Journal of Bone and Mineral Research最新文献

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.

Bone is a mechanosensitive organ, and its regeneration also depends on the ability of bone cells to perceive and react to mechanical stimuli. Macrophages are indispensable for bone formation, regeneration, and maintenance. Depletion of macrophages resulted in poor bone development, due to impaired vessels formation and osteogenesis. However, how mechanical stimulation stimulates macrophages during bone regeneration is unclear. As in many cell types, Piezo1 is part of the mechanotransduction in macrophages, and modulates macrophage activity. Here, we utilized conditional knockout of Piezo1 in LysM+ myeloid cells and in vivo mechanical loading to investigate the mechanoregulation of macrophages and their contribution to bone repair. We found that mechanical loading increased the ratio of CD206+ macrophages, angiogenesis-osteogenesis coupling, and cell proliferation within defect region, leading to enhanced bone regeneration. However, all the loading-induced upregulation were blunted by conditional knockout of Piezo1 in macrophages. Furthermore, we implanted wildtype bone marrow-derived macrophages into defect area in Piezo1 knockout mice. Wildtype macrophages rescued mechanosensitive angiogenesis-osteogenesis coupling and promoted bone regeneration in Piezo1 knockout mice. Together, our data showed that Piezo1 in macrophages is indispensable for loading-induced bone regeneration by stimulating macrophage polarization into the CD206+ phenotype, thereby facilitating the angiogenesis-osteogenesis coupling, promoting cell proliferation, and finally resulting in enhanced bone regeneration.

Patella fractures are not typically considered osteoporotic fractures. We compared bone mineral density (BMD) and microstructure in elderly women from a multiethnic population-based study in New York City with any history of a patella fracture (n = 27) to those without historical fracture (n = 384) and those with an adult fragility forearm fracture (n = 28) using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). Compared to those without fracture, women with patella fracture had 6.5% lower areal BMD (aBMD) by DXA only at the total hip (p=.007), while women with forearm fracture had lower aBMD at multiple sites and lower trabecular bone score (TBS), adjusted for age, body mass index, race and ethnicity (all p<.05). By HR-pQCT, adjusted radial total and trabecular (Tb) volumetric BMD (vBMD) and Tb number were 10%-24% lower while Tb spacing was 12-23% higher (all p<.05) in the fracture groups versus women without fracture. Women with a forearm, but not a patella, fracture also had lower adjusted radial cortical (Ct) area and vBMD and 21.8% (p<.0001) lower stiffness vs. women without fracture. At the tibia, the fracture groups had 9.3%-15.7% lower total and Tb vBMD (all p<.05) compared to the non-fracture group. Women with a forearm fracture also had 10.9, and 14.7% lower tibial Ct area and thickness versus those without fracture. Compared to women without fracture, tibial stiffness was 9.9% and 12% lower in the patella and forearm fracture groups, respectively (all p<.05). By HR-pQCT, the patella vs. forearm fracture group had 36% higher radial Tb heterogeneity (p<.05). In summary, women with patella fracture had Tb deterioration by HR-pQCT associated with lower tibial mechanical competence that was similar to those with fragility forearm fracture, a more universally accepted "osteoporotic" fracture. These data suggest patella fractures are associated with skeletal fragility and warrant skeletal evaluation.

Vertebral compression fractures (VFs) and spinal degeneration are both common causes of back pain, particularly in older adults. Previous cross-sectional studies have shown a potential association between these entities, but there is limited evidence on the role of VFs in spinal degeneration. In this longitudinal study, we evaluated the association between prevalent VFs and the subsequent progression of facet joint osteoarthritis (FJOA) and intervertebral disc height narrowing (DHN), using data from the Framingham Heart Study Offspring and Third Generation Multi-Detector Computed Tomography study. Summary indices representing the total burden of each spinal parameter (VFs, DHN, and FJOA) were calculated for each individual. We hypothesized that prevalent VFs are associated with worsening spinal degeneration. Three hundred and seventy (31%) of 1197 participants had a baseline (prevalent) VF. The change in summary index of DHN over the follow-up period was significantly higher in those with vs without prevalent VF (difference in change in DHN 0.38, 95% CI 0.18 to 0.59, p<.001), but the change in summary index of FJOA was similar between those with and without prevalent VF. However, once adjusted for age, sex, cohort, smoking status, BMI, and baseline DHN, the change in summary index of DHN did not differ by prevalent VF status. There was a modestly higher change in the FJOA summary index in those with prevalent VFs compared to those without in the fully adjusted model (difference in change in FJOA 0.62, 95% CI -0.01 to 1.24, p = .054), driven primarily by those with severe (grade 3) VF (difference in change in FJOA 4.48, 95% CI 1.99-6.97). Moreover, there was greater change in the summary index of FJOA with increasing severity of prevalent VF (linear trend p = .005). Beyond the established morbidity and mortality associated with VFs, our study suggests that VFs may also lead to worsening spine osteoarthritis.