Exhaled Breath Metabolites Reveal Postmenopausal Gut-bone Cross-talk and Non-invasive Markers for Osteoporosis

Overview

Journal Commun Med (Lond)

Publisher Nature Portfolio

Specialty General Medicine

Date 2024 Dec 29

PMID 39732987

Authors

Pritam Sukul

Dagmar-Christiane Fischer

Celine Broderius

Simon Grzegorzewski

Anja Rahn

Thomas Mittlmeier

Bernd Kreikemeyer

Daniel A Reuter

Jochen K Schubert

Wolfram Miekisch

Affiliations

Soon will be listed here.

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.

References

Navik U, Sheth V, Khurana A, Jawalekar S, Allawadhi P, Gaddam R . Methionine as a double-edged sword in health and disease: Current perspective and future challenges. Ageing Res Rev. 2021; 72:101500. DOI: 10.1016/j.arr.2021.101500. View

Doyon A, Fischer D, Bayazit A, Canpolat N, Duzova A, Sozeri B . Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One. 2015; 10(2):e0113482. PMC: 4319910. DOI: 10.1371/journal.pone.0113482. View

Sukul P, Trefz P, Kamysek S, Schubert J, Miekisch W . Instant effects of changing body positions on compositions of exhaled breath. J Breath Res. 2015; 9(4):047105. DOI: 10.1088/1752-7155/9/4/047105. View

Shah S, Bell R, Davis S . Homocysteine, estrogen and cognitive decline. Climacteric. 2006; 9(2):77-87. DOI: 10.1080/13697130600641282. View

Gaikwad N . Mass spectrometry evidence for formation of estrogen-homocysteine conjugates: estrogens can regulate homocysteine levels. Free Radic Biol Med. 2013; 65:1447-1454. DOI: 10.1016/j.freeradbiomed.2013.07.041. View

Miekisch W, Schubert J, Vagts D, Geiger K . Analysis of volatile disease markers in blood. Clin Chem. 2001; 47(6):1053-60. View

Tangerman A . Measurement and biological significance of the volatile sulfur compounds hydrogen sulfide, methanethiol and dimethyl sulfide in various biological matrices. J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877(28):3366-77. DOI: 10.1016/j.jchromb.2009.05.026. View

Fukumoto S, Martin T . Bone as an endocrine organ. Trends Endocrinol Metab. 2009; 20(5):230-6. DOI: 10.1016/j.tem.2009.02.001. View

Sukul P, Oertel P, Kamysek S, Trefz P . Oral or nasal breathing? Real-time effects of switching sampling route onto exhaled VOC concentrations. J Breath Res. 2017; 11(2):027101. DOI: 10.1088/1752-7163/aa6368. View

10.

Cappola A, Shoback D . Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture. JAMA. 2016; 316(7):715-6. DOI: 10.1001/jama.2016.11032. View

11.

Kanis J, Cooper C, Rizzoli R, Abrahamsen B, Al-Daghri N, Brandi M . Identification and management of patients at increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting. Osteoporos Int. 2017; 28(7):2023-2034. PMC: 5483332. DOI: 10.1007/s00198-017-4009-0. View

12.

Yang G, Li S, Cai S, Zhou J, Ye Q, Zhang S . Dietary methionine supplementation during the estrous cycle improves follicular development and estrogen synthesis in rats. Food Funct. 2023; 15(2):704-715. DOI: 10.1039/d3fo04106a. View

13.

Schini M, Vilaca T, Gossiel F, Salam S, Eastell R . Bone Turnover Markers: Basic Biology to Clinical Applications. Endocr Rev. 2022; 44(3):417-473. PMC: 10166271. DOI: 10.1210/endrev/bnac031. View

14.

Smolders R, de Meer K, Kenemans P, Teerlink T, Jakobs C, van der Mooren M . Hormone replacement influences homocysteine levels in the methionine-loading test: a randomized placebo controlled trial in postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2004; 117(1):55-9. DOI: 10.1016/j.ejogrb.2003.10.033. View

15.

Harada S, Rodan G . Control of osteoblast function and regulation of bone mass. Nature. 2003; 423(6937):349-55. DOI: 10.1038/nature01660. View

16.

Cagnacci A, Generali M, Pirillo D, Baldassari F, Volpe A . Effects of low- or high-dose hormone therapy on fasting and post-methionine homocysteine levels in postmenopausal women. Climacteric. 2006; 9(5):388-95. DOI: 10.1080/13697130600870352. View

17.

Sukul P, Schubert J, Kamysek S, Trefz P, Miekisch W . Applied upper-airway resistance instantly affects breath components: a unique insight into pulmonary medicine. J Breath Res. 2017; 11(4):047108. DOI: 10.1088/1752-7163/aa8d86. View

18.

Sirola J, Tuppurainen M, Honkanen R, Jurvelin J, Kroger H . Associations between grip strength change and axial postmenopausal bone loss--a 10-year population-based follow-up study. Osteoporos Int. 2005; 16(12):1841-8. DOI: 10.1007/s00198-005-1944-y. View

19.

Sukul P, Bartels J, Fuchs P, Trefz P, Remy R, Ruhrmund L . Effects of COVID-19 protective face masks and wearing durations on respiratory haemodynamic physiology and exhaled breath constituents. Eur Respir J. 2022; 60(3). PMC: 9492982. DOI: 10.1183/13993003.00009-2022. View

20.

Behrens M, Felser S, Mau-Moeller A, Weippert M, Pollex J, Skripitz R . The Bindex(®) ultrasound device: reliability of cortical bone thickness measures and their relationship to regional bone mineral density. Physiol Meas. 2016; 37(9):1528-40. DOI: 10.1088/0967-3334/37/9/1528. View