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The renin-angiotensin aldosterone system and osteoporosis: findings from the Women’s Health Initiative

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Abstract

Summary

New users of RAAS inhibitors, including ACE inhibitors and ARBs, have a small increased risk for fracture in the first 3 years of use, with a reduced risk of fracture with longer duration of use.

Introduction

Pharmacological inhibitors of the renin-angiotensin aldosterone system (RAAS) are used to treat hypertension. However, the relationship of these medications to osteoporosis is inconsistent, and no study has included simultaneous measurements of both incident fractures and bone mineral density (BMD).

Methods

The association of RAAS inhibitor use (n = 131,793) with incident fractures in new users of these medications in women in the Women’s Health Initiative over a minimum median follow-up of 6.5 years was assessed by Cox proportional hazard models. The association of incident fractures by a cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. Subgroup analysis of fracture risk by RAAS inhibitor use confined to women with hypertension was also performed (n = 33,820). The association of RAAS inhibitor use with changes in BMD of the hip was estimated by linear regression in 8940 women with dual energy X-ray absorptiometry measurements.

Results

There was no significant association between RAAS inhibitor use and all fractures in the final adjusted multivariable models including hip BMD (HR 0.86 (0.59, 1.24)). However, among users of RAAS inhibitors, including ACE inhibitors and angiotensin receptor blockers (ARBs), hazard ratios for all incident fracture sites in final multivariable models including hip BMD showed dramatic differences by duration of use, with short duration of use (3 years or less) associated with a marked increased risk for fracture (HR 3.28 (1.66, 6.48)) to (HR 6.23 (3.11, 12.46)) and use for more than 3 years associated with a reduced fracture risk (HR 0.40 (0.24, 0.68) to (HR 0.44 (0.20, 0.97)) . Findings were similar in the subgroup of women with a history of hypertension. There was no significant change in BMD of the hip by RAAS inhibitor use.

Conclusions

In postmenopausal women, use of RAAS inhibitors, including ACE inhibitors and ARBs, is associated with an increased risk for fracture among new users of these medications in the first 3 years of use. However, long-term use (> 3 years) is associated with a reduced risk. Consideration for fracture risk may be part of the decision-making process for initiation of these medications for other disease states.

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References

  1. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL (1992) Perspective. How many women have osteoporosis? J Bone Miner Res Off J Am Soc Bone Miner Res 7(9):1005–1010

    Article  Google Scholar 

  2. Kanis JA, Johnell O, Oden A, Sembo I, Redlund-Johnell I, Dawson A et al (2000) Long-term risk of osteoporotic fracture in Malmo. Osteoporosis Int 11(8):669–674

    Article  CAS  Google Scholar 

  3. Cooper C, Atkinson EJ, Jacobsen SJ, O'Fallon WM, Melton LJ 3rd (1993) Population-based study of survival after osteoporotic fractures. Am J Epidemiol 137(9):1001–1005

    Article  CAS  PubMed  Google Scholar 

  4. Leibson CL, Tosteson AN, Gabriel SE, Ransom JE, Melton LJ (2002) Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. J Am Geriatr Soc 50(10):1644–1650

    Article  PubMed  Google Scholar 

  5. CDC.gov. Women and heart disease fact sheet 2017. Available from: https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_women_heart.htm

  6. Carbone L, Buzkova P, Fink HA, Lee JS, Chen Z, Ahmed A, Parashar S, Robbins JR (2010) Hip fractures and heart failure: findings from the cardiovascular health study. Eur Heart J 31(1):77–84

    Article  PubMed  Google Scholar 

  7. Baldini V, Mastropasqua M, Francucci CM, D'Erasmo E (2005) Cardiovascular disease and osteoporosis. J Endocrinol Investig 28(10 Suppl):69–72

    CAS  Google Scholar 

  8. Harshfield GA, Dong Y, Kapuku GK, Zhu H, Hanevold CD (2009) Stress-induced sodium retention and hypertension: a review and hypothesis. Curr Hypertens Rep 11(1):29–34

    Article  CAS  PubMed  Google Scholar 

  9. Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R (2008) Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22(7):2465–2475

    Article  CAS  Google Scholar 

  10. Kaneko K, Ito M, Fumoto T, Fukuhara R, Ishida J, Fukamizu A, Ikeda K (2011) Physiological function of the angiotensin AT1a receptor in bone remodeling. J Bone Miner Res Off J Am Soc Bone Miner Res 26(12):2959–2966

    Article  CAS  Google Scholar 

  11. Li Y, Shen G, Yu C, Li G, Shen J, Gong J, Xu Y (2014) Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1-FoxO3a-MnSOD pathway. Biochem Biophys Res Commun 455(1–2):113–118

    Article  CAS  PubMed  Google Scholar 

  12. Zainabadi K, Liu CJ, Caldwell ALM, Guarente L (2017) SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis. PLoS One 12(9):e0185236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Butt DA, Mamdani M, Gomes T, Lix L, Lu H, Tu K (2014) Risk of osteoporotic fractures with angiotensin II receptor blockers versus angiotensin-converting enzyme inhibitors in hypertensive community-dwelling elderly. J Bone Miner Res Off J Am Soc Bone Miner Res 29(11):2483–2488

    Article  CAS  Google Scholar 

  14. Lynn H, Kwok T, Wong SY, Woo J, Leung PC (2006) Angiotensin converting enzyme inhibitor use is associated with higher bone mineral density in elderly Chinese. Bone 38(4):584–588

    Article  CAS  PubMed  Google Scholar 

  15. Kwok T, Leung J, Zhang YF, Bauer D, Ensrud KE, Barrett-Connor E et al (2012) Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men? Osteoporosis Int 23(8):2159–2167

    Article  CAS  Google Scholar 

  16. Zhang YF, Qin L, Leung PC, Kwok TC (2012) The effect of angiotensin-converting enzyme inhibitor use on bone loss in elderly Chinese. J Bone Miner Metab 30(6):666–673

    Article  CAS  PubMed  Google Scholar 

  17. Masunari N, Fujiwara S, Nakata Y, Furukawa K, Kasagi F (2008) Effect of angiotensin converting enzyme inhibitor and benzodiazepine intake on bone loss in older Japanese. Hiroshima J Med Sci 57(1):17–25

    PubMed  Google Scholar 

  18. Solomon DH, Mogun H, Garneau K, Fischer MA (2011) Risk of fractures in older adults using antihypertensive medications. J Bone Miner Res 26(7):1561–1567

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Y, Wang L, Song Y, Zhao X, Wong MS, Zhang W (2016) Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice. Osteoporosis Int 27(3):1083–1092

    Article  CAS  Google Scholar 

  20. Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ, Dhawan S, Khan BQ, Gupta M, Ahmad K, Khouzam RN, Dishmon DA, Nesheiwat JP, Hajjar MA, Chishti WA, Nasser W, Khan M, Womack CR, Cho T, Haskin AR, Weber KT (2008) Fracture risk in men with congestive heart failure risk reduction with spironolactone. J Am Coll Cardiol 52(2):135–138

    Article  PubMed  Google Scholar 

  21. Kwok T, Leung J, Barrett-Connor E (2017) ARB users exhibit a lower fracture incidence than ACE inhibitor users among older hypertensive men. Age Ageing 46(1):57–64

    PubMed  Google Scholar 

  22. Hargrove JL, Golightly YM, Pate V, Casteel CH, Loehr LR, Marshall SW, Stürmer T (2017) Initiation of antihypertensive monotherapy and incident fractures among Medicare beneficiaries. Inj Epidemiol 4(1):27

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chen CI, Yeh JS, Tsao NW, Lin FY, Shih CM, Chiang KH, Kao YT, Fang YA, Tsai LW, Liu WC, Nakagami H, Morishita R, Kuo YJ, Huang CY (2017) Association between renin-angiotensin-aldosterone system blockade and future osteoporotic fracture risk in hypertensive population: a population-based cohort study in Taiwan. Medicine 96(46):e8331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kunutsor SK, Blom AW, Whitehouse MR, Kehoe PG, Laukkanen JA (2017) Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies. Eur J Epidemiol 32(11):947–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schlienger RG, Kraenzlin ME, Jick SS, Meier CR (2004) Use of beta-blockers and risk of fractures. JAMA 292(11):1326–1332

    Article  CAS  PubMed  Google Scholar 

  26. Rejnmark L, Vestergaard P, Mosekilde L (2006) Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study. J Hypertens 24(3):581–589

    Article  CAS  PubMed  Google Scholar 

  27. Butt DA, Mamdani M, Austin PC, Tu K, Gomes T, Glazier RH (2012) The risk of hip fracture after initiating antihypertensive drugs in the elderly. Arch Intern Med 172(22):1739–1744

    Article  PubMed  Google Scholar 

  28. Cheng YZ, Huang ZZ, Shen ZF, Wu HY, Peng JX, Waye MM et al (2017) ACE inhibitors and the risk of fractures: a meta-analysis of observational studies. Endocrine 55(3):732–740

    Article  CAS  PubMed  Google Scholar 

  29. Chen HY, Ma KY, Hsieh PL, Liou YS, Jong GP (2016) Long-term effects of antihypertensive drug use and new-onset osteoporotic fracture in elderly patients: a population-based longitudinal cohort study. Chin Med J 129(24):2907–2912

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS (2015) Risk of fractures in subjects with antihypertensive medications: a nationwide claim study. Int J Cardiol 184:62–67

    Article  PubMed  Google Scholar 

  31. Barzilay JI, Davis BR, Pressel SL, Ghosh A, Puttnam R, Margolis KL, Whelton PK (2017) The impact of antihypertensive medications on bone mineral density and fracture risk. Curr Cardiol Rep 19(9):76

    Article  PubMed  Google Scholar 

  32. Aoki M, Kawahata H, Sotobayashi D, Yu H, Moriguchi A, Nakagami H, Ogihara T, Morishita R (2015) Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome. Geriatr Gerontol Int 15(8):1064–1072

    Article  PubMed  Google Scholar 

  33. Solomon DH, Ruppert K, Zhao Z, Lian YJ, Kuo IH, Greendale GA, Finkelstein JS (2016) Bone mineral density changes among women initiating blood pressure lowering drugs: a SWAN cohort study. Osteoporosis Int 27(3):1181–1189

    Article  CAS  Google Scholar 

  34. Hays J, Hunt JR, Hubbell FA, Anderson GL, Limacher M, Allen C, Rossouw JE (2003) The Women's Health Initiative recruitment methods and results. Ann Epidemiol 13(9 Suppl):S18–S77

    Article  PubMed  Google Scholar 

  35. Curb JD, McTiernan A, Heckbert SR, Kooperberg C, Stanford J, Nevitt M et al (2003) Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 13(9 Suppl):S122–S128

    Article  PubMed  Google Scholar 

  36. Crandall CJ, Yildiz VO, Wactawski-Wende J, Johnson KC, Chen Z, Going SB, Wright NC, Cauley JA (2015) Postmenopausal weight change and incidence of fracture: post hoc findings from Women's Health Initiative observational study and clinical trials. BMJ 350:h25

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jackson RD, LaCroix AZ, Cauley JA, McGowan J (2003) The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol ;13(9 Suppl):S98–106

    Article  PubMed  Google Scholar 

  38. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE et al (2006) Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 354(7):669–683

    Article  CAS  PubMed  Google Scholar 

  39. Anderson GL, Manson J, Wallace R, Lund B, Hall D, Davis S, Shumaker S, Wang CY, Stein E, Prentice RL (2003) Implementation of the Women's Health Initiative study design. Ann Epidemiol 13(9 Suppl):S5–17

    Article  PubMed  Google Scholar 

  40. Hall WD, Pettinger M, Oberman A, Watts NB, Johnson KC, Paskett ED et al (2001) Risk factors for kidney stones in older women in the southern United States. Am J Med Sci 322(1):12–18

    Article  CAS  PubMed  Google Scholar 

  41. Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T (1999) Measurement characteristics of the Women's Health Initiative food frequency questionnaire. Ann Epidemiol 9(3):178–187

    Article  CAS  PubMed  Google Scholar 

  42. Gong Z, Aragaki AK, Chlebowski RT, Manson JE, Rohan TE, Chen C et al (2016) Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the women's health initiative. Int J Cancer 138(8):1915–1927

    Article  CAS  PubMed  Google Scholar 

  43. WHI. Approximations of medication use history in WHI cohorts. Available from: https://www.whi.org/researchers/data/Documents/Approximations%20of%20medication%20use%20in%20WHI%20cohorts.pdf

  44. Wang Z, White DL, Hoogeveen R, Chen L, Whitsel EA, Richardson PA, Virani S, Garcia J, el-Serag H, Jiao L Anti-hypertensive medication use, soluble receptor for glycation end products and risk of pancreatic cancer in the Women's Health Initiative study. J Clin Med 2018;7(8)

    Article  PubMed Central  CAS  Google Scholar 

  45. Sink KM, Evans GW, Shorr RI, Bates JT, Berlowitz D, Conroy MB, Felton DM, Gure T, Johnson KC, Kitzman D, Lyles MF, Servilla K, Supiano MA, Whittle J, Wiggers A, Fine LJ (2018) Syncope, hypotension, and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial. J Am Geriatr Soc 66(4):679–686

    Article  PubMed  PubMed Central  Google Scholar 

  46. Moreland JD, Richardson JA, Goldsmith CH, Clase CM (2004) Muscle weakness and falls in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 52(7):1121–1129

    Article  PubMed  Google Scholar 

  47. Mertens B, Vanderheyden P, Michotte Y, Sarre S (2010) The role of the central renin-angiotensin system in Parkinson's disease. J Renin Angiotensin Aldosterone Syst 11(1):49–56

    Article  CAS  PubMed  Google Scholar 

  48. Onder G, Penninx BW, Balkrishnan R, Fried LP, Chaves PH, Williamson J et al (2002) Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study. Lancet 359(9310):926–930

    Article  CAS  PubMed  Google Scholar 

  49. Huges A (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Nuerusurg Psychiatry 55:181–184

    Article  Google Scholar 

  50. Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME (2002) Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. Heart 88(4):373–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA (2006) Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial. Ann Intern Med 144(9):660–664

    Article  CAS  PubMed  Google Scholar 

  52. Sumukadas D, Witham MD, Struthers AD, McMurdo ME (2007) Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 177(8):867–874

    Article  PubMed  Google Scholar 

  53. Ruths S, Bakken MS, Ranhoff AH, Hunskaar S, Engesaeter LB, Engeland A (2015) Risk of hip fracture among older people using antihypertensive drugs: a nationwide cohort study. BMC Geriatr 15:153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Garcia-Testal A, Monzo A, Rabanaque G, Gonzalez A, Romeu A (2006) Evolution of the bone mass of hypertense menopausal women in treatment with fosinopril. Med Clin 127(18):692–694

    Article  Google Scholar 

  55. Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158(9):915–920

    Article  PubMed  Google Scholar 

  56. Cummings SR, Nevitt MC, Kidd S (1988) Forgetting falls. The limited accuracy of recall of falls in the elderly. J Am Geriatr Soc 36(7):613–616

    Article  CAS  PubMed  Google Scholar 

  57. Tinetti ME, Williams CS (1998) The effect of falls and fall injuries on functioning in community-dwelling older persons. J Gerontol A Biol Sci Med Sci 53(2):M112–M119

    Article  CAS  PubMed  Google Scholar 

  58. Davison J, Bond J, Dawson P, Steen IN, Kenny RA (2005) Patients with recurrent falls attending accident and emergency benefit from multifactorial intervention--a randomised controlled trial. Age Ageing 34(2):162–168

    Article  PubMed  Google Scholar 

  59. Latham NK, Anderson CS, Reid IR (2003) Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review. J Am Geriatr Soc 51(9):1219–1226

    Article  PubMed  Google Scholar 

  60. Hale WA, Delaney MJ, Cable T (1993) Accuracy of patient recall and chart documentation of falls. The Journal of the American Board of Family Practice 6(3):239–242

    CAS  PubMed  Google Scholar 

  61. Cauley JA, Hovey KM, Stone KL, Andrews CA, Barbour KE, Hale L, Jackson RD, Johnson KC, LeBlanc ES, Li W, Zaslavsky O, Ochs-Balcom H, Wactawski-Wende J, Crandall CJ (2019) Characteristics of self-reported sleep and the risk of falls and fractures: the Women's Health Initiative (WHI). JBMR 34(3):464–474

    Article  CAS  Google Scholar 

  62. Cauley JA, Smagula SF, Hovey KM, Wactawski-Wende J, Andrews CA, Crandall CJ, LeBoff MS, Li W, Coday M, Sattari M, Tindle HA (2017) Optimism, cynical hostility, falls, and fractures: the Women's Health Initiative observational study (WHI-OS). J Bone Miner Res Off J Am Soc Bone Miner Res 32(2):221–229

    Article  Google Scholar 

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Acknowledgments

Drs. Carbone, Vasan, Prentice, Harshfield, Bernard, Johnson, and Cauley participated in the analysis/interpretation of the data, drafting, and/or critical analysis of the manuscript and approved the final version of the submitted manuscript. Drs. Carbone, Prentice, and Vasan accept responsibility for the integrity of the data analysis.

Additional information

A full list of all the investigators who have contributed to Women’s Health Initiative science appears at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf

The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

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Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, J. Harold Harrison MD, Distinguished University Chair in Rheumatology, Medical College of Georgia at Augusta University, Augusta, GA, USA

    L.D. Carbone

  2. Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, USA

    L.D. Carbone

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S. Vasan & R.L. Prentice

  4. Georgia Prevention Institute, Medical College of Georgia at Augusta University, Augusta, GA, USA

    G. Harshfield

  5. Department of Medicine, Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Bavaria, Germany

    B. Haring

  6. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    J.A. Cauley

  7. Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    K.C. Johnson

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  1. L.D. Carbone
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  2. S. Vasan
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Carbone, L., Vasan, S., Prentice, R. et al. The renin-angiotensin aldosterone system and osteoporosis: findings from the Women’s Health Initiative. Osteoporos Int 30, 2039–2056 (2019). https://doi.org/10.1007/s00198-019-05041-3

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