Journal of Bone and Mineral Research最新文献

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 years; n = 20) and age- and sex-matched non-diabetic 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 post-yield 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 non-diabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density (Ct.TMD), 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, 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.

Emerging evidence demonstrates an opportunity for using probiotics to support bone health but findings in humans are limited. This systematic review investigated if probiotic supplementation improves bone mineral density and bone structure in rodent models compared to no supplementation. Studies (n = 71) examining the effect of oral consumption of any probiotic strain on bone mineral density or bone structure in rodents were included. Meta-analyses were conducted separately by study model (intact, ovariectomized) and bone site (femur, tibia, spine) to determine the probiotic effect (standardized mean difference, SMD) on volumetric bone mineral density (vBMD), bone volume fraction (BV/TV) and cortical thickness (Ct.Th). Reasons for heterogeneity were explored (probiotic genus, sex, type of rodent). In intact rodents, probiotics resulted in greater vBMD (SMD = 0.43, 95% CI [0.13, 0.74], I2 = 3%, P<.05) and higher BV/TV (SMD = 0.63, 95% CI [0.25, 1.02], I2 = 57%, P<.05) at the femur without changes in cortical bone structure. In ovariectomized models, probiotic supplementation resulted in greater vBMD (femur: SMD = 1.28, 95% CI [1.01, 1.55], I2 = 3%, P<.05; tibia: SMD = 1.29, 95% CI [0.52, 2.05], I2 = 67%, P<.05; and spine: SMD = 1.47, 95% CI [0.97, 1.97], I2 = 26%, P<.05) as well as higher BV/TV (femur: SMD = 1.16, 95% CI [0.80, 1.52], I2 = 56%, P<.05; tibia: SMD = 2.13; 95% CI [1.09, 3.17], I2 = 79%, P<.05; spine: SMD = 2.04, 95% CI [1.17, 2.90], I2 = 76%, P<.05) and Ct.Th at the tibia (SMD = 2.35; 95% CI [0.72, 3.97], I2 = 82%, P<.05) but not at the femur versus control. The syntheses support probiotics as a strategy to improve bone outcomes in rodent models.

There are limited data describing the epidemiology of vertebral fractures (VF) from resource-limited settings, where the ageing population is growing most rapidly. We aimed to determine the prevalence, incidence, and risk factors for VF in The Gambia, West Africa. The Gambian Bone and Muscle Ageing Study is a prospective observational study in men and women aged 40 years and over. Rural participants had baseline measurements and plasma samples collected and were followed up 6-8 years later; urban participants had a single measurement. DXA scans were obtained to assess areal bone mineral density (aBMD), body composition and VF. Prevalence and incidence were calculated. Risk factors for prevalent and incident fracture were tested using logistic regression, in men and women separately, with and without adjustment for age and BMI. At baseline, 581 individuals (298 women) had useable scans, 214 (127 women) at follow-up. Prevalence of VF was 14.8%. Those with VF were older (65.6(11.2) vs 61.7(12.3) years, P=.01) and had lower aBMD Z-scores. For example, in women, a 1SD increase in femoral neck Z-score resulted in a lower risk of having a prevalent VF (OR [95% CI]) 0.51 [0.38, 0.73]. In men, lumbar spine Z-scores were predictive of prevalent fracture; (0.71 [0.53, 0.97]). The incidence of VF over follow-up was 12.1%. Low BMD and grip strength were associated with the odds of having an incident VF. Given the importance of prevalent VF in predicting future VF and other fragility fractures in other populations, our findings are a major cause for concern. VF prevalence in Gambian older adults is similar to elsewhere despite fractures not being a perceived issue. Risk factors were like those identified elsewhere including age, aBMD and bone resorption. Understanding the impact of these fractures is important in a region where health of the ageing population needs to be prioritized.

The ketogenic diet (KD) has demonstrated efficacy in ameliorating inflammation in rats with osteoarthritis (OA). However, the long-term safety of the KD and the underlying mechanism by which it delays OA remain unclear. We found that while long-term KD could ameliorate OA, it induced severe hepatic steatosis in mice. Consequently, we developed two versions of ketogenic-based diets: KD supplemented with vitamin D and intermittent KD. Both KD supplemented with vitamin D and intermittent KD effectively alleviated OA by significantly reducing the levels of inflammatory cytokines, cartilage loss, sensory nerve sprouting, and knee hyperalgesia without inducing hepatic steatosis. Furthermore, β-hydroxybutyrate (β-HB), a convenient energy carrier produced by adipocytes, could ameliorate OA without causing liver lesions. Mechanistically, β-HB enhanced chondrocyte autophagy and reduced apoptosis through the activation of Erb-B2 receptor tyrosine kinase 3 (ERBB3) signaling pathway; a pathway which was down-regulated in the articular chondrocytes from both OA patients and mice. Collectively, our findings highlighted the potential therapeutic value of β-HB and KD supplemented with vitamin D and intermittent KD approaches for managing OA.

Human skeletal elements are formed from distinct origins at distinct positions of the embryo. For example, the neural crest produces the facial bones, the paraxial mesoderm produces the axial skeleton, and the lateral plate mesoderm produces the appendicular skeleton. During skeletal development, different combinations of signaling pathways are coordinated from distinct origins during the sequential developmental stages. Models for human skeletal development have been established using human pluripotent stem cells (hPSCs) and by exploiting our understanding of skeletal development. Stepwise protocols for generating skeletal cells from different origins have been designed to mimic developmental trails. Recently, organoid methods have allowed the multicellular organization of skeletal cell types to recapitulate complicated skeletal development and metabolism. Similarly, several genetic diseases of the skeleton have been modeled using patient-derived induced pluripotent stem cells and genome-editing technologies. Model-based drug screening is a powerful tool for identifying drug candidates. This review briefly summarizes our current understanding of the embryonic development of skeletal tissues and introduces the current state-of-the-art hPSC methods for recapitulating skeletal development, metabolism, and diseases. We also discuss the current limitations and future perspectives for applications of the hPSC-based modeling system in precision medicine in this research field.

Hypophosphatasia (HPP) is a rare disorder of the bone metabolism, characterized by genetically-determined low alkaline phosphatase (ALP) activity. Low ALP may also be observed in some common causes of bone fragility, such as in osteoporosis treated with antiresorptive drugs. This study aimed to verify whether differences in bone turnover markers (BTMs) could help differentiate adult patients with HPP from those with osteoporosis undergoing antiresorptive treatment. In this multicenter study, we enrolled 23 adult patients with a diagnosis of HPP and compared them with 46 osteoporotic subjects previously treated with zoledronic acid or denosumab. BTMs such as C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), total ALP, and bone ALP (bALP) were measured, and ratios between BTMs were also calculated. Considering that the control group included only females, in the primary analysis we compared their characteristics with that of the 16 female patients with HPP. Both individual BTMs (CTX and P1NP) and four BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an AUC of 0.962 with a cut-off of 32 μg/L, while as for the BTMs ratios, the ALP/P1NP ratio had an AUC of 0.964 with a cut-off of 1.114. Similar results were confirmed when including male HPP patients, when adjusting for age and sex, and finally when performing a sensitivity analysis only in patients with ALP less than or equal to 32 U/L (i.e., the median of the distribution of the entire population). In cases of low ALP and bone fragility, BTM and their ratios could help distinguish HPP patients from osteoporotic individuals treated with antiresorptive drugs, aiding in accurate diagnosis and reducing the risk of inappropriate treatment.

Romosozumab following anti-resorptive can be an effective sequential treatment strategy to improve bone strength. However, whether the transition to romosozumab after denosumab is associated with greater improvement in bone mineral density (BMD) and trabecular bone score (TBS) compared to denosumab continuation remains unclear. In this propensity score-matched cohort study, we analyzed data from postmenopausal women who initiated denosumab between 2017 and 2020. Individuals who were transited to 12 months of romosozumab after denosumab were 1:1 matched to those who continued an additional 12 months of denosumab (n = 86 for each group; denosumab-romosozumab [DR] and denosumab-denosumab [DD]). Mean BMD gain by denosumab treatment in matched DR and DD groups from denosumab initiation to transition (median 4 times [range 2 to 8]) was +4.8% and + 2.0% in the lumbar spine and total hip. DR group showed greater LS BMD gain compared to the DD group (+6.8 vs. +3.3% point, P<.001) for 12 months post-transition independent of the duration of prior denosumab treatment, yielding greater overall LS BMD gain in DR compared to DD (+11.6% vs. +8.0%, P<.001). DD group showed continued improvement of hip BMD, whereas hip BMD was maintained but not improved in the DR group. DR group was associated with greater TBS improvement than the DD group (2.9% vs 1.0%, P=.042). One month after the transition to romosozumab from denosumab, P1NP immediately increased above the level of denosumab initiation with relatively suppressed CTx, creating a transient anabolic window. For 12 months follow-up, one incident morphometric vertebral fracture and one patella fracture were observed in DD, whereas one ankle fracture was observed in the DR group. Romosozumab following denosumab improved lumbar spine BMD and TBS greater than denosumab continuation in postmenopausal women.