
 atherosclerosis and osteoporosis share an age - independent bidirectional correlation [ 1 , 2 ] , although they were considered to be independent pathologies . on one hand ,
low bone mass is associated with subclinical   and clinical atherosclerosis , manifested as cardiovascular morbidity [ 4 , 5 ] and mortality . on the other hand ,
cardiovascular disease is associated with low bone mass and with a higher risk of fragility fractures .
there is no unifying theory which can explain a deterministic link between atherosclerosis and osteoporosis , if any .
certainly , bone modeling and vascular calcification have common biological processes and risk factors ( e.g. , smoking , inactivity , and inflammation ) .
we can cite ra among these factors , as a crossroad of atherosclerosis and osteoporosis .
the main cause of mortality in ra is the cardiovascular pathology [ 9 , 10 ] .
adding to the classical cardiovascular risk ( cvr ) factor , chronic inflammation [ 11 , 12 ] and disease duration   contribute decisively to the excess cardiovascular mortality in ra .
the background of this observation is the inflammatory pathogenesis of ra which is associated with accelerated atherosclerosis , both clinically and subclinically [ 14 , 15 ] .
therefore , eular recommends annual cvr evaluation in ra patients , knowing the fact that ra is an independent cvr factor , similar in importance with diabetes mellitus ( dm ) .
it appears early in the disease course , two times more prevalent than in the general population [ 18 , 19 ] .
adding to the risk factor of primary osteoporosis , the bone loss in ra is associated with the presence of autoantibodies , glucocorticoid therapy , disease activity ( the activation of osteoclasts by mean of the rank pathway ) [ 20 , 21 ] , and disability . because of the high risk of fractures in ra [ 22 , 23 ] , ra patients should routinely undergo dual x - ray absorptiometry ( dxa ) in order to diagnose and monitor osteoporosis .
the advantage is that at the same time with dxa measurements one can evaluate the patient 's body composition .
if coupled with cvr estimation , the dxa technique could become the common denominator for the complex management of atherosclerosis and osteoporosis in ra . in this context , the study aims to evaluate the correlation between the estimated cvr and whole body bone loss , emphasizing ra as a common risk factor for both conditions .
the study was cross - sectionally designed to include female in - patients , admitted to the hospital in the random order of presentation for clinical and biological reevaluation .
the subjects were classified as either ra patients , according to the 2010 acr / eular criteria , either as having no chronic inflammatory autoimmune disease .
each patient gave written informed consent and the study was approved by the local ethics committee .
the bone tissue was evaluated by a single certified clinical densitometrist ( cp ) using whole body dxa ( wbdxa ; lexxos c05lx223 ) , which records variables such as bone tissue density / mass ( btd / m ) , t- and z - scores ( t / zwb ) , and bone tissue percent ( btp ; figure 1 ) .
the classic anthropometric indices , such as height , weight , abdominal circumference ( ac ) , and hip circumference ( hc ) , were measured using a mechanical scale ( 0.1  kg maximal error ) , a wall stadiometer ( 0.3  cm maximal error ) , and a centimeter graded tape .
using these measurements , we computed the derived anthropometric indices : body mass index ( bmi ; weight divided by square height ) , waist - to - hip ratio ( whr ; ac divided by hc ) , conicity index ( ci ; ac divided by the square root of weight to height ratio multiplied by 0.109 ) .
erythrocyte sedimentation rate ( esr ) was measured by the westergren method ( normal range according to age ) . the concentration of c - reactive protein ( crp )
mg / l ) . arterial hypertension ( aht ) was defined after two measurements ( auscultatory sphygmomanometer ; 5  mmhg error ) if systolic pressure  140  mmhg , or diastolic pressure  90  mmhg , or if the patient was on blood pressure lowering therapy .
ischemic heart disease ( ihd ) was defined on electrocardiographic criteria or on a history of acute coronary syndromes , stable angina , conduction and rhythm disturbances , and ischemic heart failure .
dyslipidemia was defined as triglycerides > 150  mg / dl , total cholesterol > 200  mg / dl , low - density lipoproteins ( ldl ) > 100  mg / dl , high - density lipoproteins ( hdl ) < 50  mg / dl , or treatment with statins and fibrates .
diabetes mellitus was defined as two fasting plasma glucose levels > 126  mg / dl ( fpg ) , one fpg > 200  mg / dl , or treatment with insulin / oral antidiabetic agents .
the cvr was estimated using high risk score charts , appropriate for the romanian population , and quick check and health check procam applications , according to eular recommendations .
the normal distribution of data was assessed using descriptive statistics , normality and stem - and - leaf plots , and the lilliefors corrected kolmogorov - smirnov test .
normally distributed data were reported as means with standard deviations and their correlations and differences were assessed with pearson coefficients and t - tests , respectively .
non normally distributed data were reported as medians with intervals and their correlations and differences were assessed with spearman coefficients and mann whitney tests , respectively .
qualitative data were expressed as absolute and percent frequency and their differences were assessed using  tests ( or fisher tests where appropriate ) .
the influence of whole body bone tissue on cvr was studied using multiple linear regression and covariance analysis ( ancova ) .
all tests were considered significant if p < 0.05 and were done using spss v.17 for windows ( spss inc . ,
although ra patients do not have longer menopause duration or higher menopause frequency , most of their wbdxa indices are significantly lower than those of normal patients .
it should be noted that ra patients had a mean disease duration of 12.8  10 years , 66 patients ( 86.8% ) were rf positive and 44 patients ( 57.9% ) were anti - ccp positive .
ra was moderately active in the studied group ( mean das28 of 4.25  1.21 ; mean sdai of 63.3  40.9 ) .
as to treatment regimes , 68 patients ( 89.5% ) were receiving methotrexate , 35 patients ( 46% ) were receiving oral glucocorticoids , and 25 patients ( 32.9% ) were receiving bisphosphonates .
as pointed out in table 2 , the wbdxa indices of bone tissue are significantly and negatively correlated with the cvr estimation by all three instruments .
the covariance analysis revealed that this correlation is independent of age , menopause , ihd , smoking , bmi , obesity , aht , dyslipidemia , dm , inflammation , and metabolic syndrome .
the multiple linear regression of btp with cvr scores revealed notable results . except for btp ,
score correlated significantly with age , menopause duration , height , ac , hc , whr , bmi , ci , ldl , and total cholesterol .
of these , we excluded age , since it is part of score protocol , and whr , bmi , and ci , since they where derived from variables that were already correlated with score .
the remaining variables significantly explained 47% of score variation ( r = 0.472 ; p < 0.001 ; standard method ) , but the contribution of height , ac , hc , and total cholesterol were not significant , being thus eliminated from the regression model .
the two remaining predictors were introduced in the equation in the order ldl - btp and significantly explained 26% of score variation ( r = 0.262 ; p < 0.001 ; hierarchical method ) . in this two - parameter model ,
ldl independently explained 3.4% of score variation , while btp explained 25% . except for btp , procamqc correlated significantly with age , menopause duration , height , body mass , ac , hc , whr , bmi , ci , and glycemia .
of these , we excluded height , body mass , whr , bmi , and ci on the same grounds . the standard multiple linear regression of the remaining variables with procamqc generated a significant equation which predicted 51.3% of its variation ( r = 0.513 ; p < 0.001 ) .
the three remaining predictors ( menopause duration , glycemia , and btp ) were introduced in the equation in that order and significantly explained 50% of procamqc variation ( r = 0.497 ; p < 0.001 ; stepwise method ) . in this three - parameter model ,
menopause duration independently explained 23.3% of procamqc variation ; glycemia explained 16.6% , while btp explained 10% . as was expected from bone measurements ,
the wbdxa indices correlated significantly and negatively with age and were significantly higher in the premenopause period ( table 3 ) .
moreover , these indices correlated significantly with the classical anthropometric measurements , in an age - independent manner ( table 4 ) .
the wbdxa bone indices varied significantly according to the presence or the absence of classic cvr factors ( table 5 ) .
for example , obese patients had lower btp than nonobese patients , but their bone quantity was significantly higher .
it is interesting that patients with high fasting glycemia , when compared with normal glycemic patients , behaved in the same manner as obese patients with regard to wbdxa bone indices . in general ,
in clinical practice , bone density regions of interest in adults include the lumbar spine , the femoral neck , and the distal radius , since these measurements have a higher predicting value in the recognition of osteoporosis than the whole body measurements .
since the purpose our study was not to diagnose osteoporosis , but instead to evaluate the link between bone loss and cardiovascular risk , a whole body approach was deemed more appropriate in this fundamental science query .
the correlation between cardiovascular pathology and bone tissue has been observed in the general population , but ra is an appropriate condition in which the two entities can be studied . as to bone tissue , the previous studies noted that ra patients , compared to normal individuals , have a lower dxa bone density in the regions used for the diagnosis of osteoporosis ( lumbar spine , hip , and distal radius ) .
our study proves that the entire skeleton of ra patients exhibits lower bone density and lower bone mass than normal individuals .
it seems that inflammation , glucocorticoid treatment , and low bmi are accounting for this difference , since the two groups did not differ significantly in terms of the other osteoporosis risk factor included in the study ( age , menopause prevalence and duration , and smoking  see table 1 ) . as to atherosclerosis
, ra patients had a higher cvr than normal individuals , in spite of the fact that the control group did not have a favorable cardiovascular profile : the controls were non - ra but were admitted to the hospital for different internal medicine diagnoses .
this is why the two groups had similar prevalence of metabolic syndrome , aht , ihd , and dm and had a higher prevalence of obesity . without suggesting any deterministic direction , our study reports a correlation between wbdxa bone indices with the cvr estimated on three different scales ( table 2 ) .
this correlation is real within the study 's limitations , since it does not depend on the effect of the established cvr factors ( age , menopause , smoking , obesity , aht , dyslipidemia , inflammation , dm , and metabolic syndrome ) .
we must emphasize that all types of wbdxa bone measurement showed independent correlations with cvr , both those that estimate absolute bone mass ( g ) and those that measure aria density ( g / cm ) and body mass fraction ( % ) .
secondly , these correlations are negative , meaning that cvr increases as bone mass , density , and percent decreases .
for this reason it was used in regression models , proving to be an independent and significant predictor of cvr estimation , alongside ldl , glycemia , and menopause duration .
the correlation of wbdxa bone indices with cvr exceeds the scope of the clinical instruments used to estimate it ( score , procam ) , which do not incorporate important variables such as the presence or the absence of the metabolic syndrome .
our data showed that individuals with cardiovascular morbidity are different ( see table 5 ) .
one can argue that bmi - defined obesity protects from osteoporosis , most likely by means of adipocyte estrogen production [ 34 , 35 ] .
our data offer an extra argument in favor of obesity 's antiosteoporotic effect : patients with bmi > 30  kg / m have a higher whole body bone mass and a lower bone percent than patients with bmi < 30  kg / m . however
, resides in the definition of bone percent , defined as bone mass divided by body mass : bmi - defined obese individuals have a slightly higher bone mass than nonobese individuals , but their fat mass is disproportionally higher , enough to produce a smaller bone percent .
this explains the difference in btp , but why do bmi - defined obese individuals have more bone ?
our data indicate that bmi - defined obese and nonobese patients have similar height ( 159.4  cm ; p > 0.1 ) and similar bone density . therefore , bmi - defined obese individuals must have thicker and/or wider bones .
the second comment refers to the unusual behavior with regard to wbdxa bone indices when the study population sample was divided in two subgroups according to glycemia values : hyperglycemic patients behaved exactly like obese patients .
it is possible that this effect is the consequence of the significantly higher obesity prevalence among hyperglycemic patients ( 50% ; 34/68 ) than in normal glycemic patients ( 20.5% ; 15/73 ; p < 0.001 ) .
lastly , we must mention the effect of inflammation on wbdxa bone indices , namely , that patients with elevated inflammatory markers had less bone in terms of density and body percent . moreover , inflammation markers correlated significantly with the anthropometric predictors of cardiovascular morbidity and mortality : esr correlated positively with ac ( r = 0.175 ; p = 0.038 ) and hc ( r = 0.184 ; p = 0.029 ) and negatively with hdl ( r = 0.258 ; p = 0.002 ) , while crp correlated positively with body mass ( r = 0.215 ; p = 0.011 ) , ac ( r = 0.258 ; p = 0.002 ) , hc ( r = 0.278 ; p = 0.001 ) , bmi ( r = 0.242 ; p = 0.004 ) , and ci ( r = 0.237 ; p = 0.005 ) and negatively with hdl ( r = 0.391 ; p < 0.001 ) .
these observations strengthen the evidence that prove the involvement of inflammation in osteoporosis and atherosclerosis , so well exemplified in ra , but also raises the question of how anthropometry influences the production of inflammatory markers . integrating these results one must bear in mind study limitations , namely , the cross - sectional design , which did not allow follow - up of these patients , the lack of bone markers measurements , and the use of a surrogate cardiovascular morbidity and mortality marker .
from a deterministic point of view on atherosclerosis - bone tissue , we noted that on one hand ra patients have significantly lower whole body bone tissue indices and a significantly higher cardiovascular risk compared to normal subject , and that on the other hand inflammation is associated with lower whole body bone tissue indices and is correlated with anthropometric and nonanthropometric cardiovascular risk predictors .
these wbdxa bone indices correlate significantly , independently , and negatively with cvr estimation on three different clinical scales . of all bone measurements ,
whole body bone percent is the best predictor of cvr , which is the reason for its possible clinical application .
the connection between atherosclerosis and osteoporosis is not limited only to the correlation with cvr estimates , but we observed that patients with cardiovascular morbidity ( ihd , metabolic syndrome , dm , aht , and dyslipidemia ) had lower wbdxa bone indices .
another established cvr factor , bmi - defined obesity , is associated with a higher whole body bone mass .
this bone tissue surplus in obese patients was not accounted by whole body bone density nor by height ; therefore it is probably explained by higher individual bone thickness and/or width .
 
 introduction . 
 atherosclerosis and osteoporosis share an age - independent bidirectional correlation . 
 rheumatoid arthritis ( ra ) represents a risk factor for both conditions . objectives . 
 the study aims to evaluate the connection between the estimated cardiovascular risk ( cvr ) and the loss of bone tissue in ra patients . 
 methods . 
 the study has a prospective cross - sectional design and it includes female in - patients with ra or without autoimmune diseases ; bone tissue was measured using whole body dual x - ray absorptiometry ( wbdxa ) ; cvr was estimated using score charts and procam applications . 
 results . 
 there were 75  ra women and 66 normal women of similar age . 
 the wbdxa bone indices correlate significantly , negatively , and age - independently with the estimated cvr . 
 the whole body bone percent ( wbbp ) was a significant predictor of estimated cvr , explaining 26% of score variation along with low density lipoprotein ( p < 0.001 ) and 49.7% of procam variation along with glycemia and menopause duration ( p < 0.001 ) . 
 although obese patients had less bone relative to body composition ( wbbp ) , in terms of quantity their bone content was significantly higher than that of nonobese patients . 
 conclusions . 
 female patients with ra and female patients with cardiovascular morbidity have a lower whole body bone percent . 
 obese female individuals have higher whole body bone mass than nonobese patients . 
1. Introduction 
2. Methods and Materials
3. Results
4. Discussion
5. Conclusion