Journal of Bone and Mineral Research最新文献

Disuse-induced bone loss is a common consequence of spaceflight and prolonged bed rest. Intraosseous blood vessel volume and number are decreased in rodents after sciatic nerve resection, and femoral and tibial perfusion and blood flow to the femoral shaft and marrow are reduced after hindlimb unloading. However, it is unclear if alterations in the flow of blood contribute to botulinum toxin (BTX)-induced bone loss. The objective of this study was to assess patterns of tibial bone loss and alterations in blood flow in murine hindlimbs following BTX injection. We hypothesize that flow of blood to the affected hindlimb will diminish along with bone mass and structure. Skeletally mature C57Bl/6J female were injected with BTX (n = 15) or vehicle (n = 14). Paralysis was confirmed using digit abduction, wire hang tests, and activity analysis. In vivo microCT and ex vivo synchrotron tomography were used to assess bone mass, microstructure, (re)modeling, as well as vascular and lacunar porosity. Blood flow in the hindlimbs and cardiac structure/function was monitored by echocardiography. After 3 wk, BTX-injected tibiae had 16% lower cortical thickness and 66% lower trabecular bone volume fraction compared to baseline. MicroCT-based timelapse morphometry showed bone loss was predominantly at endocortical surfaces. Bone loss in the contralateral limb was coincident with reduced rearing capability of BTX-injected mice compared to vehicle controls. Bony vascular canal thickness and surface area were reduced, but there was no change in lacunar properties due to BTX. In vivo ultrasound demonstrated increased velocity time integral for blood flow due to BTX injection in femoral and popliteal but not in saphenous arteries. Thus, BTX led to significant bone loss in hindlimbs, while increasing blood velocity in the femoral popliteal arteries and decreasing vascular porosity. The vascular response to BTX differs from what has been observed in other hindlimb unloading models.

Pregnancy and lactation require large amounts of calcium, potentially depleting the young-adult bone. This study investigated BMD and fluctuations of BMD resulting from parity and lactation in the PEAK-25 cohort, a prospective observational study of women all aged 25 at inclusion and 35 at follow-up. The analyses used women who were nulliparous at baseline and parous (n = 573) or nulliparous (n = 177) 10 yr later. Parity, regardless of number of pregnancies, had no negative impact; indeed, spine BMD at age 35 was higher (2.1%; p = .043). Likewise, BMD did not differ in women who breastfed, were nonlactating or nulliparous. Even the cumulative duration of breastfeeding did not make a difference. Overall, regardless of parity, in the cohort, by age 35 BMD was already decreasing, with overall losses at the FN (∆, -3.4%) and TH (∆, -2.7%), although not the spine (∆, 0.9%). Yet, BMD fluctuations associated with pregnancy, lactation, and weaning were seen in the short term. Comparing those pregnant >24 mo with those <24 mo prior to DXA, BMD was lowest in women more recently pregnant (FN, -2.2%, TH -2.7%). Women pregnant within 12 mo had 4% lower TH BMD compared with more than 36 mo (p = .054, padjusted = .032). Cumulative duration of breastfeeding was associated with bone loss, particularly beyond 15 mo (FN: ∆, -4.3%; TH: ∆, -3.7%) and lower spine BMD accretion. Despite such periods of loss, BMD recovers, evidenced by time-from-weaning to DXA. Women weaning within 6 mo of measurement had lower FN BMD than those where the interval was >24 mo (6.6% vs 1.7%; p < .001). In conclusion and despite repeated fluctuations in BMD resulting from the physiological demands of multiple pregnancies and periods of breastfeeding, BMD recovers and ultimately does not differ from that of identically aged women without children.

Chronic kidney disease (CKD) may be complicated by mineral and bone disorders (CKD-MBD). Data on the association between estimated glomerular filtration rate (eGFR) and bone microarchitecture are limited. We studied the link between eGFR and bone microarchitecture (baseline, changes) assessed by high resolution peripheral quantitative computed tomography (HR-pQCT) in older men followed for 8 years. In 826 men aged ≥60, eGFR was calculated using three equations based on creatinin and cystatin C: CKDEPI-2012, EKFC without race and sex, CKDEPI-2021 without race. Bone microarchitecture was assessed at the distal radius and distal tibia by HR-pQCT at baseline, then after 4 and 8 years. Reaction force and failure load were estimated by microfinite element analysis. Changes in bone measures across the eGFR classes were explored using linear mixed effect models. At baseline, distal radius bone microarchitecture did not differ across the eGFR groups (CKDEPI-2012), whereas distal tibia trabecular measures and failure load were higher in men with decreased eGFR. During the follow-up, lower eGFR was associated with more rapid decrease in total bone mineral density (Tt.BMD), cortical area (Ct.Ar) and BMD (Ct.BMD), trabecular BMD (Tb.BMD), and failure load at the distal radius. Low eGFR was also associated with faster increase in trabecular area (Tb.Ar) and trabecular distribution heterogeneity (Tb.1/N.SD). At the distal tibia, low eGFR was associated with more rapid decrease in Tt.BMD, Ct.Ar, Ct.BMD, Tb.1/N.SD, and failure load as well as with faster increase in Tb.Ar. The patterns were similar for changes expressed as percentages. The patterns were similar for two other equations. Lower eGFR is associated with faster decline in cortical bone microarchitecture and bone strength at the distal radius and tibia in older men. This phenomenon may contribute to the higher fracture risk in older adults with CKD.

More than 770 genetic skeletal disorders have been described, most with disease-causing variants reported in one of over 550 different genes. The ClinGen Skeletal Disorders Gene Curation Expert Panel was established to determine the strength of evidence that supports specific gene-disease relationships. Such information can assist clinical testing laboratories in choosing genes that should be included on diagnostic panels. Nine genes accounting for the most frequently encountered skeletal dysplasias (COL1A1, COL1A2, COL2A1, FGFR3, SLC26A2, TRPV4, COMP, ALPL, and SOX9) associated in the medical literature with 26 different skeletal disorders were reviewed using a semi-quantitative scoring framework. This framework is utilized by ClinGen to assess the clinical validity of gene-disease relationships. All nine genes were "Definitively" associated with at least one skeletal disorder and several were associated with multiple clinically or radiographically distinct skeletal conditions. Among these 26 gene-disease relationships, the ClinGen Skeletal Disorders Gene Curation Expert Panel determined that 22 (84.6%) had Definitive relationships, 2 (7.7%) had Moderate relationships, and 2 (7.7%) had Limited relationships. None of the 26 gene-disease relationships were Disputed or Refuted. For Moderate and Limited gene-disease relationships, clinical and genetic reports from additional probands and their families are needed to upgrade these gene-disease relationships to Definitive. Up-to-date assessments about the strength of the relationship between genes and phenotypes should improve the sensitivity and specificity of genetic testing in individuals with skeletal disease. The expert curations for the nine aforementioned genes are published on the ClinGen website.

The regulation of bone physiology and pathophysiology is intricately controlled by a complex interplay of cellular and molecular mechanisms. In these processes, the precise spatiotemporal coordination of biological activities in bone-resident cells plays a central role. Recently, liquid-liquid phase separation (LLPS), a mechanism underlying membraneless biomolecular condensate formation, has emerged as a transformative area of research. LLPS refers to the phase transition of biomolecules under specific conditions, leading to the formation of biomolecular condensates, which orchestrate diverse cellular functions. In this review, we provide a comprehensive synthesis of how LLPS influences bone turnover, focusing on its role in regulating bone homeostasis and its dysregulation in bone disease pathogenesis. Furthermore, aside from addressing the current challenges and limitations in this nascent field, we explore the implications of LLPS in bone regeneration, preventive strategies, and precision medicine. Despite LLPS research being in its early stages, its rapid advancement underscores its crucial role in bone biology and highlights the urgent need to integrate LLPS insights with translational approaches to advance therapeutic interventions for bone disorders.

For a given bone mineral density, adults with type 2 diabetes (T2D) have greater fracture risk than adults without the disease. To test the hypothesis that T2D lowers the fracture resistance of human cortical bone by negatively altering the bone matrix quality, we acquired cadaveric femurs from 120 female and male donors >50 yr old: 60 without diabetes (Ctrl) & 60 with T2D for ≥10 yr). We scanned a cross-section from each diaphysis using ex vivo micro-computed tomography (μCT), followed by cyclic reference point indentation (cRPI: 0 to 10 N for 20 cycles) and impact micro-indentation on the medial surface. From the medial quadrant, a tensile specimen and a single-edge notched beam (SENB) were mechanically tested to assess differences in fracture resistance. Multiple techniques characterized the organic matrix within the SENB. The cortical bone area and thickness of the diaphysis were higher in T2D than in Ctrl. The average creep indentation distance of periosteal bone tissue was significantly lower with T2D suggesting greater resistance to micro-indentation. Bone material strength index though trended to be lowering in T2D than in Ctrl but only when the comparison was adjusted for age, sex, and body mass index. There were also T2D-related differences in the organic matrix: (i) higher non-enzymatic and mature enzymatic crosslinks, (ii) higher fluorescent advanced glycation end-products, and (iii) higher thermal stability. Despite these tissue- and molecular-level differences, mechanical properties of cortical bone were similar between the 2 groups. Tensile strength was lower (p = .035) while pentosidine was higher (p = .006) in donors with chronic kidney disease than donors without kidney disease, but the difference in strength (p = .055) and pentosidine (p = .151) were not strictly significant when adjusting for covariates. The elevated fracture risk in T2D may not be a problem of poor mechanical properties of cortical bone, despite alterations in the organic matrix.

Hypophosphatasia (HPP) is a heritable multisystem disorder caused by pathogenic variants in the tissue non-specific alkaline phosphatase (ALP)-coding gene ALPL. The genotype-phenotype correlation in heterozygous adults with HPP remains incompletely understood. In this genotype-based study, we aimed to measure the prevalence of pathogenic or likely-pathogenic ALPL variants and test the hypothesis that HPP penetrance is low in adult carriers. A total of 37,147 genomes from unselected individuals visiting a tertiary care, academic medical center were investigated. Variants classified as pathogenic or likely-pathogenic were observed with a prevalence of 0.3% (n=109) or 1/341. Variant c.571G>A was most frequent (67.9%). A subset of 70 individuals had linked electronic health records (EHRs) and were termed ALPL+. All 70 ALPL+ individuals showed mild, mainly neurological, symptoms often reported in adults with HPP. However, low serum ALP, a hallmark of HPP, was found in only 65.7% (38/70) of ALPL+ individuals, and 12.9% (9/70) met the diagnostic criteria for HPP based on consensus guidelines, thus complete penetrance was low. Compared to controls lacking pathogenic or likely-pathogenic variants (ALPL-), the ALPL+ individuals had a higher probability of progression for mobility issues (median age 73 years ALPL+ vs. 82 years ALPL-, p=0.03), as well as a similar probability of progression for fatigue, arthritis or dental problems. Unexpectedly, 3.4% (5/148) of individuals in the ALPL- group met the diagnostic criteria for HPP, possibly due to unidentified variants or non-ALPL genetic factors. Overall, the data support our hypothesis and aids the management of carries of pathogenic ALPL variants.

Vitamin C has been long recognized as an important nutrient for skeletal biology, historically attributed to its role in collagen synthesis and connective tissue integrity. Recent studies, however, reveal vitamin C as a critical epigenetic regulator of cellular differentiation. As a required cofactor for α-ketoglutarate-dependent dioxygenases, vitamin C controls the enzymatic activity of a broad array of histone and DNA demethylases, thereby modulating chromatin accessibility and driving cell-specific gene expression. This review provides a novel, integrated perspective that directly links vitamin C's epigenetic functions to osteogenesis and skeletal health, highlighting experimental evidence that redefines its role beyond collagen maturation and antioxidant defense, and elucidating its sex-dimorphic effects. Importantly, inadequate vitamin C status remains widespread across diverse socioeconomic groups even in Western countries, with low vitamin C intake associated to higher risk of osteoporosis and fractures in the elderly. Viewed through the dual lenses of epigenetic-mechanistic function and clinical relevance, vitamin C emerges as a central epigenetic determinant of skeletal health and a safe, low-cost, and scalable adjuvant to complement current bone therapies. Integrating nutrient epidemiology, clinical data and epigenetic-mechanistic insights may enable targeted interventions to enhance skeletal resilience, particularly in vulnerable populations.

Despite advancements in fracture prediction tools and osteoporosis management, hip fractures remain a significant consequence of bone fragility, with a 22% one-year mortality. Hip geometric measures (GMs) have been associated with fracture risk; however, their strong correlation hinders the identification of independent influences, leaving their relative predictive value unclear. Statistical shape modelling (SSM) provides a more holistic assessment of hip shape compared to using pre-determined GMs. This study aimed to evaluate whether SSM-derived hip shape from dual-energy X-ray absorptiometry (DXA) scans can predict hip fracture, independently of individual GMs. Previously, we applied SSM to left hip DXA images in UK Biobank, a large prospective cohort with linked hospital records, generating ten orthogonal hip shape modes (HSMs), that explained 86% of shape variance. Additionally, femoral neck width (FNW), femoral head diameter (FHD), and hip axis length (HAL) were derived from these DXAs. In the current analysis, Cox proportional hazard models, adjusted for age, sex, height, weight, bone mineral density (BMD), and GMs (FNW, HAL, FHD), were used to examine the longitudinal associations between each HSM and first incident hospital diagnosed hip fracture. A Bonferroni adjusted p-value threshold (p<0.004) was used to account for the 13 exposures. Among the 38,123 participants (mean age 63.7 years; 52% female; mean follow-up 5 years), 133 (0.35%) experienced subsequent hip fracture. HSM2, characterised by a narrower FNW, a higher neck shaft angle, and reduced acetabular coverage, showed a strong association with hip fracture risk (HR 1.32, 95% CI 1.11-1.58, P 1.47×10-3), which persisted after full adjustment (1.30, 1.09-1.55, 3.27×10-3). There was no evidence for an association with other HSMs. These findings suggest that DXA-derived hip shape is associated with hip fracture risk independently of BMD and GMs. Incorporating global hip shape into fracture risk assessment tools could enhance prediction accuracy and inform targeted interventions.

Ossification of the Posterior Longitudinal Ligament (OPLL) and Diffuse Idiopathic Skeletal Hyperostosis (DISH) are debilitating conditions characterized by pain, stiffness, myelopathy, and impaired mobility due to progressive enthesopathies and spinal fractures. These disorders worsen with age and may lead to hemiplegia. The underlying mechanisms of these diseases remain poorly understood, and effective treatments are currently lacking. To elucidate the pathogenesis of OPLL, we conducted a prospective study involving plasma analyte measurement in 50 consecutive OPLL and 25 consecutive cervical osteoarthritic (OA) patients who presented for surgical correction within the same time frame, followed by exome sequencing of 19 genes associated with phosphate wasting and spinal ligament enthesopathy/ossification. Our study identified a significant association between OPLL and ENPP1 deficiency. Specifically, we observed that OPLL patients exhibited decreased plasma levels of inorganic pyrophosphate (PPi) while maintaining unaltered alkaline phosphatase levels. Additionally, 17% of OPLL patients harbored monoallelic pathogenic variants in ENPP1, the mammalian enzyme responsible for extracellular PPi. Using Enpp1-deficient mice (Enpp1asj) to model the condition, we discovered pathologic mineralization of the spine, long bones, and tendons, alongside increased long bone and spinal fracture risk by 17 wk of age. We further assessed the therapeutic potential of two forms of ENPP1 enzyme replacement therapies. Bone-targeted ENPP1 significantly ameliorated the spinal hyperostosis, improved or normalized spinal and long bone fragility, ameliorated tendon enthesopathies, and improved trabecular microarchitecture. Meanwhile, soluble ENPP1 prevented tendon enthesopathies, normalized cortical bone microarchitecture, and improved long bone fragility. Our findings establish a clear link between decreased plasma PPi, ENPP1 deficiency, and OPLL, unveiling additional therapeutic targets to more effectively manage this poorly treated condition.