < 0.001) were negatively related to the BMD of L1-L4. As for the risk of hip fracture evaluated by WHO Fracture Risk Assessment Tool (FRAX), age (coef = 0.035, p < 0.001), use of insulin (coef = 0.31, p =0.015), and levels of BALP (coef = 0.031, p = 0.017) and CTX (coef = 0.7, p = 0.047) were positively related to the risk of hip fracture. Multivariate regression analysis showed that CTX level (coef = -1.41, p = 0.043) was still negatively related to BMD at the lumbar spine.

This study indicates that T2DM patients with DSPN have special bone metabolism represented by higher BALP level and lower CTX level which may increase BMD at the lumbar spine.

Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality.

In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses.

Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither.

Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.

As the ovaries age and women transition to menopause and postmenopause, reduced estradiol levels are associated with anxiety and depression. Exercise contributes to alleviate anxiety and depression and the bone-derived hormone osteocalcin has been reported to be necessary to prevent anxiety-like behaviors. The aim of this study was to investigate the effects of exercise on anxiety behaviors in climacteric mice and whether it was related to osteocalcin.

Menopausal mouse model was induced by intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD). Open field, elevated plus maze, and light-dark tests were used to detect anxious behavior in mice. The content of serum osteocalcin was measured and its correlation with anxiety behavior was analyzed. BRDU and NEUN co-localization cells were detected with immunofluorescence. Western blot was applied to obtain apoptosis-related proteins.

The VCD mice showed obvious anxiety-like behaviors and 10 weeks of treadmill exercise significantly ameliorated the anxiety and increased circulating osteocalcin in VCD mice. Exercise increased the number of BRDU and NEUN co-localization cells in hippocampal dentate gyrus, reduced the number of impaired hippocampal neurons, inhibited the expression of BAX, cleaved Caspase3, and cleaved PARP, promoted the expression of BCL-2. Importantly, circulating osteocalcin levels were positively associated with the improvements of anxiety, the number of BRDU and NEUN co-localization cells in hippocampal dentate gyrus and negatively related to impaired hippocampal neurons.

Exercise ameliorates anxiety behavior, promotes hippocampal dentate gyrus neurogenesis, and inhibits hippocampal cell apoptosis in VCD-induced menopausal mice. They are related to circulating osteocalcin, which are increased by exercise.

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide; and commonly used resorption markers serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen and tartrate resistant acid phosphatase type 5b. BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable components (e.g., age, gender, ethnicity) and controllable components, particularly relating to collection conditions (e.g., fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics; and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.

Osteoporosis and type 2 diabetes (T2D) have been recognized as a widespread comorbidity leading to excess mortality and an enormous healthcare burden. In T2D, bone mineral density (BMD) may underestimate the risk of low-energy fractures as bone quality is reduced. It was hypothesized that a decrease in the trabecular bone score (TBS), a parameter assessing bone microarchitecture, may be an early marker of impaired bone health in women with T2D.

To identify clinical and body composition parameters that affect TBS in postmenopausal women with T2D and normal BMD.

A non-interventional cross-sectional comparative study was conducted. Potentially eligible subjects were screened at tertiary referral center. Postmenopausal women with T2D, aged 50-75 years, with no established risk factors for secondary osteoporosis, were included. BMD, TBS and body composition parameters were assessed by dual-energy X-ray absorptiometry. In women with normal BMD, a wide range of anthropometric, general and diabetes-related clinical and laboratory parameters were evaluated as risk factors for TBS decrease using univariate and multivariate regression analysis and analysis of receiver operating characteristic (ROC) curves.

Three hundred twelve women were initially screened, 176 of them met the inclusion criteria and underwent dual X-ray absorptiometry. Those with reduced BMD were subsequently excluded; 96 women with normal BMD were included in final analysis. Among them, 43 women (44.8%) showed decreased TBS values (≤ 1.31). Women with TBS ≤ 1.31 were taller and had a lower body mass index (BMI) when compared to those with normal TBS (Р = 0.008 and P = 0.007 respectively). No significant differences in HbA1c, renal function, calcium, phosphorus, alkaline phosphatase, PTH and 25(ОН)D levels were found. In a model of multivariate linear regression analysis, TBS was positively associated with gynoid fat mass, whereas the height and androgen fat mass were associated negatively (all P < 0.001). In a multiple logistic regression, TBS ≤ 1.31 was associated with lower gynoid fat mass (adjusted odd ratio [OR], 0.9, 95% confidence interval [CI], 0.85-0.94, P < 0.001), higher android fat mass (adjusted OR, 1.13, 95%CI, 1.03-1.24, P = 0.008) and height (adjusted OR, 1.13, 95%CI, 1.05-1.20, P < 0.001). In ROC-curve analysis, height ≥ 162.5 cm (P = 0.04), body mass index ≤ 33.85 kg/m2 (P = 0.002), gynoid fat mass ≤ 5.41 kg (P = 0.03) and android/gynoid fat mass ratio ≥ 1.145 (P < 0.001) were identified as the risk factors for TBS reduction.

In postmenopausal women with T2D and normal BMD, greater height and central adiposity are associated with impaired bone microarchitecture.

Increased fracture risk represents an emerging and severe complication of diabetes. The resulting prolonged immobility and hospitalisations can lead to substantial morbidity and mortality. In type 1 diabetes, bone mass and bone strength are reduced, resulting in up to a five-times greater risk of fractures throughout life. In type 2 diabetes, fracture risk is increased despite a normal bone mass. Conventional dual-energy x-ray absorptiometry might underestimate fracture risk, but can be improved by applying specific adjustments. Bone fragility in diabetes can result from cellular abnormalities, matrix interactions, immune and vascular changes, and musculoskeletal maladaptation to chronic hyperglycaemia. This Review summarises how the bone microenvironment responds to type 1 and type 2 diabetes, and the mechanisms underlying fragility fractures. We describe the value of novel imaging technologies and the clinical utility of biomarkers, and discuss current and future therapeutic approaches that protect bone health in people with diabetes.