Mei Y, Wang Z, Ren N
… +19 more, Shen L, Li X, Yue H, Zhang H, Gu J, Hu W, Wang J, Li S, Gao C, Wei Z, Xu Y, Xu S, Hong W, Shi Q, Wang Y, Xu J, Gao G, Zhang Z, Wang C
Osteoporos Int
· 2026 May · PMID 42113233
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UNLABELLED: This study systematically analyzed 72 adults with genetically confirmed hypophosphatasia and compared them with 36 individuals with persistent hypophosphatasemia but negative ALPL variants. Using four routine...UNLABELLED: This study systematically analyzed 72 adults with genetically confirmed hypophosphatasia and compared them with 36 individuals with persistent hypophosphatasemia but negative ALPL variants. Using four routinely available indicators, a simplified diagnostic tool was developed and externally validated to facilitate the early identification of adult hypophosphatasia in clinical practice. PURPOSE: Hypophosphatasia (HPP), an underdiagnosed inborn error of disorder caused by ALPL mutations, poses diagnostic challenges in adults due to phenotypic heterogeneity. This study aimed to establish a large adult HPP cohort in China and develop a practical diagnostic tool using routine clinical parameters. METHODS: Clinical and genetic characteristics were systematically analyzed in 72 genetically confirmed adult HPP patients and 36 individuals with persistent hypophosphatasemia and negative ALPL genetic testing. Two models were developed to predict HPP: Model 0 (alkaline phosphatase (ALP)+pyridoxal-5'-phosphate (PLP)) and Model 1 (ALP+height Z-score+family history+chronic musculoskeletal pain). Model performance was evaluated by tenfold cross-validation, decision curve analysis (DCA) and external validation (n = 40, including 28 HPP). RESULTS: HPP patients exhibited lower ALP (27.0 (21.8, 33.3) U/L vs. 36.00 (32.0, 38.0) U/L; P < 0.001), elevated PLP (214.3 (121.3, 457.7) nmol/L vs. 42.6 (31.9, 63.5) nmol/L; P < 0.001), growth impairment, and higher prevalence of chronic musculoskeletal pain and family history. Optimal ALP and PLP cutoffs were 28.2 U/L and 114.9 nmol/L, respectively. Compound heterozygotes and crown domain variants in ALPL gene showed lower ALP and higher PLP levels. Model 1 performed comparably to Model 0 (AUC 0.918 vs. 0.896; P = 0.513), remained robust in the age-stratified sensitivity analysis (<50 years), and achieved an AUC of 0.833 in external validation. A nomogram based on Model 1 was constructed. CONCLUSION: This study provides the largest clinical-genetic characterization of adult HPP in China and proposes a simple four-variable nomogram that enables accurate recognition of HPP without PLP testing, facilitating earlier diagnosis in routine practice.
Burden AM, la Torre AM, Immoos M
… +4 more, Burkard T, Hofbauer LC, Rauner M, Steinbicker AU
Osteoporos Int
· 2026 May · PMID 42113232
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UNLABELLED: Anemia seems to be associated with an increased risk of fracture. This cohort study of the UK primary care data shows in 84,932 anemic patients and 158,731 controls an increased fracture risk in anemic patien...UNLABELLED: Anemia seems to be associated with an increased risk of fracture. This cohort study of the UK primary care data shows in 84,932 anemic patients and 158,731 controls an increased fracture risk in anemic patients, also including patients < 50 years of age. Severe anemia was associated with 2 × vertebral fracture risk. Awareness of this clinically relevant association should increase. PURPOSE: In this study, we evaluated the risk of fracture among adult patients with anemia, compared to propensity score matched controls, stratifying by fracture site, age, and severity of anemia. METHODS: We conducted a cohort study using the UK IQVIA Medical Research Database (IMRD), incorporating The Health Improvement Network (THIN), a Cegedim database. Adults with a diagnosis of anemia and an eligible hemoglobin value (< 13 g/dL (men) or < 12 g/dL (women)) were matched to controls using propensity score matching. Cox proportional hazard models estimated the hazard ratios (HRs) for the risk of any fracture (stratified by fracture site, sex, and age (defined < 50 years and > = 50 years)). RESULTS: 84,932 anemic patients were matched to 158,731 controls. Overall, anemia was associated with a significant 20% risk of any fracture (driven by a 32% (HR 1.32, 1.20-1.47) increase among males, no difference among females). When stratified by sex, males had a significant risk at all fracture sites (27% (HR 1.27, 1.03-1.58) risk for vertebral, 89% (HR 1.89, 1.52-2.34) risk for humerus fractures). In females, only hip (HR 1.14, 1.05-1.25) and vertebral fractures (HR 1.24, 1.07-1.43) were significantly associated with anemia. Patients ≥ 50 years had elevated risks for all sites. In patients < 50 years, only hip fracture was elevated (HR 1.86, 1.04-3.33). CONCLUSION: Anemia was associated with a significant 20% increase of any fracture; however, this was driven by the elevated risk among males and those over the age of 50 years. Among females, only hip and vertebral fracture risk was elevated, while males had an elevated risk at all sites.
Osteoporos Int
· 2026 May · PMID 42105011
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UNLABELLED: In this global real-world study, fragility fractures of the pelvis were associated with increased risks of mortality (HR 1.63; 95% CI 1.58-1.69) and subsequent fractures (HR 2.95) in older adults with osteopo...UNLABELLED: In this global real-world study, fragility fractures of the pelvis were associated with increased risks of mortality (HR 1.63; 95% CI 1.58-1.69) and subsequent fractures (HR 2.95) in older adults with osteoporosis. Subgroup analyses further indicated markedly higher relative fracture risks among patients aged 75-79 years (HR 4.94). PURPOSE: Fragility fractures of the pelvis (FFPs) are increasingly recognized in older adults with osteoporosis; however, their long-term prognostic impact remains incompletely defined. This study evaluated the risks of mortality, hospital readmission, subsequent fractures, and immobility-related complications associated with FFP in osteoporotic older adults. METHODS: We conducted a global, retrospective cohort study using the TriNetX Research Network. Patients aged 65 years or older with osteoporosis were categorized into an FFP group and a non-FFP control group. Propensity score matching was performed in a 1:1 ratio to balance baseline covariates. Primary outcomes included mortality, hospital readmission, and subsequent fractures, assessed at 1-, 3-, and 5-year follow-up. Secondary outcomes comprised immobility-related complications. Age-stratified subgroup analyses were conducted to evaluate differential risk patterns. RESULTS: After matching, 76,556 patients (38,278 per group) were included. Over 5 years of follow-up, patients with FFP exhibited significantly higher risks of mortality (HR 1.59; 95% CI 1.54-1.64), hospital readmission (HR 1.98; 95% CI 1.93-2.03), and subsequent fractures (HR 2.86; 95% CI 2.76-2.96) compared with controls. FFP was also associated with increased risks of immobility-related complications, including infections, thromboembolic events, and pressure ulcers. Analyses stratifying patients aged 65-79 years into three subgroups yielded consistent and highly elevated relative risks across all strata, whereas absolute event burdens were greatest among those aged 80 years or older. CONCLUSIONS: FFPs are associated with substantially increased long-term mortality, morbidity, and healthcare utilization in older adults with osteoporosis. These findings establish FFP as a high-risk condition warranting proactive, age-tailored secondary prevention, functional rehabilitation, and long-term care strategies.
Messina OD, Clark P, Torres JM
… +15 more, Dankers W, Cruz-Priego GA, Neira LFV, Raterman H, Giselle M, Adami G, Molina FC, Kluwak G, Mansur JL, Reginster JY, Neyro JL, Zakraoui L, Binkley N, Vidal M, Lems WF
Osteoporos Int
· 2026 May · PMID 42104141
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PURPOSE: To critically evaluate the current evidence on the role of vitamin D in inflammatory rheumatic diseases, including its association with disease activity, potential immunomodulatory effects, and the clinical impa...PURPOSE: To critically evaluate the current evidence on the role of vitamin D in inflammatory rheumatic diseases, including its association with disease activity, potential immunomodulatory effects, and the clinical impact of supplementation. METHODS: A narrative review was conducted based on a comprehensive search of MEDLINE, Cochrane Library, and Epistemonikos databases up to October 2025. Eligible studies included randomized controlled trials, observational studies, systematic reviews, and meta-analyses evaluating vitamin D status and/or supplementation in adult patients with inflammatory rheumatic diseases. Evidence was synthesized qualitatively, prioritizing study design and level of evidence. RESULTS: Vitamin D deficiency is highly prevalent across inflammatory rheumatic diseases and is associated with higher disease activity, fatigue, and poorer musculoskeletal outcomes. Experimental data support immunomodulatory effects; however, clinical evidence remains heterogeneous. Randomized controlled trials demonstrate that supplementation effectively corrects deficiency and is safe, with modest improvements in disease activity and fatigue mainly in patients with low baseline 25(OH)D levels. In contrast, large trials and Mendelian randomization studies do not support a causal role of vitamin D in disease onset or sustained remission. Meta-analyses show small and inconsistent benefits, limited by heterogeneity in study design, dosing regimens, and populations. CONCLUSION: Vitamin D deficiency is a common and clinically relevant finding in inflammatory rheumatic diseases. While supplementation reliably restores adequate levels and may provide modest clinical benefits in deficient patients, current evidence does not support a causal or disease-modifying role. Maintaining serum 25(OH)D ≥30 ng/mL remains advisable for skeletal health, whereas its immunological benefits require further investigation through well-designed randomized trials.
Fernández-González M, Mora-Traverso M, Molina-Garcia P
… +4 more, Prieto-Moreno R, Ortiz-Piña M, Contreras-Gutiérrez J, Ariza-Vega P
Osteoporos Int
· 2026 May · PMID 42101660
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Osteoporotic vertebral fractures (OVFs) are the second most common fractures in osteoporosis, often leading to reduced functional capacity, chronic pain, and lower quality of life. Physical exercise and health education...Osteoporotic vertebral fractures (OVFs) are the second most common fractures in osteoporosis, often leading to reduced functional capacity, chronic pain, and lower quality of life. Physical exercise and health education are considered promising options for managing these symptoms. To determine the effectiveness and safety of exercise and health education compared to usual care in patients with OVFs. A literature search up to April 2024 was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library. Clinical trials involving adults with OVFs were included, focusing on physical capacity (primary outcome) and other health outcomes. Study selection, bias assessment, and data extraction were independently conducted by two authors, with a third author resolving conflicts. Nineteen studies were included in the meta-analysis of exercise interventions. Exercise interventions were analyzed using a standardized mean difference (SMD) meta-analysis, with additional sensitivity analyses. Physical exercise significantly improves functional capacity (SMD -0.41; 95% CI -0.69 to -0.14; p 0.003), aerobic capacity, balance, trunk muscle strength, pain, and quality of life in patients with OVF. No significant effects were observed on thoracic posture or fear of falling. Adverse event risk was low (6%), comparable to usual care or daily activities. Health education interventions (two studies) were synthetized narratively, both showing improvements in pain, mobility, and patient knowledge. Physical exercise is effective and safe in the recovery of OVFs; thus, its prescription is recommended. Most interventions focus first on core strength and motor control and then on aerobic and resistance training. Further evidence is needed to demonstrate the effectiveness of health education.
Yukishima T, Kobayakawa T, Hirano Y
… +11 more, Kanayama Y, Niimi R, Etani Y, Noguchi T, Noguchi T, Shimoyama K, Maekawa Y, Ojima T, Nakata K, Okada S, Ebina K
Osteoporos Int
· 2026 May · PMID 42101658
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UNLABELLED: This multicenter retrospective cohort compared romosozumab outcomes between oral glucocorticoid users and non-users. Bone turnover marker responses and lumbar spine bone mineral density gains were similar, wh...UNLABELLED: This multicenter retrospective cohort compared romosozumab outcomes between oral glucocorticoid users and non-users. Bone turnover marker responses and lumbar spine bone mineral density gains were similar, whereas total hip bone mineral density gains were smaller among glucocorticoid users. PURPOSE: To investigate the impact of oral glucocorticoids (GC) on the effectiveness of romosozumab by comparing outcomes between GC users and non-users after adjusting for patient background. METHODS: This multicenter, retrospective cohort study analyzed patients who completed 12 months of therapy (n = 428). Inverse probability of treatment weighting was employed to construct a pseudo-population with balanced baseline characteristics, yielding 40 GC users and 39.8 non-users (95.3% female, mean age 76.6 years; mean lumbar spine T-score -2.7; mean GC dose 5.4 mg/day [prednisolone equivalent]). Percentage changes in bone turnover markers (BTMs) and bone mineral density (BMD) over 12 months were compared between groups. Factors affecting BMD changes were identified using multivariable analysis. RESULTS: GC use did not significantly affect the changes in PINP and TRACP-5b levels. The 12-month increase in lumbar spine BMD was comparable between groups (GC users 9.7% vs. non-users 10.7%; P = 0.55). In contrast, the increase in total hip BMD was significantly lower in GC users compared with non-users (2.8% vs. 5.6%; P = 0.003). Multivariable analysis revealed that baseline PINP was significantly associated with the BMD increase at the lumbar spine, whereas daily GC dose was a significant factor for the total hip. CONCLUSION: Oral GC use did not significantly affect changes in BTMs or BMD increases at the lumbar spine. Smaller gains in total hip BMD were observed in GC users, which may have reflected not only GC use but also underlying disease-related factors.
de Andrade JG, de Oliveira ARL, Calumby BSA
… +4 more, de Figueiredo Alves GG, de Melo AKG, de Sousa Braz A, Soares MRMP
Osteoporos Int
· 2026 May · PMID 42101657
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Romosozumab, a monoclonal antibody targeting sclerostin, is an effective anabolic therapy for patients with severe osteoporosis at very high fracture risk. Its safety profile has been considered favorable, and to our kno...Romosozumab, a monoclonal antibody targeting sclerostin, is an effective anabolic therapy for patients with severe osteoporosis at very high fracture risk. Its safety profile has been considered favorable, and to our knowledge, no previous reports of serious liver injury have been associated with clinical doses of romosozumab. We report a rare case of drug-induced liver injury with autoimmune-like features temporally associated with romosozumab therapy. A 72-year-old woman developed marked elevations in aminotransferases after 3 monthly doses of romosozumab, with liver enzymes exceeding 20 times the upper limit of normal. Extensive evaluation excluded viral, metabolic, and other autoimmune liver diseases. Liver histology demonstrated portal inflammation with eosinophils, periportal necroinflammatory activity, and centrilobular necrosis, compatible with drug-induced liver injury. Autoimmune-like features, including smooth-muscle antibody positivity, were present, while serum IgG levels remained within the normal range. Causality assessment using the Roussel Uclaf Causality Assessment Method yielded a score of 6, indicating a probable association. Transaminase levels improved incompletely after drug withdrawal and normalized only after corticosteroid therapy, with relapse following early taper and sustained remission after prolonged treatment. This case suggests that, although rare, immune-mediated liver injury may occur in association with romosozumab therapy and highlights the importance of clinical awareness.
Barzilay JI, Bůžková P, Fink HA
… +5 more, Cauley JA, Robbins JA, Elam R, Carbone L, Mukamal KJ
Osteoporos Int
· 2026 May · PMID 42065751
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The association between circulating soluble klotho (s-klotho) levels and hip fracture risk is uncertain. We assessed this relationship in 4428 older adults followed for a median of 11.8 years, during which 602 hip fractu...The association between circulating soluble klotho (s-klotho) levels and hip fracture risk is uncertain. We assessed this relationship in 4428 older adults followed for a median of 11.8 years, during which 602 hip fractures occurred. In the overall cohort, s-klotho levels were marginally but not significantly associated with hip fracture risk (hazard ratio (HR) per standard deviation increase, 0.92; 95% CI, 0.83-1.01; p = 0.075). In exploratory analyses, participants in the highest 5% of s-klotho levels (> 1615.2 pg/ml) exhibited a substantially lower risk of hip fracture (adjusted HR, 0.48; 95% CI, 0.27-0.85; p = 0.01), suggesting a threshold effect in which only very high s-klotho concentrations are associated with reduced risk. This finding may help explain inconsistencies in prior studies.
Scala A, Delbarba A, Ceolin C
… +9 more, Camozzi V, Giannini S, Procacci S, Silvestrini I, Ferlin A, Sergi G, Cappelli C, Garolla A, Gender Incongruence Interdisciplinary Group (GIIG)
UNLABELLED: In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in...UNLABELLED: In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available. PURPOSE: Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT). MATERIALS AND METHODS: We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth - AFAB and 96 AMAB) aged 18-43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored. RESULTS: Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4-0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1%), whereas AFAB participants generally maintained normal BMD. However, FRAX scores remained low. BMI and 25-OH vitamin D levels were independent predictors of BMD and Z-scores in AMAB individuals. CONCLUSIONS: The choice of reference gender significantly influences densitometric interpretation in young transgender adults. Until further evidence becomes available, calculating Z-scores using both male and female reference databases is advisable. Early preventive interventions remain essential to preserve bone health.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and variable skeletal deformities. While SP7 variants typically underlie autosomal recessive OI, a single heterozygous SP7 variant h...Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and variable skeletal deformities. While SP7 variants typically underlie autosomal recessive OI, a single heterozygous SP7 variant has recently been reported to cause autosomal dominant OI. Given the limited family-based genetic studies of OI in Malaysian populations, its inheritance patterns and molecular spectrum remain poorly defined. Here, we investigated a three-generation Malaysian family with three individuals (the 7-year-old proband, her 8-year-old brother, and 34-year-old mother) presenting with lower limb bowing, impaired fracture healing, despite preserved lumbar spine areal bone mineral density. Three affected individuals and seven unaffected relatives were recruited for clinical evaluation and genetic analysis. Targeted sequencing and whole-exome sequencing (WES) revealed a heterozygous SP7 missense variant, NM_001173467.2:c.1019A>C (p.Glu340Ala), initially classified as a variant of uncertain significance, in all affected individuals. Variant evaluation using in silico tools (CADD-Phred, 27.2; REVEL, 0.812; PROVEAN, 0.887), protein stability modeling (ΔΔG = -1.05 kcal/mol), and conservation analysis across orthologs predicted a deleterious effect. The variant met six ACMG/AMP criteria (PS3, PM1, PM2, PP1, PP2, PP4) and was reclassified as pathogenic. Sanger sequencing confirmed variant presence in all affected individuals and absence in unaffected relatives, with Fisher's exact test demonstrating a significant association with the disease (p = 0.0083). This study represents the first family-based genetic investigation of OI in Malaysia and provides independent evidence that SP7-related OI can manifest as autosomal dominant disease with preserved bone mineral density and defective fracture healing. This supports a haploinsufficiency mechanism with important implications for genetic diagnosis and counseling.
UNLABELLED: Osteoarthritis patients undergoing THA or TKA were studied to compare the cumulative incidence of revision after perioperative denosumab versus alendronate. Denosumab was not associated with differences in th...UNLABELLED: Osteoarthritis patients undergoing THA or TKA were studied to compare the cumulative incidence of revision after perioperative denosumab versus alendronate. Denosumab was not associated with differences in the incidence of revision after THA but was associated with a higher revision incidence after TKA, mainly driven by aseptic tibial loosening. BACKGROUND: Osteoarthritis is highly prevalent, and the number of total hip (THA) and knee arthroplasties (TKA) continues to rise. This study aimed to evaluate the risk of revision associated with perioperative exposure to denosumab versus alendronate in patients undergoing THA or TKA for osteoarthritis. METHODS: This retrospective cohort study used data from the Emilia-Romagna Registry of Orthopedic Prosthetic Implants (RIPO). Patients undergoing primary THA or TKA for osteoarthritis between 2011 and 2023 were included. Perioperative exposure was defined as at least one dispensing of denosumab or alendronate within 180 days before or after surgery. The primary outcome was first revision. Revision risk was analysed using cumulative incidence functions, treating death and emigration as competing events, and groups were compared using Gray's test. RESULTS: The THA cohort comprised 129 denosumab and 922 alendronate users. Revision occurred in 4 denosumab (3.1%) and 21 alendronate patients (2.3%); no significant difference was observed in competing risk analyses (Gray's p = 0.623). In the TKA cohort, 117 denosumab and 940 alendronate users were analysed. Here 8 denosumab patients (6.8%) and 18 alendronate patients (1.9%) required revision, with a significant difference in cumulative incidence (Gray's p = 0.002). Revisions in denosumab users were mainly due to aseptic tibial loosening. CONCLUSIONS: Perioperative denosumab exposure was associated with a higher cumulative incidence of revision after TKA in this cohort. These findings should be interpreted cautiously and do not imply causality. The observed pattern may reflect complex interactions between antiresorptive therapy and joint-specific biomechanical factors, which warrant further investigation.
UNLABELLED: Using highly precise measurements, we found obstructive sleep apnea (OSA) was linked to poorer bone health at most sites. Higher oxygen saturation, rather than sleep efficiency, was beneficial. Total sleep du...UNLABELLED: Using highly precise measurements, we found obstructive sleep apnea (OSA) was linked to poorer bone health at most sites. Higher oxygen saturation, rather than sleep efficiency, was beneficial. Total sleep duration was partially nonlinearly related to bone health. Patients with chronic sleep problems should be screened for low BMD. AIM: Previous studies have shown associations between sleep characteristics and bone health, but findings are inconsistent. This study investigated the relationships between objectively measured sleep characteristics and bone mineral density (BMD) as well as bone mineral content (BMC) using dual-energy X-ray absorptiometry (DXA) measurements at various skeletal sites. METHODS: The analysis included data from 4690 participants aged 40-70 years in the Human Phenotype Project (HPP) cohort. Associations between total sleep time, mean oxygen saturation (%), sleep efficiency, and obstructive sleep apnea (OSA) indices-respiratory disturbance index (RDI), apnea-hypopnea index (AHI), and oxygen desaturation index (ODI)-measured by a sleep apnea monitoring device, and BMD/BMC assessed by DXA imaging of various skeletal components were examined using multivariable linear regression models. All associations were tested for interactions with age. RESULTS: OSA indices (AHI, ODI, RDI) showed linear or non-linear inverse associations with BMD or BMC at most bone sites. The negative associations of AHI and ODI with spine outcomes were non-linear, with stronger effects at higher index ranges. Total sleep time was inversely associated with BMC of the legs, femoral neck, and femoral shaft, with consistent estimates for BMD. U-shaped associations were observed between total sleep time and BMC of both arms and spine L2. Oxygen saturation was positively associated with BMD and BMC of the total body, arms, head, and spine. Sleep efficiency showed no association with any outcomes. Age-stratified analyses revealed stronger estimates in younger participants. CONCLUSIONS: OSA appears to be associated with reduced BMD and BMC, even in individuals without other major health conditions. These findings highlight the need for increased clinical awareness, including BMD screening for OSA patients, and, on the other hand, the detection of sleep problems in patients with osteoporosis or reduced BMD and BMC.