Journal of Bone and Mineral Research最新文献

Bone quality is a critical determinant of outcomes following spine fusion surgery. However, patients with skeletal deficits are often only identified intra-operatively when there are unexpected problems with hardware placement, or post-operatively, when bone-related complications occur. MRI is routinely performed for diagnosis and surgical planning, making a technique based on clinical MRI ideal to opportunistically evaluate bone health. Texture analysis of trabecular bone from MRI has recently emerged as a biomarker of bone quality. This prospective study related pre-operative MRI-based texture from standard clinical images and areal BMD (aBMD) by DXA to post-operative outcomes following spine fusion. T1-weighted MR images were acquired from patients undergoing instrumented lumbar spine fusion. The following texture features were derived within the L1-L5 vertebral bodies to characterize the local distribution and spatial organization of signal intensity: contrast (variability) and entropy (disorder) for which higher values reflect high heterogeneity; angular second moment (ASM; uniformity) and inverse difference moment (IDM; homogeneity) for which higher values reflect low heterogeneity. Of 72 patients enrolled, mean age was 63 years (54% female). Patients were followed for a median of 13 months after surgery. Skeletal complications occurred in 27 patients (38%); proximal junctional kyphosis and screw loosening were the most common. There was no association between new complications and aBMD at any site. In contrast, patients who developed post-operative complications had greater pre-operative MRI-texture heterogeneity than those who did not, specifically higher contrast (26%) and entropy (12%), lower ASM (-13%) and IDM (-25%, p < 0.01 for all). In summary, greater heterogeneity of pre-operative bone texture from clinical MRIs was associated with skeletal complications following spine fusion. These findings support this novel method as an opportunistic screening technique to foster earlier identification of high-risk patients who would benefit from interventions to improve surgical outcomes.

The repair of alveolar bone is of vital importance for maintaining oral health and promoting recovery following injury or disease. Functioning as an NAD+-dependent protein deacetylase, SIRT1 modulates diverse physiological activities, with particular relevance to metabolism and osteogenesis. However, its specific role in alveolar bone repair and the associated metabolic pathways have not been fully elucidated. In this study, we explored the function of SIRT1 in alveolar bone healing using a conditional knockout mouse model (Wnt1-Cre; SIRT1fl/fl mice) and evaluated its involvement in glycolytic metabolism through the Wnt/β-catenin signaling pathway. The deletion of SIRT1 resulted in significantly impaired bone healing within extraction sockets. Notably, bioinformatics analysis suggested that SIRT1 deficiency may alter the metabolic profile of orofacial mesenchymal stem cells (OMSCs). Consistently, glycolytic activity was markedly reduced in SIRT1-deficient OMSCs, as evidenced by decreased extracellular acidification rate (ECAR), reduced lactate production, and lower expression levels of glycolytic enzymes. Mechanistically, we demonstrated that SIRT1 interacts with β-catenin and that SIRT1 deficiency is associated with increased β-catenin acetylation and reduced nuclear localization, thereby impairing Wnt/β-catenin signaling and glycolytic metabolism. Both in vivo and in vitro rescue experiments using SKL2001, a Wnt/β-catenin signaling pathway agonist, revealed that SKL2001 was able to restore β-catenin nuclear translocation, enhance glycolytic metabolism, and improve the impaired osteogenic differentiation caused by SIRT1 deficiency. The results of this study highlight a previously unidentified role of SIRT1 in promoting alveolar bone repair by modulating glycolysis through the Wnt/β-catenin pathway. These findings not only advance our understanding of bone repair at the metabolic level but also propose SIRT1 and Wnt signaling as viable therapeutic avenues.

The molecular mechanisms causing heritable disorders of hypo- and hyperphosphatemia involving the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho (KL) have sprung new concepts underlying the endocrine control of phosphate and calcium (Ca), as well as the regulation of the active form of vitamin D, 1α,25-dihydroxy vitamin D3 (1,25D). These critical developments have proven important for the understanding and treatment of both rare, Mendelian diseases as well as for important implications for common disorders of blood phosphate excess and dysregulated 1,25D metabolism such as chronic kidney disease (CKD). The heritable and acquired diseases associated with FGF23 are caused by changes in the levels and proteolytic control of this hormone, revealing novel mechanisms dictating FGF23 synthesis and systemic mineral metabolism. Further, new interactions between FGF23, 1,25D, and parathyroid hormone (PTH) on phosphate, Ca, and 1,25D at the molecular and genomic level are emerging particularly in the bone-kidney axis. These disorders will be reviewed herein, including considerations for genetic analyses and therapeutic strategies, recently discovered regulation of critically intertwined signaling that controls endocrine-mediated bone and mineral metabolism, as well as gaps in our current knowledge.

Type 1 diabetes mellitus (T1D) is associated with a marked increase in fracture risk, a phenomenon not entirely explained by lower DXA-BMD. Emerging evidence suggests T1D may adversely affect bone microarchitecture, though findings are inconsistent. We aimed to characterize bone microarchitecture and estimated bone strength in adults with longstanding T1D. We enrolled 96 individuals with T1D (median HbA1c 7.0% [IQR 6.3,7.7], mean diabetes duration 46±10 years) and 57 individuals without diabetes, all aged >50 years. Assessments included areal BMD (aBMD) at the lumbar spine, femoral neck, and total hip via DXA, trabecular bone score (TBS), and high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate volumetric BMD (vBMD), bone microarchitecture, and estimated failure load at the distal radius and tibia. Individuals with T1D were more likely to report prior history of fracture compared to controls (26% vs 4%, p<0.001). After adjusting for age, sex, height, and weight, aBMD and TBS did not differ between groups. HR-pQCT revealed modest cortical deficits in the T1D group, with largely preserved trabecular microarchitecture and no significant difference in estimated failure load compared to control participants. Within the T1D group, those who reported a prior fracture had lower spine aBMD and lower estimated strength at the tibia. Notably, individuals diagnosed with T1D at or before age 12 years had worse trabecular parameters at the radius than those diagnosed later, with no corresponding differences at the tibia and no differences seen on DXA. Retinopathy was associated with lower aBMD at the hip and femoral neck and with reductions in trabecular thickness, area, failure load, and stiffness at the tibia. The minor differences in bone microarchitecture observed in this study may partly contribute to the increased fracture risk among patients with T1D, though more research examining mediating factors both intrinsic and extrinsic to bone is needed.

Osteoanabolic therapies such as parathyroid hormone (PTH) analogs (teriparatide, abaloparatide) and the sclerostin inhibitor romosozumab rapidly stimulate new bone deposition but their bone-building effects are not indefinite. Clinical trials including bone turnover markers and bone histomorphometry studies show that the initial gains in bone formation and density wane with continued therapy - typically within 12-18 months for PTH analogs and even sooner for romosozumab. This invited review explores the biological mechanisms that may explain this waning response, including receptor desensitization at the PTH1 receptor level, depletion or saturation of bone-forming surfaces, exhaustion or downregulation of osteoblast progenitors, upregulation of endogenous Wnt pathway antagonists (e.g. sclerostin, DKK1), and mechanostatic feedback from increased bone mass. The contrasting kinetics of teriparatide, abaloparatide and romosozumab are compared, highlighting how their modes of action (remodeling- vs. modeling-based formation) influence the duration of anabolic activity. Finally, potential strategies to extend or rekindle anabolic effects are discussed - including sequential and combination therapies and adjunctive mechanical loading - with a view toward maximizing bone gains and reducing fracture risk. Understanding why anabolic drug efficacy attenuates provides insight into bone biology and guides the design of regimens to achieve more sustained increases in bone mass and strength.

Leptin, a hormone produced by adipose tissue, stimulates bone production of FGF-23 in pre-clinical studies and thus may impact vitamin D metabolism. We investigated the association between longitudinal changes in visceral (VAT) and subcutaneous adipose tissue (SAT) and vitamin D metabolism in patients receiving hemodialysis. This cohort study of clinical trial participants included adult patients receiving hemodialysis who were not taking active vitamin D therapy at baseline (n=30) and 1 year (n=26). VAT and SAT cross-sectional area was measured by MDCT scanner and SliceOMatic software. Vitamin D metabolites were measured with mass spectroscopy and expressed as vitamin D metabolite ratios (VMR). FGF-23, leptin and adiponectin were measured by ELISA. Spearman correlation and Wilcoxan rank-sum tests were used to evaluate baseline and relative change variables. Linear regression was used to evaluate the relationship between changes in FGF-23 and leptin. The progression towards increased fat in the visceral area (VSR) was associated with an increase in FGF-23 and leptin and a decline in the ratio between the active vitamin D hormone, 1,25(OH)2D3, and the 25(OH)D3 precursor molecule. The relative change in leptin as well as the leptin to adiponectin ratio was associated with the change in FGF-23 controlling for baseline FGF-23 and PTH. Adipose tissue may contribute to altered vitamin D metabolism. This effect appeared primarily related to visceral adipose tissue and the progression towards increased fat in the viscera. Whether the changes in vitamin D metabolism are directly related to the observed changes in FGF-23 and leptin, or a local effect within adipocytes, requires further study. Consideration of body composition may be one step towards personalizing the care and treatment of CKD-associated mineral and bone disorders based on individual characteristics.

Background: Women living with HIV (WLWH) in resource-limited settings have benefited greatly from antiretroviral therapy (ART). However, they have several risk factors that can affect their bone health including being female, high parity/breastfeeding, use of life-long ART, and HIV disease itself. This study assessed bone mineral density (BMD) among recently pregnant WLWH (WLWH-P), and compared BMD changes over three years with WLWH who were not pregnant (WLWH-NP) and with recently pregnant HIV-negative women (HIV-neg-P).

Methods: We co-enrolled 104 WLWH-P from an ongoing cohort study in Malawi and Uganda, and used linear mixed models to compare standardized BMD values over 30-36 mo with 109 HIV-neg-P women matched for age-group/parity, and 99 age-group/parity matched WLWH who did not plan to become pregnant over 36 mo. BMD was assessed via dual x-ray absorptiometry (DXA) at baseline, 12, 24 and 30-36 mo.

Results: At baseline, median age of WLWH was 33 yr with HIV-neg-P being 32 yr. 91.4% of WLWH-P, and 87.9% of WLWH-NP were on Tenofovir-ART regimens. At baseline, 12, 24 and 30-36 mo postpartum, WLWH-P had lower mean standardized BMD values for femoral neck (FN), lumbar spine (LS) and total hip (TH) compared to HIV-neg-P women, although differences were not statistically significant except for baseline TH. Both groups demonstrated BMD increase to above baseline scores by 30-36 mo. For WLWH-P compared to WLWH-NP, mean standardized BMD values trended lower between baseline and 24 mo.

Conclusions: Both WLWH-P and HIV-neg-P women showed BMD recovery to baseline for FN, LS and TH by 30-36 mo postpartum. However, mean BMD standard-scores trended lower throughout follow-up for WLWH-P compared to HIV-neg-P women. WLWH-P and WLWH-NP women had similar BMD standardized scores by 30-36 mo. The BMD recovery results are encouraging, but longer follow-up is needed to assess fracture risk among older WLWH compared to HIV-negative women.