María del Carmen Navarro*, Pedro Saavedra, Esteban Jódar, Mª Jesús Gómez de Tejada, Ana Mirallave and Manuel Sosa **

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1 Clinical Endocrinology (2013) 78, doi: /cen ORIGINAL ARTICLE Osteoporosis and metabolic syndrome according to socioeconomic status, contribution of PTH, vitamin D and body weight: The Canarian Osteoporosis Poverty Study (COPS) María del Carmen Navarro*, Pedro Saavedra, Esteban Jódar, Mª Jesús Gómez de Tejada, Ana Mirallave and Manuel Sosa ** *Research Group on Education and Promotion of Health, University of Las Palmas de Gran Canaria, Department of Mathematics, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Canary Islands, Endocrinology Service, University Hospital Quirón Madrid, European University Madrid, Madrid, Department of Medicine, University of Seville, Seville, Research Group on Osteoporosis and Bone Mineral Diseases, University of Las Palmas de Gran Canaria and **Bone Metabolic Unit, Insular University Hospital, Las Palmas de Gran Canaria, Canary Islands, Spain Summary Correspondence: Esteban Jódar, Servicio de Endocrinología y Nutrición Clínica, Hospital Universitario Quirón Madrid, C/ Diego de Velazquez 2, Pozuelo de Alarcón, 28223, Madrid, Spain. Fax: ; Tel.: ; esteban.jodar@gmail.com Competing interests: Nothing to declare. Background Poverty is associated with a great number of diseases, but the prevalence of vitamin D deficiency, secondary hyperparathyroidism and the potential association of osteoporosis, osteoporotic fractures and metabolic syndrome in this situation are less well known. Objective To evaluate the associations between poverty, bone density, fragility fractures and metabolic syndrome in a population of southern European postmenopausal women. Also, to assess the potential role of vitamin D and parathyroid hormone (PTH) levels in these associations. Method Cross-sectional study was carried out in postmenopausal Caucasian Spanish women. The socio-economic status of the participants was determined after a personal interview, according to the criteria of the Spanish Institute of Statistics. Participants were divided into two socio-economic levels: low (poverty) and medium or high socioeconomic level. The study protocol included a health questionnaire, a complete physical examination, lateral radiograph of the dorsal and lumbar spine and measurement of bone mineral density (BMD) at the lumbar spine (L2-L4) and proximal femur. Fasting blood was obtained to measure 25-hydroxy-vitamin D (25-OHD), intact PTH and selected biochemical variables. Results Low socio-economic status was associated with 25-OHD insufficiency, higher values of PTH, higher body weight and body mass index (BMI), lower values of BMD at the lumbar spine and a higher prevalence of fragility fractures, both vertebral and nonvertebral. Poverty was also associated with higher prevalence of metabolic syndrome, but this association was driven mainly by the higher BMI and not by poverty itself. Both vitamin D insufficiency and elevated PTH were consistently related to poverty and osteoporotic fractures. Conclusions Poor postmenopausal women in southern Europe have a high prevalence of metabolic syndrome and osteoporotic fractures. Poverty was associated with higher BMI and metabolic syndrome on the one hand and, on the other, with 25OHD insufficiency, higher PTH levels and osteoporosis. 25OHD insufficiency and/or secondary hyperparathyroidism do not have a significant influence on the presence of metabolic syndrome in this population. (Received 23 May 2012; returned for revision 23 August 2012; finally revised 31 August 2012; accepted 16 September 2012) Introduction Vitamin D is required for adequate absorption of dietary calcium and for mineralization of bone. The first well-known clinical entities associated with vitamin D deficit were rickets and osteomalacia. Nowadays, less severe vitamin D deficiency, often described as vitamin D insufficiency or inadequacy, 1,2 is much more frequent and causes stimulation of the parathyroid glands, which may lead to high bone turnover, bone loss and hip fractures. 3,4 More recently, low serum 25-hydroxy-vitamin D (25-OHD) has been implicated in the development of a number or diseases including diabetes, hypertension and metabolic syndrome. 5, 6 On the other hand, poverty is one of the biggest public health problems today. 7 In this particular population low income, the elderly or children the existence of vitamin D insufficiency has been previously described and may lead to the development of secondary hyperparathyroidism and an increase in bone turnover. 8, 9 681

2 682 M. d. C. Navarro et al. We have previously published the finding that fragility fractures are more frequent in poor postmenopausal women. 10 The aim of this study was to evaluate the associations between poverty, bone density, fragility fractures and metabolic syndrome and to assess the potential role of vitamin D and PTH levels in these associations in a population of southern European postmenopausal women. Methods Subjects Between January 2007 and January 2009, postmenopausal Caucasian women attending a metabolic bone clinic in the Spanish public health system (Canary Islands; Latitude/Longitude 28 o 06 N, 15 o 24 W) as outpatients were included in this study. The inclusion criteria were as follows: age between 40 and 85 years, being born and resident in the Canary Islands, postmenopausal state last menstrual period at least one year previously, and having given written informed consent. Medications likely to influence skeletal metabolism or the interpretation of results (i.e. thiazides, hormonal replacement therapy) were recorded. Women treated with anti-osteoporosis medications including calcium and vitamin D supplements and those with known malabsorption, cancer or other serious diseases were excluded from the study. The participants were referred from Gynaecology, Endocrinology and Internal Medicine Services after ruling out secondary causes of osteoporosis. The younger women had suffered a bilateral oophorectomy without malignancy. The Ethics Committee of the Insular University Hospital of Gran Canaria approved the study. A previously validated questionnaire concerning health, diet, drug use, lifestyle and reproductive history was obtained. 11 A complete physical examination was also performed. The socioeconomic status of the participants was stated after a personal interview, following the criteria of the Spanish Institute of Statistics (poverty is defined as an annual income lower than Euros per capita/family member). 12 Estimated calcium intake was assessed using a validated questionnaire. 13 Biochemical measurements Serum specimens were obtained after an overnight fast. Blood was collected without additives between 800 and 900 a.m. After centrifugation at g for 10 min, serum was aliquoted and frozen at 20 C within 1 h of phlebotomy until the biochemical analyses were performed. Glucose, urea, calcium, phosphorus, alkaline phosphatase, albumin, creatinine, total-, HDL- and LDL cholesterol and triglycerides were analysed by standard methods. Filtration rate (GFR) was estimated according to MDRD-4 (GFR (MDRD-4) = (Cr age 0203 ) ) as recommended by the National Kidney Foundation practice guideline 14 for Caucasian women. Serum parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25-OHD) were measured by electrochemiluminescence with Elecsys 170 PP (Modular Analytics) of Roche Diagnostic (Basel, Switzerland). Bone mass and osteoporotic fracture assessment Bone mass was assessed by dual-energy X-ray absorptiometry (DXA) at lumbar spine (L 2 L 4 ) and femoral neck, with a Hologic QDR-4500 densitometer. Precision was 075 ± 016% with a densitometric range of 06 11%. Values were compared to national standards. 15 All measurements were made by the same operator, to limit interobserver variation. Prevalent vertebral fractures were assessed on standard lateral spine radiographs in all subjects. Vertebral fractures were defined following the radiological semiquantitative criteria of Genant. 16 The presence of nonvertebral fractures was documented by a self-reported history with later confirmation in medical hospital records or X-ray films. Statistical analysis The categorical variables were summarized as percentages and the continuous ones as means and standard deviations when the data followed a normal distribution or medians and interquartile range (IQR) when they did not. Logarithmic relationship between serum 25-OHD and PTH levels was calculated. To assess the differences between the subjects with low and medium high socio-economical status, percentages were compared using the chi-square test, means by the t-test and medians by the Wilcoxon test. For DXA results, means were adjusted by age and BMI and compared using the corresponding F-test. Fracture rates were adjusted by age using logistic regression. Logistic regression analysis using a retrospective method based on the Akaike s information criterion was performed to study the association between poverty and the study variables. This analysis was repeated for the presence of metabolic syndrome. The resulting model was summarized in P-values and adjusted odd ratios, which were estimated by 95% CIs. Statistical significance was set at P < 005. Data were analysed with the SPSS statistical program (150, SPSS, Chicago, IL, USA). Results Women were placed into two groups according to their socioeconomic status: poverty and medium or high economic status. Table 1 shows the characteristics of our population. Poorer postmenopausal women were older and had higher values of BMI than women from medium and high economic status. Poorer menopausal women showed a higher rate of alcohol and tobacco consumption and thiazide use and lower rates of HRT. They also showed higher PTH and lower 25-OHD levels. Although more than 80% of poor postmenopausal women had 25-OHD values lower than 30 ng/ml, the prevalence of 25-OHD insufficiency was also high (692%) in postmenopausal women with medium to high economic status. 190% of women in poverty had high levels of PTH secondary hyperparathyroidism vs 140% in the other group, and PTH levels were 25% higher in poor women compared to the other group. The adjustment of 25-OHD levels according to the season of the extraction of the sample did not change the results (data not

3 Table 1. Characteristics of the study population according their economic status Poverty, osteoporotic fractures and metabolic syndrome, role of vitamin D insufficiency 683 Poverty Yes n = 474 No n = 776 P value Age (years) 566 ± ± 116 <0001 Weight (kg) 705 ± ± 116 <0001 Height (cm) 156 ± ± 63 <0001 Body mass 291 ± ± 47 <0001 index (kg/m 2 ) Calcium 610 ( ) 650 ( ) 0945 intake (mg/24 h) Alcohol <0001 consumption (%) Tobacco <0001 consumption (%) HRT use (%) Thiazides use (%) Low physical activity (%) PTH (pg/ml)* 409 ( ) 373 ( ) 0001 PTH > pg/ml (%) 25-OHD (ng/ml)* 21 (17 25) 25 (21 32) < OHD status (%) <50 nmol/l (%) < nmol/l (%) >75 nmol/l (%) Obesity (%) <0001 Diabetes mellitus (%) Hypertension (%) Total cholesterol 244 ± ± (mg/dl) LDL cholesterol 163 ± ± (mg/dl) HDL cholesterol 53 (43 62) 57 (48 69) <0001 (mg/dl)* Triglycerides 121 (91 171) 107 (82 151) 0001 (mg/dl)* Metabolic syndrome (%) MDRD-4 (ml/min/173 m 2 )* 656 ( ) 640 ( ) 0119 Data are expressed as mean ± SD except as marked: (*) Median (interquartile range); HRT, hormone replacement therapy; 25-OHD, 25-hydroxy-vitamin D; MDRD-4, glomerular filtration rate calculated as MDRD (Modification of Diet in Renal Disease) study equation; PTH, parathyroid hormone. shown). PTH and 25-OHD showed a logarithmic relationship (R 2 = 038) (Fig. 1). The prevalence of components of metabolic syndrome and metabolic syndrome itself was also greater among poor women. Interestingly, no differences were found in renal function assessed as MDRD-4. Postmenopausal women with low economic status had lower lumbar spine BMD (Table 2) and higher rates of vertebral and nonvertebral fractures (Table 3). Fig. 1 Logarithmic relationship between serum 25-hydroxy-vitamin D and parathyroid hormone levels (R 2 = 038). Table 2. Comparison of bone mineral density values measured by dualenergy X-ray absorptiometry according to economic status Poverty Yes n = 474 No n = 776 Lumbar spine (L2 L4) g/cm ± ± T score 1648 ± ± 1861 Adjusted mean* 0865 (0008) 0896 (0006) 0003 Femoral neck g/cm ± ± T score 1021 ± ± 1221 Adjusted mean* 0726 (0006) 0729 (0004) 0726 Total Hip g/cm ± ± T score 1197 ± ± 1474 Adjusted mean* 0798 (0006) 0802 (0005) 0569 *Adjusted for age and BMI. Data are expressed as mean ± SD or as mean (SE). BMI, body mass index. The logistic multivariate analysis for the variable poverty is shown in Table 4. The variables with an independent relationship with poverty were BMI, PTH, 25-OHD, MDRD-4 and presence of vertebral fracture. Age, weight, height, alcohol intake, tobacco consumption, HRT and thiazide use did not add any significant information to the model. The presence of metabolic syndrome was strongly associated with BMI (data not shown). To further explore the potential association of metabolic syndrome with PTH and 25-OHD levels, a logistic multivariate analysis for the variable metabolic syndrome was performed (Table 5) but only BMI and age showed independent associations. PTH, 25-OHD and presence of poverty were not independently associated with metabolic syndrome and were excluded from the model. P

4 684 M. d. C. Navarro et al. Table 3. Comparison of fragility fractures (total and vertebral fractures) according to economic level Fractures Discussion Poverty Yes (n = 474) No (n = 776) P value OR (95% CI) Total Crude, n (%) 147 (310) 177 (228) (118; 197) Adjusted* (%) (098; 170) Vertebral Crude, n (%) 87 (193) 81 (122) (124; 239) Adjusted* (%) (108; 113) *Estimated for the mean age of 548 years for each group. Table 4. Multivariate logistic regression. Variables independently associated with the presence of poverty Variable P value OR (95% CI) BMI (per Kg/m 2 ) < (1067; 1132) PTH (per pg/ml) (0976; 0994) 25-OHD (per nmol/l) < (0950; 0969) MDRD-4 (per ml/min/173 m 2 ) (1000; 1011) Vertebral fracture (1257; 2610) BMI, body mass index; 25-OHD, 25-hydroxy-vitamin D; PTH, parathyroid hormone; MDRD-4, glomerular filtration rate calculated with MDRD (Modification of Diet in Renal Disease) study equation; PTH (parathyroid hormone). Table 5. Multivariate logistic regression. Variables independently associated with the presence of metabolic syndrome. Variable P value OR (95% CI) BMI < (1194; 1292) Age < (1014; 1048) BMI, body mass index. We have shown that women with a low socio-economic level have a high prevalence of obesity and metabolic syndrome. These women have a high prevalence of vitamin D insufficiency, which leads to the development of secondary hyperparathyroidism. Vitamin D insufficiency and secondary hyperparathyroidism result in lower BMD and a higher prevalence of vertebral fractures. Nevertheless, 25-OHD insufficiency and secondary hyperparathyroidism were not related to the high prevalence of metabolic syndrome. Although there is a wide controversy related to the optimal levels of 25-OHD as a marker of vitamin D status, 17, 18 vitamin D deficiency has been defined recently by the Endocrine Society as 25-OHD below 20 ng/ml (50 nmol/l) and vitamin D insufficiency as 25-OHD between 21 and 29 ng/ml ( nmol/l). 19 In accordance with these definitions, it has been estimated that % of United States and European elderly men and women 5, still living in the community are vitamin D deficient. Among European postmenopausal women, the prevalence of 25-OHD inadequacy was 796% and 321% when considering cut-offs of 32 and 20 ng/ml (80 and 50 nmol/l), respectively. Interestingly, in the subgroup of patients up to 65 years, the prevalence reached 86% (cut-off of 32 ng/ml) and 45% (cut-off of 20 ng/ml). 23 In our population, the prevalence of vitamin D inadequacy is comparable but two differences must be kept in mind: the first is the mean age of our sample, almost 20 years younger than the sample of the above study 23 ; the second is related to the geographical localization, the Canary Islands being located off the north-western coast of Africa in the southern part of Europe (Latitude/Longitude 28 o 06 N, 15 o 24 W), with a mean of h of sunshine during the last year (more than 190 sunshine hours every month) compared to h/year in Brussels, in Berlin or in Copenhagen. Moreover, in accord with previous studies, 8,9,24 poverty was associated with lower values for 25-OHD, which may be related to the higher BMI in poorer women 25,26 or to nutritional deficiencies associated with poverty. 27 A potential inefficiency of skin production has been suggested but not proven in this population. It is also important to note that the glomerular filtration rate was comparable between our two study groups, which removes the influence of kidney function on vitamin D status. Low 25-OHD and secondary hyperparathyroidism are wellknown factors implicated in osteoporosis and osteoporotic fractures. 5,19,28 In fact, although the poor women in our study were heavier, we have shown lower lumbar BMD and higher rates of osteoporotic fractures in these women. Moreover, there is a difference in the use of thiazide diuretics in the two groups higher in the poorer women which may result in an underestimation of the difference in BMD as thiazides reduce urinary calcium excretion and PTH and increase BMD. 29 In any case, both groups had a very low intake of dietary calcium compared to the recommended dietary reference intakes. 17 This could particularly affect poor women with lower 25-OHD level as shown in US adults. 30 The multivariate analysis identified higher BMI, PTH, GFR, number of fractures and lower 25-OHD as independent factors associated with poverty. Thus, our data support a role for vitamin D deficiency and higher PTH levels as factors implicated in the development of low bone mineral density and osteoporotic fractures in poverty. Vitamin D deficiency has also been linked with diabetes, hypertension, myocardial infarction and stroke, as well as other cardiovascular-related diseases, such as congestive heart failure, peripheral vascular disease or endothelial dysfunction. 6,25 However, few randomized, controlled trials have evaluated the effect of vitamin D replacement on cardiovascular outcomes, and the results have been inconclusive or contradictory. 19,31 The PTH level, but not the vitamin D level, has been proposed as an independent predictor of metabolic syndrome in morbidly obese

5 Poverty, osteoporotic fractures and metabolic syndrome, role of vitamin D insufficiency 685 Caucasian women and men. 32 Our data do not support this view as long as metabolic syndrome prevalence was driven just by age and, mainly, BMI. 25-OHD and PTH did not show any independent association with metabolic syndrome prevalence in the multivariate analyses according to previous cross-sectional studies in overweight and obese adults of different ethnicities. 26 Very recently, in a similar number of older Dutch subjects (mean age 75 years) of both sexes, there was a significantly increased risk of metabolic syndrome in the subjects with 25-OHD insufficiency. 33 The higher prevalence of metabolic syndrome (more than 1/3), the lower BMI and other potential factors such as GFR, age or sex could explain the differences. Thus, the present study highlights the importance of excess body weight over vitamin D status or PTH levels in the development of the metabolic syndrome in young postmenopausal women. There are two main limitations to this study: Firstly, it is a cross-sectional study in which only prevalent osteoporotic fractures or metabolic syndrome prevalence was analysed; thus, prospective studies are necessary to confirm the results. Secondly, the study was conducted in a relatively small sample, not randomly selected from the Canarian population. However, we consider that our sample was representative of the population, because it was composed of subjects who agreed to participate in several epidemiological studies and BMD values obtained at different age groups did not differ from reference values published for the Canarian and Spanish population. 15,34,35 The strength of our study is that there are no previously published studies that establish the association between poverty, vitamin D status, PTH, osteoporosis and metabolic syndrome. In conclusion, poorer postmenopausal women living in southern Europe are more vulnerable to suffering from osteoporotic fractures and metabolic syndrome but, although bone loss and fractures seem to be related to vitamin D insufficiency and high PTH levels, metabolic syndrome prevalence is influenced only by age and BMI. References 1 McKenna, M.J. (1992) Differences in vitamin D status between countries in young adults and the elderly. 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