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Original Research

Cardiology 2010;117:184–189 DOI: 10.1159/000321418

Bisphosphonates in Calcific Aortic Stenosis: Association with Slower Progression in Mild Disease – A Pilot Retrospective Study

Gabriela Sterbakova   a Vaclav Vyskocil   b Katerina Linhartova   c  

a   First Department of Medicine and b   Department of Orthopedic Surgery, Charles University School ofMedicine Hospital, Pilsen , and c   Department of Cardiology, Cardiovascular Center, Charles University Second School of Medicine Hospital Motol, Prague , Czech Republic

0.002) and was negatively associated with bisphosphonate treatment ( � coefficient –2.36%, 95% confidence interval –4.47 to –0.26; p = 0.028) independent of age, gender and baseline gradient. Conclusion: Bisphosphonate treatment was independently associated with slower progression of mild AS in patients with preserved renal function.

Copyright © 2010 S. Karger AG, Basel

Introduction

Aortic stenosis (AS) affects 2–3% of elderly patients in developed countries [1] , and its incidence is likely to rise with aging of the population. Currently, there is no well-supported pharmacological approach for the medical management of AS. Of 4 randomized clinical trials, 1 [2] found slower progression of AS associated with statin treatment, but the others did not show any effect of statins on the course of AS [3–5] . Thus, there is a clear clinical need for new pharmacological agents to treat AS prior to the onset of symptoms, at which point valve replacement or implantation is typically performed.

In the pathogenesis of AS, active valve calcification with features of bone formation causes outflow obstruc-tion. An association between aortic valve calcification and low skeletal bone mineral density, the main feature

Key Words

Aortic stenosis � Valve calcification � Bisphosphonates � Osteoporosis

Abstract

Objectives: An association between aortic valve calcifica-tion and osteoporosis has been observed. The aim of this study was to assess the association between bisphospho-nate treatment for osteoporosis and the progression of cal-cific aortic stenosis (AS). Methods: A retrospective study of patients with AS (mean gradient 6 10 mm Hg), preserved re-nal function and two echocardiographies 1 8 months apart was performed. The patients were divided into those treated with bisphosphonates for osteoporosis and those not treat-ed and then subdivided into mild (mean gradient ! 30 mm Hg) and moderate-to-severe AS groups. We compared the annualized gradient change between the groups and identi-fied predictors of AS progression. Results: We analyzed the outcomes of 103 patients (51% females, age 68 8 10 years, follow-up 29 8 13 months), of whom 57 had mild and 46 moderate-to-severe AS. Bisphosphonates were taken by 28 patients, of whom 22 had mild and 6 moderate-to-severe AS. In the patients with mild AS, the annualized mean gradient change was lower in the bisphosphonate-treated than in the untreated patients (0.1 8 3.3 vs. 2.8 8 3.3 mm Hg/year; p =

Received: July 4, 2010 Accepted after revision: August 31, 2010 Published online: November 16, 2010

Assoc. Prof. Kateřina Linhartová, MD, PhD Department of Cardiology, Cardiovascular Center Charles University Second School of Medicine Hospital Motol, V Úvalu 84 CZ–150 06 Prague (Czech Republic) Tel. +420 2 2443 4904, Fax +420 2 2443 4920, E-Mail linhartkaterina   @   seznam.cz

© 2010 S. Karger AG, Basel0008–6312/10/1173–0184$26.00/0

Accessible online at:www.karger.com/crd

For editorial comment see p. 229

Bisphosphonates in Aortic Stenosis Cardiology 2010;117:184–189 185

of osteoporosis, has been observed [6] . Dysregulation of calcium/phosphate metabolism has been reported in pa-tients with AS and preserved renal function [7] .

Bisphosphonates are used to treat osteoporosis by blocking bone resorption. They have also been shown to inhibit vascular and valvular calcification in experimen-tal models and in hemodialysis patients [8–10] . In our pilot retrospective study, we aimed to assess the associa-tion between bisphosphonate treatment for osteoporosis and the rate of hemodynamic AS progression in patients with preserved renal function.

Methods

Study Sample We performed a retrospective analysis of the medical records

of consecutive patients with AS followed at the Charles Univer-sity School of Medicine Hospital in Pilsen, Czech Republic, be-tween January 2003 and April 2009. From this database, patients with AS and a mean transaortic gradient 6 10 mm Hg at the first echocardiography and at least two echocardiographic examina-tions more than 8 months apart were identified. In total, 308 pa-tients were initially selected. Subsequently, 158 patients were ex-cluded due to more than mild aortic or mitral regurgitation, mi-tral stenosis, rheumatic AS, a known bicuspid aortic valve, left ventricular dysfunction (ejection fraction ! 50%), malignant pro-cess, renal dysfunction requiring dialysis, prior aortic valve re-placement or unstable hemodynamic condition (systolic blood pressure ! 100 mm Hg). Patient data were reviewed to determine those patients with a diagnosis of osteoporosis who had received medical treatment. Of those, only patients on bisphosphonate treatment during the whole follow-up period were included in the study; we excluded 30 patients in whom bisphosphonate treat-ment was withdrawn during the follow-up, 3 patients who re-ceived other osteoporosis treatment (i.e. teriparatide) and 14 pa-tients who had missing clinical data. Ultimately, 103 patients were included in the final data analysis. For the study comparison, the patients were divided into those treated with bisphosphonates and those not treated and then subdivided into mild (mean baseline gradient ! 30 mm Hg) and moderate-to-severe AS groups (mean baseline gradient 6 30 mm Hg).

Clinical Evaluation Blood pressure and anthropometric data had been obtained at

the time of the echocardiography examinations. Laboratory and clinical data, including complete medication records during the follow-up period, were taken from the patient records.

Echocardiography Standard transthoracic echocardiography had been per-

formed in all patients, and transesophageal echocardiography had been performed when clinically indicated, using commer-cially available machines (GE System Five; Vivid Five; GE Ving-med Ultrasound AS, Horten, Norway, and iE33; Philips, Andover, Mass., USA). At the time of the examination, peak and mean aor-tic velocities were measured by continuous-wave Doppler, and the

gradients were calculated using the modified Bernoulli equation [11] . The degree of regurgitation was assessed semiquantitatively according to the American Society of Echocardiography guide-lines [12] . The left ventricular and aortic dimensions were mea-sured from the two-dimensional long-axis parasternal view, and the left ventricular ejection fraction was assessed from the M mode using the Teichholz formula or from the two-dimensional 4-chamber view using Simpson’s formula, following the standard American Society of Echocardiography criteria [13] . For the pur-poses of our study, the echocardiographic images were reviewed by one of the authors blinded to the data on bisphosphonate treat-ment. The annualized maximal and mean transaortic gradient change per year was calculated in each patient as the difference between the gradient at her/his first and last echocardiography, divided by the years of follow-up.

Statistics We firstly compared the baseline characteristics and param-

eters of AS progression between the bisphosphonate-treated and untreated group and secondly between the treated and untreated patients within the subgroups of mild and moderate-to-severe AS. A post hoc power analysis of the bisphosphonate-treated versus untreated patients with a two-tailed test ( � error 5%) yielded a statistical power of 56% for the whole study sample and 85% for the subgroup of patients with mild AS.

The categorical variables are shown as numbers and percent-ages, and the continuous variables as means and standard devia-tions. The � 2 test was used to compare categorical variables and the Mann-Whitney U test to compare the continuous ones. Last-ly, multiple regression analysis was used to assess the independent predictors of AS progression within the groups of mild and mod-erate-to-severe AS, entering the annualized mean gradient change as the dependent variable and age, gender, body mass index, dia-betes, bisphosphonate treatment, statin treatment, total choles-terol level and baseline mean transaortic gradient as the indepen-dent variables. We used Statgraphics Centurion version XV.2 (Statpoint Inc., Herndon, Va., USA) for statistical evaluation. p ! 0.05 was considered statistically significant.

The study protocol was approved by the institutional ethical committee and followed the principles established in the Declara-tion of Helsinki.

Results

We included 103 patients with AS in this study; of those, 28 (27%) were treated with bisphosphonates with-out interruption of therapy during the follow-up period. Of the total 103 patients, 57 (55%) had mild AS and 46 (45%) had moderate-to-severe AS. The mean interval be-tween the initial and final echocardiographic examina-tion was 29 8 13 months (range 8–74 months) and did not differ significantly between the groups. The bisphos-phonates that the patients received were either alendro-nate (70 mg orally once a week), in 24 patients (86%), or ibandronate (150 mg orally once a month), in 4 patients (14%).

Sterbakova   /Vyskocil   /Linhartova  

Cardiology 2010;117:184–189 186

In the bisphosphonate-treated group, 19 patients (70%) were also treated with oral vitamin D, 800–1,200 IU dai-ly. None of these medications were taken by patients in the untreated group.

Statin treatment included atorvastatin in 27 patients (45%), simvastatin in 26 (43%), fluvastatin in 6 (10%) and rosuvastatin in 1 (2%).

The baseline characteristics of the patients and com-parisons between bisphosphonate-treated and untreated patients in the mild and moderate-to-severe AS groups are shown in table 1 . For mild AS, women and nonsmok-ers prevailed among the bisphosphonate-treated patients, while diabetes was more frequent in the untreated group. For moderate-to-severe AS, the subgroup analysis did not reveal any significant differences in the recorded cardio-vascular risk profile variables between the bisphospho-nate-treated and untreated patients.

Comparison of echocardiographic characteristics be-tween bisphosphonate-treated and untreated patients in the mild and moderate-to-severe AS groups is shown in table 2 .

Within the group of bisphosphonate-treated patients, we did not observe a significant difference between those who received vitamin D and those who did not (p = 0.48), nor in the subgroup with mild AS (p = 0.15; data not

shown). In the moderate-to-severe AS group, the low number of observations did not allow statistical analysis.

Bisphosphonate treatment was identified as the only significant independent negative predictor of mild AS progression ( table 3 ).

In the moderate-to-severe AS group, only the mean baseline gradient was identified as an independent nega-tive predictor of AS progression ( � coefficient –0.20, 95% confidence interval –0.34 to –0.06; p = 0.005; data not shown).

Discussion

In this study, bisphosphonate treatment for osteoporo-sis was independently associated with slower progression of mild calcific AS in patients with preserved renal func-tion. To our knowledge, this is the first study that has evaluated the association between bisphosphonate-only treatment and AS progression at different stages of the disease. The present study extends the results of Skolnick et al. [14] , who found slower AS progression in a retro-spective analysis of 18 patients treated for osteoporosis by several pharmacologic agents with different modes of ac-tion, specifically bisphosphonates, calcitonin or estrogen

Table 1. C omparison of baseline characteristics between the bisphosphonate-treated and untreated patients in the whole study sample and within the subgroups of mild and moderate-to-severe AS

All patients (n = 103) Mild AS (n = 57) M oderate-to-severe AS (n = 46)

bisphospho-nate-treated(n = 28)

untreated(n = 75)

p bisphospho-nate-treated(n = 22)

untreated(n = 35)

p bisphospho -nate-treated(n = 6)

untreated(n = 40)

p

Women 22 (79%) 31 (41%) <0.001 18 (82%) 14 (40%) 0.002 4 (67%) 17 (40%) 0.246Age, years 7187 68810 0.239 7188 69811 0.799 7183 66810 0.347Follow-up, months 32815 29813 0.315 32816 30812 0.538 30814 28814 0.666Body mass index 2886 2884 0.553 2785 2884 0.512 30810 2885 1.0Systolic BP, mm Hg 141823 133818 0.145 145823 134820 0.116 127817 132816 0.581Diastolic BP, mm Hg 80811 77810 0.337 79811 79811 0.953 8488 7689 0.034Hypertension 25 (89%) 60 (79%) 0.226 19 (86%) 31 (89%) 0.805 6 (100%) 29 (71%) 0.125Diabetes mellitus 10 (36%) 29 (38%) 0.819 7 (32%) 19 (54%) 0.097 3 (50%) 10 (24%) 0.190Smoking 3 (11%) 33 (43%) 0.002 1 (5%) 15 (43%) 0.002 2 (33%) 18 (44%) 0.625Dyslipidemia 23 (82%) 55 (72%) 0.307 20 (91%) 25 (71%) 0.079 3 (50%) 30 (73%) 0.246Statin treatment 13 (46%) 43 (57%) 0.357 10 (45%) 19 (54%) 0.516 3 (50%) 24 (59%) 0.693Serum creatinine, �mol/l 98823 98820 0.900 97819 94820 0.644 112828 98822 0.151Total cholesterol, mmol/l 5.181.1 4.681.1 0.052 5.281.1 4.581.1 0.037 5.181.5 4.781.1 0.932LDL cholesterol, mmol/l 2.980.8 2.880.9 0.838 3.080.9 2.881.0 0.545 2.580.2 2.880.8 0.465HDL cholesterol, mmol/l 1.380.3 1.380.3 0.487 1.380.4 1.180.3 0.121 1.380.2 1.480.4 0.597Triglycerides, mmol/l 1.380.3 1.380.4 0.516 1.580.8 1.580.8 0.888 1.280.4 1.480.6 0.177

Con tinuous variables are shown as means and standard deviations. Categorical variables are shown as numbers and percentages. BP = Blood pres-sure; LDL = low-density lipoprotein; HDL = high-density lipoprotein.

Bisphosphonates in Aortic Stenosis Cardiology 2010;117:184–189 187

receptor modulators, when compared with untreated, nonosteoporotic patients with AS.

Osteoporosis is a systemic disease defined by low bone mass and deterioration of bone tissue, resulting in a high risk of fracture [15] . This is due to accelerated bone re-sorption, decreased bone formation or both. Osteoporo-

sis affects an estimated 10% of the general population and up to 50% of those older than 50 years; women are af-fected twice as frequently as men are. Typically, the dis-ease course is progressive, but the patient remains asymp-tomatic; osteoporosis is usually not diagnosed until hip or vertebral fracture occurs. In the general population, bone mineral density is not routinely screened, and os-teoporosis is thus underdiagnosed and undertreated. Therefore, its true coincidence with calcific AS is not known and remains to be assessed.

Current pharmacologic interventions in osteoporosis include agents that decrease bone resorption, i.e. bisphos-phonates [16] , estrogen, the estrogen agonist/antagonist raloxifene, calcitonin and the anabolic agent teriparatide, which promotes bone formation. Historically, pyrophos-phate analogues, including bisphosphonates, were first used to inhibit ectopic calcification by the physicochem-ical blocking effect on calcium phosphate crystallization. This was achieved by much higher doses than those used for osteoporosis treatment, and this mechanism could be operative only in a state of pyrophosphate deficiency, as in end-stage renal disease [17] .

In osteoporosis, bisphosphonates inhibit bone resorp-tion by blocking the function of osteoclasts and inducing their apoptosis. In the more potent nitrogen-containing compounds, including those used in our study patients,

Table 2. C omparison of echocardiographic characteristics between the bisphosphonate-treated and untreated patients in the whole study sample and within the subgroups of mild and moderate-to-severe AS

All patients(n = 103)

Mild AS(n = 57)

Moderate-to-severe AS(n = 46)

bisphospho-nate-treated(n = 28)

untreated(n = 75)

p bisphospho-nate-treated(n = 22)

untreated(n = 35)

p bispho spho-nate-treated(n = 6)

untreated(n = 40)

p

BaselineLVEF, % 6189 6089 0.446 61810 57810 0.096 6286 6388 0.561LVd, mm 4987 4987 0.755 4987 5186 0.252 5188 4887 0.396Maximal gradient, mm Hg 35828 52826 <0.001 2288 30811 0.003 82825 70820 0.219Mean gradient, mm Hg 23820 33819 <0.001 1484.9 1786.1 0.010 56818 46815 0.202

FinalLVEF, % 56813 57813 0.535 57812 55815 0.694 52817 59811 0.228LVd, mm 4989 4988 0.707 4988 5187 0.252 5089 4889 0.452Maximal gradient, mm Hg 39833 62829 <0.001 27816 41816 <0.001 86837 81824 0.566Mean gradient, mm Hg 23820 38819 <0.001 1589 24810 0.001 53821 51816 0.632Annualized maximal gradient change

mm Hg/year 1.586.7 4.787.2 0.008 1.285.2 4.385.7 0.013 2.3811 5.188 0.300Annualized mean gradient change

mm Hg/year –0.384.8 2.085.7 0.007 0.183.3 2.883.3 0.002 –1.789 1.387 0.264

Val ues are shown as means and standard deviations. LVEF = Left ventricular ejection fraction; LVd = left ventricular diastolic dimension.

Table 3. B isphosphonate treatment as an independent predictor of mild AS progression

� coeffi-cient

95% CI p

Bisphosphonate treatment –2.36 –4.47 to –0.26 0.028Age 0.07 –0.04 to 0.18 0.181Gender –0.30 –2.89 to 2.09 0.810Body mass index –0.08 –2.9 to 0.13 0.450Diabetes mellitus –1.09 –3.12 to 0.94 0.285Statin treatment –0.33 –2.10 to 1.44 0.709Total cholesterol –0.46 –1.31 to 0.40 0.307Mean baseline gradient –0.01 –0.19 to 0.20 0.938Smoking 0.17 –2.61 to 2.94 0.709

M ultiple regression with all variables fitted and annualized mean gradient change as the dependent variable.

CI = Confidence interval.

Sterbakova   /Vyskocil   /Linhartova  

Cardiology 2010;117:184–189 188

this effect is accomplished by blocking farnesyl pyro-phosphate synthase, a key enzyme in the mevalonate pathway of sterol synthesis, thereby disrupting the pro-duction of key proteins regulating osteoclast activity [16] . The mechanism of the possible inhibitory effect of bisphosphonates on valvular calcification remains un-clear, but several hypotheses exist to explain it. Firstly, nitrogen-containing bisphosphonates may exert a direct effect on the calcifying cells with an osteoblast pheno-type, as their apoptotic effect on the osteoblastic lineage has recently been reported in vitro [18] . Secondly, bisphos-phonates may affect other regulatory factors or pathways common to both bone turnover and ectopic calcification. This is supported by the finding of a correlation between serum bone G1a protein levels, ibandronate treatment and artery calcification in a uremic rat calcification mod-el [19] . Thirdly, decreased availability of phosphate for calcification by blocking bone resorption remains among the working hypotheses [17, 19] .

Our analysis is a pilot retrospective study of strictly consecutive patients; thus, women prevailed in the bisphosphonate group and, surprisingly, the patients in the bisphosphonate-treated group had less severe AS at baseline than those in the untreated group. Clinically sig-nificant osteoporosis was confirmed only in the bisphos-phonate-treated patients, but silent osteoporosis or osteo-penia was not assessed and would be expected to occur in a significant percentage of the untreated patients. Vita-min D is included in osteoporosis treatment unless con-traindications exist, and more than two thirds of our bisphosphonate-treated patients were also treated with vitamin D. Among the bisphosphonate-treated patients, we did not observe any difference between those who re-ceived vitamin D and those who did not. However, more

data would be needed to separately evaluate the effect of vitamin D on the course of AS. We may expect a syner-gistic effect of bisphosphonates and vitamin D on the progression of AS, as only toxic vitamin D doses have been associated with excessive calcification, while physi-ologic levels may exert direct antiinflammatory and cal-cification-blocking effects [20] . Further, the positive ef-fect of a significantly lower percentage of smokers in the bisphosphonate-treated group cannot be fully excluded from our data, as smoking had previously been identified as a risk factor for AS progression [21] . The number of identified bisphosphonate-treated patients with moder-ate-to-severe AS was too low to draw conclusions on the bisphosphonate effect in this group; however, our find-ings may suggest a stage-related effect on AS similar to that observed with statins [22] .

To conclude, in mild AS, slower hemodynamic pro-gression was associated with oral alendronate and iban-dronate osteoporosis treatment in patients with pre-served renal function. The results of our pilot retrospec-tive study suggest a favorable link between osteoporosis treatment and progression of calcific AS that should be further evaluated in a prospective study.

Acknowledgement

This study was supported by the cardiovascular research proj-ect of the Czech Ministry of Health, MZOFNM2005.

Conflict of Interest

The authors have no conflict of interest to declare.

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