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PubMed2026

Fractures are highly correlated with bone density and inversely correlated with bone turnover markers in autosomal dominant osteopetrosis.

Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r = 0.87, p < .001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Humans↗

PubMed2026

The HOXA gene cluster: a critical regulator in bone-related disorders.

BACKGROUND: Skeletal homeostasis relies on the dynamic balance between bone formation and bone resorption. The disruption of this balance acts as the central pathological mechanism of multiple metabolic bone diseases including osteoporosis, and is closely correlated with the progression of various other bone-related disorders. As pivotal transcription factors regulating embryonic development and cell fate, the homeobox A (HOXA) gene family plays an essential role in skeletal physiological and pathological processes. METHODS: This review systematically summarizes recent research advances of the HOXA gene family in bone-related diseases, concludes the evolutionarily conserved regulatory patterns of HOXA members, and clarifies the molecular mechanisms by which HOXA genes mediate bone metabolic disorders and the occurrence as well as development of bone diseases. RESULTS: Accumulating evidence demonstrates that HOXA family members present complex functions and strong heterogeneity in bone-related diseases. They participate in the pathogenesis of bone diseases via three evolutionarily conserved regulatory manners: determining regional patterning, modulating signaling pathways, and integrating epigenetic and non-coding RNA (ncRNA) regulatory networks. CONCLUSION: Further exploring the underlying mechanisms of the HOXA family in bone-related diseases provides novel insights into the pathogenesis of bone disorders. Meanwhile, it also supplies solid theoretical basis and potential therapeutic targets for the development of novel HOXA-targeted therapeutic strategies against bone diseases.

Humans↗

PubMed2026

Inhibition of EED enhances osteogenic differentiation and bone formation: a potential therapeutic strategy for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders primarily caused by dominant mutations in COL1A1 or COL1A2 that impair type I procollagen folding and secretion. Misfolded collagen accumulates in the endoplasmic reticulum (ER), triggering ER stress and osteoblast dysfunction, and bone fragility. Current pharmacologic therapy focuses on inhibiting bone resorption but has limited efficacy and does not address the underlying biology of the disease. The epigenetic regulator polycomb-repressive complex 2 (PRC2) has emerged as an important regulator of bone formation. Genetic and pharmacologic disruption of PRC2 enhanced osteogenic differentiation in WT cells. Here, we demonstrate that inhibition of the PRC2 through targeting its essential component embryonic ectoderm development (EED) enhances osteogenic differentiation, improves bone architecture in male Col1a2 +/G610C OI mouse models, modulates the integrated stress response (ISR), and improves ER morphology in OI cells. These findings identify EED inhibition as a novel epigenetic strategy to restore collagen homeostasis and improve skeletal integrity in OI.

ER stress↗

PubMed2026

Integrative Genomic and Functional Investigation of the Multi-Layered Genetic Architecture Between Anorexia Nervosa and Bone Loss.

OBJECTIVE: Bone loss is a severe and often irreversible complication of anorexia nervosa (AN), yet the genetic mechanisms underlying this comorbidity remain underexplored. This study focuses on constructing a comprehensive genetic architecture between AN and estimated calcaneal bone mineral density (eBMD). METHOD: We applied an integrative framework incorporating genetic correlation, pleiotropic association, and causal inference across single-variant, multi-variant, and gene expression levels. Functional validation was conducted in vitro to investigate the biological role of the key candidate gene. RESULTS: Local genetic correlation analysis identified significant signals at 8p21.2 and 10q26.3, despite the lack of significant global correlation. Mendelian randomization analysis pointed to a suggestive negative causal effect of genetically predisposed AN on eBMD. Extensive pleiotropic signals were detected, particularly at 3p21.31 and 10q26.3, loci enriched with genes associated with both traits. Notably, we identified a novel pleiotropic signal near NCAM1 at 11q23.2, which was supported by multi-layered genetic evidence and confirmed through in vitro functional experiments. NCAM1, a well-established neural-associated gene, promoted osteoclastic differentiation and bone resorption when overexpressed in osteoclast precursor cells, indicating that NCAM1 possesses distinct functional roles in both neural and skeletal tissues. DISCUSSION: This study constructs a comprehensive genetic architecture underlying AN and eBMD and highlights NCAM1 as a key pleiotropic gene.

anorexia nervosa↗

PubMed2026

Sex-specific biomarkers predict bone mineral density loss at the contralateral hip after hip fracture.

OBJECTIVE: To identify inflammatory and hormonal biomarkers that predict bone loss at the contralateral (non-fractured) hip following hip fracture in males and females. METHODS: White participants who were not receiving pre-fracture glucocorticoids, sex-hormone therapy, or bone-active medications (100 males, 76 females) with hip fractures. Data were collected within 22 days of hip fracture and at 2, 6, and 12 months follow-up. Biomarkers were categorized into tertiles: estradiol, 25-hydroxyvitamin D3/D2, intact parathyroid hormone (iPTH), interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), soluble tumor necrosis factor-α receptor 1, sex hormone-binding globulin, and testosterone. Femoral neck bone mineral density (BMD) at the contralateral hip was assessed, and losses exceeding the mean decline were classified as greater than average. Logistic regression models, stratified by sex, were adjusted for confounders and evaluated selected biomarker associations. RESULTS: Among males, the 2nd (OR = 4.79, P = 0.012) and 3rd (OR = 6.36, P = 0.005) IGF-1 tertiles were associated with greater odds of BMD loss than the 1st tertile. The 3rd iPTH tertile (OR = 3.79, P = 0.037) was similarly associated with increased odds. Among females, the 3rd (OR = 0.20, P = 0.031) IL-1RA tertile was associated with lower odds of BMD loss compared to the 1st tertile, while the 2nd IL-6 tertile (OR = 5.99, P = 0.036) was associated with higher odds. CONCLUSION: These findings suggest that inflammatory and hormonal biomarkers may be sex-specific predictors of accelerated BMD loss following hip fracture.

Biomarkers↗

PubMed2026

Lymphatic vascular aging and age-related bone loss: current status and future perspectives.

Age-related bone loss is a major contributor to osteoporosis and fragility fractures in older adults. Skeletal aging is accompanied by reduced bone mineral density, impaired bone microarchitecture, chronic low-grade inflammation, and immune dysregulation. Lymphatic vascular aging refers to age-related structural and functional decline of lymphatic vessels. This decline impairs immune surveillance and inflammatory mediator clearance, thereby disrupting tissue homeostasis. Age-related lymphatic dysfunction impairs drainage and inflammatory clearance. This allows inflammatory mediators, including IL-6 and TNF-α, to persist in bone-associated tissues, thereby promoting osteoclastogenesis and resorption-dominant remodeling. Age-related lymphatic dysfunction also affects VEGF-C/VEGFR-3 signaling, chemokine-mediated immune trafficking, and marrow niche support. These changes link drainage failure to osteoimmune imbalance and delayed bone repair. Current evidence supports a link between lymphatic vascular dysfunction and skeletal degeneration. Most evidence comes from animal models, bone injury studies, or diseases with secondary lymphatic defects, whereas direct clinical evidence in human age-related osteoporosis remains limited. This review summarizes current evidence linking lymphatic dysfunction to skeletal degeneration, examines the context-dependent roles of lymphatic remodeling in skeletal homeostasis, and discusses emerging therapeutic strategies targeting the lymphatic-bone axis. Future studies should define clinically relevant lymphatic alterations and determine whether restoring lymphatic homeostasis can mitigate age-related bone loss.

Humans↗