Bone [JOURNAL]
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200 papers
Baseline β-CTX and BMI predict suitability for deferred zoledronic acid redosing beyond 12 months in postmenopausal Indian women with osteoporosis.
Jha V, Bhadada SK, Mukherjee S … +2 more , Pal R, Kharbanda C
Bone · 2026 Jul · PMID 42398845 · Publisher ↗
PURPOSE: To evaluate whether baseline bone turnover markers (BTMs), particularly plasma β-C-terminal telopeptide of type I collagen (β-CTX), and body mass index (BMI) predict the feasibility and short-term safety of defe...
PURPOSE: To evaluate whether baseline bone turnover markers (BTMs), particularly plasma β-C-terminal telopeptide of type I collagen (β-CTX), and body mass index (BMI) predict the feasibility and short-term safety of deferring zoledronic acid redosing beyond 12 months in postmenopausal Indian women with osteoporosis. METHODS: In this prospective observational study, 50 treatment-naïve postmenopausal women with DXA-confirmed osteoporosis received intravenous zoledronic acid (5 mg). At the 12-month visit, β-CTX guided repeat dosing: women with β-CTX ≥300 pg/mL were redosed, whereas those with β-CTX <300 pg/mL underwent 12-weekly biochemical surveillance, with redosing deferred until β-CTX recovery or a maximum of 24 months. Multivariable logistic regression identified baseline predictors of delayed redosing (>12 months). RESULTS: Twenty-five women underwent delayed redosing (median interval 18.5 months). Compared with standard dosing, the delayed group had lower baseline β-CTX (582 vs 866 pg/mL; p < 0.001) and lower BMI (23.4 ± 5.5 vs 25.7 ± 2.0 kg/m; p = 0.008). On multivariable analysis, lower baseline β-CTX (adjusted OR per 100 pg/mL 0.48; 95% CI 0.31-0.73; p = 0.001) and lower BMI (adjusted OR per kg/m 0.81; 95% CI 0.67-0.98; p = 0.031) independently predicted delayed redosing. BMD gains were comparable between groups and no new vertebral fractures occurred during 2-year follow-up. CONCLUSION: Lower baseline bone turnover and lower BMI were associated with delayed zoledronic acid redosing, supporting a biomarker-guided approach to individualized treatment intervals.
Bone density-based maturation of the midpalatal suture in children aged 8-15 years.
My LHT, Quynh NLX
Bone · 2026 Jul · PMID 42392243 · Publisher ↗
BACKGROUND: Morphological maturation of the midpalatal suture (MPS) has been widely used to guide maxillary expansion. However, whether densitometric maturation follows the same posterior-to-anterior developmental sequen...
BACKGROUND: Morphological maturation of the midpalatal suture (MPS) has been widely used to guide maxillary expansion. However, whether densitometric maturation follows the same posterior-to-anterior developmental sequence or represents a distinct biological process remains unclear. This study aimed to evaluate bone density-based maturation of the MPS in children aged 8-15 years and its relationship to morphological maturation. METHODS: This retrospective cross-sectional study included 100 multislice computed tomography (MSCT) scans of patients aged 8-15 years. MPS maturation was classified according to Angelieri stages (A-E). Bone density was quantified in Hounsfield units (HU) at standardized anterior, middle, and posterior regions. Statistical analyses included repeated-measures ANOVA, nonparametric tests, Spearman correlation, and multivariable linear regression. RESULTS: Bone density showed significant regional variation, with consistently higher values in the middle palatal region compared with the anterior and posterior regions (p < 0.001). Bone density increased with age and differed significantly by sex (p < 0.001). In multivariable regression, age was independently and positively associated with bone density (B = 32.47 HU/year, p < 0.001), with a significant age-by-sex interaction indicating that this increase was approximately 18 HU/year slower in males (p = 0.020). In contrast, the MPS morphological stage did not retain statistical significance after adjustment (p = 0.190). CONCLUSIONS: MPS bone density exhibits a region-specific and age-dependent pattern that does not parallel morphological maturation, suggesting a biological process potentially influenced by functional loading. These findings further suggest that densitometric and morphological maturation may represent partially overlapping yet distinct aspects of MPS development.
Disrupted phosphate metabolism and SIBLING/ASARM peptide accumulation underlie impaired bone mineralization in klotho-deficient (kl/kl) mice.
Hasegawa T, Yamamoto T, Liu X … +6 more , Yimin, Haraguchi-Kitakamae M, Sakakibara M, Shimizu T, Li M, Amizuka N
Bone · 2026 Jul · PMID 42386140 · Publisher ↗
Klotho-deficient (kl/kl) mice exhibit severely impaired bone matrix mineralization despite marked hyperphosphatemia, suggesting that local mechanisms, rather than systemic mineral availability, regulate skeletal minerali...
Klotho-deficient (kl/kl) mice exhibit severely impaired bone matrix mineralization despite marked hyperphosphatemia, suggesting that local mechanisms, rather than systemic mineral availability, regulate skeletal mineralization. Therefore, to clarify the underlying mechanisms, this study aimed to examine phosphate metabolism, pyrophosphate (PPi) homeostasis, and SIBLING/ASARM peptide accumulation in the femora of kl/kl mice maintained on either normal- or low-phosphate (low-Pi) diets. Histochemical and ultrastructural analyses revealed extensive unmineralized bone matrix, impaired mineralized nodule formation, and abnormal accumulation of organic materials around osteoblasts and osteocytes in kl/kl mice. These abnormalities were associated with reduced expression of the phosphate-supplying enzymes tissue-nonspecific alkaline phosphatase (ALP) and PHOSPHO1, together with increased expression of the PPi-generating factors ENPP1 and ANK. Consistent with these findings, bone PPi levels were significantly elevated in kl/kl mice. Dentin matrix protein 1 (DMP1), osteopontin, and phosphorylated acidic serine- and aspartate-rich motif (pASARM) peptides also accumulated in osteocytes and the surrounding bone matrix. Dietary phosphate restriction reduced serum phosphate and bone PPi levels, partially restored ALP and PHOSPHO1 expression, attenuated ENPP1, ANK, DMP1, and pASARM accumulation, and improved bone mineralization. Phosphate exposure induced phosphate- and mineralization-related genes in vitro in osteocytic MLO-Y4 and osteoblastic MC3T3-E1 cells, whereas phosphate normalization partially reversed these changes. Collectively, these findings support the concept that hyperphosphatemia contributes to defective bone mineralization in klotho deficiency by disrupting phosphate/PPi homeostasis and enhancing the accumulation of SIBLING-derived mineralization inhibitors. These findings suggest that PPi dysregulation and the SIBLING/ASARM axis are important contributors to impaired bone mineralization in kl/kl mice.
Linking genetic variants to bone microstructure: Histological signatures of osteogenesis imperfecta subtypes.
Wu Z, Scheepens K, den Haan S … +5 more , Nijhuis W, Weinans H, Sakkers R, Spaans A, Warmink K
Bone · 2026 Jul · PMID 42386139 · Publisher ↗
Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility, skeletal deformities, and wide clinical variability. While clinical manifestations of OI are well re...
Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility, skeletal deformities, and wide clinical variability. While clinical manifestations of OI are well recognized, the microstructural relationships of specific genetic subtypes remain less systematically addressed. Therefore, we aimed to examine and review mutations in genes involved in collagen type I biosynthesis and its processing and relate these genetic alterations to mineralization patterns and distinct histological bone signatures. Common features across OI types include irregular lamellae, excessive woven bone, and abnormal mineralization, whereas subtype-specific changes, such as hyperplastic callus in type V, osteomalacia in type VI, and collagen overmodification in CRTAP related OI, highlight unique pathogenic pathways. By integrating genetic, histological, and clinical perspectives, we underscore the value of genotype-phenotype relationships in refining diagnosis and informing therapeutic strategies. This synthesis emphasizes that understanding the relationship between mutation and histology is central to advancing personalized management in OI.
The impact of alcohol consumption on bone mineral density: Insights from cross-sectional and Mendelian randomization studies.
He X, Lu H, Ghatan S … +5 more , Li J, Koromani F, Medina-Gomez C, Zillikens MC, Trajanoska K
Bone · 2026 Jun · PMID 42379332 · Publisher ↗
INTRODUCTION: Alcohol use is widely prevalent across different regions and cultural settings worldwide. While prior studies have suggested a positive impact of light alcohol consumption on bone mineral density (BMD), the...
INTRODUCTION: Alcohol use is widely prevalent across different regions and cultural settings worldwide. While prior studies have suggested a positive impact of light alcohol consumption on bone mineral density (BMD), the relationship between different levels of alcohol intake and BMD remains controversial. This study conducted cross-sectional analyses within the Rotterdam Study (RS) and UK Biobank (UKB) to examine this association, followed by one- and two-sample Mendelian randomization (MR) to assess potential causality. METHODS: This study included 4087 Europeans from the Rotterdam Study and 29,856 from the UK Biobank. In the cross-sectional analyses, multilinear regression was used to examine the association between alcohol consumption (g/day) and bone outcomes [i.e., bone mineral density (BMD) and trabecular bone score (TBS)]. For MR analyses, genetic variants associated with alcohol consumption and problematic alcohol use [defined as a combination of alcohol use disorders (AUD), alcohol dependence, and measures of Alcohol Use Disorders Identification Test-Problems (AUDIT-P)] were used as the instrumental variable (IV) for both exposures in both one- and two-sample MR. RESULTS: Cross-sectional analyses revealed a positive relationship between alcohol consumption and lumbar spine BMD (LS-BMD) (RS: β = 0.108, p = 0.009; UKB: β = 0.095, p = 6.87 × 10), femoral neck BMD (FN-BMD) (RS: β = 0.140, p = 0.001; UKB: β = 0.102, p = 3.42 × 10), and lumbar spine TBS (LS-TBS) (RS: β = 0.128, p = 0.004; UKB: β = 0.084, p = 6.53 × 10) in both studies, while alcohol consumption was only significantly associated with total body BMD (TB-BMD) (RS: β = 0.059, p = 0.087; UKB: β = 0.058, p = 7.48 × 10) in UKB. However, both one-sample and two-sample MR analyses found no evidence for a causal effect of genetically predicted alcohol consumption or problematic alcohol consumption on bone outcomes. CONCLUSION: In two independent studies, we observed a positive cross-sectional association of alcohol consumption with femoral neck BMD, lumbar spine BMD and TBS in European participants. However, MR findings did not demonstrate a causal link, suggesting that other factors or biases may confound the observed positive relationship. Further research is warranted to better understand the underlying mechanisms and potential confounders of this association.
Systemic and local predictors of medication-related osteonecrosis of the jaw in patients receiving antiresorptive therapy: The Shizuoka Kokuho Database study.
Tsuboi K, Kinoshita K, Matsushita F … +1 more , Sato Y
Bone · 2026 Jun · PMID 42372806 · Publisher ↗
INTRODUCTION: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive therapy. We aimed to identify dose-specific predictors for MRONJ risk stratification. METHODS: We c...
INTRODUCTION: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive therapy. We aimed to identify dose-specific predictors for MRONJ risk stratification. METHODS: We conducted a retrospective cohort study using the Shizuoka Kokuho Database, an insurance claims database. Patients ≥40 years with osteoporosis or cancer who initiated bisphosphonate or denosumab between April 2015 and September 2022 were stratified into low- and high-dose groups. The outcome was MRONJ. Candidate predictors were defined using the information available before initiation of antiresorptive therapy, including demographics, comorbidities, medications, and dental care in the preceding month (no visit, maintenance, or oral risk treatment). We estimated the subdistribution hazard ratio (SHR) and its 95% confidence interval (CI) using Fine-Gray competing risk models with all-cause mortality as the competing risk. RESULTS: Among 104,349 patients (low-dose, 99,572; high-dose, 4777), MRONJ occurred in 148 (46.7/100,000 person-years) and 105 (2116/100,000 person-years), respectively. Oral risk treatment within 1 month before therapy initiation was associated with MRONJ in both groups (low-dose: SHR 2.99 [95% CI 1.47-6.07]); high-dose: 4.28 [2.47-7.42]). Additional predictors were anemia (1.89 [1.31-2.71]) and oral corticosteroid use (2.27 [1.43-3.62]) in the low-dose group. CONCLUSION: Predictors of MRONJ differed between antiresorptive dose groups. Oral risk treatment immediately before therapy initiation was consistently associated with higher MRONJ occurrence, suggesting that oral risk conditions near initiation may be important for risk stratification.
Long-term exposure to ambient air pollution and risk of non-traumatic osteonecrosis of the femoral head: A nationwide cohort study.
Nguyen DT, Chen CC, Lian YZ … +3 more , Nguyen NTB, Kuo YJ, Chen YP
Bone · 2026 Jun · PMID 42365937 · Publisher ↗
INTRODUCTION: Non-traumatic osteonecrosis of the femoral head (ONFH) results from chronic ischemia and impaired bone remodeling, but whether long-term air pollution contributes to its development remains unclear. This st...
INTRODUCTION: Non-traumatic osteonecrosis of the femoral head (ONFH) results from chronic ischemia and impaired bone remodeling, but whether long-term air pollution contributes to its development remains unclear. This study evaluated the association between chronic exposure to ambient air pollutants and the risk of ONFH in a nationwide cohort. METHODS: We analyzed 585,334 adults from Taiwan's Longitudinal Health Insurance Database 2000, followed from 1993 to 2013. Ten-year cumulative exposures to sulfur dioxide (SO₂), carbon monoxide (CO), particulate matter ≤2.5 μm (PM₂.₅) and ≤ 10 μm (PM₁₀), nitrogen oxides (NOX, NO, NO₂), total hydrocarbons (THC), non-methane hydrocarbons (NMHC), and methane (CH₄) were estimated using residential postal codes linked to environmental monitoring data. Cox proportional-hazards models were applied to estimate adjusted hazard ratios (HRs) for incident ONFH, with Bonferroni correction applied in sensitivity analyses. RESULTS: Prolonged exposure to all pollutants was significantly associated with higher ONFH incidence. Adjusted HRs (95% CI) per standard-deviation increase were: SO₂ 1.31 (1.23-1.39), CO 1.78 (1.69-1.86), PM₂.₅ 1.76 (1.63-1.90), PM₁₀ 1.44 (1.33-1.55), NOX 1.56 (1.47-1.65), NO 1.40 (1.32-1.48), NO₂ 1.59 (1.49-1.69), THC 1.64 (1.55-1.72), NMHC 1.18 (1.11-1.24), and CH₄ 2.15 (2.02-2.29). Tertile analyses demonstrated consistent dose-response trends, with highest-tertile associations remaining significant after Bonferroni correction. CONCLUSIONS: Long-term exposure to multiple ambient pollutants is associated with an increased risk of non-traumatic ONFH. These findings highlight air pollution as a modifiable environmental determinant of musculoskeletal health and emphasize the need for continued efforts to improve air-quality standards.
Burden of disease in US patients with skeletal versus muscular or pain manifestations of hypophosphatasia: An analysis from the Global HPP Registry.
Kishnani PS, Ing S, Hoover-Fong J … +6 more , Pallais JC, Voskopoja A, Fang S, Mowrey WR, Rush E, Dahir K
Bone · 2026 Jun · PMID 42365936 · Publisher ↗
BACKGROUND: Hypophosphatasia (HPP) is a metabolic disorder characterized by deficient alkaline phosphatase (ALP) activity, defective mineralization of bones and teeth, and non-skeletal manifestations. We compared disease...
BACKGROUND: Hypophosphatasia (HPP) is a metabolic disorder characterized by deficient alkaline phosphatase (ALP) activity, defective mineralization of bones and teeth, and non-skeletal manifestations. We compared disease burden between patients with skeletal and non-skeletal manifestations. METHODS: Data from US adults enrolled in the Global HPP Registry through July 2024 were analyzed to compare baseline characteristics, genetic testing results, functional outcomes, and patient-reported outcomes between participants with and without overt skeletal manifestations. Patients who had only dental manifestations were excluded. RESULTS: Of 283 participants, 234 (82.7%) had skeletal manifestations (79.1% female; 89.3% White; median age 48.7 years) and 49 (17.3%) had only non-skeletal manifestations (69.4% female; 83.7% White; median age 41.5 years) at baseline. Muscular/pain symptoms were reported in 79.5% of skeletal and 100% of non-skeletal group participants. The skeletal group was more likely to have dental signs/symptoms (prevalence ratio 1.4), early loss of primary teeth (1.7), other dental signs/symptoms (1.5), abnormal gait (2.9), any neurologic signs/symptoms (4.4), seizures (2.6), and use of mobility aids (3.7) at baseline. Results of the 6-Minute Walk Test and self-reported pain (BPI-SF), disability (HAQ-DI), and health-related quality of life (SF-36v2) scores were similar between the two groups. Disease-causing genetic variants were reported in 94.5% (skeletal group) and 93.6% (non-skeletal group) of participants. CONCLUSION: HPP is associated with substantial disease burden, including reduced mobility and quality of life, even in the absence of skeletal manifestations. These findings highlight the importance of considering HPP in patients with low ALP activity, an ALPL variant, and muscular/pain manifestations.
Co-treatment with metformin and naringin attenuates bone alterations induced by a high-fructose diet in male Wistar rats.
Ávila Sabattini GN, Combina Herrera MP, Rizzi MA … +4 more , Brun LR, Tirao G, Picotto G, Rodríguez VA
Bone · 2026 Jun · PMID 42364838 · Publisher ↗
INTRODUCTION: A high-fructose diet (HFD) is associated with skeletal alterations, including bone loss and increased fracture risk. Metformin (Met) is widely used to treat metabolic syndrome, although it does not fully re...
INTRODUCTION: A high-fructose diet (HFD) is associated with skeletal alterations, including bone loss and increased fracture risk. Metformin (Met) is widely used to treat metabolic syndrome, although it does not fully reverse associated complications. Naringin (NAR), a natural flavonoid, has shown antioxidant and osteoprotective properties. This study aimed to evaluate whether the co-administration of Met and NAR attenuates bone alterations during the progression of HFD-induced metabolic dysfunction. METHODS: Male Wistar rats were divided: 1) control; 2) HFD (10% w/v fructose); 3) HFD + Met (100 mg/kg/day, oral); 4) HFD + NAR (40 mg/kg/day, subcutaneous); 5) HFD + Met+NAR. Treatments began on day 21 of HFD administration and continued until day 60. Bone mineral density (BMD), μCT analysis, histomorphometry, histology, and oxidative stress parameters were assessed. RESULTS: HFD increased body weight, waist circumference, triglycerides, and reduced HDL-C. Treatments normalized waist circumference, while NAR and Met+NAR improved the lipid profile. HFD reduced BMD, bone volume, and trabecular thickness, and increased trabecular separation. These alterations were attenuated by all treatments, with Met+NAR showing the greatest improvement, including normalization of trabecular structure and increased trabecular thickness beyond control values. HFD also increased marrow adiposity and reduced osteocyte number, whereas NAR and Met+NAR restored these parameters. Oxidative stress was elevated in HFD rats and improved with treatments. DISCUSSION: Co-administration of Met and NAR ameliorates HFD-induced bone alterations, likely through modulation of oxidative stress. These findings provide preclinical evidence supporting the potential utility of this combination in mitigating diet-induced skeletal alterations.
Osteoblast-specific deletion of NF-κB p65 enhances trabecular bone formation and BMP-2-induced osteogenesis in mice.
Rezwana R, Hiura F, Li A … +5 more , Zhuo Y, Kuratani M, Tsukamoto S, Katagiri T, Jimi E
Bone · 2026 Jun · PMID 42362100 · Publisher ↗
The nuclear factor κB (NF-κB) pathway plays critical roles in bone resorption and bone formation; however, the osteoblast-intrinsic function of NF-κB remains incompletely understood. In this study, we generated tamoxifen...
The nuclear factor κB (NF-κB) pathway plays critical roles in bone resorption and bone formation; however, the osteoblast-intrinsic function of NF-κB remains incompletely understood. In this study, we generated tamoxifen-inducible osteoblast-specific p65 (RelA)-deficient mice (p65) using a Col1a1-CreERT2 system. Specific deletion of p65 in osteoblast-lineage cells was confirmed by immunohistochemical analysis. Primary analyses were performed using male mice, with selected findings validated in female mice. Osteoblast-specific deletion of p65 resulted in a significant increase in trabecular bone mass without affecting cortical bone, including approximately 20% higher total bone mineral density (total BMD), 25-30% higher trabecular bone mineral density (trabecular BMD), a 20-30% increase in bone volume fraction (BV/TV), a twofold increase in trabecular number (Tb.N), a 60-70% increase in trabecular thickness (Tb.Th), and a 50-60% reduction in trabecular separation (Tb.Sp). Histological analysis confirmed expansion of trabecular bone in the secondary spongiosa, and dynamic histomorphometry demonstrated increased bone formation rates, whereas osteoclast parameters remained unchanged. Similar skeletal phenotypes were observed in female mice, at later time points, and in the lumbar vertebrae. Furthermore, BMP-2-induced ectopic bone formation was enhanced in p65 mice. In primary osteoblast cultures, p65 deletion increased alkaline phosphatase activity under both basal osteogenic and BMP-2-stimulated conditions, whereas BMP-2-induced Smad1/5 phosphorylation remained unchanged. Collectively, these findings identify p65 as an intrinsic negative regulator of osteoblast-mediated bone formation and suggest that p65 suppresses osteoblast differentiation without altering BMP-2-induced Smad1/5 phosphorylation. These findings highlight p65-related pathways as potential targets for anabolic bone regeneration.
Osteoporosis treatment adherence trajectories, comedication patterns, and romosozumab persistence among early users: A data-driven analysis.
Liu Y, Wu H, Arora T … +4 more , Burden AM, Danila MI, Saag KG, Curtis JR
Bone · 2026 Jun · PMID 42362099 · Publisher ↗
PURPOSE: To evaluate whether previous osteoporosis treatment adherence trajectories and comedication patterns at romosozumab initiation are associated with romosozumab treatment persistence among Medicare beneficiaries i...
PURPOSE: To evaluate whether previous osteoporosis treatment adherence trajectories and comedication patterns at romosozumab initiation are associated with romosozumab treatment persistence among Medicare beneficiaries initiating romosozumab in the early post-approval period. METHODS: We used Medicare data (2016-2022) to identify women aged ≥65 initiating romosozumab in 2019. Prior osteoporosis treatment over the 36-month baseline was summarized as monthly proportion of days covered and grouped into adherence trajectories using group-based trajectory modeling (GBTM). Comedication patterns on the romosozumab initiation day were derived from eight drug categories using consensus clustering. Primary outcome was early romosozumab persistence, assessed in three successive 60-day windows (30-day dosing interval plus 30-day permissible gap) after the first, second, and third doses, defined as receipt of the subsequent dose. Secondary analysis assessed romosozumab discontinuation. Models adjusted for covariables selected via LASSO approach. RESULTS: Among 1746 early romosozumab users, 70.8% had prior osteoporosis therapy, with four adherence trajectories identified by GBTM. Compared with consistently high prior adherence, no prior therapy was associated with lower treatment persistence (adjusted HR[aHR] = 0.91, 95% CI[0.85, 0.97], p = 0.003), while declining prior adherence was associated with increased risk of romosozumab discontinuation before completion (aHR = 1.35[1.09, 1.68], p = 0.007). Consensus clustering analysis identified five comedication patterns. Patterns characterized by antidepressants and/or antihypertensives were associated with increased risk of discontinuation compared with those using none of the eight drug categories at romosozumab initiation. CONCLUSIONS: Data-driven stratification based on prior treatment behavior and comedications identifies romosozumab early users at higher risk of non-persistence and may inform individualized support to maintain treatment persistence.
Local delivery of rhBMP-2 affects systemic metabolic response during healing of critically-sized segmental defects in a rat model.
Schwiebert EM, Strait LK, Moore SG … +3 more , Gaul DA, Fernández FM, Guldberg RE
Bone · 2026 Jun · PMID 42349530 · Publisher ↗
Understanding the biological mechanisms behind fracture nonunions and their treatments remains incomplete. Since these mechanisms are linked to phenotypic expression, studying the longitudinal metabolic profile of bone r...
Understanding the biological mechanisms behind fracture nonunions and their treatments remains incomplete. Since these mechanisms are linked to phenotypic expression, studying the longitudinal metabolic profile of bone regeneration has emerged as a potential way to better understand healing progress and treatment effectiveness. In this study, we tracked the serum metabolome of rats with critically-sized femoral defects treated with either a control, a minimum effective dose, or a supraphysiologic dose of rhBMP-2 over time. We observed distinct changes in the metabolome across control, impaired healing, and rhBMP-2-treated animals. Early in the process, we saw increased levels of metabolites that support angiogenesis in the rhBMP-2 groups. Supraphysiologic doses of rhBMP-2 significantly affected metabolite expression, especially in pathways related to angiogenesis, fatty acid metabolism, and ATP production. These longitudinal trends and individual metabolite changes provide a deeper understanding of rhBMP-2's mechanisms, improve our knowledge of its biological effects-guiding appropriate dosing-and offer a metabolic profile that may indicate healing impairment.
Subtype-specific bone mineralization defects and early treatment amelioration in murine models of autosomal recessive osteopetrosis revealed by Raman spectroscopy.
Ventura M, Alcolea-Rodriguez V, Agrimi C … +12 more , Schiavone ML, Vernuccio F, Behrouzitabar M, Strina D, Puri C, De la Cadena A, Antonacci G, Cerullo G, Polli D, Shah FA, Sobacchi C, Vanna R
Bone · 2026 Jun · PMID 42341893 · Publisher ↗
Autosomal recessive osteopetrosis is a rare genetic disorder caused by impaired osteoclast function, leading to excessive bone mass, defective remodeling, and fragility fractures. While bone density alterations are well...
Autosomal recessive osteopetrosis is a rare genetic disorder caused by impaired osteoclast function, leading to excessive bone mass, defective remodeling, and fragility fractures. While bone density alterations are well recognized, compositional parameters remain poorly characterized. Here, we applied Raman spectroscopy to characterize bone defects in two murine models, the RANKL-deficient Rankl (mild form) and the TCIRG1-deficient oc/oc (severe form), compared with healthy controls. Raman analysis revealed a gradient in mineral-to-matrix ratio, progressively showing lower values from healthy to Rankl and to oc/oc (skull: 2.93 ± 0.02 vs. 2.19 ± 0.31 vs. 1.72 ± 0.15, p < 0.05; long bone: 3.59 ± 0.56 vs. 2.60 ± 0.53 vs. 1.86 ± 0.17, p < 0.05 for all pairs except Rankl vs oc/oc). Crystallinity showed overall lower values in osteopetrotic bones compared to WT, with partially overlapping distributions between Rankl and oc/oc mice (skull: 0.050 ± 0.001 vs. 0.046 ± 0.001 vs. 0.048 ± 0.001; long bone: 0.050 ± 0.001 vs. 0.047 ± 0.001 vs. 0.048 ± 0.001 for WT, Rankl and oc/oc, respectively). Multivariate analysis achieved 95% classification accuracy under exploratory animal-level cross-validation. In oc/oc mice treated with bone marrow transplantation, Raman analysis detected a significantly higher mineral-to-matrix ratio at day 18 compared to untreated oc/oc mice (2.668 ± 0.124 vs. 2.207 ± 0.311; p = 0.040, respectively). These findings identify genotype-specific compositional alterations in ARO models and provide proof-of-concept that Raman spectroscopy can characterize mineralization defects in intact bones ex vivo, suggesting that further development of non-invasive or minimally invasive Raman-based approaches may enable future studies of ARO progression and therapeutic response in clinically relevant settings.
Validation of 3D-DXA-derived proximal femur measurements against QCT across international clinical cohorts.
Bracco MI, Black DM, Sone T … +4 more , Del Rio L, de Gregorio S, Malouf J, Humbert L
Bone · 2026 Jun · PMID 42336072 · Publisher ↗
Three-dimensional dual-energy X-ray absorptiometry (3D-DXA) reconstructs proximal femur models from standard DXA scans to estimate cortical and trabecular bone parameters. The aim of this study was to evaluate 3D-DXA aga...
Three-dimensional dual-energy X-ray absorptiometry (3D-DXA) reconstructs proximal femur models from standard DXA scans to estimate cortical and trabecular bone parameters. The aim of this study was to evaluate 3D-DXA against quantitative computed tomography (QCT) across independent international cohorts. The study included 531 subjects from four cohorts: an adult population from Spain, a postmenopausal female population from the United States, an osteoarthritis population and a young population, both from Japan. Subjects underwent both 3D-DXA and QCT imaging. Accuracy was assessed using linear regression and Bland-Altman analysis to evaluate systematic and random errors. 3D-DXA parameters strongly correlated with QCT across all datasets, with correlation coefficients between 0.82 and 0.97. Random errors were consistent across cohorts and ranged between 16.55 and 19.91 mg/cm for integral volumetric bone mineral density (vBMD), between 13.52 and 18.47 mg/cm for trabecular vBMD, and between 9.13 and 11.37 mg/cm for cortical surface bone mineral density (sBMD). Systematic errors ranged between -14.84 and 4.50 mg/cm for integral vBMD, between -8.31 and 14.41 mg/cm for trabecular vBMD, and between -5.58 and 3.21 mg/cm for cortical sBMD. The variations in systematic errors were likely attributable to differences in QCT acquisition protocols. Overall, these results demonstrate consistent agreement between 3D-DXA and QCT across sex, age, ethnicity, geographic regions, and clinical profiles. Taken together, these findings support the use of 3D-DXA as an accurate, non-invasive, and clinically accessible technology for advanced assessment of the cortical and trabecular compartments of the proximal femur.
Lrsam1 deficiency suppresses osteoclastogenesis and attenuates bone loss through the JNK2-NFATc1 axis.
Wang X, Yu G, Fang C … +3 more , Xu L, Wang Y, Zhao Q
Bone · 2026 Jun · PMID 42320778 · Publisher ↗
Excessive osteoclast-mediated bone resorption is a major contributor to osteoporosis and other osteolytic diseases. Here, we investigated the role of the E3 ubiquitin ligase Lrsam1 in osteoclastogenesis and bone metaboli...
Excessive osteoclast-mediated bone resorption is a major contributor to osteoporosis and other osteolytic diseases. Here, we investigated the role of the E3 ubiquitin ligase Lrsam1 in osteoclastogenesis and bone metabolism using myeloid-specific Lrsam1-deficient mice. Lrsam1 deletion increased trabecular bone mass in vivo, reduced osteoclast numbers in the distal femur, and attenuated ovariectomy-induced bone loss without significantly affecting bone formation parameters. In vitro, Lrsam1-deficient bone marrow-derived macrophages exhibited impaired RANKL-induced osteoclast differentiation, as indicated by fewer TRAP-positive multinucleated cells, impaired F-actin ring formation, and reduced expression of osteoclast-related genes and proteins. Proteomic analysis identified JNK2 as a candidate mediator of Lrsam1 deficiency. Consistently, JNK2 protein levels were elevated in Lrsam1-deficient cells, whereas inhibition of JNK signaling partially rescued osteoclast differentiation and restored NFATc1 nuclear translocation. Taken together, these findings identify Lrsam1 as a positive regulator of osteoclastogenesis and suggest that its effects on osteoclast differentiation are associated, at least in part, with JNK2-dependent regulation of NFATc1 nuclear translocation.
Development of the Fibrodysplasia Ossificans Progressiva FLare EXperience Revised (FOP-FLEX-R©) Questionnaire: A patient-reported outcome measure.
Pignolo RJ, Hsiao EC, Al Mukaddam M … +9 more , Brova M, Olonilua D, Shields AL, LaBranche TP, Sherwin CA, Boing EA, Karimian N, Solanke O, Kaplan FS
Bone · 2026 Jun · PMID 42314957 · Publisher ↗
BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, genetic disorder mainly characterized by progressive heterotopic ossification (HO). Flare-ups in FOP, involving soft tissue swelling, pain, warmth...
BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, genetic disorder mainly characterized by progressive heterotopic ossification (HO). Flare-ups in FOP, involving soft tissue swelling, pain, warmth, and stiffness, often precede HO. We report development of the FOP-FLEX-R© questionnaire (Ipsen, 2026), providing clinical researchers with a comprehensive tool to assess patient experiences during flare-ups, and address the limitations of existing patient-reported outcome measures (PROMs). METHODS: The FOP-FLEX questionnaire was developed through: a targeted literature review to identify signs, symptoms, and impacts of FOP; concept selection and questionnaire development activities; validation of content and readability in expert consultations and patient interviews; revisions to create the FOP-FLEX-R© questionnaire. RESULTS: The literature review identified 42 'sign and symptom' and 28 'impact' concepts. Ten concepts were selected for inclusion in the initial FOP-FLEX: swelling, pain, skin warmth, stiffness, skin redness, impaired daily activities, frustration, bother, fatigue/tiredness, and appetite loss. Consultations with clinical experts (n = 5) and interviews with patients (n = 12) affirmed these concepts. Cognitive debriefing with the same patients indicated the FOP-FLEX was understandable and easy to complete, though some revisions were made, including those to enable the assessment to be completed by younger patients and to remove non-flare-up items. CONCLUSIONS: The FOP-FLEX-R© questionnaire offers a comprehensive, content-validated PROM for use in clinical trials, to understand the lived experience of flare-ups in FOP and evaluate the benefit of new therapies.
"Weekend warrior" physical activity pattern and risk of low bone mass and related fractures: Results from two nationwide population-based surveys.
Zhang YW, Wei P, Feng LS … +12 more , Dong ZL, Hu Y, Zhang H, Fan ZH, Wang P, Wang GC, Ma YH, He CR, Peng JP, Chen X, Zheng HF, Su JC
Bone · 2026 Jun · PMID 42309247 · Publisher ↗
BACKGROUND: Physical activity (PA) is crucial for maintaining bone mass. However, it remains unclear whether the "weekend warrior" (WW) pattern, namely condensing moderate-to-vigorous physical activity (MVPA) into 1 or 2...
BACKGROUND: Physical activity (PA) is crucial for maintaining bone mass. However, it remains unclear whether the "weekend warrior" (WW) pattern, namely condensing moderate-to-vigorous physical activity (MVPA) into 1 or 2 days per week, is beneficial for bone health. This study aimed to assess the association between the WW pattern and risk of low bone mass and related fractures. METHODS: We conducted a population-based study based on two nationwide databases, including 6972 participants aged 20-59 from the National Health and Nutrition Examination Survey (NHANES), 2007-2010 & 2013-2014 cycles, in which PA was self-reported via the Global Physical Activity Questionnaire; and 52,989 participants aged 37-60 years from UK Biobank (UKB), in which PA was measured by wrist-worn accelerometers over 7 days (2013-2015). In both surveys, lumbar spine and femoral neck bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry (DXA). Associations were analyzed using survey-weighted linear regression (in NHANES), multivariable linear regression (in UKB), and Cox proportional hazards models for incident fracture (in UKB). RESULTS: In NHANES, both the WW pattern and the regular active (RA) pattern were associated with higher femoral neck BMD compared with the inactive group (WW: β = 0.021, 95% CI 0.008-0.035, P = 0.004; RA: β = 0.015, 95% CI 0.007-0.023, P = 0.001), and both were associated with significantly lower odds of low bone mass. In UKB, similar favorable BMD associations were observed, and the WW pattern was associated with a lower hazard of incident fracture compared with both the inactive group (HR = 0.899, 95% CI 0.824-0.981, P = 0.017) and the RA group (HR = 0.897, 95% CI 0.823-0.976, P = 0.012). CONCLUSIONS: Meeting weekly PA guidelines is associated with favorable bone health indicators and lower fracture risk, regardless of whether activity is concentrated on weekends or distributed throughout the week. The WW pattern may serve as a time-efficient alternative for bone health maintenance.
EP4 agonist KMN-159 induces osteogenesis in rodent and porcine dental models.
Owen TA, Rzeczycki P, Leguizamon NDP … +6 more , Jin Q, Patel C, Wei S, Barrett SD, van Wijnen AJ, Morano MI
Bone · 2026 Jun · PMID 42309246 · Publisher ↗
The selective EP4 receptor (PTGER4) agonist KMN-159 stimulates osteoblast function and may support applications in dental bone tissue regeneration and tissue engineering. The goal of this study was to further validate st...
The selective EP4 receptor (PTGER4) agonist KMN-159 stimulates osteoblast function and may support applications in dental bone tissue regeneration and tissue engineering. The goal of this study was to further validate stimulation of osteogenic differentiation ex vivo and in vivo by KMN-159. We tested KMN-159 in cultured human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) and rat BM-MSCs grown in a three-dimensional deproteinized bone explant culture model. The effects of KMN-159 treatment in vivo were also investigated in two different alveolar bone repair models (i.e., male rat tooth socket model with and without a dental implant), as well as in a pilot study with a dental repair model in which human implants were insert into the mandibles of male minipigs. Our results show that KMN-159 promotes osteogenic differentiation of human BM-MSCs, (e.g., ALPL enzyme and mineralization) and the temporal expression of osteoblast markers (e.g., RUNX2, SP7, BMP2, TNFRSF11B) and extracellular matrix (ECM) proteins (e.g., BGLAP). KMN-159 also stimulates osteogenesis in rat BM-MSCs in bone-derived 3D scaffolds by accelerating proliferation and modulating expression of osteoblast phenotype markers. In the in vivo studies of bone repair KMN-159 increases bone volume in the tooth socket or around the coronal aspect of the implant in the rat maxillary extraction models. Similar results were obtained in the porcine dental implant repair model. We conclude that KMN-159 is a viable pharmacotherapeutic candidate to promote bone mass accrual or to support bone tissue engineering in dental, craniofacial and skeletal applications.
Morphological micro-computed tomography assessment of cleaned freeze-dried compacted cancellous bone allografts.
Putzer D, Spiegel C, Pallua J … +4 more , Degenhart G, Coraça-Huber D, Nogler M, Arora R
Bone · 2026 Jun · PMID 42302907 · Publisher ↗
Bone grafting is widely used in reconstructive surgery, with allogeneic grafts serving as an important alternative to autologous bone. The influence of compaction on the microarchitecture of cleaned cancellous bone allog...
Bone grafting is widely used in reconstructive surgery, with allogeneic grafts serving as an important alternative to autologous bone. The influence of compaction on the microarchitecture of cleaned cancellous bone allografts remains insufficiently understood. This study investigated the effects of different compaction levels on cleaned cancellous bone chips using micro-computed tomography (micro-CT), with particular focus on structural parameters relevant to graft architecture. Cancellous bone from 15 femoral heads was processed into bone chips, chemically cleaned, and compacted to three density levels (low: 0.15 g/cm, medium: 0.26 g/cm, high: 0.41 g/cm). A structural allograft served as a reference. Microarchitectural parameters, including bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), connectivity density (Conn.D), structure model index (SMI), and degree of anisotropy (DA), were analyzed. Increasing compaction led to a significant increase in BV/TV (7.0% to 13.6%), Tb.N, and Conn.D, along with a marked reduction in Tb.Sp (1.97 mm to 0.85 mm; p < 0.001). At high compaction, BV/TV, Tb.N, and Tb.Sp approached the values of the structural allograft reference. However, Tb.Th decreased slightly, and SMI remained consistently high (approximately 2.4), indicating a predominantly rod-like architecture. Compared with the reference, morselized grafts showed lower anisotropy and connectivity. In conclusion, compaction significantly altered graft microarchitecture, increasing density and connectivity while reducing pore size. At high compaction, selected parameters approached those of the structural allograft reference, although differences in Tb.Th, Conn.D, SMI, and DA remained. Even at high compaction, comparatively large pore sizes were maintained, but the biological implications of this finding cannot be determined from micro-CT data alone. These findings highlight the need to balance structural densification with preservation of microarchitectural features potentially relevant for graft incorporation.
Childhood cancer survivors with premature ovarian insufficiency have low bone mineral density at long term follow-up.
Netterlid A, Mörse H, Åkesson KE … +6 more , Giwercman A, Henic E, Nyström A, Erfurth EM, Becker C, Elfving M
Bone · 2026 Jun · PMID 42302906 · Publisher ↗
BACKGROUND: Childhood cancer survivors (CCS) are reported to have decreased bone mineral density (BMD). PURPOSE: Is premature ovarian insufficiency (POI) an important risk factor for low BMD in CCS at long term follow-up...
BACKGROUND: Childhood cancer survivors (CCS) are reported to have decreased bone mineral density (BMD). PURPOSE: Is premature ovarian insufficiency (POI) an important risk factor for low BMD in CCS at long term follow-up? PATIENTS AND METHODS: Altogether 167 female CCS, median age 34 (19-57) years, treated for childhood cancer under age 18 years between 1964 and 2008, with a follow-up time of 25 (12-41) years, and 164 matched controls took part in this cross-sectional study, including blood samples, anthropometric measurements, dual-energy X-ray absorptiometry (DXA), and questionnaires. RESULTS: CCS with primary POI (n = 22) had lower BMD in lumbar spine L1-L4 1.13 (0.79-1.39) g/cm compared with controls 1.20 (0.84-1.56) g/cm (p = 0.005) and lower BMD in femoral neck 0.89 (0.72-1.16) g/cm compared with controls 1.00 (0.69-1.48) g/cm (p = 0.020). CCS with primary POI had significantly reduced levels of androgens and low BMI < 20 kg/m (p = 0.003). Odds Ratio for a low BMD < - 1 SD in L1-L4 was increased among CCS with primary POI (2.76 (1.01-7.52)), but also after abdominal irradiation (3.42 (1.52-7.70)) and all irradiation (1.98 (1.05-3.76)). CONCLUSIONS: Female childhood cancer survivors are at risk of low BMD and POI is an additional risk factor at long term follow-up. Besides hypogonadism and insufficient Hormone Replacement Therapy (HRT), abdominal radiotherapy, low levels of androgens and low BMI may confer to the risk.
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