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Inverse association between bone mineral density and risk of aortic stenosis in men and women in EPIC–Norfolk prospective study

2014; Elsevier BV; Volume: 178; Linguagem: Inglês

10.1016/j.ijcard.2014.10.065

1874-1754

Roman Pfister, Guido Michels, Stephen J. Sharp, Robert Luben, Nicholas J. Wareham, Kay‐Tee Khaw,

Orthopaedic implants and arthroplasty

Calcification processes with pathological bone formation play a key role for development and progression of degenerative aortic valve stenosis [[1]Rajamannan N.M. Evans F.J. Aikawa E. Grande-Allen K.J. Demer L.L. Heistad D.D. Simmons C.A. Masters K.S. Mathieu P. O'Brien K.D. Schoen F.J. Towler D.A. Yoganathan A.P. Otto C.M. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease—2011 update.Circulation. 2011; 124: 1783-1791Crossref PubMed Scopus (582) Google Scholar]. A study in mice suggested a potential link between bone metabolism and valve calcification by showing an inverse correlation [[2]Hjortnaes J. Butcher J. Figueiredo J.L. Riccio M. Kohler R.H. Kozloff K.M. Weissleder R. Aikawa E. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation.Eur. Heart J. 2010; 31: 1975-1984Crossref PubMed Scopus (163) Google Scholar]. Notably, disorders involving bone mineral metabolism such as Paget disease and haemodialysis [[3]Urena P. Malergue M.C. Goldfarb B. Prieur P. Guedon-Rapoud C. Petrover M. Evolutive aortic stenosis in hemodialysis patients: analysis of risk factors.Nephrologie. 1999; 20: 217-225PubMed Google Scholar] are associated with an increased prevalence of aortic stenosis. A working group of the National Heart, Lung, and Blood Institute has recently underscored the importance of identifying the relationship between calcification of the aortic valve and bone and the reciprocal regulation of these processes as a basis for better understanding pathogenesis of calcific aortic stenosis and development of preventive interventions [[1]Rajamannan N.M. Evans F.J. Aikawa E. Grande-Allen K.J. Demer L.L. Heistad D.D. Simmons C.A. Masters K.S. Mathieu P. O'Brien K.D. Schoen F.J. Towler D.A. Yoganathan A.P. Otto C.M. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease—2011 update.Circulation. 2011; 124: 1783-1791Crossref PubMed Scopus (582) Google Scholar]. The aim of this study was to investigate the prospective association of bone mineral density measured as broadband ultrasound attenuation by quantitative ultrasound of the heel with the risk of developing aortic stenosis in a population of middle-aged men and women participating in the "European Prospective Investigation into Cancer and Nutrition" (EPIC) study in Norfolk. EPIC–Norfolk is a prospective population study of 25,639 men and women recruited between 1993 and 1997, resident in Norfolk, UK [[4]Day N. Oakes S. Luben R. Khaw K.T. Bingham S. Welch A. Wareham N. EPIC–Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer.Br. J. Cancer. 1999; 80: 95-103PubMed Google Scholar]. The EPIC–Norfolk study was approved by the Norfolk Local Research Ethics Committee, and participants gave signed informed consent at each contact. Between January 1998 and October 2000 15,786 of the participants attended a follow-up assessment which constitutes the baseline for the current analyses. At this visit, quantitative broadband ultrasound measurements of the calcaneum were obtained as reported previously [[5]Pfister R. Michels G. Sharp S.J. Luben R. Wareham N.J. Khaw K.T. Low bone mineral density predicts incident heart failure in men and women: the EPIC (European Prospective Investigation Into Cancer and Nutrition)–Norfolk prospective study.JACC Heart Fail. 2014; 2: 380-389Crossref PubMed Scopus (37) Google Scholar]. Broadband ultrasound attenuation is strongly related to bone quantity, i.e. bone mineral density [[6]Wear K.A. Nagaraja S. Dreher M.L. Gibson S.L. Relationships of quantitative ultrasound parameters with cancellous bone microstructure in human calcaneus in vitro.J. Acoust. Soc. Am. 2012; 131: 1605-1612Crossref PubMed Scopus (60) Google Scholar], and performed equally well compared to dual-energy X-ray absorptiometry (DEXA) in predicting different fracture outcomes. Incident cases of aortic stenosis were ascertained by using hospital record linkage with virtually complete follow-up and were defined as "International Classification of Disease" (ICD)-10 hospital discharge code I35. The current study is based on follow-up through March 2009. We excluded 119 participants with missing measures for broadband ultrasound attenuation and 16 participants with hospitalization with diagnosis of aortic stenosis between initial cohort recruitment and the second attendance, here defined as baseline. We present baseline characteristics adjusted for age and sex because both variables are strong determinants of bone mineral density and may confound associations of broadband ultrasound attenuation with other risk factors. Using Cox proportional hazards models, we calculated hazard ratios (HR) for hospitalization for aortic stenosis comparing tertiles of broadband ultrasound attenuation, and also per one standard deviation (SD) of broadband ultrasound attenuation using a continuous linear model in order to increase statistical power, since risk estimates of tertiles suggested a linear association. All analyses were undertaken using Stata statistical software, version 12.1 (Stata Corporation, College Station, Texas). The mean (SD) age of the study population was 62.1 (9.1) years and mean (SD) of broadband ultrasound attenuation of the heel was 80.0 (19.2) db/MHz. Table 1 shows characteristics of the participants according to tertiles of broadband ultrasound attenuation. Increasing broadband ultrasound attenuation was associated with increasing BMI, proportion of males, history of diabetes, use of antihypertensive drugs and diuretics, and physical activity, and was associated with decreasing age and lower rates of smoking and history of osteoporosis.Table 1Association of tertiles of broadband ultrasound attenuation with age, sex, and age/sex-adjustedaMeans and percentage calculated from linear and logistic regression adjusted for age and sex. baseline characteristics: EPIC–Norfolk study 1998 to 2009 of 15,651 men and women aged 42–82 years.Tertile 1N = 5217Tertile 2N = 5215Tertile 3N = 5219p-ValueBUA dB/MHz (mean SD)59 (9)79 (5)101 (11) 87.6Gender, male (%)17.842.670.9<0.0001Age (years) (mean SD)64.7 (8.8)61.0 (8.8)60.6 (9.0)<0.0001BMI (kg/m2)25.627.027.6<0.0001Systolic BP (mm Hg)1351351350.54Diastolic BP (mm Hg)82.182.182.00.69Smoking (%)9.58.17.10.0006Cardiovascular disease (%)6.25.55.10.08Diabetes (%)2.83.23.90.03Antihypertensive drugs (%)21.425.523.8<0.0001Lipid lowering drugs (%)5.44.94.70.35Steroid/NSAID (%)22.524.124.40.07Diuretic use (%)8.210.910.3<0.0001Ca/vitamin D suppl. (%)32.534.334.60.09Dietary vitamin D intake μg/day3.403.373.380.79Osteoporosis (%)4.13.62.30.0004Physical activity (%)<0.0001Inactive8.98.16.7Mod. inactive39.036.035.3Mod. active22.223.624.0Active29.932.234.0BMI: body mass index, BP: blood pressure, NSAID: non-steroidal anti-inflammatory drug, Ca: calcium.a Means and percentage calculated from linear and logistic regression adjusted for age and sex. Open table in a new tab BMI: body mass index, BP: blood pressure, NSAID: non-steroidal anti-inflammatory drug, Ca: calcium. During a mean follow-up of 9.3 years, 122 incident cases of aortic stenosis (77 cases in men, 45 cases in women) were identified. We did not observe a significant gender × broadband ultrasound attenuation interaction (p for interaction 0.11) and hence report gender combined results. Table 2 shows HR for aortic stenosis comparing middle and top tertiles of broadband ultrasound attenuation with the lowest tertile. The hazard of aortic stenosis decreased with increasing tertiles of broadband ultrasound attenuation. Every SD increase in broadband ultrasound attenuation was associated with a 20% relative reduction in hazard for aortic stenosis, independently of age, sex, smoking, systolic blood pressure, diabetes, BMI, antihypertensive and lipid lowering medication and cardiovascular disease. The results were unchanged when additionally adjusting for calcium/vitamin D supplement use, diuretic use, history of osteoporosis, physical activity and use of anti-inflammatory drugs (data not shown).Table 2Unadjusted and adjusted hazard ratios (95% confidence intervals) for incident aortic stenosis by broadband ultrasound attenuation: EPIC–Norfolk study 1998 to 2009 of 15,651 men and women aged 42–82 years.Tertile 1Tertile 2Tertile 3Per 1 SDp-ValueaReferring to hazard ratio per 1 SD, 1 SD=19.2db/MHz.Events/N42/521742/521538/5219Unadjusted11.0 (0.65–1.53)0.91 (0.58–1.41)0.94 (0.79–1.13)0.53Age/sex adjusted10.97 (0.61–1.54)0.72 (0.43–1.20)0.85 (0.69–1.04)0.11Age/sex/BMI adjusted10.89 (0.56–1.41)0.64 (0.38–1.07)0.80 (0.64–0.99)0.04MultivariablebAdjusted for age, gender, BMI, systolic blood pressure, antihypertensive drug use, smoking, diabetes, lipid lowering drug use, and cardiovascular disease. adjusted10.90 (0.56–1.44)0.66 (0.39–1.11)0.80 (0.65–0.996)0.046a Referring to hazard ratio per 1 SD, 1 SD = 19.2 db/MHz.b Adjusted for age, gender, BMI, systolic blood pressure, antihypertensive drug use, smoking, diabetes, lipid lowering drug use, and cardiovascular disease. Open table in a new tab We observed an inverse association between bone mineral density and the risk of aortic stenosis in a middle-aged population independently of known risk factors and potential confounders. This might have important implications if confirmed in other cohorts. Low bone mineral density and consequential osteoporosis are new risk markers for development of aortic stenosis. This is of clinical relevance since both conditions are common, particularly in the elderly, and screening for osteoporosis is recommended for large parts of the elderly population [[7]Screening for osteoporosis: U.S. preventive services task force recommendation statement.Ann. Intern. Med. 2011; 154: 356-364Crossref PubMed Scopus (384) Google Scholar]. Hence, information on the presence of this risk marker will be readily available and might be used to select people for further diagnostic evaluation. Furthermore, our findings add to the evidence for a reciprocal regulation of bone metabolism and calcification of the aortic valve. It seems less likely that valve calcification is a secondary phenomenon of catabolic bone metabolism resulting in osteoporosis given that for instance bisphosphonate treatment did not have relevant impact on the progression of aortic stenosis in a retrospective analysis [[8]Aksoy O. Cam A. Goel S.S. Houghtaling P.L. Williams S. Ruiz-Rodriguez E. Menon V. Kapadia S.R. Tuzcu E.M. Blackstone E.H. Griffin B.P. Do bisphosphonates slow the progression of aortic stenosis?.J. Am. Coll. Cardiol. 2012; 59: 1452-1459Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. More plausibly, common mechanisms underlie both osteoporosis and calcific aortic disease. In support of this, a genetic polymorphism within the vitamin D receptor gene which is associated with low bone mineral density [[9]Morrison N.A. Qi J.C. Tokita A. Kelly P.J. Crofts L. Nguyen T.V. Sambrook P.N. Eisman J.A. Prediction of bone density from vitamin D receptor alleles.Nature. 1994; 367: 284-287Crossref PubMed Scopus (1752) Google Scholar] was also shown to be associated with risk of calcific aortic stenosis [[10]Ortlepp J.R. Hoffmann R. Ohme F. Lauscher J. Bleckmann F. Hanrath P. The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis.Heart. 2001; 85: 635-638Crossref PubMed Scopus (147) Google Scholar], suggesting that the vitamin D pathway might be one potential common regulator of bone metabolism and aortic valve calcification. Additionally, an animal study suggested that inflammatory processes involving macrophages are involved in both calcification of the aortic valve and loss of bone mineral density [[2]Hjortnaes J. Butcher J. Figueiredo J.L. Riccio M. Kohler R.H. Kozloff K.M. Weissleder R. Aikawa E. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation.Eur. Heart J. 2010; 31: 1975-1984Crossref PubMed Scopus (163) Google Scholar]. Hence, further study is warranted on potential common mechanisms underlying osteoporosis and calcific aortic stenosis in order to develop preventive interventions. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. All authors have no conflict of interest to declare. We thank all of the participants in this study and the EPIC–Norfolk study staff at the University of Cambridge, Department of Public Health and Primary Care.