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Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens.
Open accessAbstract
The purpose of this study was to determine whether bone density in older men was associated with serum sex steroids or sex hormone binding globulin (SHBG). Bone density and sex steroids were measured in men over age 65 at 6-mo intervals for an average of 2.1 yr. Bone density was significantly positively associated with greater serum E2 concentrations (+0.21 < r < +0.35; 0.01 < P < 0.05) at all skeletal sites. There were weak negative correlations between serum testosterone and bone density (-0.20 < r < -0.28; 0.03 < P < 0.10) at the spine and hip. SHBG was negatively associated only with bone density in the greater trochanter (r = -0.26, P < 0.05). Greater body weight was associated with lower serum testosterone and SHBG, and greater E2. Because of these associations, regression models which adjusted for age, body weight, and serum sex steroids were constructed; these accounted for 10-30% of the variability in bone density, and showed consistent, significant positive associations between bone density and serum E2 concentrations in men, even after adjustments for weight and SHBG. These data suggest that estrogens may play an important role in the development or maintenance of the male skeleton, much as is the case for the female skeleton. These data also indicate that, within the normal range, lower serum testosterone concentrations are not associated with low bone density in men.
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“Moreover, in men, bone mineral density (BMD) at the greater trochanter, femoral neck and the lumbar spine is negatively correlated with concentrations of SHBG [146, 150–152].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [151]
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“These confounding results leave uncertainty in the relationship between T levels in aging and bone health.”
From Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications (2021) · cites this paper as [175]
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The role of estrogens for male bone health
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Role of sex steroids in the regulation of bone morphology in men. The MINOS study
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Role of persistent amenorrhea in bone mineral metabolism of young hemodialyzed women
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“Recent data suggest that as in the case of the female skeleton, estrogens have more relevance than testosterone in the development or maintenance of the male skeleto”
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BackgroundTargeting Cell Senescence for the Treatment of Age-Related Bone Loss
Pignolo, R. J., Samsonraj, R. M., Law, S. F., Wang, H., & Chandra, A. (2019) · Current Osteoporosis Reports · doi:10.1007/s11914-019-00504-2 · Cited by 52
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“…investigated and its association with BMD, bone markers, vertebral fractures and bone loss was suggested in several studies (Greendale et al., 1997; Slemenda et al., 1997; Khosla et al., 1998, 2001; Amin et al., 2000; Barrett-Connor et al., 2000; Szulc et al., 2001a; van Pottelbergh et al.,…”
ResultBody Composition, Sex Steroids, IGF-1, and Bone Mineral Status in Aging Men
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IS THERE A CLINICAL RELEVANCE OF PARTIAL ANDROGEN DEFICIENCY OF THE AGING MALE?
Christ‐Crain, M., Müeller, B., Gasser, T. C., Kraenzlin, M., Trummler, M., Huber, P., & Meier, C. (2004) · The Journal of Urology · doi:10.1097/01.ju.0000135303.96496.ee · Cited by 47
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“Although a negative correlation between SHBG and BMD has been previously described [23, 26 ], only one recent report has found an independent effect of SHBG on bone mass in elderly men [30].”
BackgroundInfluentialOsteoporosis: gender differences and similarities
Khosla, S., Melton, L. J., & Riggs, B. L. (1999) · Lupus · doi:10.1177/096120339900800513 · Cited by 48
Androgens and the ageing male and female
Yialamas, M. A., & Hayes, F. J. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00018-6 · Cited by 46
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“Those studies [ 8 , 11, 12] which also examined the relationship between SHBG and bone density generally observed negative correlations between SHBG and BMD at multiple sites, including the hip, spine, radius and whole body.”
The role of estrogens in men and androgens in women
Khosla, S., & Bilezikian, J. P. (2003) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(02)00087-7 · Cited by 43
“Slemenda and colleagues [35] found that BMD at various sites in 93 healthy men over age 55 years correlated with serum estradiol levels (correlation coefficients, depending on the site, of þ0.”
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Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men
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“receptor-a gene or the aromatase gene are osteoporotic [51–53], and numerous epidemiological studies have reported associations between serum estradiol levels and BMD or fracture in adult men [54–62].”
BackgroundLate‐onset Hypogonadism: Bone health
Rochira, V. (2020) · Andrology · doi:10.1111/andr.12827 · Cited by 49
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The relation between bone density, free androgen index, and estradiol in men 60 to 70 years old
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The Pathogenesis, Treatment and Prevention of Osteoporosis in Men
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“In addition, bone mineral density was positively associated with greater serum 17b-oestradiol concentrations in elderly men ( 51 ).”
BackgroundWu, J., Wang, X. X., Chiba, H., Higuchi, M., Takasaki, M., Ohta, A., & Ishimi, Y. (2003) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00498.2002 · Cited by 42
“Recently, results from clinical investigations indicated that bone loss in elderly men is more significantly correlated with declining estrogen levels than with androgen levels (17, 31).”
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Taguchi, A., Fujiwara, S., Masunari, N., & Suzuki, G. (2004) · Osteoporosis International · doi:10.1007/s00198-004-1609-2 · Cited by 43
“regulating the skeleton in both sexes [22,23,24,25,26].”
The epidemiology of osteoporosis and fractures in geriatric medicine
Wehren, L. E. (2003) · Clinics in Geriatric Medicine · doi:10.1016/s0749-0690(02)00072-1 · Cited by 42
“In men, testosterone has been considered to be of primary importance in the regulation of BMD; however, recent reports have suggested that estrogen is necessary as well, for acquisition of peak bone mass and for maintenance of bone later in life [27–30].”
BackgroundBone Density, Structure and Strength, and Their Determinants in Aging Sprint Athletes
Korhonen, M. T., Heinonen, A. O., SIEKKINEN, J., Isolehto, J., Alén, M., Kiviranta, I., & Suominen, H. (2012) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e318267c954 · Cited by 41
Taxel, P., FALL, P. M., Albertsen, P. C., Dowsett, R. D., Trahiotis, M., Zimmerman, J., Ohannessian, C. M., & Raisz, L. G. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020539 · Cited by 40
“4908 J Clin Endocrinol Metab, November 2002, 87(11):4907–4913 Taxel et al.”
BackgroundInfluentialEstrone sulfate Is a Major source of local estrogen formation in human bone
Muir, M., Romalo, G., Wolf, L., Elger, W., & Schweikert, H.-U. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0049 · Cited by 41
Smith, M. R., Malkowicz, S. B., Brawer, M. K., Hancock, M. L., Morton, R. A., & Steiner, M. S. (2011) · The Journal of Urology · doi:10.1016/j.juro.2011.07.090 · Cited by 40
Gonadal sex steroid status and bone health in middle-aged and elderly European men
The EMAS Study Group, Vanderschueren, D., Pye, S. R., Venken, K., Borghs, H., Gaytant, J., Huhtaniemi, I. T., Adams, J. E., Ward, K. A., Bártfai, G., et al. (2009) · Osteoporosis International · doi:10.1007/s00198-009-1144-2 · Cited by 39
Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review
Russo, V., Chen, R., & Armamento‐Villareal, R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.607240 · Cited by 41
“In a study on 93 healthy men over 55 years of age, BMD at various sites correlated with serum E2 levels, and inversely with serum T levels (69).”
BackgroundManagement of Bone Loss in Men With Prostate Cancer
Higano, C. S. (2003) · The Journal of Urology · doi:10.1097/01.ju.0000097351.48848.1f · Cited by 40
Rhee, E., Oh, K.-W., Lee, W., Kim, S.-W., Oh, E.-S., Baek, K., Kang, M.-I., Park, C., Choi, M. G., Yoo, H.-J., et al. (2004) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-003-0500-0 · Cited by 39
Impact of sex hormone-binding globulin on the human phenome
Arathimos, R., Millard, L. A. C., Bell, J. A., Relton, C. L., & Suderman, M. J. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddz269 · Cited by 39
“Previous studies have suggested that estrogen levels (which are regulated by SHBG) control BMD in both men and women (28).”
BackgroundTrabert, B. L., Graubard, B. I., Nyante, S. J., Rifai, N., Bradwin, G., Platz, E. A., McQuillan, G. M., & McGlynn, K. A. (2012) · Cancer Causes & Control · doi:10.1007/s10552-012-0024-9 · Cited by 38
“The results from our analysis support the findings of other studies that bone mineral density is inversely associated with SHBG [17, 18, 21, 27, 29, 30].”
ResultPang, M. Y. C., Ashe, M. C., & Eng, J. J. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080224 · Cited by 38
Aromatase Activity and Bone Loss in Men
Merlotti, D., Gennari, L., Stolakis, K., & Nuti, R. (2011) · Journal of Osteoporosis · doi:10.4061/2011/230671 · Cited by 41
“In fact, in most of these studies BMD and bone loss were more directly related to declining estrogen levels than declining androgen levels, particularly, when circulating bioavailable fractions of these steroids were considered [8– 10, 60–66].”
BackgroundEndocrine regulation of bone turnover in men
Meier, C., Liu, P. Y., Handelsman, D. J., & Seibel, M. J. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02333.x · Cited by 36
Sex steroid metabolism in the regulation of bone health in men
Vandenput, L., & Ohlsson, C. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.03.067 · Cited by 37
Doumouchtsis, K., Kostakis, A., Doumouchtsis, S. K., Grapsa, E., Passalidou, I., Tziamalis, M. P., Poulakou, M. V., Vlachos, I. S., & Perrea, D. N. (2008) · Hemodialysis International · doi:10.1111/j.1542-4758.2008.00249.x · Cited by 37
Role of Hormonal Changes in the Pathogenesis of Osteoporosis in Men
Khosla, S. (2004) · Calcified Tissue International · doi:10.1007/s00223-004-0290-y · Cited by 37
DHEA and the Skeleton (Through the Ages)
Gordon, C. M., Glowacki, J., & LeBoff, M. S. (1999) · Endocrine · doi:10.1385/endo:11:1:1 · Cited by 37
Bone Density and Bone-Related Biochemical Variables in Normal Men: A Longitudinal Study
Scopacasa, F., Wishart, J., Need, A. G., Horowitz, M., Morris, H. A., & Nordin, B. E. C. (2002) · The Journals of Gerontology Series A · doi:10.1093/gerona/57.6.m385 · Cited by 37
“1,25D (pmol/l) 68 125 (36) 122 (31) 50–160 NS”
BackgroundDavid, K., Narinx, N., Antonio, L., Evenepoel, P., Claessens, F., Decallonne, B., & Vanderschueren, D. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-022-09738-5 · Cited by 37
“[90] 1 3 Slemenda et al., 1997 [316] Longitudinal (2.1y) 93 men mean 67.3 +/-4.3y | Total T (RIA) – freeT measured Total E2 (RIA) – freeE2 measured Total E1 (RIA) SHBG aBMD LS, FN and trochanter (DXA) Positive association between total E2 levels and all sites.”
BackgroundInfluentialDeterminants of bone mineral density in Chinese men
Cheung, E. Y. N., Ho, A. Y. Y., Lam, K., Tam, S., & Kung, A. W. C. (2005) · Osteoporosis International · doi:10.1007/s00198-005-2000-7 · Cited by 35
Bauman, W. A., Spungen, A. M., Wang, J., Pierson, R. N., & Schwartz, E. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00250.2005 · Cited by 36
Hesperidin Prevents Androgen Deficiency‐induced Bone Loss in Male Mice
Chiba, H., Kim, H., Matsumoto, A., Akiyama, S., Ishimi, Y., Suzuki, K., & Uehara, M. (2013) · Phytotherapy Research · doi:10.1002/ptr.5001 · Cited by 34
“This increase occurs because of an increase in both bone formation and bone resorption that is in part associated with E2 (Carani et al., 1997; Morishima et al., 1995; Smith et al., 1994).”
BackgroundFilipović, B. R., Šošić‐Jurjević, B., Ajdžanović, V. Z., Brkić, D., Manojlović‐Stojanoski, M., Milošević, V., & Sekulić, M. (2009) · Osteoporosis International · doi:10.1007/s00198-009-1092-x · Cited by 35
Quantification of the relative contribution of estrogen to bone mineral density in men and women
Ho-Pham, L. T., Nguyen, N. D., & Nguyen, T. V. (2013) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-14-366 · Cited by 36
“ies have further demonstrated a significant positive relationship between serum E levels and BMD in men [8-14].”
BackgroundPharmacogenetics of the vitamin D receptor and osteoporosis.
Eisman, J. A. (2001) · PubMed · Cited by 35
Osteoporosis in Men: Epidemiology, Pathophysiology, and Clinical Characterization
ORWOLL, E. S., & KLEIN, R. F. (2008) · Elsevier eBooks · doi:10.1016/b978-012370544-0.50044-6 · Cited by 35
Boonen, S., Kaufman, J., Goemaere, S., Bouillon, R., & Vanderschueren, D. (2007) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2006.09.005 · Cited by 34
Serum Estradiol Levels Are Inversely Associated With Cortical Porosity in Older Men
Vandenput, L., Lorentzon, M., Sundh, D., Nilsson, M., Karlsson, M. K., Mellström, D., & Ohlsson, C. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1319 · Cited by 33
“Still, serum levels of estradiol (E2) are more strongly associated with areal bone mineral density (BMD) and BMD loss than serum T levels are (2, 3).”
Background
Metadata
- Authors
- Slemenda, C. W., Longcope, C., Zhou, L., Hui, S. L., Peacock, M., & Johnston, C. C.
- Affiliations
- Indiana University Indianapolis (US)
- University of Massachusetts Chan Medical School (US)
- Indiana University School of Medicine (US)
- Indiana University Bloomington (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1997-10-01
- Volume
- 100
- Issue
- 7
- Pages
- 1755-1759
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508359
- OpenAlex
- W1993231839
- Cited by
- 455
- References
- 28
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 6 · 2013: 7 · 2012: 16
- FWCI
- 24.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ag005793-15)
- National Institute on Aging (P01-AG-05793)
- National Center for Research Resources (M01RR000750)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- sex steroids, bone mineral density, older men, serum estrogen, estradiol, testosterone, sex hormone-binding globulin, bone mass, body weight, male skeleton
- MeSH terms
- Aged, Androgens, Body Constitution, Dehydroepiandrosterone, Estradiol, Estrogens, Estrone, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Regression Analysis, Sex Hormone-Binding Globulin, Testosterone, Models, Statistical, Bone Density, Dehydroepiandrosterone Sulfate
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