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Archives of cardiovascular diseases
Volume 108, n° 8-9
pages 412-419 (août 2015)
Doi : 10.1016/j.acvd.2015.01.015
Received : 27 May 2014 ;  accepted : 28 January 2015
Association of osteoprotegerin with peripheral artery disease in patients with type 2 diabetes
Association d’ostéopotégérine avec l’artériopathie oblitérante des membres inférieurs chez le patient ayant un diabète de type 2

Alireza Esteghamati , Maryam Aflatoonian, Mona Vahidi Rad, Tina Mazaheri, Mostafa Mousavizadeh, Manouchehr Nakhjavani, Sina Noshad
 Endocrinology and Metabolism Research Centre (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran 

Corresponding author.

Osteoprotegerin plays a critical role in the pathogenesis of atherosclerosis. Elevated osteoprotegerin concentrations have been reported in microvascular complications of diabetes. Patients with diabetes are at increased risk of macrovascular complications, particularly peripheral artery disease (PAD).


To investigate the association between osteoprotegerin concentration and PAD in diabetes.


In a cross-sectional setting, patients with type 2 diabetes for>5 years and no apparent diabetic foot ulcer were recruited. Patients underwent colour Doppler ultrasonography of lower limbs and were designated PAD+ if arterial narrowing was detected. Ankle-brachial index (ABI) was measured. Serum osteoprotegerin concentrations were determined.


Ninety-eight patients (47 PAD+, 51 PAD–) were recruited. Osteoprotegerin concentrations (median [interquartile range]) were significantly higher in PAD+ versus PAD– patients (0.80 [0.50–1.95] ng/mL vs 0.30 [0.25–0.40] ng/mL; P <0.001). In logistic regression, log-osteoprotegerin was a predictor of PAD in univariate and multivariable analyses. In the final multivariable model, adjusting for age, sex, body mass index, smoking, hypertension, glycaemic control, lipid profile, renal function and C-reactive protein, one standard deviation increase in log-osteoprotegerin was associated with a more than twofold increase in the risk of having PAD (odds ratio 2.26, 95% confidence interval 1.50–3.40). In PAD+ patients, osteoprotegerin was a significant predictor of disease severity, determined by ABI and percentage of vessel occlusion in univariate and multivariable models.


Osteoprotegerin concentrations are increased in patients with diabetes and PAD. Osteoprotegerin is an independent predictor of the presence and severity of PAD in diabetic patients.

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L’ostéoprotégérine joue un rôle critique dans la pathogénie de l’athérosclérose. Des concentrations élevées d’ostéoprotégérine sont associées aux complications microvasculaires du diabète. Les patients diabétiques sont à risque accru de complications macrovasculaires en particulier d’artériopathie oblitérante des membres inférieurs (AOMI).


Évaluer l’association entre les concentrations d’ostéoprotégérine et l’artériopathie oblitérante des membres inférieurs chez les patients diabétiques.


Cette étude transversale a inclus des patients ayant un diabète de type 2 datant de plus de 5 ans et pas de pied diabétique. Les patients ont eu une échographie Doppler des membres inférieurs et ont été caractérisés comme ayant une artériopathie oblitérante des membres inférieurs en présence d’une sténose artérielle. L’index de pression systolique a été mesuré. Les concentrations d’ostéoprotégérine ont été déterminées.


Quatre-vingt-dix-huit patients (47 AOMI+, 51 AOMI–) ont été inclus. Les concentrations d’ostéoprotégérine (valeur médiane, interquartile range) ont été significativement plus élevées chez les patients à AOMI+ versus les patients AOMI– (0,80 (0,50–1,95) ng/mL versus 0,30 (0,25–0,40) ng/mL, p  < 0,001). En régression logistique, le log ostéoprotégérine était un prédicteur de l’AOMI en analyses univariée et multivariée. Dans le modèle d’analyse multivariée final, ajusté sur l’âge, le sexe, l’indice de masse corporelle, le tabac, l’hypertension artérielle, le contrôle glycémique, le profil lipidique, la fonction rénale et la CRP, une augmentation d’une déviation standard de la valeur log-ostéoprotégérine est associée avec une augmentation d’au moins deux fois le risque de présenter une AOMI (odds ratio 2,26), IC 95 % 1,50–3,40). Chez les patients AOMI+, l’ostéoprotégérine est un prédicteur significatif de la sévérité de la maladie artérielle périphérique déterminée par l’index de pression systolique et la sévérité de l’occlusion artérielle en analyse univariée et mutivariée.


Les concentrations d’ostéoprotégérine sont augmentées chez les patients diabétiques ayant une AOMI. L’ostéoprotégérine est un prédicteur indépendant de la présence et de la sévérité d’une AOMI chez les patients diabétiques.

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Keywords : Osteoprotegerin, Peripheral vascular diseases/diagnosis, Severity of Illness Index, Type 2 diabetes mellitus, Ankle-brachial index

Mots clés : Ostéoprotégérine, Artériopathie oblitérante des membres inférieurs, Index de sévérité, Diabète de type 2, Index de pression systolique

Abbreviations : ABI, BMI, HbA1c , HDL-C, hsCRP, LDL-C, PAD, PSV, RANKL


Peripheral artery disease (PAD) is characterized by gradual and progressive narrowing and subsequent occlusion of the arteries of the lower extremities secondary to atherosclerosis [1, 2]. Potentially life-threatening in cases with complete vessel blockade, PAD is associated with significant pain, loss of function and disability [3, 4, 5]. Given the shared cause, patients with PAD are also at increased risk of cardiovascular and cerebrovascular diseases [5].

PAD is a major risk factor for lower-extremity amputation, especially in patients with diabetes [4]. Indeed, diabetes carries an additional risk for having PAD [4, 5, 6, 7]. Determining the exact prevalence of PAD in patients with diabetes has been difficult, but available estimates suggest that about 10.8% of diabetic patients have PAD, roughly three times as many as non-diabetic individuals [2]. If a patient is diagnosed with PAD, there is a 26.4% chance of diabetes being present [2]. Furthermore, in patients with diabetes, PAD assumes a more notorious trajectory, leading to more amputations and a higher risk of mortality [7].

Osteoprotegerin, a secretory basic glycoprotein, is a member of the tumour necrosis factor receptor superfamily and acts as an inhibitor of bone resorption [8]. Osteoprotegerin is produced by various organs and tissues, such as the lungs, intestines, kidneys, bones and the cardiovascular system (heart, arteries and veins), and also by haematopoietic and immune cells [8]; it acts as an important regulatory molecule in the vasculature [9]. Osteoprotegerin-deficient mice develop severe osteoporosis and calcification of the aorta and renal artery. Interestingly, the process follows a pattern similar to that of the medial calcification commonly seen in vascular complications of diabetes [10]. Serum osteoprotegerin concentrations are associated with the severity of coronary artery stenosis, and a modest correlation is also found with the number of involved vessels [11, 12]. Moreover, Ziegler et al. reported a positive correlation between serum concentrations of osteoprotegerin and severity of PAD [13].

Previous studies have shown that plasma concentrations of osteoprotegerin are increased in diabetic versus non-diabetic individuals [14, 15, 16, 17]. Elevated concentrations of osteoprotegerin have also been reported in diabetic patients with non-proliferative retinopathy or microalbuminuria [16]. Despite a confirmed role for osteoprotegerin in macro- and microvascular complications of diabetes, the possibility of a link between osteoprotegerin and PAD in patients with diabetes has received little attention. Therefore, the present study was designed to investigate whether serum osteoprotegerin concentrations are associated with PAD in patients with type 2 diabetes.


In the present cross-sectional study, consecutive patients with type 2 diabetes who visited the outpatient diabetes clinic of Vali-Asr Hospital (a teaching hospital affiliated with Tehran University of Medical Sciences, Tehran, Iran) from March 2012 to March 2013, were assessed and, if eligible, were enrolled. Patients were included if they had had type 2 diabetes for>5 years and agreed to undergo colour Doppler ultrasonographic evaluation of the lower extremities. Diabetes was diagnosed according to the criteria delineated by the American Diabetes Association [18]. As the diagnosis had been made at least 5 years earlier, the recently annexed HbA1c criterion was not employed. Patients were not included if they were diagnosed with chronic diseases of the liver, lungs or kidneys, or if they had had a recent acute infection. Patients were also ineligible if they were taking vitamin D, calcium supplements, bisphosphonates or corticosteroids. A complete medical history was obtained and a thorough physical examination performed. Patients were then sent for ultrasonographic evaluation of the lower extremities in the hospital's radiology department. Written informed consent was obtained from all participants. All procedures dealing with human subjects were conducted in accordance with the latest revision of the Declaration of Helsinki. The ethics committee of the hospital approved the study protocol.


Physical examination included the measurement of height and weight and determination of ankle-brachial index (ABI). Height was measured with the patient standing erect in front of a standard stadiometer and was recorded to the nearest 0.1cm. Weight was measured with subjects wearing only light clothing, using a calibrated scale, and was recorded to the nearest 0.1kg. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). ABI was measured with patient lying in the supine position. After at least 10minutes of resting, brachial systolic blood pressure was measured with an appropriately sized cuff and a Doppler ultrasonographic probe being placed in the antecubital fossa. Systolic blood pressure was measured from both arms and the higher of the two readings was designated as brachial pressure. An appropriately sized cuff was then placed around the leg between malleolus and the calf. Using a similar technique, systolic blood pressure was measured by placing the probe on the anterior tibialis and dorsalis pedis arteries, and the point of signal reappearance when deflating the cuff was recorded. The higher of the two measurements was then regarded as the ankle pressure. Finally, ABI was calculated by dividing ankle by brachial systolic pressures.

All ultrasonographic evaluations were performed by a single experienced radiologist. Colour Doppler ultrasonography was used to detect PAD and its severity. Peak systolic velocity (PSV) was determined by using a 7MHz convex transducer (SonoScape, Shenzhen, China) in each arterial segment. The PSV ratio was then defined as the ratio of the PSV at the site of measurement divided by the PSV in the proximal (approximately 4cm) artery. A PSV ratio of 2.4 was used to define significant stenosis, corresponding to>50% narrowing in the diameter of the arterial lumen. For severity of stenosis, reference PSV ratio values developed by Ranke et al. [19] were used. Based on their report, PSV ratio values of ≥2.9, ≥3.4, ≥4.7 and ≥7.0 correlated with ≥60%, ≥70%, ≥80% and ≥90% stenosis, respectively, in angiographic assessment [19].

Laboratory evaluations

Antecubital venous blood samples were collected after at least 12hours of fasting. Serum concentrations of fasting plasma glucose were determined using the glucose oxidase method. Percentage of glycated haemoglobin A1c (HbA1c ) was determined using the high performance liquid chromatography method. The lipid profiles of patients, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, were determined using enzymatic methods (ParsAzmun, Karaj, Iran). The Jaffe method was employed to assess serum concentrations of creatinine (ParsAzmun, Karaj, Iran). In PAD+ patients, high sensitivity C-reactive protein (hsCRP) concentrations were assessed with commercial kits (Diagnostics Biochem Canada Inc., Dorchester, ON, Canada), using the enzyme-linked immunosorbent assay method. Serum calcium and phosphorus concentrations were measured with an autoanalyser (Hitachi 704, Tokyo, Japan). Serum osteoprotegerin concentrations were determined using a human osteoprotegerin enzyme-linked immunosorbent assay kit (Cusabio, Wuhan, China).

Statistical analysis

Data were analysed using SPSS version 16 for Windows (SPSS Inc., Chicago, IL, USA). Continuous variables with normal distribution are presented as means±standard deviations and categorical variables are presented as proportions. Baseline characteristics of patients with and without PAD were compared using an independent t test or the chi-square test. Initially, given the non-normal distribution and right-sided skewness, osteoprotegerin concentrations were presented as medians (25th–75th percentiles) and were compared between patients with and without PAD using the Mann-Whitney U test. For all subsequent parametric analyses, a logarithmic transformation was done and log-osteoprotegerin was used instead. To assess the association between log-osteoprotegerin and the presence of PAD, univariate and multivariable logistic regression models were constructed. Odds ratios and 95% confidence intervals were calculated in each model per one standard deviation increase in log-osteoprotegerin. To investigate the association between osteoprotegerin and PAD severity, linear regression was used in the subset of PAD+ patients. In univariate and multivariable regression models, ABI (or the percentage of arterial occlusion) served as the dependent variable and the standardized beta coefficient for log-osteoprotegerin was calculated. In all tests, the null hypothesis was rejected where P was<0.05.


A total of 98 patients (51 PAD–, 47 PAD+) were included in the analysis. Baseline characteristics of enrolled patients are presented in Table 1, according to PAD group. The average age of the participants was 64 years (range, 36–89 years) and was not different between the two groups. Patients in the PAD–group were more likely to be female (65% vs 45%); however, the difference did not reach statistical significance. Mean BMI was also similar in the two groups. Patients with PAD were more likely to have hypertension and also to have a positive history of PAD in their first-degree relatives; in both cases the difference was not statistically significant. Patients were diagnosed with type 2 diabetes for a minimum and maximum of 5 and 30 years, respectively. Duration of diabetes was similar in the two groups. Significantly better glycaemic control was achieved in PAD– patients; on average, their HbA1c values were 0.9% lower than in those with PAD (P =0.016). A worse lipid profile was observed in PAD+ patients; they had higher concentrations of serum triglycerides, total cholesterol and LDL-C, but not HDL-C (Table 1). No patient had a serum creatinine concentration>1.4mg/dL. On average, patients in the PAD+ group had higher serum creatinine concentrations (P =0.046). Calcium and phosphorus concentrations were similar in the two groups. Osteoprotegerin concentrations were significantly higher in PAD+ versus PAD– patients (0.80 [0.50–1.95] ng/mL vs 0.30 [0.25–0.40] ng/mL; P <0.001). Osteoprotegerin concentrations were similar in women and men (0.40 [0.30–0.73] ng/mL in women and 0.50 [0.30–0.80] ng/mL in men; P =0.60).

Results of binary logistic regression models for the association of log-osteoprotegerin with the presence of PAD in patients with diabetes are depicted in Table 2. In the univariate model, each standard deviation increment in log-osteoprotegerin was associated with a twofold increase in the chance of having PAD on colour Doppler US. After controlling for the effects of multiple confounding variables, including age, sex, BMI, hypertension, cigarette smoking, HbA1c , triglycerides, HDL-C, total cholesterol, creatinine, calcium and phosphorus, the observed relationship retained its significance, indicating that log-osteoprotegerin is an independent predictor of PAD irrespective of various demographic, clinical and laboratory variables. In the final multivariable model, for one standard deviation increase in log-osteoprotegerin, the risk of having PAD rose by 226% (odds ratio 2.26, 95% confidence interval 1.50–3.40).

The group of patients with PAD was further analysed to investigate whether log-osteoprotegerin is a significant predictor of PAD severity; the findings are summarized in Table 3. Log-osteoprotegerin values were significantly and negatively associated with ABI in the univariate linear regression model. After controlling for the effects of the confounders mentioned above plus hsCRP, the relationship persisted (standardized beta for the final model=–0.407; P =0.045). On the other hand, log-osteoprotegerin was significantly and positively associated with degree of vessel occlusion on Doppler ultrasonography; the higher the log-osteoprotegerin value, the more obstructed the artery (standardized beta for univariate model=0.306; P =0.037). This observation was replicated in multivariable linear regression models as well, suggesting that the association between log-osteoprotegerin and arterial occlusion is independent of age, sex, hypertension, cigarette smoking, diabetes duration, glycaemic control, lipid profile, renal function or inflammation (Table 3).


In the present study, we demonstrated that serum concentrations of osteoprotegerin are significantly elevated in type 2 diabetes patients with versus without PAD. Moreover, in PAD+ patients, osteoprotegerin was a significant predictor of disease severity, as measured by ABI and percentage of arterial occlusion on colour Doppler ultrasonography. The relationship retained its significance after adjustment for potential confounding variables, suggesting that the relationship is not dependent on or mediated by age, sex, BMI, smoking status, hypertension, glycaemic control, serum lipid profile, renal function and chronic inflammation.

Previous reports have postulated that serum osteoprotegerin might be an independent risk factor for the development and progression of atherosclerosis in coronary arteries [20]. In a sample of 201 patients with stable angina undergoing coronary angiography, Jono et al. demonstrated that serum osteoprotegerin concentrations are elevated in patients with coronary artery disease compared with those in patients with no stenosis. Moreover, in the subset of diseased individuals, osteoprotegerin concentrations increased progressively when moving from single-vessel to three-vessel disease [11]. Similar results have also been replicated in a population of patients with type 2 diabetes with no known coronary artery disease [21]. In 2005, Ziegler et al. [13], in a study of 67 patients with advanced PAD of the lower extremities, showed a strong relationship between serum osteoprotegerin concentrations and PAD severity. More recently, Ali et al. (2009) lent further credence to the discourse by showing that serum osteoprotegerin concentrations are an independent predictor of PAD (defined as ABI<0.9) in large populations of African-Americans and non-Hispanic whites [22]. In the present report, we extended previous research by demonstrating that osteoprotegerin concentrations are also elevated in a population of PAD patients with type 2 diabetes.

Elevated concentrations of osteoprotegerin in the sera of diabetic patients with micro- and macrovascular complications suggest that osteoprotegerin may indeed be involved in the pathogenesis of endothelial dysfunction and vascular damage [16]. The precise mechanisms by which osteoprotegerin advances atherogenesis remain speculative for the most part; however, few compelling hypotheses have been formed.

A key step in the pathogenesis of atherosclerosis is increased binding of monocytes to adhesion molecules on endothelial cells [23]. An in vitro assay by Mangan et al. [24] indicated that when human endothelial cells were incubated with osteoprotegerin, a dose-dependent increase in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin ensued. As a result, endothelial cells are more sensitized to the proinflammatory effects of tumour necrosis factor alpha, leading to an enhanced capacity for monocyte binding to endothelial cells [24]. Furthermore, osteoprotegerin may also be involved in the calcification process of the vascular cells undergoing apoptosis. Enhanced expression of osteoprotegerin has been detected in the proximity of calcified neointimal lesions [25]. Of note, however, a parallel conjecture can also be considered. Increased osteoprotegerin expression might be a counter-regulatory mechanism aimed at negating the calcification process of the arteries [25, 26]. Although intravenous infusion of recombinant osteoprotegerin and transgenic overexpression of osteoprotegerin in homozygote osteoprotegerin-deficient mice do not diminish the already-present arterial calcification, they can avert its further formation [27]. Therefore, it can be hypothesized that the increased osteoprotegerin concentrations in patients with PAD may well be an attempt, albeit unsuccessful, to impede the calcification process in the arterial lesion [13]. Hyperglycaemia observed in diabetes is able to modulate osteoprotegerin release by endothelial cells via a tumour necrosis factor alpha-dependent pathway [28, 29]. However, increased osteoprotegerin concentrations in patients with diabetes are not accompanied by a concomitant increase in its ligand (receptor activator of nuclear factor kappa-B ligand [RANKL]) [28]. An imbalance between osteoprotegerin/RANKL, resulting from an isolated increase in osteoprotegerin, but not its ligand, might explain why, despite increased concentrations in diabetes, additional vasculoprotective benefits are not seen [28].

A direct link between glycaemic control and reduced PAD morbidity is by no means clear-cut. The United Kingdom Prospective Diabetes Study (UKPDS) indicated that tight glycaemic control does not reduce the risk of amputations due to diabetic foot [30, 31]. Our findings are in accord with and support these findings; while patients with higher concentrations of HbA1c had, at the same time, higher osteoprotegerin concentrations, when the glycaemic control factor was accounted for, the osteoprotegerin-PAD link still retained its significance in the multivariable model.

In our study, patients with PAD were more likely to have hypertension and also had a worse lipid profile. Previous studies have conclusively demonstrated that each of these risk factors can contribute to the emergence and progression of PAD [22, 30, 32]. Osteoprotegerin is, in turn, associated with various traditional and non-traditional atherosclerosis risk factors, including, but not limited to, insulin resistance, hypertension, adiposity, cigarette smoking and hsCRP [22]. However, we have shown that if these potential confounding variables are accounted for, the association between osteoprotegerin and PAD remains robust. In line with our observations, Ali et al. also demonstrated that the association between osteoprotegerin and diminished ABI persists after adjustment for age, sex, diabetes, hypertension, lipid profile, history of cardio- and cerebrovascular disease, the medications used and CRP [22]. Therefore, it could be argued that the putative mechanisms by which osteoprotegerin acts are not entirely dependent upon and are not confounded by the factors mentioned above.

Study limitations

A number of limitations in our study deserve mention. First, the cross-sectional design of the study precludes us from drawing cause and effect inferences from the osteoprotegerin and PAD relationship, and caution should be exercised when interpreting the direction of the association. Second, the gold standard method for diagnosis of PAD is arterial angiography. However, angiography is invasive, laborious and costly, and it increases the risk of contrast-induced nephropathy in diabetes patients [5]. It has been suggested that angiography should not be performed for diagnosing PAD in the first instance, and that other less invasive imaging modalities be used instead [31]. Increasing clinical experience with colour Doppler ultrasonography, and its high sensitivity (88%), specificity (95%) and accuracy (93%), have made this technique a valuable non-invasive screening tool, sparing low-risk patients from unnecessary arterial angiography [33, 34, 35].


Despite the aforementioned limitations, our study contributes to the current understanding of the multifaceted role of osteoprotegerin in diabetes and atherosclerosis. Osteoprotegerin is associated with the presence and severity of lower extremity atherosclerosis in diabetic patients, independent of traditional and non-traditional risk factors. Further studies need to elucidate the exact molecular mechanisms involved and also examine the possible clinical utility of osteoprotegerin as a surrogate diagnostic and prognostic marker for PAD in patients with diabetes.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Sources of funding: this study was funded by the Endocrinology and Metabolism Research Centre (EMRC), Tehran University of Medical Sciences, Tehran, Iran.


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