Journal of Bone and Mineral Research最新文献

Vitamin D dysregulation can occur in people living with HIV, disrupting calcium homeostasis, and bone turnover. We aimed to investigate the potential mechanisms by which vitamin D regulates bone turnover in adolescents living with perinatally-acquired HIV (ALWH) in Southern Africa. A pre-planned secondary analysis was performed of baseline data from the vitamin D for adolescents with HIV to reduce musculoskeletal morbidity and immunopathology trial (PACTR20200989766029) which enrolled ALWH (11-19 yr) taking antiretroviral therapy for ≥6 mo, and recorded socio-demographic, clinical and dietary data. After over-night fasting, vitamin D metabolites (25(OH)D, 1,25(OH)2D, and 24,25(OH)2D), intact parathyroid hormone (PTH), and bone turnover markers (BTMs) (C-terminal telopeptide of type I collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)) were measured. Tandem Mass Spectrometry measured vitamin D metabolites, while intact PTH and BTMs were analyzed by electrochemiluminescence immunoassay. Stratified by 25(OH)D (<75 vs ≥75 nmol/L), associations between standardized concentrations (β = standard deviations) of vitamin D metabolites, intact PTH and BTMs were assessed using structural equations modelling (SEM) adjusted for age, sex, and country (Zimbabwe/Zambia). Among the 842 ALWH enrolled, the median dietary calcium intake was 100 mg (IQR: 55-145). The SEM showed PTH was positively associated (β: 0.21; 95% CI, 0.1, 0.32) with 1,25(OH)2D, only when 25(OH)D was <75 vs ≥75 nmol/L (β: 0.23; 95%CI, -0.13, 0.59), with evidence of an interaction (β: -0.11; 95%CI, -0.20, -0.02). A positive relationship between 25(OH)D and 24,25(OH)2D was seen irrespective of 25(OH)D concentration. 24,25(OH)2D was inversely related to BTMs, particularly when 25(OH)D was <75 nmol/L (CTX: β: -0.15; 95% CI, -0.24, -0.06 and P1NP: β: -0.14; 95%CI, -0.22, -0.06). There was interaction between dietary calcium and 25(OH)D on PTH (β: -0.15; 95% CI, -0.22, -0.07) suggesting an interaction between low 25(OH)D and low dietary calcium which increases PTH. In conclusion, associations between 25(OH)D, PTH, 1,25(OH)2D, and BTMs in ALWH appear dependent upon 25(OH)D concentrations <75 nmol/L and calcium intake. A novel, potentially causal pathway between 25(OH)D, 24,25(OH)2D, and BTMs was seen. Findings enhance understanding of vitamin D metabolism in people living with HIV.

Physical activity (PA), sedentary behavior (SB), and sleep are each individually associated with falls and fractures, but often are not examined simultaneously. Compositional data analysis examined the combined prospective associations between the proportion of time in PA, SB, and sleep relative to the remaining behaviors with recurrent falls (2+ falls in any yr), any fractures, and major osteoporotic fracture (MOF) from tri-annual questionnaires, with adjudication for fractures, in 2918 older men aged 78.9 ± 5.1 yr in the Osteoporotic Fractures in Men (MrOS) Study. Accelerometers were worn on the right tricep for seven consecutive 24-h periods and measured PA (>1.5 METs), SB (≤1.5 METs), and sleep. Generalized estimating equations evaluated associations with recurrent falls. Cox proportional hazards regression estimated any incident fracture and MOF risk separately. Over 4 yr of follow-up, 1025 (35.2%) experienced recurrent falls; over 10 ± 4 yr of follow-up, 669 (22.9%) experienced incident fractures, and 370 (12.7%) experienced a MOF. Higher proportions of PA relative to SB and sleep were associated with lower odds of recurrent falls [odds ratio (OR): 0.87, 95% CI: 0.76-0.99]. Higher proportions of SB relative to PA and sleep were associated with a higher odds of recurrent falls (OR: 1.38, 95% CI: 1.06-1.81) and a higher risk of any fracture [hazard ratio (HR): 1.42, 95% CI: 1.05-1.92]. Higher proportions of sleep relative to PA and SB were associated with a lower risk of fracture (HR: 0.74, 95% CI: 0.54-0.99). No associations of activity composition with MOF were observed. When accounting for the co-dependence of daily activities, higher proportions of SB relative to the proportion of PA and sleep were associated with higher odds of recurrent falls and fracture risk. Results suggest reducing SB (and increasing PA) may lower fall and fracture risk in older men, which could inform future interventions.

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 (BMD) and bone structure in rodent models compared to no supplementation. Studies (n = 71) examining the effect of oral consumption of any probiotic strain on BMD 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 BMD (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 < 0.05) and higher BV/TV (SMD = 0.63, 95% CI [0.25, 1.02], I2 = 57%, p < 0.05) 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 < 0.05; tibia: SMD = 1.29, 95% CI [0.52, 2.05], I2 = 67%, p < 0.05; and spine: SMD = 1.47, 95% CI [0.97, 1.97], I2 = 26%, p < 0.05) as well as higher BV/TV (femur: SMD = 1.16, 95% CI [0.80, 1.52], I2 = 56%, p < 0.05; tibia: SMD = 2.13, 95% CI [1.09, 3.17], I2 = 79%, p < 0.05; spine: SMD = 2.04, 95% CI [1.17, 2.90], I2 = 76%, p < 0.05) and Ct.Th at the tibia (SMD = 2.35; 95% CI [0.72, 3.97], I2 = 82%, p < .0.05) but not at the femur versus control. The syntheses support probiotics as a strategy to improve bone outcomes in rodent models.

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 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 4 BTM ratios (ALP/P1NP, bALP/P1NP, ALP/CTX, and bALP/CTX) showed satisfactory discriminatory power, outperforming ALP alone. P1NP, in particular, had an area under the curve (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 (ie, 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.

Atypical femur fractures (AFFs) are rare adverse events associated with bisphosphonate use, having unclear pathophysiology. AFFs also cluster in families and have occurred in patients with monogenetic bone diseases sometimes without bisphosphonate use, suggesting an underlying genetic susceptibility. Our aim was to identify a genetic cause for AFF in a Caucasian family with 7 members affected by osteoporosis, including 3 siblings with bisphosphonate-associated AFFs. Using whole-exome sequencing, we identified a rare pathogenic variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the 3 siblings with AFFs. The same variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF and in 1 of 73 unrelated European AFF patients. LOXL4 is involved in collagen cross-linking and may be relevant for microcrack formation and bone repair mechanisms. Preliminary functional analysis showed that skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with 2 controls. In conclusion, this LOXL4 variant may underlie AFF susceptibility possibly due to abnormal collagen metabolism, leading to increased formation of microdamage or compromised healing of microcracks in the femur.

There are limited data describing the epidemiology of vertebral fractures (VF) from resource-limited settings, where the aging 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 yr and over. Rural participants had baseline measurements and plasma samples collected and were followed up 6-8 yr later; urban participants had a single measurement. DXA scans were obtained to assess areal BMD (aBMD), body composition, and VF. Prevalence and incidence were calculated. Risk factors for prevalent and incident fractures 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) yr, p = .01) and had lower aBMD Z-scores. For example, in women, a 1 SD 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 the health of the aging population needs to be prioritized.

Recent advancements in deep learning (DL) have revolutionized the capability of artificial intelligence (AI) by enabling the analysis of large-scale, complex datasets that are difficult for humans to interpret. However, large amounts of high-quality data are required to train such generative AI models successfully. With the rapid commercialization of single-cell sequencing and spatial transcriptomics platforms, the field is increasingly producing large-scale datasets such as histological images, single-cell molecular data, and spatial transcriptomic data. These molecular and morphological datasets parallel the multimodal text and image data used to train highly successful generative AI models for natural language processing and computer vision. Thus, these emerging data types offer great potential to train generative AI models that uncover intricate biological processes of bone cells at a cellular level. In this Perspective, we summarize the progress and prospects of generative AI applied to these datasets and their potential applications to bone research. In particular, we highlight three AI applications: predicting cell differentiation dynamics, linking molecular and morphological features, and predicting cellular responses to perturbations. To make generative AI models beneficial for bone research, important issues, such as technical biases in bone single-cell datasets, lack of profiling of important bone cell types, and lack of spatial information, needs to be addressed. Realizing the potential of generative AI for bone biology will also likely require generating large-scale, high-quality cellular-resolution spatial transcriptomics datasets, improving the sensitivity of current spatial transcriptomics datasets, and thorough experimental validation of model predictions.

Opportunistic screening is essential to improve the identification of individuals with osteoporosis. Our group has utilized image texture features to assess bone quality using clinical MRIs. We have previously demonstrated that greater heterogeneity of MRI texture related to history of fragility fractures, lower bone density, and worse microarchitecture. The present study investigated relationships between MRI-based texture features and biomechanical properties of bone using CT-based finite element analyses (FEA). We hypothesized that individuals with greater texture heterogeneity would have lower stiffness and failure load. Thirty individuals included in this prospective study had CT and MRI of L1 and L2 vertebrae. Using T1-weighted MR images, a gray-level co-occurrence matrix was generated to characterize the distribution and spatial organization of voxelar signal intensities to derive the following texture features: contrast (variability), entropy (disorder), angular second moment (ASM; uniformity), and inverse difference moment (IDM; homogeneity). Features were calculated in five directions relative to the image plane. Whole-bone stiffness and failure load were calculated from phantom-calibrated lumbar QCT. Mean age of subjects was 59 ± 11 years (57% female). Individuals with lower vertebral stiffness had greater texture heterogeneity; specifically, higher contrast (r = -0.54, P<.01), higher entropy (r = -0.52, P<.01), lower IDM (r = 0.54, P<.01) and lower ASM (r = 0.51, P<.01). Lower vertebral failure load and lower vBMD were similarly associated with greater texture heterogeneity. Relationships were unchanged when using the average of texture in all directions or the vertical direction in isolation. In summary, individuals with more heterogeneous MRI-based trabecular texture had lower stiffness and failure load by FEA, and lower vBMD by central quantitative CT. These results-the first relating MRI-based texture features and biomechanical properties of bone-provide further support that MRI-based texture measurements can be used to opportunistically detect skeletal fragility.

Chondrodysplasias with multiple dislocations are rare skeletal disorders characterized by hyperlaxity, joint dislocations, and growth retardation. Chondrodysplasias with multiple dislocations have been linked to pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis. In this study, by exome sequencing analysis, we identified a homozygous nonsense variant (NM_001297654.2: c.1825C > T, p.Arg609*) in the discoidin domain receptor 1 (DDR1) gene in a patient presenting joint dislocations, hyperlaxity, and cerebellar hypoplasia. Functional studies revealed decreased proteoglycan production in patient fibroblasts. We further demonstrated that DDR1 inhibition impaired the Indian Hedgehog (IHH) signaling pathway in chondrocytes, decreased differentiation and mineralization in osteoblasts, and disrupted p38 MAPK signaling in both cell types. Additionally, we showed that DDR1 inhibition affected the non-canonical WNT signaling pathway in human skeletal cells and decreased proteoglycan production in chondrocytes. These findings suggest that DDR1 is a new gene involved in the group of chondrodysplasias with multiple dislocations and highlights its essential role in human skeletal and brain development.

Bone vasculature is richly innervated by an extensive network of sympathetic nerves. However, our understanding of bone blood flow regulation and its contribution to human bone health is limited. Here, we further our previous findings by characterizing bone vascular responses in the absence of sympathetic control - studying individuals with spinal cord injury (SCI), a population with known peripheral sympathetic disruption. We assessed tibial vascular responses to isometric handgrip exercise (IHE) in individuals with SCI (n = 12) and controls (n = 12). When sustained to fatigue, IHE increases perfusion pressure and sympathetic vasoconstriction in the non-active tissues of the legs. During IHE, we measured blood pressure, whole leg blood velocity via ultrasound, and tibial perfusion (as hemoglobin content) via near-infrared spectroscopy. Controls demonstrated active sympathetic vasoconstriction in the whole leg (i.e., increased vascular resistance, arterial pressure/leg blood velocity) and tibia (i.e., decreased hemoglobin). In contrast, SCI individuals demonstrated modest whole leg vasoconstriction with lesser increases in vascular resistance than controls (P<.04). Tibial vasculature evidenced absent or blunted vasoconstriction compared to controls (P<.01), indicated by increasing tibial hemoglobin until plateauing at higher pressure levels. This suggests that, in the absence of sympathetic control, tibial vascular response may involve other regulatory mechanisms like myogenic vasoconstriction. Lastly, we leveraged existent whole-body Dual Energy X-ray Absorptiometry scans in a subgroup of nine individuals with SCI and we found a strong relationship between leg bone mineral density (BMD) and tibial hemoglobin at end of IHE (r2 = 0.67, P<.01). Our findings indicate that in the absence of sympathetic mechanisms, myogenic control may play a compensatory role in regulating blood flow, though to a lesser extent in bone compared to muscle. The close relationship between lesser declines in bone blood content and higher BMD underscores the link between blood flow and bone health.