Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study



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.

Fig. 1
Fig. 2

Data availability

BioLINCC CHS data package was last updated in June of 2016; researchers can request data but must be registered on the CHS website.


  1. 1.

    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

    Article  Google Scholar 

  2. 2.

    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

    Article  Google Scholar 

  3. 3.

    Kanis JA (2002) Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359(9321):1929–1936

    Article  Google Scholar 

  4. 4.

    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

    Article  Google Scholar 

  5. 5.

    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

    Article  Google Scholar 

  6. 6.

    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

    CAS  Article  Google Scholar 

  7. 7.

    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

  8. 8.

    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

    CAS  Article  Google Scholar 

  9. 9.

    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

    CAS  Article  Google Scholar 

  10. 10.

    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

    Article  Google Scholar 

  11. 11.

    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

    Article  Google Scholar 

  12. 12.

    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

    CAS  Article  Google Scholar 

  13. 13.

    Looker A (2014) Hemoglobin and hip fracture risk in older non-Hispanic white adults. Osteoporos Int 25(10):2389–2398

    CAS  Article  Google Scholar 

  14. 14.

    Valderrabano RJ, Wu JY (2018) Bone and blood interactions in human health and disease. Bone.

  15. 15.

    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

    Article  Google Scholar 

  16. 16.

    Wu JY, Kronenberg HM (2015) Bone marrow hematopoietic niches. Osteoimmunology: Interactions of the Immune and Skeletal Systems:103–119

  17. 17.

    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

    CAS  Article  Google Scholar 

  18. 18.

    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

    CAS  Article  Google Scholar 

  19. 19.

    Wu C, Giaccia AJ, Rankin EB (2014) Osteoblasts: a novel source of erythropoietin. Curr Osteoporos Rep. 12(4):428–432

    Article  Google Scholar 

  20. 20.

    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

    CAS  Article  Google Scholar 

  21. 21.

    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

    Article  Google Scholar 

  22. 22.

    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

    Article  Google Scholar 

  23. 23.

    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

    Article  Google Scholar 

  24. 24.

    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

    CAS  Article  Google Scholar 

  25. 25.

    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

    CAS  Article  Google Scholar 

  26. 26.

    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

    CAS  Article  Google Scholar 

  27. 27.

    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

  28. 28.

    Team RC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014. 2014

  29. 29.

    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

    CAS  Article  Google Scholar 

  30. 30.

    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

    CAS  Article  Google Scholar 

  31. 31.

    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

    CAS  Article  Google Scholar 

  32. 32.

    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

    CAS  Article  Google Scholar 

  33. 33.

    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

    Article  Google Scholar 

  34. 34.

    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

    Article  Google Scholar 

  35. 35.

    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

    CAS  Article  Google Scholar 

  36. 36.

    Bohannon AD (1999) Osteoporosis and African American women. Journal of women’s health & gender-based medicine 8(5):609–615

    CAS  Article  Google Scholar 

  37. 37.

    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

    Article  Google Scholar 

  38. 38.

    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

    Article  Google Scholar 

  39. 39.

    Osunkwo I (2013) An update on the recent literature on sickle cell bone disease. Curr Opin Endocrinol Diabetes Obes 20(6):539–546

    CAS  Article  Google Scholar 

  40. 40.

    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

    Article  Google Scholar 

  41. 41.

    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

    Article  Google Scholar 

  42. 42.

    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

    Article  Google Scholar 

  43. 43.

    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

  44. 44.

    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

Download references


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 The content is solely our responsibility and does not necessarily represent the official views of the National Institute of Health.

Author information





Study design: RV, JW, and JL. Study conduct: HF and JR. Data collection: HF and JR. Data analysis: PB. Data interpretation: RV, PC, HF, JR, JW, and JL. Drafting manuscript: RV. Revising manuscript content: RV, PB, PC, NZ, HF, JW, JL. Approving final version of manuscript: RV, PB, PC, NZ, HF, JR, JW, JL. RV takes responsibility for the integrity of the data analysis.

Corresponding authors

Correspondence to R.J. Valderrábano or J.Y. Wu.

Ethics declarations

Conflicts of interest


Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information


(DOCX 14 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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).

Download citation


  • Anemia
  • Fracture prevention
  • Fracture risk assessment
  • Hip fracture
  • Osteoporosis