Semin Reprod Med 2014; 32(06): 454-462
DOI: 10.1055/s-0034-1384629
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Insights into the Epidemiology of Postmenopausal Osteoporosis: The Women's Health Initiative

Rebecca D. Jackson
1   Departments of Internal Medicine, the Ohio State University, Columbus, Ohio
2   Division of Endocrinology, Diabetes and Metabolism and Physical Medicine and Rehabilitation, the Ohio State University, Columbus, Ohio
,
W. Jerry Mysiw
2   Division of Endocrinology, Diabetes and Metabolism and Physical Medicine and Rehabilitation, the Ohio State University, Columbus, Ohio
› Author Affiliations
Further Information

Publication History

Publication Date:
16 October 2014 (online)

Abstract

Osteoporosis and its associated increased risk for fragility fracture is one of the most disabling consequences of aging in women. To successfully reduce the public health burden of this pervasive disease, it is necessary to develop strategies that permit the earlier identification of women at risk for fracture and ensure that preventive interventions to reduce the risk for fracture are both safe and effective. The Women's Health Initiative offers the unprecedented opportunity to systematically address both of these issues. Eleven clinically available risk factors (age, race/ethnicity, self-reported health, weight, height, physical activity, parental hip fracture, fracture history after age 54, current smoking, corticosteroid use, and history of treated diabetes), have been identified to predict 5-year hip fracture risk in white women. Two of these factors (age and fracture history) also predict risk for total fractures in women irrespective of race-ethnicity. Biomarkers including low vitamin D or bioavailable testosterone and/or high cystatin C, pro-inflammatory cytokines, osteoprotegerin and sex hormone-binding globulin also predict risk for hip fracture independent of clinical risk factors. Two cornerstones of therapy for postmenopausal osteoporosis-postmenopausal hormone therapy and calcium plus vitamin D supplementation- were rigorously studied. Estrogen with or without a progestin was effective at preventing bone loss and reducing risk for hip, clinical vertebral and total fractures but the balance of risks and benefits failed to show an overall benefit of taking estrogen-alone or estrogen plus progestin as a preventive strategy for skeletal health. Calcium plus vitamin D supplementation also demonstrated a small but significant favorable effect on hip bone density but in contrast, the modest effect did not translate into a significant reduction in the risk of fractures in intent-to-treat analyses. Data such as these have helped to lay a foundation for the more effective management of postmenopausal osteoporosis.

 
  • References

  • 1 Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007; 22 (3) 465-475
  • 2 Magaziner J, Hawkes W, Hebel JR , et al. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci 2000; 55 (9) M498-M507
  • 3 Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol 2014; 142C: 155-170
  • 4 WHO (cited 2014 March 1, 2014) WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level; 2004. . Available at: http://www.who.int/chp/topics/Osteoporosis.pdf . Accessed on September 17, 2014
  • 5 Teng GG, Curtis JR, Saag KG. Mortality and osteoporotic fractures: is the link causal, and is it modifiable?. Clin Exp Rheumatol 2008; 26 (5) (Suppl. 51) S125-S137
  • 6 van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone 2001; 29 (6) 517-522
  • 7 Cauley JA, Wampler NS, Barnhart JM , et al; Women's Health Initiative Observational Study. Incidence of fractures compared to cardiovascular disease and breast cancer: the Women's Health Initiative Observational Study. Osteoporos Int 2008; 19 (12) 1717-1723
  • 8 Brown CA, Starr AZ, Nunley JA. Analysis of past secular trends of hip fractures and predicted number in the future 2010-2050. J Orthop Trauma 2012; 26 (2) 117-122
  • 9 Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998; 339: 733-738
  • 10 Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 2003; 13 (9, Suppl): S107-S121
  • 11 Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 (9, Suppl): S98-S106
  • 12 Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 (9, Suppl): S78-S86
  • 13 Marks R, Allegrante JP, Ronald MacKenzie C, Lane JM. Hip fractures among the elderly: causes, consequences and control. Ageing Res Rev 2003; 2 (1) 57-93
  • 14 Sambrook P, Cooper C. Osteoporosis. Lancet 2006; 367 (9527) 2010-2018
  • 15 Heaney RP ; Robert P. Heaney. Remodeling and skeletal fragility. Osteoporos Int 2003; 14 (Suppl. 05) S12-S15
  • 16 Johnell O, Kanis JA, Oden A , et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005; 20 (7) 1185-1194
  • 17 Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A. Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone 2000; 27 (5) 585-590
  • 18 Cauley JA. Defining ethnic and racial differences in osteoporosis and fragility fractures. Clin Orthop Relat Res 2011; 469 (7) 1891-1899
  • 19 Cauley JA, Wu L, Wampler NS , et al. Clinical risk factors for fractures in multi-ethnic women: the Women's Health Initiative. J Bone Miner Res 2007; 22 (11) 1816-1826
  • 20 LaCroix AZ, Beck TJ, Cauley JA , et al. Hip structural geometry and incidence of hip fracture in postmenopausal women: what does it add to conventional bone mineral density?. Osteoporos Int 2010; 21 (6) 919-929
  • 21 LaFleur J, McAdam-Marx C, Kirkness C, Brixner DI. Clinical risk factors for fracture in postmenopausal osteoporotic women: a review of the recent literature. Ann Pharmacother 2008; 42 (3) 375-386
  • 22 Kanis JA, Oden A, Johnell O , et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007; 18 (8) 1033-1046
  • 23 Robbins J, Aragaki AK, Kooperberg C , et al. Factors associated with 5-year risk of hip fracture in postmenopausal women. JAMA 2007; 298 (20) 2389-2398
  • 24 Black DM, Steinbuch M, Palermo L , et al. An assessment tool for predicting fracture risk in postmenopausal women. Osteoporos Int 2001; 12 (7) 519-528
  • 25 Dargent-Molina P, Douchin MN, Cormier C, Meunier PJ, Bréart G ; EPIDOS Study Group. Use of clinical risk factors in elderly women with low bone mineral density to identify women at higher risk of hip fracture: The EPIDOS prospective study. Osteoporos Int 2002; 13 (7) 593-599
  • 26 Miller PD, Barlas S, Brenneman SK , et al. An approach to identifying osteopenic women at increased short-term risk of fracture. Arch Intern Med 2004; 164 (10) 1113-1120
  • 27 McGrother CW, Donaldson M-MK, Clayton D, Abrams KR, Clarke M. Evaluation of a hip fracture risk score for assessing elderly women: the Melton Osteoporotic Fracture (MOF) study. Osteoporos Int 2002; 13 (1) 89-96
  • 28 Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008; 19 (4) 385-397
  • 29 Kanis JA , on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health-care level. Technical Report 2008; WHO Collaborating Center, University of Sheffield, UK
  • 30 Siris E, Delmas PD. Assessment of 10-year absolute fracture risk: a new paradigm with worldwide application. Osteoporos Int 2008; 19 (4) 383-384
  • 31 Barrett-Connor E, Siris ES, Wehren LE , et al. Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res 2005; 20 (2) 185-194
  • 32 IOM (Institute of Medicine). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011
  • 33 Cranney A, Horsley T, O'Donnell S , et al. Effectiveness and safety of vitamin D in relation to bone health. Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment; 158. 2007
  • 34 Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, Lichtenstein A, Patel K, Raman G, Tatsioni A, Terasawa T, Trikalinos TA. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep) 2009; (183) 1-420
  • 35 Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001; 22 (4) 477-501
  • 36 Cauley JA, Lacroix AZ, Wu L , et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008; 149 (4) 242-250
  • 37 Cauley JA, Danielson ME, Boudreau R , et al. Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI). J Bone Miner Res 2011; 26 (10) 2378-2388
  • 38 Cummings SR, Browner WS, Bauer D , et al; Study of Osteoporotic Fractures Research Group. Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 1998; 339 (11) 733-738
  • 39 Lee JS, LaCroix AZ, Wu L , et al. Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women. J Clin Endocrinol Metab 2008; 93 (5) 1796-1803
  • 40 Kimble RB, Matayoshi AB, Vannice JL, Kung VT, Williams C, Pacifici R. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period. Endocrinology 1995; 136 (7) 3054-3061
  • 41 Weitzmann MN, Cenci S, Rifas L, Haug J, Dipersio J, Pacifici R. T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms. J Bone Miner Res 2001; 16 (2) 328-337
  • 42 Kostenuik PJ, Shalhoub V. Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des 2001; 7 (8) 613-635
  • 43 Cenci S, Toraldo G, Weitzmann MN , et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A 2003; 100 (18) 10405-10410
  • 44 Jilka RL, Hangoc G, Girasole G , et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257 (5066) 88-91
  • 45 Cauley JA, Danielson ME, Boudreau RM , et al; Health ABC Study. Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. J Bone Miner Res 2007; 22 (7) 1088-1095
  • 46 Barbour KE, Boudreau R, Danielson ME , et al. Inflammatory markers and the risk of hip fracture: the Women's Health Initiative. J Bone Miner Res 2012; 27 (5) 1167-1176
  • 47 Cummings SR, Black DM, Nevitt MC , et al; The Study of Osteoporotic Fractures Research Group. Bone density at various sites for prediction of hip fractures. Lancet 1993; 341 (8837) 72-75
  • 48 LaCroix AZ, Jackson RD, Aragaki A , et al. OPG and sRANKL serum levels and incident hip fracture in postmenopausal Caucasian women in the Women's Health Initiative Observational Study. Bone 2013; 56 (2) 474-481
  • 49 LaCroix AZ, Lee JS, Wu L , et al; Women's Health Initiative Observational. Cystatin-C, renal function, and incidence of hip fracture in postmenopausal women. J Am Geriatr Soc 2008; 56 (8) 1434-1441
  • 50 Ensrud KE, Barbour K, Canales MT , et al. Renal function and nonvertebral fracture risk in multiethnic women: the Women's Health Initiative (WHI). Osteoporos Int 2012; 23 (3) 887-899
  • 51 Anderson GL, Limacher M, Assaf AR , et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291 (14) 1701-1712
  • 52 Rossouw JE, Anderson GL, Prentice RL , et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288 (3) 321-333
  • 53 Heiss G, Wallace R, Anderson GL , et al; WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008; 299 (9) 1036-1045
  • 54 Cauley JA, Robbins J, Chen Z , et al; Women's Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003; 290 (13) 1729-1738
  • 55 Jackson RD, Wactawski-Wende J, LaCroix AZ , et al; Women's Health Initiative Investigators. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. J Bone Miner Res 2006; 21 (6) 817-828
  • 56 LaCroix AZ, Chlebowski RT, Manson JE , et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011; 305 (13) 1305-1314
  • 57 Cauley JA, LaCroix AZ, Robbins JA , et al. Baseline serum estradiol and fracture reduction during treatment with hormone therapy: the Women's Health Initiative randomized trial. Osteoporos Int 2010; 21 (1) 167-177
  • 58 Manson JE, Chlebowski RT, Stefanick ML , et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013; 310 (13) 1353-1368
  • 59 Jackson RD, LaCroix AZ, Gass M , et al; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354 (7) 669-683
  • 60 Wactawski-Wende J, Kotchen JM, Anderson GL , et al; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006; 354 (7) 684-696
  • 61 Prentice RL, Pettinger MB, Jackson RD , et al. Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study. Osteoporos Int 2013; 24 (2) 567-580
  • 62 Cauley JA, Chlebowski RT, Wactawski-Wende J , et al. Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women's Health Initiative. J Womens Health (Larchmt) 2013; 22 (11) 915-929
  • 63 Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342: d2040
  • 64 Manson JE, Allison MA, Carr JJ , et al; Women's Health Initiative and Women's Health Initiative-Coronary Artery Calcium Study Investigators. Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative. Menopause 2010; 17 (4) 683-691
  • 65 Robbins JA, Aragaki A, Crandall CJ , et al. Women's Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause 2014; 21 (2) 116-123