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Role of the renin–angiotensin–aldosterone system in bone metabolism

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Abstract

With the acceleration of population aging, the incidence of osteoporosis has gradually increased, and osteoporosis and fractures caused by osteoporosis have gradually become a serious social public health problem. The classic role of the renin–angiotensin–aldosterone system (RAAS) is to keep blood pressure stable. However, as the components of RAAS were found in bone tissues, their functions of stimulating osteoclast formation and inhibiting osteoblast activity thus inducing bone loss have gradually emerged. RAAS blockers can prevent osteoporotic fractures which may be related to angiotensin type 1 (AT1) receptor, osteoprotegerin (OPG)/nuclear factor-κB ligand (RANKL), and angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7) (Ang (1–7))/G protein-coupled receptor (Mas) cascade. However, some studies suggest that RAAS blockers do not prevent osteoporotic fractures. This article reviews the effects of RAAS and RAAS inhibitors on bone metabolism and provides new ideas for the prevention of osteoporosis.

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References

  1. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, Weber KT (2005) Hyperparathyroidism and the calcium paradox of aldosteronism. Circulation 111:871–878

    Article  CAS  PubMed  Google Scholar 

  2. 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. Osteoporos Int 27:1083–1092

    Article  CAS  PubMed  Google Scholar 

  3. Zhang Y, Li XL, Sha NN, Shu B, Zhao YJ, Wang XL, Xiao HH, Shi Q, Wong MS, Wang YJ (2017) Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss. Bone 97:222–232

    Article  CAS  PubMed  Google Scholar 

  4. McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, Oldfield BJ, Mendelsohn FA, Chai SY (2003) The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 35:901–918

    Article  CAS  PubMed  Google Scholar 

  5. White AJ, Cheruvu SC, Sarris M, Liyanage SS, Lumbers E, Chui J, Wakefield D, McCluskey PJ (2015) Expression of classical components of the renin-angiotensin system in the human eye. J Renin Angiotensin Aldosterone Syst 16:59–66

    Article  CAS  PubMed  Google Scholar 

  6. Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH, Ruan DT, Williams GH, Adler GK, Vaidya A (2014) Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension 63:273–280

    Article  CAS  PubMed  Google Scholar 

  7. Queiroz-Junior CM, Santos A, Galvao I, Souto GR, Mesquita RA, Sa MA, Ferreira AJ (2019) The angiotensin converting enzyme 2/angiotensin-(1–7)/Mas Receptor axis as a key player in alveolar bone remodeling. Bone 128:115041

    Article  CAS  PubMed  Google Scholar 

  8. Garcia P, Schwenzer S, Slotta JE, Scheuer C, Tami AE, Holstein JH, Histing T, Burkhardt M, Pohlemann T, Menger MD (2010) Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation - role of a local renin-angiotensin system. Br J Pharmacol 159:1672–1680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guan XX, Zhou Y, Li JY (2011) Reciprocal roles of angiotensin II and Angiotensin II Receptors Blockade (ARB) in regulating Cbfa1/RANKL via cAMP signaling pathway: possible mechanism for hypertension-related osteoporosis and antagonistic effect of ARB on hypertension-related osteoporosis. Int J Mol Sci 12:4206–4213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beavan S, Horner A, Bord S, Ireland D, Compston J (2001) Colocalization of glucocorticoid and mineralocorticoid receptors in human bone. J Bone Miner Res 16:1496–1504

    Article  CAS  PubMed  Google Scholar 

  11. Rossi GP, Ragazzo F, Seccia TM, Maniero C, Barisa M, Calo LA, Frigo AC, Fassina A, Pessina AC (2012) Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma. Hypertension 60:431–436

    Article  CAS  PubMed  Google Scholar 

  12. Mazzocchi G, Aragona F, Malendowicz LK, Nussdorfer GG (2001) PTH and PTH-related peptide enhance steroid secretion from human adrenocortical cells. Am J Physiol Endocrinol Metab 280:E209–E213

    Article  CAS  PubMed  Google Scholar 

  13. Hagstrom E, Hellman P, Larsson TE, Ingelsson E, Berglund L, Sundstrom J, Melhus H, Held C, Lind L, Michaelsson K, Arnlov J (2009) Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation 119:2765–2771

    Article  CAS  PubMed  Google Scholar 

  14. Bernini G, Moretti A, Lonzi S, Bendinelli C, Miccoli P, Salvetti A (1999) Renin-angiotensin-aldosterone system in primary hyperparathyroidism before and after surgery. Metabolism 48:298–300

    Article  CAS  PubMed  Google Scholar 

  15. Shen L, Ma C, Shuai B, Yang Y (2017) Effects of 1,25-dihydroxyvitamin D3 on the local bone renin-angiotensin system in a murine model of glucocorticoid-induced osteoporosis. Exp Ther Med 13:3297–3304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang Y, Kong J, Deb DK, Chang A, Li YC (2010) Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system. J Am Soc Nephrol 21:966–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Petramala L, Zinnamosca L, Settevendemmie A, Marinelli C, Nardi M, Concistre A, Corpaci F, Tonnarini G, De Toma G, Letizia C (2014) Bone and mineral metabolism in patients with primary aldosteronism. Int J Endocrinol 2014:836529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ismail NA, Kamaruddin NA, Azhar Shah S, Sukor N (2020) The effect of vitamin D treatment on clinical and biochemical outcomes of primary aldosteronism. Clin Endocrinol (Oxf) 92:509–517

    Article  CAS  Google Scholar 

  19. Witham MD, Price RJ, Struthers AD, Donnan PT, Messow CM, Ford I, McMurdo ME (2013) Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med 173:1672–1679

    CAS  PubMed  Google Scholar 

  20. Law PH, Sun Y, Bhattacharya SK, Chhokar VS, Weber KT (2005) Diuretics and bone loss in rats with aldosteronism. J Am Coll Cardiol 46:142–146

    Article  CAS  PubMed  Google Scholar 

  21. Maniero C, Fassina A, Guzzardo V, Lenzini L, Amadori G, Pelizzo MR, Gomez-Sanchez C, Rossi GP (2011) Primary hyperparathyroidism with concurrent primary aldosteronism. Hypertension 58:341–346

    Article  CAS  PubMed  Google Scholar 

  22. Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z, Smith RA, Gerling IC, Weber KT (2004) Loss of bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ Physiol 287:H2023–H2026

    Article  CAS  PubMed  Google Scholar 

  23. Zia AA, Kamalov G, Newman KP, McGee JE, Bhattacharya SK, Ahokas RA, Sun Y, Gerling IC, Weber KT (2010) From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation (in eng). Hypertens Res 33:1091–1101

    Article  CAS  PubMed  Google Scholar 

  24. Notsu M, Yamauchi M, Yamamoto M, Nawata K, Sugimoto T (2017) Primary aldosteronism as a risk factor for vertebral fracture. J Clin Endocrinol Metab 102:1237–1243

    Article  PubMed  Google Scholar 

  25. Wen Y, Shangguan Y, Pan Z, Hu H, Magdalou J, Chen L, Wang H (2019) Activation of local bone RAS by maternal excessive glucocorticoid participated in the fetal programing of adult osteopenia induced by prenatal caffeine exposure. Toxicol Appl Pharmacol 363:1–10

    Article  CAS  PubMed  Google Scholar 

  26. Gu SS, Zhang Y, Li XL, Wu SY, Diao TY, Hai R, Deng HW (2012) Involvement of the skeletal renin-angiotensin system in age-related osteoporosis of ageing mice. Biosci Biotechnol Biochem 76:1367–1371

    Article  CAS  PubMed  Google Scholar 

  27. Kuipers AL, Kammerer CM, Pratt JH, Bunker CH, Wheeler VW, Patrick AL, Zmuda JM (2016) Association of circulating renin and aldosterone with osteocalcin and bone mineral density in african ancestry families. Hypertension 67:977–982

    Article  CAS  PubMed  Google Scholar 

  28. Shuai B, Yang YP, Shen L, Zhu R, Xu XJ, Ma C, Lv L, Zhao J, Rong JH (2015) Local renin-angiotensin system is associated with bone mineral density of glucocorticoid-induced osteoporosis patients. Osteoporos Int 26:1063–1071

    Article  CAS  PubMed  Google Scholar 

  29. Oliveira SHP, Brito VGB, Frasnelli SCT, Ribeiro BDS, Ferreira MN, Queiroz DP, Beltan CT, Lara VS, Santos CF (2019) Aliskiren attenuates the inflammatory response and wound healing process in diabetic mice with periodontal disease. Front Pharmacol 10:708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen XF, Li XL, Liu JX, Xu J, Zhao YY, Yang M, Zhang Y (2018) Inhibition on angiotensin-converting enzyme exerts beneficial effects on trabecular bone in orchidectomized mice. Pharmacol Rep 70:705–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shimizu H, Nakagami H, Osako MK, Nakagami F, Kunugiza Y, Tomita T, Yoshikawa H, Rakugi H, Ogihara T, Morishita R (2009) Prevention of osteoporosis by angiotensin-converting enzyme inhibitor in spontaneous hypertensive rats. Hypertens Res 32:786–790

    Article  CAS  PubMed  Google Scholar 

  32. 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 J 22:2465–2475

    Article  CAS  PubMed  Google Scholar 

  33. Cheng YZ, Yang SL, Wang JY, Ye M, Zhuo XY, Wang LT, Chen H, Zhang H, Yang L (2018) Irbesartan attenuates advanced glycation end products-mediated damage in diabetes-associated osteoporosis through the AGEs/RAGE pathway. Life Sci 205:184–192

    Article  CAS  PubMed  Google Scholar 

  34. Fumoto T, Ishii KA, Ito M, Berger S, Schutz G, Ikeda K (2014) Mineralocorticoid receptor function in bone metabolism and its role in glucocorticoid-induced osteopenia. Biochem Biophys Res Commun 447:407–412

    Article  CAS  PubMed  Google Scholar 

  35. Boschmann M, Nussberger J, Engeli S, Danser AH, Yeh CM, Prescott MF, Dahlke M, Jordan J (2012) Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin-angiotensin system activity in obese hypertensive patients. J Hypertens 30:561–566

    Article  CAS  PubMed  Google Scholar 

  36. Rianon N, Ambrose CG, Pervin H, Garcia M, Mama SK, Schwartz AV, Lee B, Harris T (2017) Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos 12:94

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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] (in spa). Med Clin (Barc) (Evolucion de la densidad osea de mujeres menopausicas hipertensas en tratamiento con fosinopril.) 127:692–694

  38. 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 15:1064–1072

    Article  PubMed  Google Scholar 

  39. 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 46:57–64

    PubMed  Google Scholar 

  40. Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ et al (2008) Fracture risk in men with congestive heart failure risk reduction with spironolactone. J Am Coll Cardiol 52:135–138

    Article  PubMed  Google Scholar 

  41. Salcuni AS, Palmieri S, Carnevale V, Morelli V, Battista C, Guarnieri V, Guglielmi G, Desina G, Eller-Vainicher C, Beck-Peccoz P, Scillitani A, Chiodini I (2012) Bone involvement in aldosteronism. J Bone Miner Res 27:2217–2222

    Article  CAS  PubMed  Google Scholar 

  42. Nakai K, Kawato T, Morita T, Yamazaki Y, Tanaka H, Tonogi M, Oki H, Maeno M (2015) Angiotensin II suppresses osteoblastic differentiation and mineralized nodule formation via AT1 receptor in ROS17/2.8 cells. Arch Med Sci 11:628–637

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mulinari-Santos G, de Souza Batista FR, Kirchweger F, Tangl S, Gruber R, Okamoto R (2018) Losartan reverses impaired osseointegration in spontaneously hypertensive rats (in eng). Clin Oral Implants Res

  44. Zhang Y, Wang L, Liu JX, Wang XL, Shi Q, Wang YJ (2016) Involvement of skeletal renin-angiotensin system and kallikrein-kinin system in bone deteriorations of type 1 diabetic mice with estrogen deficiency. J Diabetes Complications 30:1419–1425

    Article  CAS  PubMed  Google Scholar 

  45. Yongtao Z, Kunzheng W, Jingjing Z, Hu S, Jianqiang K, Ruiyu L, Chunsheng W (2014) Glucocorticoids activate the local renin-angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis. Endocrine 47:598–608

    Article  PubMed  CAS  Google Scholar 

  46. Abuohashish HM, Ahmed MM, Sabry D, Khattab MM, Al-Rejaie SS (2017) ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats. Biomed Pharmacother 92:58–68

    Article  CAS  PubMed  Google Scholar 

  47. Diao TY, Pan H, Gu SS, Chen X, Zhang FY, Wong MS, Zhang Y (2014) Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes. J Bone Miner Metab 32:261–270

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Wu VC, Chang CH, Wang CY, Lin YH, Kao TW, Lin PC, Chu TS, Chang YS, Chen L, Wu KD, Chueh SJ (2017) Risk of fracture in primary aldosteronism: a population-based cohort study. J Bone Miner Res 32:743–752

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Dong Zhao or Baoyu Zhang.

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Mo, C., Ke, J., Zhao, D. et al. Role of the renin–angiotensin–aldosterone system in bone metabolism. J Bone Miner Metab 38, 772–779 (2020). https://doi.org/10.1007/s00774-020-01132-y

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