- Email: [email protected]
Low calcium intake and inadequate vitamin D status in postmenopausal osteoporotic women
Journal of Steroid Biochemistry & Molecular Biology 136 (2013) 175–177
Contents lists available at SciVerse ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Review
Low calcium intake and inadequate vitamin D status in postmenopausal osteoporotic women José Manuel Quesada-Gómez a,∗,1 , Manuel Diaz-Curiel b,1 , Manuel Sosa-Henriquez c,1 , ˜ g,1 , Jorge Malouf-Sierra d,1 , Xavier Nogues-Solan e,1 , Carlos Gomez-Alonso f,1 , Leocadio Rodriguez-Manas h,1 i,1 j,1 Jose Luis Neyro-Bilbao , Xavier Cortes , Joaquín Delgadillo a
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain Servicio de Medicina Interna, Fundación Jimenez Diaz, Madrid, Spain c Unidad Metabólica Ósea, Hospital Universitario Insular, Las Palmas, Spain d Servicio de Medicina Interna, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e Servicio de Medicina Interna, Universidad Autónoma de Barcelona, Hospital del Mar, Barcelona, Spain f Instituto Reina Sofía de Investigación, Hospital Universitario Central de Asturias, Oviedo, Spain g Fundación para la Investigación Biomédica, Servicio de Geriatría, Hospital Universitario de Getafe, Madrid, Spain h Servicio Obstetricia y Ginecología, Hospital de Cruces, Baracaldo, Vizcaya, Spain i Ferrer Internacional, Barcelona, Spain j Almirall, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 7 July 2012 Received in revised form 8 October 2012 Accepted 12 October 2012 Keywords: Osteoporosis treatment Vitamin D Vitamin D insufficiency Vitamin D deficiency Calcium intake Inadequate response
a b s t r a c t An observational cross-sectional study was conducted to assess calcium intake and vitamin D status by measurement of 25-hydroxyvitamin D (25(OH)D), in postmenopausal osteoporotic women (PMOW) treated and untreated for osteoporosis. To assess the influence of sunlight exposure on vitamin D status, the study group was categorized on the basis of sunlight exposure (above or below 2500 sunlight h/year). A group of 336 PMOW older than 65 years was identified (190 [56.5%] treated and 146 [43.5%] untreated for osteoporosis). The demographic and clinical data of the PMO women included history of prior fractures, pharmacological treatments and dietary calcium intake. BMD was measured by DEXA and 25(OH)D was determined by an HPLC method. Results: vitamin D serum levels were lower in the untreated group as compared with the treated group (58 ± 27 vs. 67 ± 27 nmol/l; p = 0.006). Prevalence of vitamin D deficiency (cut-off point set at <50 nmol/l) was higher in the non-treated group (43.8% vs. 29.5%; p = 0.009). Nearly all PMOW, whether treated or not for osteoporosis had a total calcium intake of less than 1200 mg. Sunlight exposure did not influence the vitamin D status. Conclusions: vitamin D deficiency and an insufficient calcium intake are highly prevalent in both treated and untreated Spanish PMOW older than 65 years. This can be related to low therapeutic adherence and/or insufficient prescription. Therefore physician’s and patient’s knowledge regarding the optimization of vitamin D status and calcium intake should be improved and implemented. This article is part of a Special Issue entitled ‘Vitamin D workshop’. © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
176 176 176 177 177 177 177
∗ Corresponding author at: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, RETICEF, Avda, Menendez Pidal, s/n, 14004 Córdoba, Spain. Tel.: +34 620714145. E-mail addresses: [email protected], [email protected] (J.M. Quesada-Gómez). 1 On behalf of Previcad Study Group, RETICEF, Reina Sofia Hospital, Córdoba, Spain. 0960-0760/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsbmb.2012.10.013
176
J.M. Quesada-Gómez et al. / Journal of Steroid Biochemistry & Molecular Biology 136 (2013) 175–177
1. Introduction Calcium is the most important nutrient for preventing bone loss with aging. Vitamin D is required to optimize the absorption of calcium, being essential for bone health. Thus, treatment with calcium and vitamin D is included in all available guidelines for the treatment and prevention of osteoporosis [1]. Considering all the available sources of calcium intake, the Food and Nutrition Board of the Institute of Medicine has suggested a daily calcium intake of 1200 mg from 50 years old onwards [2]. However, the daily dietary intake of calcium is commonly below these recommendations [3]. Vitamin D deficiency has been reported worldwide across all ethnicities in more than 50% of PMOW, especially in those with osteoporosis [4–6]. This deficiency not only affects bone metabolism, but also involves muscle function, with an increased risk of falls and bone fractures, and could be a cause of inadequate response to treatment with powerful osteoporosis drugs [5,6]. Nevertheless, there is a sizeable gap between the recommendations and clinical practice. Based on the important contribution of sunlight exposure to vitamin D levels, it is commonly assumed by patients and clinicians that vitamin D insufficiency is negligible in lower latitudes. However, high amounts of sun exposure do not ensure what is currently considered as vitamin D adequacy [7]. PREVICAD is an observational, epidemiologic and crosssectional study designed to assess calcium intake and serum vitamin D levels in postmenopausal osteoporotic women treated and non-treated for osteoporosis, and to evaluate the influence of sunlight exposure on vitamin D serum levels.
2. Patients and methods PREVICAD is an observational epidemiologic and cross-sectional study conducted in Spanish hospitals and primary care centers distributed across the country and categorized on the basis of their sunlight exposure (above or below 2500 sunlight h/year (http://www.aemet.es)). Each center was asked to recruit at least six consecutive Caucasian PMO women over 65 years (three treated for at least one year for osteoporosis, and three untreated). Recruitment period began on 15th February and ended on 15th May 2009. Exclusion criteria were malignancies, renal failure, and liver disease or malabsorption syndromes. Ethical approval was obtained from all the Local Institutional Research Committees and all participants
provided written informed consent. Calcium dietary intake was assessed using an approved questionnaire for evaluating calcium consumption in our population [3]. Individual serum samples were collected and kept at −80 ◦ C on site and then sent on dry ice to a central laboratory (Hospital “Reina Sofía”, Córdoba, Spain). Biochemistry analyses included serum calcium, phosphorous, creatinine, alkaline phosphatase, osteocalcin, serum C-telopeptide of type 1 collagen (CTX), and PTH. Serum 25-hydroxyvitamin D (25(OH)D) was measured by an automatic on-line solid-phase extraction system for cleanup-preconcentration, coupled with and high-pressure liquid chromatography (HPLC) and ultraviolet detection method [8]. Descriptive statistics are presented as mean ± standard deviation or as percentages. The selected cut-off point for calcium intake was 1200 mg/day and <50 nmol/l and <75 nmol/l for 25(OH)D serum levels for vitamin D deficiency and insufficiency, respectively. Procedures were carried out using the SPSS computer program version 13.0 (IBM, Armonk, NY, USA). All continuous variables were compared between groups using the t-test. 2 tests were used for categorical data. Associations between continuous variables and 25(OH)D levels were examine using a regression lineal simple. Differences were considered significant at <0.05.
3. Results A total of 336 PMO women were enrolled, from which 190 (56.5%) were being treated for osteoporosis (Group 1) and 146 (43.5%) were untreated (Group 2). Among the treated group, bisphosphonates were the most often used therapeutic class (70%), followed by selective estrogen receptor modulators (12%), while the rest (18%) received other drugs for osteoporosis. Table 1 shows the main clinical and biochemical characteristics of the study population, the frequencies of different 25(OH)D3 serum levels and calcium intake cut-off points and 25(OH)D serum levels according to sunlight exposure and geographical region (coast line). Within the untreated group, the prevalence of vitamin D deficiency (<50 nmol/l) and vitamin D insufficiency (<75 nmol/l) was 44% and 76%, respectively. On the other hand, 78% PMO women without treatment had a calcium dietary intake of less than 1200 mg. The 25(OH)D serum concentrations significantly correlated with body mass index (BMI), serum PTH, phosphate, magnesium, serum CTX, osteocalcin and total alkaline phosphatase.
Table 1 Clinical and biochemical data of the study population, the frequencies for different 25(OH)D serum levels and calcium intake cut-off points and 25(OH)D serum levels according to sunlight exposure and geographical region (coast line).
Number Age (years) BMI (kg/m2 ) T score spine BMD T score femoral neck BMD S. calcium (mmol/l) S. phosphorus (mmol/l) S. magnesium (mmol/l) S. alkaline phosphatase (U/l) S. osteocalcin (nmol/l) S. C-telopeptide of type 1 collagen (CTX) (ng/l) S. parathyroid hormone (ng/l) S. 25-hydroxyvitamin D (nmol/l) Dietary calcium intake (mg/day) Dietary calcium intake <1200 mg/day S. 25(OH)D <30 ng/ml S. 25(OH)D <20 ng/ml S. 25(OH)D <30 ng/ml <2500 h/year S. 25(OH)D <30 ng/ml >2500 h/year S. 25(OH)D <30 ng/ml >2500 h/year and coast line
Not treated
Treated
p
146 71.2 ± 5 30.2 ± 1.8 −3.0 ± 0.8 −2.3 ± 0.8 2.3 ± 0.1 1.2 ± 0.2 0.82 ± 0.1 71.4 ± 24 3.2 ± 1.6 0.35 ± 0.16 45.3 ± 22 58.4 ± 27.46 989 ± 433 78.4% 76.4% 43.8% 21.9 ± 11% 24.1 ± 12% 22.3 ± 10%
190 71.2 ± 5 29.2 ± 1.5 −3.07 ± 0.9 −2.2.6 ± 0.8 2.3 ± 0.1 1.2 ± 0.2 0.78 ± 0.2 65.6 ± 20 2.7 ± 1.6 0.30 ± 0.17 42.2 ± 20 67.4 ± 27.46 1040 ± 480 71.3% 63.2% 29.5% 21.9 ± 11% 28.8 ± 13% 26.7 ± 10%
0.94 0.37 0.37 0.47 0.2 0.03 0.3 0.0005 0.004 0.024 0.15 0.006 0.33 0.16 0.009 0.009 0.21 0.03 0.01
J.M. Quesada-Gómez et al. / Journal of Steroid Biochemistry & Molecular Biology 136 (2013) 175–177
Although treatment compliance was considered good by direct questioning of participants, 30% of PMO women were vitamin D deficient and only 37% had levels of 25(OH)D above 75 nmol/l. 71% of PMO women on osteoporosis treatment had a total calcium intake below 1200 mg. There were no statistically significant differences, neither considering a <75 nmol/l cut-off nor a 50 nmol/l cut-off point in serum levels of vitamin D between different regions of sun exposure (less than 2500 h/year and more than 2500 h/year) in PMO women treated and untreated. In treated women there was statistical difference when considering the results obtained regions of sun exposure and in coastal areas, which could potentially facilitate sun exposure. Not surprisingly, the bone turnover markers are lower in women undergoing treatment than in untreated women.
177
In addition, vitamin D inadequacy has been associated as a contributing factor in a variety of diseases [6,8], as well as an independent risk factor for mortality in the general population [12]. Thus, vitamin D deficiency is now emerging as a particularly important public health concern. In conclusion, even in sunny regions, it is important to highlight the need for improving physician and patient’s knowledge regarding the optimization of calcium intake and vitamin D status in postmenopausal osteoporotic women. This would increase treatment adherence, therefore optimizing bone health by the improvement of the bone response to osteoporosis drugs. Conflict of interest No potential conflict of interest to disclose for this work.
4. Discussion This study is in agreement with the overwhelming amount of evidence confirming the high prevalence of inadequate vitamin D status in Europe, even in southern and sunny countries such as Spain [6,7], despite the potential availability to acquire adequate vitamin D levels by exposure to sunlight. There are important discrepancies when it comes to define such an inadequacy. Recently, the Institutes of Medicine (IOM) revised the recommended 25(OH)D serum levels, setting it at or above 50 nmol/l to sustain bone density, calcium absorption, and to minimize the risk of osteomalacia [3]. However, the International Osteoporosis Foundation (IOF) defines as 75 nmol/l the threshold of 25(OH)D to reduce falls and fractures. Such recommendation has been endorsed by the US Endocrine Society [9]. Nevertheless, if we consider the important methodological problems associated with the measurement of serum 25(OH)D [10], this subtle difference of 25 nmol/l does not seem to be relevant from a public health point of view. In any case, in this study we found that in a sunny country of the Northern Hemisphere such as Spain, there is a large prevalence of vitamin D inadequacy, as defined by 25(OH)D serum levels lower than 50 or 75 nmol/l amongst both untreated and treated PMOW. Moreover it is particularly striking that this high prevalence of serum vitamin D inadequacy also persists amongst postmenopausal osteoporotic women treated with anti-resorptive drugs. Our data also confirm a dietary calcium intake well below the commonly established recommendations [2,3]. All clinical trials concerning anti-resorptive and anabolic therapies were carried out in calcium and vitamin D replete individuals [1]. Even though the impact of calcium and vitamin D insufficiency has not been studied for all the osteoporosis drugs, the available evidence shows that insufficient calcium intake and vitamin D status impair the effects of osteoporosis therapies. This could be the reason for an inadequate response to osteoporosis treatment [11]
Acknowledgements This manuscript is based on work funded by the Grupo CTS 413 (Junta de Andalucía) and RETICEF (Ministerio de Ciencia y Innovación, Spain). References [1] J.M. Quesada Gomez, J. Blanch Rubio, M. Diaz Curiel, A. Diez Perez, Calcium citrate and vitamin D in the treatment of osteoporosis, Clinical Drug Investigation 31 (5) (2011) 285–298. [2] Institute of Medicine (IOM), Dietary Reference Intakes for Calcium and Vitamin D, National Academies Press, Washington, DC, 2011. [3] O. Bruyere, C. De Cock, C. Mottet, A. Neuprez, O. Malaise, J.Y. Reginster, Low dietary calcium in European postmenopausal osteoporotic women, Public Health Nursing 12 (1) (2009) 111–114. [4] P. Lips, D. Hosking, K. Lippuner, J.M. Norquist, L. Wehren, G. Maalouf, S. RagiEis, J. Chandler, The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation, Journal of Internal Medicine 260 (3) (2006) 245–254. [5] M.F. Holick, Vitamin D deficiency, New England Journal of Medicine 357 (3) (2007) 266–281. [6] R. Bouillon, H. Bischoff-Ferrari, W. Willett, Vitamin D and health: perspectives from mice and man, Journal of Bone and Mineral Research 23 (7) (2008) 974–979. [7] N. Binkley, R. Novotny, D. Krueger, T. Kawahara, Y.G. Daida, G. Lensmeyer, B.W. Hollis, M.K. Drezner, Low vitamin D status despite abundant sun exposure, Journal of Clinical Endocrinology and Metabolism 92 (6) (2007) 2130–2135. [8] J.M. Mata-Granados, J.M. Quesada Gomez, M.D. Luque de Castro, Fully automatic method for the determination of fat soluble vitamins and vitamin D metabolites in serum, Clinica Chimica Acta 403 (1–2) (2009) 126–130. [9] M.F. Holick, N.C. Binkley, H.A. Bischoff-Ferrari, C.M. Gordon, D.A. Hanley, R.P. Heaney, M.H. Murad, C.M. Weaver, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, Journal of Clinics in Endocrinology and Metabolism 96 (7) (2011) 1911–1930. [10] G.D. Carter, 25-Hydroxyvitamin D: a difficult analyte, Clinical Chemistry 58 (3) (2012) 486–488. [11] P. Peris, A. Martinez-Ferrer, A. Monegal, M.J. Martinez de Osaba, A. Muxi, N. ˜ 25 hydroxyvitamin D serum levels influence adequate response to Guanabens, bisphosphonate treatment in postmenopausal osteoporosis, Bone 51 (1) (2012) 54–58. [12] M.L. Melamed, E.D. Michos, W. Post, B. Astor, 25-Hydroxyvitamin D levels and the risk of mortality in the general population, Archives of Internal Medicine 168 (15) (2008) 1629–1637.
Contents lists available at SciVerse ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Review
Low calcium intake and inadequate vitamin D status in postmenopausal osteoporotic women José Manuel Quesada-Gómez a,∗,1 , Manuel Diaz-Curiel b,1 , Manuel Sosa-Henriquez c,1 , ˜ g,1 , Jorge Malouf-Sierra d,1 , Xavier Nogues-Solan e,1 , Carlos Gomez-Alonso f,1 , Leocadio Rodriguez-Manas h,1 i,1 j,1 Jose Luis Neyro-Bilbao , Xavier Cortes , Joaquín Delgadillo a
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain Servicio de Medicina Interna, Fundación Jimenez Diaz, Madrid, Spain c Unidad Metabólica Ósea, Hospital Universitario Insular, Las Palmas, Spain d Servicio de Medicina Interna, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e Servicio de Medicina Interna, Universidad Autónoma de Barcelona, Hospital del Mar, Barcelona, Spain f Instituto Reina Sofía de Investigación, Hospital Universitario Central de Asturias, Oviedo, Spain g Fundación para la Investigación Biomédica, Servicio de Geriatría, Hospital Universitario de Getafe, Madrid, Spain h Servicio Obstetricia y Ginecología, Hospital de Cruces, Baracaldo, Vizcaya, Spain i Ferrer Internacional, Barcelona, Spain j Almirall, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 7 July 2012 Received in revised form 8 October 2012 Accepted 12 October 2012 Keywords: Osteoporosis treatment Vitamin D Vitamin D insufficiency Vitamin D deficiency Calcium intake Inadequate response
a b s t r a c t An observational cross-sectional study was conducted to assess calcium intake and vitamin D status by measurement of 25-hydroxyvitamin D (25(OH)D), in postmenopausal osteoporotic women (PMOW) treated and untreated for osteoporosis. To assess the influence of sunlight exposure on vitamin D status, the study group was categorized on the basis of sunlight exposure (above or below 2500 sunlight h/year). A group of 336 PMOW older than 65 years was identified (190 [56.5%] treated and 146 [43.5%] untreated for osteoporosis). The demographic and clinical data of the PMO women included history of prior fractures, pharmacological treatments and dietary calcium intake. BMD was measured by DEXA and 25(OH)D was determined by an HPLC method. Results: vitamin D serum levels were lower in the untreated group as compared with the treated group (58 ± 27 vs. 67 ± 27 nmol/l; p = 0.006). Prevalence of vitamin D deficiency (cut-off point set at <50 nmol/l) was higher in the non-treated group (43.8% vs. 29.5%; p = 0.009). Nearly all PMOW, whether treated or not for osteoporosis had a total calcium intake of less than 1200 mg. Sunlight exposure did not influence the vitamin D status. Conclusions: vitamin D deficiency and an insufficient calcium intake are highly prevalent in both treated and untreated Spanish PMOW older than 65 years. This can be related to low therapeutic adherence and/or insufficient prescription. Therefore physician’s and patient’s knowledge regarding the optimization of vitamin D status and calcium intake should be improved and implemented. This article is part of a Special Issue entitled ‘Vitamin D workshop’. © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
176 176 176 177 177 177 177
∗ Corresponding author at: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, RETICEF, Avda, Menendez Pidal, s/n, 14004 Córdoba, Spain. Tel.: +34 620714145. E-mail addresses: [email protected], [email protected] (J.M. Quesada-Gómez). 1 On behalf of Previcad Study Group, RETICEF, Reina Sofia Hospital, Córdoba, Spain. 0960-0760/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsbmb.2012.10.013
176
J.M. Quesada-Gómez et al. / Journal of Steroid Biochemistry & Molecular Biology 136 (2013) 175–177
1. Introduction Calcium is the most important nutrient for preventing bone loss with aging. Vitamin D is required to optimize the absorption of calcium, being essential for bone health. Thus, treatment with calcium and vitamin D is included in all available guidelines for the treatment and prevention of osteoporosis [1]. Considering all the available sources of calcium intake, the Food and Nutrition Board of the Institute of Medicine has suggested a daily calcium intake of 1200 mg from 50 years old onwards [2]. However, the daily dietary intake of calcium is commonly below these recommendations [3]. Vitamin D deficiency has been reported worldwide across all ethnicities in more than 50% of PMOW, especially in those with osteoporosis [4–6]. This deficiency not only affects bone metabolism, but also involves muscle function, with an increased risk of falls and bone fractures, and could be a cause of inadequate response to treatment with powerful osteoporosis drugs [5,6]. Nevertheless, there is a sizeable gap between the recommendations and clinical practice. Based on the important contribution of sunlight exposure to vitamin D levels, it is commonly assumed by patients and clinicians that vitamin D insufficiency is negligible in lower latitudes. However, high amounts of sun exposure do not ensure what is currently considered as vitamin D adequacy [7]. PREVICAD is an observational, epidemiologic and crosssectional study designed to assess calcium intake and serum vitamin D levels in postmenopausal osteoporotic women treated and non-treated for osteoporosis, and to evaluate the influence of sunlight exposure on vitamin D serum levels.
2. Patients and methods PREVICAD is an observational epidemiologic and cross-sectional study conducted in Spanish hospitals and primary care centers distributed across the country and categorized on the basis of their sunlight exposure (above or below 2500 sunlight h/year (http://www.aemet.es)). Each center was asked to recruit at least six consecutive Caucasian PMO women over 65 years (three treated for at least one year for osteoporosis, and three untreated). Recruitment period began on 15th February and ended on 15th May 2009. Exclusion criteria were malignancies, renal failure, and liver disease or malabsorption syndromes. Ethical approval was obtained from all the Local Institutional Research Committees and all participants
provided written informed consent. Calcium dietary intake was assessed using an approved questionnaire for evaluating calcium consumption in our population [3]. Individual serum samples were collected and kept at −80 ◦ C on site and then sent on dry ice to a central laboratory (Hospital “Reina Sofía”, Córdoba, Spain). Biochemistry analyses included serum calcium, phosphorous, creatinine, alkaline phosphatase, osteocalcin, serum C-telopeptide of type 1 collagen (CTX), and PTH. Serum 25-hydroxyvitamin D (25(OH)D) was measured by an automatic on-line solid-phase extraction system for cleanup-preconcentration, coupled with and high-pressure liquid chromatography (HPLC) and ultraviolet detection method [8]. Descriptive statistics are presented as mean ± standard deviation or as percentages. The selected cut-off point for calcium intake was 1200 mg/day and <50 nmol/l and <75 nmol/l for 25(OH)D serum levels for vitamin D deficiency and insufficiency, respectively. Procedures were carried out using the SPSS computer program version 13.0 (IBM, Armonk, NY, USA). All continuous variables were compared between groups using the t-test. 2 tests were used for categorical data. Associations between continuous variables and 25(OH)D levels were examine using a regression lineal simple. Differences were considered significant at <0.05.
3. Results A total of 336 PMO women were enrolled, from which 190 (56.5%) were being treated for osteoporosis (Group 1) and 146 (43.5%) were untreated (Group 2). Among the treated group, bisphosphonates were the most often used therapeutic class (70%), followed by selective estrogen receptor modulators (12%), while the rest (18%) received other drugs for osteoporosis. Table 1 shows the main clinical and biochemical characteristics of the study population, the frequencies of different 25(OH)D3 serum levels and calcium intake cut-off points and 25(OH)D serum levels according to sunlight exposure and geographical region (coast line). Within the untreated group, the prevalence of vitamin D deficiency (<50 nmol/l) and vitamin D insufficiency (<75 nmol/l) was 44% and 76%, respectively. On the other hand, 78% PMO women without treatment had a calcium dietary intake of less than 1200 mg. The 25(OH)D serum concentrations significantly correlated with body mass index (BMI), serum PTH, phosphate, magnesium, serum CTX, osteocalcin and total alkaline phosphatase.
Table 1 Clinical and biochemical data of the study population, the frequencies for different 25(OH)D serum levels and calcium intake cut-off points and 25(OH)D serum levels according to sunlight exposure and geographical region (coast line).
Number Age (years) BMI (kg/m2 ) T score spine BMD T score femoral neck BMD S. calcium (mmol/l) S. phosphorus (mmol/l) S. magnesium (mmol/l) S. alkaline phosphatase (U/l) S. osteocalcin (nmol/l) S. C-telopeptide of type 1 collagen (CTX) (ng/l) S. parathyroid hormone (ng/l) S. 25-hydroxyvitamin D (nmol/l) Dietary calcium intake (mg/day) Dietary calcium intake <1200 mg/day S. 25(OH)D <30 ng/ml S. 25(OH)D <20 ng/ml S. 25(OH)D <30 ng/ml <2500 h/year S. 25(OH)D <30 ng/ml >2500 h/year S. 25(OH)D <30 ng/ml >2500 h/year and coast line
Not treated
Treated
p
146 71.2 ± 5 30.2 ± 1.8 −3.0 ± 0.8 −2.3 ± 0.8 2.3 ± 0.1 1.2 ± 0.2 0.82 ± 0.1 71.4 ± 24 3.2 ± 1.6 0.35 ± 0.16 45.3 ± 22 58.4 ± 27.46 989 ± 433 78.4% 76.4% 43.8% 21.9 ± 11% 24.1 ± 12% 22.3 ± 10%
190 71.2 ± 5 29.2 ± 1.5 −3.07 ± 0.9 −2.2.6 ± 0.8 2.3 ± 0.1 1.2 ± 0.2 0.78 ± 0.2 65.6 ± 20 2.7 ± 1.6 0.30 ± 0.17 42.2 ± 20 67.4 ± 27.46 1040 ± 480 71.3% 63.2% 29.5% 21.9 ± 11% 28.8 ± 13% 26.7 ± 10%
0.94 0.37 0.37 0.47 0.2 0.03 0.3 0.0005 0.004 0.024 0.15 0.006 0.33 0.16 0.009 0.009 0.21 0.03 0.01
J.M. Quesada-Gómez et al. / Journal of Steroid Biochemistry & Molecular Biology 136 (2013) 175–177
Although treatment compliance was considered good by direct questioning of participants, 30% of PMO women were vitamin D deficient and only 37% had levels of 25(OH)D above 75 nmol/l. 71% of PMO women on osteoporosis treatment had a total calcium intake below 1200 mg. There were no statistically significant differences, neither considering a <75 nmol/l cut-off nor a 50 nmol/l cut-off point in serum levels of vitamin D between different regions of sun exposure (less than 2500 h/year and more than 2500 h/year) in PMO women treated and untreated. In treated women there was statistical difference when considering the results obtained regions of sun exposure and in coastal areas, which could potentially facilitate sun exposure. Not surprisingly, the bone turnover markers are lower in women undergoing treatment than in untreated women.
177
In addition, vitamin D inadequacy has been associated as a contributing factor in a variety of diseases [6,8], as well as an independent risk factor for mortality in the general population [12]. Thus, vitamin D deficiency is now emerging as a particularly important public health concern. In conclusion, even in sunny regions, it is important to highlight the need for improving physician and patient’s knowledge regarding the optimization of calcium intake and vitamin D status in postmenopausal osteoporotic women. This would increase treatment adherence, therefore optimizing bone health by the improvement of the bone response to osteoporosis drugs. Conflict of interest No potential conflict of interest to disclose for this work.
4. Discussion This study is in agreement with the overwhelming amount of evidence confirming the high prevalence of inadequate vitamin D status in Europe, even in southern and sunny countries such as Spain [6,7], despite the potential availability to acquire adequate vitamin D levels by exposure to sunlight. There are important discrepancies when it comes to define such an inadequacy. Recently, the Institutes of Medicine (IOM) revised the recommended 25(OH)D serum levels, setting it at or above 50 nmol/l to sustain bone density, calcium absorption, and to minimize the risk of osteomalacia [3]. However, the International Osteoporosis Foundation (IOF) defines as 75 nmol/l the threshold of 25(OH)D to reduce falls and fractures. Such recommendation has been endorsed by the US Endocrine Society [9]. Nevertheless, if we consider the important methodological problems associated with the measurement of serum 25(OH)D [10], this subtle difference of 25 nmol/l does not seem to be relevant from a public health point of view. In any case, in this study we found that in a sunny country of the Northern Hemisphere such as Spain, there is a large prevalence of vitamin D inadequacy, as defined by 25(OH)D serum levels lower than 50 or 75 nmol/l amongst both untreated and treated PMOW. Moreover it is particularly striking that this high prevalence of serum vitamin D inadequacy also persists amongst postmenopausal osteoporotic women treated with anti-resorptive drugs. Our data also confirm a dietary calcium intake well below the commonly established recommendations [2,3]. All clinical trials concerning anti-resorptive and anabolic therapies were carried out in calcium and vitamin D replete individuals [1]. Even though the impact of calcium and vitamin D insufficiency has not been studied for all the osteoporosis drugs, the available evidence shows that insufficient calcium intake and vitamin D status impair the effects of osteoporosis therapies. This could be the reason for an inadequate response to osteoporosis treatment [11]
Acknowledgements This manuscript is based on work funded by the Grupo CTS 413 (Junta de Andalucía) and RETICEF (Ministerio de Ciencia y Innovación, Spain). References [1] J.M. Quesada Gomez, J. Blanch Rubio, M. Diaz Curiel, A. Diez Perez, Calcium citrate and vitamin D in the treatment of osteoporosis, Clinical Drug Investigation 31 (5) (2011) 285–298. [2] Institute of Medicine (IOM), Dietary Reference Intakes for Calcium and Vitamin D, National Academies Press, Washington, DC, 2011. [3] O. Bruyere, C. De Cock, C. Mottet, A. Neuprez, O. Malaise, J.Y. Reginster, Low dietary calcium in European postmenopausal osteoporotic women, Public Health Nursing 12 (1) (2009) 111–114. [4] P. Lips, D. Hosking, K. Lippuner, J.M. Norquist, L. Wehren, G. Maalouf, S. RagiEis, J. Chandler, The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation, Journal of Internal Medicine 260 (3) (2006) 245–254. [5] M.F. Holick, Vitamin D deficiency, New England Journal of Medicine 357 (3) (2007) 266–281. [6] R. Bouillon, H. Bischoff-Ferrari, W. Willett, Vitamin D and health: perspectives from mice and man, Journal of Bone and Mineral Research 23 (7) (2008) 974–979. [7] N. Binkley, R. Novotny, D. Krueger, T. Kawahara, Y.G. Daida, G. Lensmeyer, B.W. Hollis, M.K. Drezner, Low vitamin D status despite abundant sun exposure, Journal of Clinical Endocrinology and Metabolism 92 (6) (2007) 2130–2135. [8] J.M. Mata-Granados, J.M. Quesada Gomez, M.D. Luque de Castro, Fully automatic method for the determination of fat soluble vitamins and vitamin D metabolites in serum, Clinica Chimica Acta 403 (1–2) (2009) 126–130. [9] M.F. Holick, N.C. Binkley, H.A. Bischoff-Ferrari, C.M. Gordon, D.A. Hanley, R.P. Heaney, M.H. Murad, C.M. Weaver, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, Journal of Clinics in Endocrinology and Metabolism 96 (7) (2011) 1911–1930. [10] G.D. Carter, 25-Hydroxyvitamin D: a difficult analyte, Clinical Chemistry 58 (3) (2012) 486–488. [11] P. Peris, A. Martinez-Ferrer, A. Monegal, M.J. Martinez de Osaba, A. Muxi, N. ˜ 25 hydroxyvitamin D serum levels influence adequate response to Guanabens, bisphosphonate treatment in postmenopausal osteoporosis, Bone 51 (1) (2012) 54–58. [12] M.L. Melamed, E.D. Michos, W. Post, B. Astor, 25-Hydroxyvitamin D levels and the risk of mortality in the general population, Archives of Internal Medicine 168 (15) (2008) 1629–1637.