Metabolite Profiling of Osteoporosis and Atherosclerosis in Postmenopausal Women: A Cross-Sectional Study

Abstract

Purpose

Atherosclerosis (AS) and osteoporosis (OP) are common causes of morbidity and mortality in postmenopausal women and are connected via an unknown mechanistic link. Metabolite profiling of blood samples may allow the identification of new biomarkers and pathways for this enigmatic association.

Patients and Methods

We studied the difference in 148 metabolite levels from serum samples in postmenopausal women with AS and OP compared with those in healthy participants in this cross-sectional study. Quantitative AS was assessed by carotid artery intima-media thickness (cIMT) and carotid artery calcifications (CACs) by ultrasound, as well as OP by femoral neck (FN) bone mineral density (BMD) and 148 metabolic measures with high-throughput proton (¹H) nuclear magnetic resonance (NMR) in serum samples from 280 postmenopausal (PM) women. Subjects were a randomly selected subsample from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The final study population included the following groups: OP with CAC (n=16, group I), non-OP with no CAC (n=59, group II), high cIMT tertile with OP (n=11, group III) and low cIMT tertile without OP (n=48, group IV).

Results

There were differences in several metabolite levels between groups I and II. The acetate level was lower in group I compared to that in group II (group I mean ± SD: 0.033 ± 0.0070; group II: 0.041 ± 0.014, CI95%: 0.018‒0.15, p=0.014). The result was similar with diacylglycerol (p=0.002), leucine (p=0.031), valine (p=0.022) and several very low-density lipoprotein (VLDL) metabolite levels, which were lower in group I compared to those in group II. However, no associations were found in adjusted analyses with total body (TB) fat mass (FM), age and statin use (p>0.05).

Conclusion

Our novel study found differences in the metabolite profiling of altered amino acid and lipoprotein metabolism in participants with OP and AS compared with those in healthy women. The causative mechanisms remain unknown and further studies are needed.

Keywords:

• metabolomics
• carotid artery calcification
• postmenopausal women
• osteoporosis
• carotid intima-media thickness
• acetate

Abbreviations

AS, atherosclerosis; OP, osteoporosis; cIMT, carotid intima-media thickness; CAC, carotid artery calcification; CVD, cardiovascular disease; PM, postmenopausal; DXA, dual energy X-ray absorptiometry; CCA, common carotid artery; FDR, false discovery rate; MUFA, monounsaturated fatty acid; OSTPRE, Kuopio Osteoporosis Risk Factor and Prevention Study; OSTPRE-BBA, Kuopio Osteoporosis Risk Factor and Prevention Study – Bone, Brain and Atherosclerosis; ¹H, proton; APOB, apolipoprotein B; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; TB, total body; FN, femoral neck; FM, fat mass; BMD, bone mineral density; NMR, nuclear magnetic resonance; BMI, body mass index; HT, postmenopausal hormone therapy; VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Acknowledgments

We thank Jussi Paananen and Oskari Timonen for statistical help with metabolomics data, Mika Alakorpela and Pasi Soininen for NMR analyses and Jarmo Tiikkainen for performing IMT measurements. We also thank Tuomas Selander for the help with statistical analyses.

Disclosure

All authors report no conflict of interests in this work.

Additional information

Funding

Academy of Finland (Kröger H, grant number 250707), Kuopio University Hospital EVO-grants (Tuppurainen M, grant number 5302460), Kuopio University Hospital Funding (V.T.R. grant number 5203024), the Ministry of Education and Culture of Finland (grant numbers 116/626/2012, 46/627/2011 and 93/627/2010), and Strategic Funding of the University of Eastern Finland (grant number 931053) provided funding for this study. The foregoing grants were appropriated for the original OSTPRE study for 20- and 25-year follow-up measurements and analyses. Finnish Medical Society Duodecim grant of a young researcher (Eka Grant, 2016), abetment grant (grant number 2038) and Finnish Menopause Society personal grant (2018) were appropriated as personal grants for MV for his PhD thesis.