Editorial Comment Cardiology 2015;132:9–10 DOI: 10.1159/000398788
Received: April 7, 2015 Accepted: April 7, 2015 Published online: May 19, 2015
Osteoporosis and Aortic Stenosis: ‘Killing Two Birds with One Stone’? George Lazaros Georgios Benetos Konstantinos Toutouzas Dimitris Tousoulis
Calcific aortic stenosis is the most common form of valve disease in Western countries and represents a major healthcare problem because of increasingly higher life expectancy [1]. Moreover, the establishment of transcatheter aortic valve implantation in everyday clinical practice has further attracted the attention of the community to this disease. In the past decades, efforts have been made to identify the underlining pathophysiology of calcific aortic stenosis, and to redefine it as an actively regulated process and not just passive, age-related degeneration. The pathobiology of the disease shares many mechanisms with atherosclerosis in the early stages and active bone formation later, with inflammation, fibrosis and calcification playing an important role in the active narrowing of valves. The impact of several pharmaceutical interventions on the rate of progression or even regression of aortic stenosis has been studied in both experimental and human studies. In fact, the antifibrotic action of angiotensinconverting enzyme inhibitors in human aortic stenosis has been evaluated retrospectively, with controversial results [2, 3]. In addition, the beneficial effects of potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zolendronate) on aortic valve structure have been also demonstrated. These agents inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway, and hence prevent posttranslational modifications, potentially leading to macrophage apoptosis and exhibiting anti-inflammatory actions. Alternatively, the cardiovascular effects © 2015 S. Karger AG, Basel 0008–6312/15/1321–0009$39.50/0 E-Mail [email protected] www.karger.com/crd
of bisphosphonates could also be explained by the inhibition of bone resorption and the release of calcium phosphate particles in the circulation. Systematic administration of these agents exhibits a beneficial effect on cardiovascular calcification in animal models [4]. In 2 echocardiographic studies [5, 6], bisphosphonates have shown a potential benefit in slowing the progression of human calcific aortic stenosis, but the results of 2 largescale retrospective analyses in elderly women have proved controversial [7, 8]. The most extensively studied pharmaceutical intervention in the natural history of aortic stenosis is statins. As lipids play an important role in the active biologic process of valvular calcification, hypercholesterolemic animal models have been used in experimental studies [9, 10]. Cholesterol-lowering in such models improved various features associated with atherogenesis and aortic valve calcification. The signaling pathways implicated in the beneficial action of statins in aortic valve disease are currently under intense investigation. Hence, atorvastatin-mediated attenuation of aortic valve calcification is mediated in part by LDL receptor-related protein 5-Lrp5/ beta-catenin pathway [10]. In this issue of Cardiology, Rajamannan [11] shows a beneficial effect of statins in two distinct processes, namely aortic valve calcification and osteoporotic bone resorption, in an experimental hypercholesterolemic mouse model. By means of histology, fluorescence and microcomputed tomography measurement of LDLr–/– mice George Lazaros, MD University of Athens Medical School Hippokration Hospital, 114 Vas. Sofias Ave. GR–115 27 Athens (Greece) E-Mail glaz35 @ hotmail.com
Downloaded by: Dahlgree Med. Library, Goergetown Univ. 141.161.91.14 - 5/27/2015 2:31:54 PM
First Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece
heart valves and femurs, the author showed that a cholesterol diet induced bone formations in the calcified aortic valves and an increase in macrophage infiltration whereas atorvastatin attenuated mineralization in the aortic valves and bone loss in the femurs. This study further reinforces the theory of active bone turnover in aortic valve stenosis and, more interestingly, provides both a potential link between aortic stenosis and osteoporosis as well as implications for future therapeutic approaches. Nevertheless, human studies on the impact of statins in the progression of aortic valve stenosis have shown controversial results. Despite the documented presence of both inflammation and calcification in human aortic valve stenosis from imaging studies [12], randomized studies have proved negative [13–15]. Consequently, no animal model can precisely reproduce the human aortic valve disease process, although each model provides a new mechanistic insight. It is expected that proper risk stratification models could, in the near future, identify those patients at a higher risk for rapid disease progression, and hence also the subgroups that would most benefit from a timely medical intervention. However, to date, there are no reliable biomarkers for predicting the progression of aortic stenosis. Moreover, the timing of intervention with statins may
also play a role. Inflammation is regarded as an initiating event in aortic valve stenosis, so statin therapy before the beginning of an osteoblastic calcification process could prove more effective in preventing disease progression. Appropriate dosing and the duration of therapy are also important aspects of the impact of statins on the rate of progression, or even regression, of human aortic valve stenosis. As there are pathobiologic similarities between aortic valve disease and bone metabolism, new agents, including bisphosphonates which are already used in osteoporosis treatment, are emerging in the field of the medical treatment of aortic valve stenosis. However, specific pharmacokinetic considerations should be addressed, as these agents at high doses could endanger normal bone metabolism. Local administration also seems feasible, and has been shown in a recent experimental study [16]. Prospective human studies with this category of drugs are necessary to confirm whether we will be able to ‘kill two birds with one stone’.
Conflict of Interest There were no conflicts of interest.
References
10
Cardiology DOI: 10.1159/000398788
6 Innasimuthu AL, Katz WE: Effect of bisphosphonates on the progression of degenerative aortic stenosis. Echocardiography 2011; 28: 1–7. 7 Aksoy O, Cam A, Goel SS, et al: Do bisphosphonates slow the progression of aortic stenosis? J Am Coll Cardiol 2012;59:1452–1459. 8 Elmariah S, Delaney JA, O’Brien KD, et al: Bisphosphonate use and prevalence of valvular and vascular calcification in women MESA (The Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2010;56:1752–1759. 9 Rajamannan NM, Subramaniam M, Springett M, et al: Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105:2660–2665. 10 Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC: Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation 2005;112:I229–I234. 11 Rajamannan NM: Atorvastatin attenuates bone loss and aortic valve atheroma in LDLR–/– mice. Cardiology 2015; 132: 11–15.
12 Dweck MR, Jones C, Joshi NV, et al: Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation 2012; 125:76–86. 13 Rossebo AB, Pedersen TR, Boman K, et al: Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–1356. 14 Cowell SJ, Newby DE, Prescott RJ, et al: A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–2397. 15 Chan KL, Teo K, Dumesnil JG, Ni A, Tam J: Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:3063–3014. 16 Synetos A, Toutouzas K, Benetos G, et al: Catheter based inhibition of arterial calcification by bisphosphonates in an experimental atherosclerotic rabbit animal model. Int J Cardiol 2014;176:177–181.
Lazaros/Benetos/Toutouzas/Tousoulis
Downloaded by: Dahlgree Med. Library, Goergetown Univ. 141.161.91.14 - 5/27/2015 2:31:54 PM
1 Lazaros G, Toutouzas K, Drakopoulou M, Boudoulas H, Stefanadis C, Rajamannan N: Aortic sclerosis and mitral annulus calcification: a window to vascular atherosclerosis? Expert Rev Cardiovasc Ther 2013; 11: 863– 877. 2 O’Brien KD, Probstfield JL, Caulfield MT, et al: Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med 2005;165:858–862. 3 Rosenhek R, Rader F, Loho N, et al: Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291–1295. 4 Price PA, Faus SA, Williamson MK: Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 2001;21:817–824. 5 Sterbakova G, Vyskocil V, Linhartova K: Bisphosphonates in calcific aortic stenosis: association with slower progression in mild disease – a pilot retrospective study. Cardiology 2010;117:184–189.
Received: April 7, 2015 Accepted: April 7, 2015 Published online: May 19, 2015
Osteoporosis and Aortic Stenosis: ‘Killing Two Birds with One Stone’? George Lazaros Georgios Benetos Konstantinos Toutouzas Dimitris Tousoulis
Calcific aortic stenosis is the most common form of valve disease in Western countries and represents a major healthcare problem because of increasingly higher life expectancy [1]. Moreover, the establishment of transcatheter aortic valve implantation in everyday clinical practice has further attracted the attention of the community to this disease. In the past decades, efforts have been made to identify the underlining pathophysiology of calcific aortic stenosis, and to redefine it as an actively regulated process and not just passive, age-related degeneration. The pathobiology of the disease shares many mechanisms with atherosclerosis in the early stages and active bone formation later, with inflammation, fibrosis and calcification playing an important role in the active narrowing of valves. The impact of several pharmaceutical interventions on the rate of progression or even regression of aortic stenosis has been studied in both experimental and human studies. In fact, the antifibrotic action of angiotensinconverting enzyme inhibitors in human aortic stenosis has been evaluated retrospectively, with controversial results [2, 3]. In addition, the beneficial effects of potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zolendronate) on aortic valve structure have been also demonstrated. These agents inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway, and hence prevent posttranslational modifications, potentially leading to macrophage apoptosis and exhibiting anti-inflammatory actions. Alternatively, the cardiovascular effects © 2015 S. Karger AG, Basel 0008–6312/15/1321–0009$39.50/0 E-Mail [email protected] www.karger.com/crd
of bisphosphonates could also be explained by the inhibition of bone resorption and the release of calcium phosphate particles in the circulation. Systematic administration of these agents exhibits a beneficial effect on cardiovascular calcification in animal models [4]. In 2 echocardiographic studies [5, 6], bisphosphonates have shown a potential benefit in slowing the progression of human calcific aortic stenosis, but the results of 2 largescale retrospective analyses in elderly women have proved controversial [7, 8]. The most extensively studied pharmaceutical intervention in the natural history of aortic stenosis is statins. As lipids play an important role in the active biologic process of valvular calcification, hypercholesterolemic animal models have been used in experimental studies [9, 10]. Cholesterol-lowering in such models improved various features associated with atherogenesis and aortic valve calcification. The signaling pathways implicated in the beneficial action of statins in aortic valve disease are currently under intense investigation. Hence, atorvastatin-mediated attenuation of aortic valve calcification is mediated in part by LDL receptor-related protein 5-Lrp5/ beta-catenin pathway [10]. In this issue of Cardiology, Rajamannan [11] shows a beneficial effect of statins in two distinct processes, namely aortic valve calcification and osteoporotic bone resorption, in an experimental hypercholesterolemic mouse model. By means of histology, fluorescence and microcomputed tomography measurement of LDLr–/– mice George Lazaros, MD University of Athens Medical School Hippokration Hospital, 114 Vas. Sofias Ave. GR–115 27 Athens (Greece) E-Mail glaz35 @ hotmail.com
Downloaded by: Dahlgree Med. Library, Goergetown Univ. 141.161.91.14 - 5/27/2015 2:31:54 PM
First Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece
heart valves and femurs, the author showed that a cholesterol diet induced bone formations in the calcified aortic valves and an increase in macrophage infiltration whereas atorvastatin attenuated mineralization in the aortic valves and bone loss in the femurs. This study further reinforces the theory of active bone turnover in aortic valve stenosis and, more interestingly, provides both a potential link between aortic stenosis and osteoporosis as well as implications for future therapeutic approaches. Nevertheless, human studies on the impact of statins in the progression of aortic valve stenosis have shown controversial results. Despite the documented presence of both inflammation and calcification in human aortic valve stenosis from imaging studies [12], randomized studies have proved negative [13–15]. Consequently, no animal model can precisely reproduce the human aortic valve disease process, although each model provides a new mechanistic insight. It is expected that proper risk stratification models could, in the near future, identify those patients at a higher risk for rapid disease progression, and hence also the subgroups that would most benefit from a timely medical intervention. However, to date, there are no reliable biomarkers for predicting the progression of aortic stenosis. Moreover, the timing of intervention with statins may
also play a role. Inflammation is regarded as an initiating event in aortic valve stenosis, so statin therapy before the beginning of an osteoblastic calcification process could prove more effective in preventing disease progression. Appropriate dosing and the duration of therapy are also important aspects of the impact of statins on the rate of progression, or even regression, of human aortic valve stenosis. As there are pathobiologic similarities between aortic valve disease and bone metabolism, new agents, including bisphosphonates which are already used in osteoporosis treatment, are emerging in the field of the medical treatment of aortic valve stenosis. However, specific pharmacokinetic considerations should be addressed, as these agents at high doses could endanger normal bone metabolism. Local administration also seems feasible, and has been shown in a recent experimental study [16]. Prospective human studies with this category of drugs are necessary to confirm whether we will be able to ‘kill two birds with one stone’.
Conflict of Interest There were no conflicts of interest.
References
10
Cardiology DOI: 10.1159/000398788
6 Innasimuthu AL, Katz WE: Effect of bisphosphonates on the progression of degenerative aortic stenosis. Echocardiography 2011; 28: 1–7. 7 Aksoy O, Cam A, Goel SS, et al: Do bisphosphonates slow the progression of aortic stenosis? J Am Coll Cardiol 2012;59:1452–1459. 8 Elmariah S, Delaney JA, O’Brien KD, et al: Bisphosphonate use and prevalence of valvular and vascular calcification in women MESA (The Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2010;56:1752–1759. 9 Rajamannan NM, Subramaniam M, Springett M, et al: Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105:2660–2665. 10 Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC: Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation 2005;112:I229–I234. 11 Rajamannan NM: Atorvastatin attenuates bone loss and aortic valve atheroma in LDLR–/– mice. Cardiology 2015; 132: 11–15.
12 Dweck MR, Jones C, Joshi NV, et al: Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation 2012; 125:76–86. 13 Rossebo AB, Pedersen TR, Boman K, et al: Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–1356. 14 Cowell SJ, Newby DE, Prescott RJ, et al: A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–2397. 15 Chan KL, Teo K, Dumesnil JG, Ni A, Tam J: Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:3063–3014. 16 Synetos A, Toutouzas K, Benetos G, et al: Catheter based inhibition of arterial calcification by bisphosphonates in an experimental atherosclerotic rabbit animal model. Int J Cardiol 2014;176:177–181.
Lazaros/Benetos/Toutouzas/Tousoulis
Downloaded by: Dahlgree Med. Library, Goergetown Univ. 141.161.91.14 - 5/27/2015 2:31:54 PM
1 Lazaros G, Toutouzas K, Drakopoulou M, Boudoulas H, Stefanadis C, Rajamannan N: Aortic sclerosis and mitral annulus calcification: a window to vascular atherosclerosis? Expert Rev Cardiovasc Ther 2013; 11: 863– 877. 2 O’Brien KD, Probstfield JL, Caulfield MT, et al: Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. Arch Intern Med 2005;165:858–862. 3 Rosenhek R, Rader F, Loho N, et al: Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291–1295. 4 Price PA, Faus SA, Williamson MK: Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 2001;21:817–824. 5 Sterbakova G, Vyskocil V, Linhartova K: Bisphosphonates in calcific aortic stenosis: association with slower progression in mild disease – a pilot retrospective study. Cardiology 2010;117:184–189.
