Coronary artery calcium and bone mineral density by serial CTA: Does menopausal hormone therapy modify the association?


      • Osteoporosis (ie, reduced bone mass and micro architectural deterioration) and coronary artery disease (CAD) are age related conditions associated with significantly high morbidity and mortality in post-menopausal women.
      • Women with osteoporosis and osteopenia are more prone to atherosclerotic cardiovascular disease compared with women without this condition.
      • Increased mortality rates due to cardiovascular disorders have been observed in postmenopausal women with low BMD.
      • Therefore, in postmenopausal women diagnosed with osteoporosis, it is critical to consider not only clinical management for fracture prevention, but also cardiovascular intervention to minimize the risk of adverse outcomes related to atherosclerotic vascular disease.
      • The KEEPS trial is an ideal setting to assess the correlation between progression of CAC and changes in volumetric BMD and the effect of early initiation of MHT on that association, as the inclusion criteria for KEEPS was a CAC score ≤ 50 Agatston Units.
      • Our current study demonstrated that, MHT (o-CEE and t-E2) decreases the bone loss among postmenopausal women with CAC progression and would encourage further research.



      Both osteoporosis and cardiovascular disease (CVD) increase in women after menopause. Estrogen deficiency is thought to be an underlying mechanism for both these conditions.


      Healthy menopausal women (n = 374, age 42–58 years) underwent cardiac CT scans over four years as participants in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, controlled trial to Women randomized to either oral conjugated equine estrogens (o-CEE, n = 104), transdermal 17β-estradiol (t-E2, n = 119) or placebo (n-115). CAC (Agatston units, AU), and BMD (mg/cm3) were measured from thoracic vertebrae at baseline and at the 4 years of the study using validated software. ANOVA and multiple linear regression analyzed the association between incident CAC or progression of CAC and BMD among the treatment groups.


      At baseline 374 women, 40 participants with CAC >0 had greater decrements in BMD than the 334 participants with CAC = 0 at baseline, The average change in BMD in o-CEE group with CAC was −9.6 ± 13.3 versus −3.1 ± 19.5 in those with zero CAC, p = 0.0018. With t-E2, BMD changed by −11.7 ± 26.2 in those with CAC versus +5.7 ± 26.2 in the zero CAC group, p ≤ 0. 0001. Similarly in the 66 participants that showed progression of CAC >1, had more BMD loss, than those with stable CAC regardless of the treatment.


      Progression of bone loss is reduced among women treated with o-CEE or t-E2. Progression of CAC is associated with greater BMD loss, a relationship that is differentially modified by t-E2 and o-CEE.


      ANOVA (analysis of variance), BMI (body mass index), BMD (bone mineral density), CAC (coronary artery calcium), CAD (coronary artery disease), CT (computed tomography), CVD (cardiovascular disease), DXA (dual-energy X-ray absorptiometry), ECG (electrocardiogram), ERT (estrogen replacement therapy), IQR (interquartile range), KEEPS (Kronos Early Estrogen Prevention Study), LDL (low-density lipoprotein), MHT (menopausal hormonal therapy), NF-kB (nuclear factor kappa B), o-CEE (oral conjugated equine estrogens), PEPI (Postmenopausal Estrogen/Progestin Interventions), RANKL (receptor activator of NF-kB ligand), ROI (Region of Interest), SAS (Statistical Analysis System), SD (standard deviation), t-E2 (transdermal 17β-estradiol), WHI (Women's Health Initiative)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Imaging
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Warburton D.E.R.
        • Nicol C.W.
        • Gatto S.N.
        • Bredin S.S.D.
        Cardiovascular disease and osteoporosis: balancing risk management.
        Vasc Health Risk Manag. 2007; 3: 673-689
        • Miyabara Y.
        • Camp J.
        • Holmes D.
        • Lahr B.
        • Bailey K.
        • Miller V.M.
        • et al.
        Coronary arterial calcification and thoracic spine mineral density in early menopause.
        Climacteric. 2011; 14: 438-444
        • Cherukuri L.
        • Birudaraju D.
        • Budoff M.J.
        Coronary artery calcium score: pivotal role as a predictor for detecting coronary artery disease in symptomatic patients.
        Coron Artery Dis. 2021; 32: 575-585
        • Miyabara Y.
        • Holmes D.
        • Camp J.
        • Miller V.M.
        • Kearns A.E.
        Comparison of calibrated and uncalibrated bone mineral density by CT to DEXA in menopausal women.
        Climacteric. 2012; 15: 374-381
        • Thompson B.
        • Towler D.A.
        Arterial calcification and bone physiology: role of the bone-vascular axis.
        Nat Rev Endocrinol. 2012; 8: 529-543
        • Tankó L.B.
        • Christiansen C.
        • Cox D.A.
        • Geiger M.J.
        • McNabb M.A.
        • Cummings S.R.
        Relationship between osteoporosis and cardiovascular disease in postmenopausal women.
        J Bone Miner Res. 2005; 20: 1912-1920
        • Mao S.S.
        • Li D.
        • Syed Y.S.
        • Gao Y.
        • Luo Y.
        • Flores F.
        • et al.
        Thoracic quantitative computed tomography (QCT) can sensitively monitor bone mineral metabolism: comparison of thoracic QCT vs lumbar QCT and dual-energy X-ray absorptiometry in detection of age-relative change in bone mineral density.
        Acad Radiol. 2017; 24: 1582-1587
        • Lambrinoudaki I.
        • Armeni E.
        • Georgiopoulos G.
        • Kazani M.
        • Kouskouni E.
        • Creatsa M.
        • et al.
        Subclinical atherosclerosis in menopausal women with low to medium calculated cardiovascular risk.
        Int J Cardiol. 2013; 164: 70-76
        • Farhat G.N.
        • Cauley J.A.
        • Matthews K.A.
        • Newman A.B.
        • Johnston J.
        • Mackey R.
        • et al.
        Volumetric BMD and vascular calcification in middle-aged women: the study of women's health across the nation.
        J Bone Miner Res. 2006; 21: 1839-1846
        • Barengolts E.I.
        • Berman M.
        • Kukreja S.C.
        • Kouznetsova T.
        • Lin C.
        • Chomka E.V.
        Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women.
        Calcif Tissue Int. 1998; 62: 209-213
        • Syed F.
        • Khosla S.
        Mechanisms of sex steroid effects on bone.
        Biochem Biophys Res Commun. 2005; 328: 688-696
        • Osako M.K.
        • Nakagami H.
        • Koibuchi N.
        • Shimizu H.
        • Nakagami F.
        • Koriyama H.
        • et al.
        Estrogen inhibits vascular calcification via vascular RANKL system: common mechanism of osteoporosis and vascular calcification.
        Circ Res. 2010; 107: 466-475
        • Garnero P.
        • Sornay-Rendu E.
        • Chapuy M.C.
        • Delmas P.D.
        Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
        J Bone Miner Res. 1996 Mar; 11: 337-349
        • The NAMS 2017 Hormone Therapy Position Statement Advisory Panel
        The 2017 hormone therapy position statement of The North American Menopause Society.
        Menopause. 2017; 24: 728-753
        • Manson J.E.
        • Allison M.A.
        • Rossouw J.E.
        • Carr J.J.
        • Langer R.D.
        • Hsia J.
        • et al.
        Estrogen therapy and coronary-artery calcification.
        N Engl J Med. 2007; 356: 2591-2602
      1. Effects of hormone therapy on bone mineral density.
        JAMA. 1996; 276: 1389
        • Lewiecki E.M.
        Prevention and treatment of postmenopausal osteoporosis.
        Obstet Gynecol Clin North Am. 2008; 35 (ix): 301-315
        • Wells G.
        • Tugwell P.
        • Shea B.
        • Guyatt G.
        • Peterson J.
        • Zytaruk N.
        • et al.
        Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women.
        Endocr Rev. 2002; 23: 529-539
      2. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI.
        JAMA. 1996; 276: 1389-1396
        • Lindsay R.
        • Gallagher J.C.
        • Kleerekoper M.
        • Pickar J.H.
        Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.
        JAMA. 2002; 287: 2668-2676
        • Harman S.M.
        • Brinton E.A.
        • Cedars M.
        • Lobo R.
        • Manson J.E.
        • Merriam G.R.
        • et al.
        KEEPS: the kronos early estrogen prevention study.
        Climacteric. 2005; 8: 3-12
        • Harman S.M.
        • Black D.M.
        • Naftolin F.
        • Brinton E.A.
        • Budoff M.J.
        • Cedars M.I.
        • et al.
        Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial.
        Ann Intern Med. 2014; 161: 249-260
        • Wolff E.F.
        • He Y.
        • Black D.M.
        • Brinton E.A.
        • Budoff M.J.
        • Cedars M.I.
        • et al.
        Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the kronos early estrogen prevention study (KEEPS).
        Fertil Steril. 2013; 99: 1385-1391
        • Budoff M.J.
        • Hamirani Y.S.
        • Gao Y.L.
        • Ismaeel H.
        • Flores F.R.
        • Child J.
        • et al.
        Measurement of thoracic bone mineral density with quantitative CT.
        Radiology. 2010; 257: 434-440
        • Cherukuri L.
        • Kinninger A.
        • Birudaraju D.
        • Lakshmanan S.
        • Li D.
        • Flores F.
        • et al.
        Effect of body mass index on bone mineral density is age-specific.
        Nutr Metab Cardiovasc Dis. 2021; 31: 1767-1773
        • Hmamouchi I.
        • Allali F.
        • Khazzani H.
        • Bennani L.
        • El Mansouri L.
        • Ichchou L.
        • et al.
        Low bone mineral density is related to atherosclerosis in postmenopausal moroccan women.
        BMC Public Health. 2009; 14: 388
        • Hajsadeghi S.
        • Khamseh M.-E.
        • Larijani B.
        • Abedin B.
        • Vakili-Zarch A.
        • Meysamie A.-P.
        • et al.
        Bone mineral density and coronary atherosclerosis.
        J Saudi Heart Assoc. 2011; 23: 143-146
        • Ye C.
        • Xu M.
        • Wang S.
        • Jiang S.
        • Chen X.
        • Zhou X.
        • et al.
        Decreased bone mineral density is an independent predictor for the development of atherosclerosis: a systematic review and meta-analysis.
        PLoS One. 2016; 11e0154740
        • Seibel M.J.
        Biochemical markers of bone turnover part II: clinical applications in the management of osteoporosis.
        Clin Biochem Rev. 2006; 27: 123-138
        • Hla M.M.
        • Davis J.W.
        • Ross P.D.
        • Yates J.
        • Wasnich R.D.
        • Ravn P.
        • et al.
        Relation between body composition and biochemical markers of bone turnover among early postmenopausal women.
        J Clin Densitom. 2000; 3: 365-371
        • Riis B.J.
        The role of bone turnover in the pathophysiology of osteoporosis.
        Br J Obstet Gynaecol. 1996; 103 (discussion 14): 9-14
        • Lopes N.H.M.
        The Interface between osteoporosis and atherosclerosis in postmenopausal women.
        Arq Bras Cardiol. 2018; 110: 217-218
        • Szulc P.
        Association between cardiovascular diseases and osteoporosis-reappraisal.
        Bonekey Rep. 2012; 8: 144
        • Melton L.J.
        • Crowson C.S.
        • O’Fallon W.M.
        • Wahner H.W.
        • Riggs B.L.
        Relative contributions of bone density, bone turnover, and clinical risk factors to long-term fracture prediction.
        J Bone Miner Res. 2003 Feb; 18: 312-318
        • Grampp S.
        • Jergas M.
        • Lang P.
        • Steiner E.
        • Fuerst T.
        • Glüer C.C.
        • et al.
        Quantitative CT assessment of the lumbar spine and radius in patients with osteoporosis.
        AJR Am J Roentgenol. 1996; 167: 133-140