In a multi-site longitudinal cohort study, decreasing hemoglobin was associated with increased hip fracture risk in men. Anemia was associated with hip fracture in men and in African American women. Decreasing hemoglobin may be a marker of progressing bone fragility, making its serial measurement useful for fracture risk stratification.
Hematopoiesis and bone health are interdependent. Anemia has been associated with risk of fracture in humans. To further elucidate this relationship, we hypothesized that decreasing hemoglobin could indicate defective hematopoiesis and would also predict fracture risk.
We performed a prospective analysis from study baseline (1992) of the Cardiovascular Health Study, a multi-site longitudinal cohort study. A total of 4670 men and women, ages >65 years, who were able to consent and not institutionalized or wheelchair bound, had hemoglobin (Hb) measured in 1992. For 4006 subjects, Hb change from 1989 to 1992 was annualized and divided into sex-specific quartiles. Incident hip fractures were verified against Medicare claims data during a median follow-up of 11.8 years.
Nested Cox proportional-hazard models estimated association of hip fracture with anemia (men Hb <13 g/dL, women Hb <12 g/dL) and separately, greatest Hb decrease (versus others). Anemia was associated with increased hip fracture risk in all men (HR 1.59; 95% CI 1.01–2.50) and African American women (HR 3.21; 95% CI 1.07–9.63). In men, an annualized Hb loss of >0.36 g/dL/year was associated with a higher risk of hip fracture (HR 1.67; 95% CI 1.10–2.54), which was lessened by anemia at the start of fracture follow-up (HR 1.53; 95% CI 0.99–2.39).
Decreasing Hb may be an early marker for subsequent hip fracture risk in men, which may be less informative once an anemia threshold is crossed. Only African American women with anemia had increased hip fracture risk, suggesting a race difference in this relationship.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
BioLINCC CHS data package was last updated in June of 2016; researchers can request data but must be registered on the CHS website.
Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH (2002) Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med 162(19):2217–2222
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 22(3):465–475
Kanis JA (2002) Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359(9321):1929–1936
Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164(10):1108–1112
Johnell O, Kanis JA, Oden A, Johansson H, de Laet C, Delmas P, Eisman JA, Fujiwara S, Kroger H, Mellstrom D, Meunier PJ, Melton LJ III, O'Neill T, Pols H, Reeve J, Silman A, Tenenhouse A (2005) Predictive value of BMD for hip and other fractures. J Bone Miner Res 20(7):1185–1194
Kanis JA, Johnell O, De Laet C et al (2004) A meta-analysis of previous fracture and subsequent fracture risk. Bone. 35(2):375–382
Health UDo, Services H. Bone health and osteoporosis: a report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General. 2004;87
Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD (2012) FRAX® with and without bone mineral density. Calcif Tissue Int 90(1):1–13
Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E (2008) FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 19(4):385–397
Valderrábano RJ, Lee J, Lui L-Y, Hoffman AR, Cummings SR, Orwoll ES, Wu JY, for the Osteoporotic Fractures in Men (MrOS) Study Research Group (2017) Older men with anemia have increased fracture risk independent of bone mineral density. The Journal of Clinical Endocrinology & Metabolism 102(7):2199–2206
Chen Z, Thomson CA, Aickin M, Nicholas JS, van Wyck D, Lewis CE, Cauley JA, Bassford T, Short list of Women's Health Initiative Investigators (2010) The relationship between incidence of fractures and anemia in older multiethnic women. J Am Geriatr Soc 58(12):2337–2344
Jorgensen L, Skjelbakken T, Lochen ML et al (2010) Anemia and the risk of non-vertebral fractures: the Tromso study. Osteoporos Int 21(10):1761–1768
Looker A (2014) Hemoglobin and hip fracture risk in older non-Hispanic white adults. Osteoporos Int 25(10):2389–2398
Valderrabano RJ, Wu JY (2018) Bone and blood interactions in human health and disease. Bone.
Panaroni C, Tzeng YS, Saeed H, Wu JY (2014) Mesenchymal progenitors and the osteoblast lineage in bone marrow hematopoietic niches. Curr Osteoporos Rep 12(1):22–32
Wu JY, Kronenberg HM (2015) Bone marrow hematopoietic niches. Osteoimmunology: Interactions of the Immune and Skeletal Systems:103–119
Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL (2004) Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 103(9):3258–3264
Rankin EB, Wu C, Khatri R, Wilson TLS, Andersen R, Araldi E, Rankin AL, Yuan J, Kuo CJ, Schipani E, Giaccia AJ (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 149(1):63–74
Wu C, Giaccia AJ, Rankin EB (2014) Osteoblasts: a novel source of erythropoietin. Curr Osteoporos Rep. 12(4):428–432
Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, O'Leary DH, Psaty B, Rautaharju P, Tracy RP, Weiler PG (1991) The cardiovascular health study: design and rationale. Ann Epidemiol 1(3):263–276
Robinson-Cohen C, Katz R, Mozaffarian D, Dalrymple LS, de Boer I, Sarnak M, Shlipak M, Siscovick D, Kestenbaum B (2009) Physical activity and rapid decline in kidney function among older adults. Arch Intern Med 169(22):2116–2123
Mozaffarian D, Kamineni A, Carnethon M, Djoussé L, Mukamal KJ, Siscovick D (2009) Lifestyle risk factors and new-onset diabetes mellitus in older adults: the cardiovascular health study. Arch Intern Med 169(8):798–807
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F, Centers for Disease Control and Prevention, American Heart Association (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 107(3):499–511
Erlandsen E, Randers E, Kristensen J (1999) Evaluation of the Dade Behring N latex cystatin C assay on the Dade Behring nephelometer II system. Scand J Clin Lab Invest 59(1):1–8
Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40(2):221–226
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, van Lente F, Zhang YL, Coresh J, Levey AS, CKD-EPI Investigators (2012) Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367(1):20–29
Valderrábano RJ, Lee J, Lui L-Y, et al. Older men with anemia have increased fracture risk independent of bone mineral density. The Journal of Clinical Endocrinology & Metabolism. 2017
Team RC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014. 2014
Kellert L, Martin E, Sykora M, Bauer H, Gussmann P, Diedler J, Herweh C, Ringleb PA, Hacke W, Steiner T, Bösel J (2011) Cerebral oxygen transport failure?: decreasing hemoglobin and hematocrit levels after ischemic stroke predict poor outcome and mortality: STroke: RelevAnt impact of hemoGlobin, hematocrit and transfusion (STRAIGHT)—an observational study. Stroke. 42(10):2832–2837
Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J, Greenland S, Kalantar-Zadeh K (2006) Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 17(4):1181–1191
Zakai NA, French B, Arnold AM, Newman AB, Fried LF, Robbins J, Chaves P, Cushman M (2013) Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. Am J Hematol 88(1):5–9
Rikkonen T, Sirola J, Salovaara K, Tuppurainen M, Jurvelin JS, Honkanen R, Kröger H (2012) Muscle strength and body composition are clinical indicators of osteoporosis. Calcif Tissue Int 91(2):131–138
Van Staa T, Leufkens H, Cooper C (2002) Utility of medical and drug history in fracture risk prediction among men and women. Bone. 31(4):508–514
Lee EA, Shin DW, Yoo JH, Ko HY, Jeong SM (2019) Anemia and risk of fractures in older Korean adults: a nationwide population-based study. J Bone Miner Res 34(6):1049–1057
Leavy B, Michaëlsson K, Åberg AC, Melhus H, Byberg L (2017) The impact of disease and drugs on hip fracture risk. Calcif Tissue Int 100(1):1–12
Bohannon AD (1999) Osteoporosis and African American women. Journal of women’s health & gender-based medicine 8(5):609–615
Zakai NA, McClure LA, Prineas R et al (2008) Correlates of anemia in American blacks and whites: the REGARDS renal ancillary study. Am J Epidemiol 169(3):355–364
Solovieff N, Hartley SW, Baldwin CT, Klings ES, Gladwin MT, Taylor JG VI, Kato GJ, Farrer LA, Steinberg MH, Sebastiani P (2011) Ancestry of African Americans with sickle cell disease. Blood Cell Mol Dis 47(1):41–45
Osunkwo I (2013) An update on the recent literature on sickle cell bone disease. Curr Opin Endocrinol Diabetes Obes 20(6):539–546
Penninx BW, Pahor M, Cesari M et al (2004) Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am Geriatr Soc 52(5):719–724
Zakai NA, Katz R, Hirsch C, Shlipak MG, Chaves PHM, Newman AB, Cushman M (2005) A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the cardiovascular health study. Arch Intern Med 165(19):2214–2220
Silva JC, de Moraes ZV, Silva C, de Barros Mazon S, Guariento ME, Neri AL, Fattori A (2014) Understanding red blood cell parameters in the context of the frailty phenotype: interpretations of the FIBRA (frailty in Brazilian seniors) study. Arch Gerontol Geriatr 59(3):636–641
Hassan EB, Vogrin S, Hernandez Vina I, Boersma D, Suriyaarachchi P, Duque G. Hemoglobin levels are low in sarcopenic and osteosarcopenic older persons. Calcified Tissue International. 2020
Kirk B, Feehan J, Lombardi G, Duque G. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Current Osteoporosis Reports. 2020:1–13
This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely our responsibility and does not necessarily represent the official views of the National Institute of Health.
Conflicts of interest
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Valderrábano, R., Buzkova, P., Chang, PY. et al. Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study. Osteoporos Int (2021). https://doi.org/10.1007/s00198-021-05873-y
- Fracture prevention
- Fracture risk assessment
- Hip fracture