**Background:** Osteoporosis is a chronic skeletal disorder characterized by compromised bone mineral density (BMD) and increased fracture risk. While numerous risk factors for reduced BMD are known—including nutritional, genetic, metabolic, and lifestyle factors—the role of environmental chemical exposures remains incompletely understood. Most prior studies focused on single environmental factors and assumed that fracture risk was mediated through BMD reduction. This study aimed to assess the association of multiple environmental chemical factors with both osteopenia and bone fractures using nationally representative data.
**Methods:** Data were extracted from the 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES). From an initial sample of 9,254 individuals, 3,419 adults aged 20–59 years completed demographic questionnaires. After applying dual-energy X-ray absorptiometry (DXA) inclusion/exclusion criteria (excluding pregnancy, recent contrast use, weight >450 lbs, height >6'5"), the final valid dataset comprised 2,640 individuals for BMD analysis and 292 individuals aged 50–59 years for fracture analysis. Urine samples were analyzed for metals via inductively coupled plasma–mass spectrometry with dynamic reaction cell technology, for volatile organic compound (VOC) metabolites via ultra-performance liquid chromatography–tandem mass spectrometry, and for speciated arsenic via high-performance liquid chromatography coupled to ICP-DRC-MS. Osteopenia was defined as BMD between 1 and 2.5 standard deviations below the reference mean (T-score). Multivariate logistic regression models were adjusted for age, gender, body mass index (BMI), race/ethnicity, education level, country of birth, family income-to-poverty ratio, and current smoking status.
**Key Results:** Among the 2,253 individuals with DXA data (1,073 men [47.63%] and 1,180 women [52.33%]), females (p<0.001), those over 65 years (p<0.001), those with lower BMI (p<0.001), lower education (p=0.049), and foreign-born status (p=0.008) had higher osteopenia risk. For total body BMD, lower urinary mercury (OR 0.567; CI 0.357–0.900; p=0.016), 2-methylhippuric acid (OR 0.425; CI 0.232–0.778; p=0.006), and N-acetyl-S-(2-hydroxypropyl)-L-cysteine (OR 0.415; CI 0.175–0.982; p=0.045) were significantly associated with osteopenia. High urinary manganese was associated with osteopenia in the left arm (OR 1.610; CI 1.015–2.554; p=0.043) and pelvis (OR 1.587; CI 1.001–2.516; p=0.05), and monomethylarsonic acid with lumbar spine osteopenia (OR 1.451; CI 1.007–2.090; p=0.046). For fracture outcomes (hip, wrist, spine combined), high levels of arsenous acid (OR 2.578; CI 1.358–4.893; p=0.004), arsenobetaine (OR 2.978; CI 1.052–8.427; p=0.04), dimethylarsinic acid (OR 2.087; CI 1.06–4.112; p=0.033), monomethylarsonic acid (OR 2.276; CI 1.225–4.226; p=0.009), and 2-thioxothiazolidine-4-carboxylic acid (OR 1.804; CI 1.004–3.242; p=0.048) were associated with increased fracture prevalence. Notably, the chemicals associated with fracture were entirely different from those associated with reduced BMD.
**Clinical Implications:** This study provides evidence that environmental chemical exposures may increase fracture risk through mechanisms independent of BMD reduction, likely involving bone microarchitecture and bone quality. The finding that arsenic compounds (arsenous acid, arsenobetaine, dimethylarsinic acid, monomethylarsonic acid) significantly increase fracture risk without affecting BMD suggests that relying solely on BMD measurements may underestimate fracture risk in populations with environmental chemical exposures. These results support incorporating bone turnover markers and bone quality assessment into clinical routine care, as BMD alone may not capture the full fracture risk profile. Limitations include the cross-sectional design (precluding causal inference), relatively small sample size for site-specific fracture analysis, and the short-term exposure window from a single NHANES cycle. Future research should explore the exact mechanisms by which these environmental chemicals affect bone quality and investigate longer-term exposure effects.