Abstract
BACKGROUND: Menopause driven decline in estrogen exposes women to risk of osteoporosis. Detection of early onset and silent progression are keys to prevent fractures and associated burdens. METHODS: In a discovery cohort of 120 postmenopausal women, we combined repeated quantitative pulse-echo ultrasonography of bone, assessment of grip strength and serum bone markers with mass-spectrometric analysis of exhaled metabolites to find breath volatile markers and quantitative cutoff levels for osteoporosis. Obtained markers and cutoffs were validated in an independent cohort of 49 age-matched women with six months apart seasonal follow-ups. RESULTS: Here, within the discovery cohort, concentrations of exhaled end-tidal dimethyl sulfide (DMS), allyl-methyl sulfide, butanethiol and butyric acid are increased (p ≤ 0.005) pronouncedly in subjects with bone mineral density (BMD) at high-risk of osteoporosis and fracture, when compared to subjects with normal BMD. Increased age and decreased grip strength are concomitant. All changes are reproduced during independent validation and seasonal follow-ups. Exhaled metabolite expressions remain age independent. Serum markers show random expressions without reproducibility. DMS exhalations differs between patients with recent, old and without fractures. Metabolite exhalations and BMDs are down-regulated during winter. ROC analysis in discovery cohort yields high classification accuracy of DMS with a cutoff for osteoporosis, which predicts subjects at high-risk within the independent validation cohort with >91% sensitivity and specificity. CONCLUSIONS: Non-invasive analysis of exhaled DMS allowed more reliable classification of osteoporosis risk than conventional serum markers. We identified associations of exhaled organosulfur and short-chain fatty acids to bone metabolism in postmenopausal osteoporosis via a gut-bone axis.