Vitamin D status varies with age, sex, body mass index (BMI), race, skin color, latitudes, sun exposure, and dietary intake [1]. A level between 52 and 72 nmol/l (21–29 ng/ml) has been defined as a state of insufficiency and a level of <50 nmol/l (<20 ng/ml) as vitamin D deficiency [2]. Vitamin D deficiency has been found to be common among the healthy Saudi population [3, 4]. Homozygous sickle cell disease (SCD-SS) is also common in Saudi Arabia, affecting up to 5.27% of the population [5]. Young Saudi patients with homozygous sickle cell disease were found to have high prevalence of low bone mass [6, 7]. We hypothesize that low 25(OH)D could be one of the influencing factors among Saudi patients with homozygous SCD for decreased bone density. The objectives of this study are as follows: (1) to study the prevalence of low 25(OH)D among Saudi patients with homozygous SCD and to compare it with a healthy Saudi reference group living in the same geographic area and (2) to evaluate the contribution of vitamin D status to bone mass among Saudi patients with homozygous SCD. Demographic data for both patients and control are shown in Supporting Information. The two groups are comparable in age. Alkaline phosphatase and PTH are significantly higher, (Pvalue 0.001 and 0.01, respectively), whereas 25(OH)D is significantly lower (12.58 ± 8.7 vs. 35.95 ± 3.4, P value <0.001) in patients with SCD. The comparison between male and female patients with SCD reveal that age, BMI, and number of blood transfusions were not different between the two groups. Females have significantly higher number of painful crises (3.7 ± 1.6 vs. 2.6 ± 1.9) and hospital admissions (2.29 ± 1.35 vs. 1.96 ± 1.1) per year. The mean percent of hemoglobin S (HbS%) is significantly lower among males compared with females (P value 0.004) and associated with higher mean hemoglobin level (9.2 ± 1.7 vs. 8.3 ± 0.56 mg/dl, P < 0.001). Female patients with SCD have significantly lower 25(OH)D (P < 0.001) and alkaline phosphatase (P < 0.01). The mean PTH level is higher than normal in both gender and significantly higher in females (P < 0.01). Only 6% of female and 10.5% of male patients with homozygous SCD have normal vitamin D status, defined as 25(OH)D level of >30 ng/ml, compared with around 70% of both males and females from the control group. In contrast, 92% of female and 70.9% of male patients with SCD have vitamin D deficiency, defined as 25(OH)D of level <20 ng/ml, compared with only 11% of female and 10% of male individuals in the control group. Table I shows that mean ± SD of BMD, T score, and Z Score of lumbar spine and proximal femur for study and control groups in addition to the prevalence of osteopenia and osteoporosis. In general, the BMD is significantly lower in the study population compared with the control subjects (P < 0.001 for both proximal femur and spine regions). Patients with SCD have higher prevalence of osteopenia and osteoporosis than individuals from the control group. The prevalence of osteoporosis (T score of less than (2.5 SD) among SCD patients with vitamin D deficiency is 73.8% (45/61) in males and 92.4% (85/92) in females. In contrast, the prevalence of osteoporosis among individuals with vitamin D deficiency in the control group is only 30% for males and 63.6% for females. The results of Pearson's correlation coefficient between the baseline clinical and biochemical characteristics of patients with SCD and BMD at lumbar spine and proximal femur are shown in Supporting Information. Lumbar spine BMD positively correlated with age of the patients (r = 0.14, P < 0.05), number of hospital admissions (r = 0.16, P < 0.05), percentage of HbS (r = 0.18, P < 0.01), serum calcium and vitamin D level (r = 0.36 and 0.65 respectively, P < 0.01), and negatively correlated with PTH (r = −0.72, P < 0.01). The correlation between lumbar spine BMD and other parameters studied is not significant. Proximal femur BMD positively correlated with patient age (r = 0.15, P < 0.05), number of hospital admissions (r = 0.22, P < 0.01), BMI (r = 0.14, P < 0.05), serum calcium and vitamin D level (r= 0.21 and 0.76 respectively, P < 0.01), and negatively correlated with PTH (r = −0.57, P < 0.01). The correlation between proximal femur BMD and other parameters did not reach statistical significance. We have shown in this study that the prevalence of vitamin D deficiency in Saudi adult patients with SCD exceeded that of age- and gender-matched healthy controls. Goodman et al. [8] recently evaluated vitamin D status among 142 patients from the USA with SCD and found that 98% of their patients had 25(OH)D of <30 ng/ml. In addition to the difference in race and mean age, only 67% of their patients had homozygous SCD. Few studies also evaluated vitamin D status among children with sickle cell disease [9-11]. Our finding of significantly elevated serum alkaline phosphatase and PTH levels in the presence of low vitamin D status in patients with SCD compared with the control indicates metabolic consequences of the low 25(OH)D. Possible explanations for the low vitamin D status of patients with sickle cell disease include fat soluble vitamin malabsorption [12], decreased vitamin D consumption [13, 14], decreased activity related to repeated crisis and concern regarding the risk of dehydration [15], lower sun exposure for Saudi women compared with men [16], and possibly excess hepatic iron caused by blood transfusions [17, 18]. Low serum 25(OH)D negatively correlated with serum ferritin level in patients with thalassemia and hereditary hemochromatosis [19, 20]. Decreased bone mass among patients with SCD is also multifactorial, with possible causes being hypogonadism and altered sex hormones [21] and hypovitaminosis D [22]. Low 25(OH)D may also contribute to the presentation of painful crisis in patients with SCD, as high prevalence of vitamin D deficiency was found in patients with nonspecific musculoskeletal pain [23, 24]. There is possibility that such risk can be minimized through treatment of vitamin D deficiency [25]. Our study has some limitations, including the fact that endocrine dysfunctions such as hypogonadism were ruled out by clinical evaluation only. Vitamin D intake and markers of iron overload were not evaluated. Additionally, this is a single-center study from Saudi Arabia and the results may differ from other regions. These findings need to be confirmed by larger national or international studies. It will be also interesting to evaluate the effect of correcting hypovitaminosis D and observing the frequency or severity of painful crisis. This cross-sectional study was conducted in the period between January 2009 and June 2010. One hundred and eighty-six Saudi Arabian nationals (86 males and 100 females) known to have homozygous SCD diagnosed on the basis of hemoglobin electrophoresis and who were at least 18 years of age were recruited from the hematology and orthopedic clinics of King Fahd Hospital of the University (KFHU) in the eastern province of Saudi Arabia (Latitude 26°30′ N, Longitude 50°12′ E). All patients originated from the eastern province of Saudi Arabia and were expected to have the Asian (Saudi-Indian) haplotype. Another 200 age- and gender-matched healthy Saudi nationals living in the same geographical area were recruited from the medical students and medical staff of the same hospital as the control group. Patients were excluded if they had only the sickle cell trait or other hemoglobinopaties; if they had stroke or underwent hip replacement; if they had osteoporosis or other diseases that affect vitamin D status such as malabsorption, renal impairment, or elevated hepatic transaminases more than three times normal; and if they had a blood transfusion over the two 2 months before the study. Patients receiving vitamin D supplement or treatment for osteoporosis were also excluded. In addition, females with SCD were excluded if they had amenorrhea for more than 6 months and if they were pregnant or lactating. The study was approved by the ethical and research committee of KFHU and the University of Dammam, Dammam. All study participants gave an informed verbal consent. Such consent is in compliance with the guidelines of the local ethical committee. None of the participants received any form of remuneration for participation in this study. Clinical information was collected from participants on a predesigned data collection sheet and included information such as age, gender, age of the diagnosis of SCD in years, average number of emergency room visits and hospital admissions for painful crisis, history of stroke, history of aseptic necrosis of the head of the femur or hip replacement, and date of last blood transfusion. Height and weight were measured and BMI was calculated as weight in kilograms over the height square in meters (kg/m2). Physical examination was carried out to evaluate for secondary causes of osteoporosis such as hypogonadism or hypercortisolism and possible causes of altered vitamin D metabolism such as chronic liver disease. A blood sample was collected from all participants between 7:00 am and 10:00 am after an overnight fast. Serum samples were stored at −20°C until analysis. Complete blood count, serum calcium (mg/dl), serum phosphorus (mg/dl), and alkaline phosphatase (IU/l) were measured using standard laboratory procedures. Intact PTH (pmol/l) was determined by immunoradiometric assay, and serum level of 25-hydroxy vitamin D (ng/ml) was measured by competitive radioimmunoassay using Wallac1470 Gamma Counter (Wallac, Gaithersburg, MD). Bone mineral density (BMD) measurement of hip area and lumbar spine (Lumbar 1–4 vertebra) using a dual X-ray absorptiometry (DEXA) scan (Hologic, Waltham, MA) was performed for all patients and the control group. The standard deviations (SDs) of the BMD from the young adult normal mean (T-score) and from the age-matched mean (Z-score) were documented. Patients with a T score of less than −2.5 SD were considered to have osteoporosis and those with a T score between −1 and −2.5 SD were considered to have osteopenia. The reference value of T and Z scores were entered in the DEXA machine with software having Asian normative data. Data was analyzed using the Statistical Package for the Social Sciences (SPSS), version 14.0 (Chicago, Illinois). Results were expressed as mean ± SD for continuous variables unless stated otherwise. Continuous variables were compared using a t-test or Mann-Whitney's U test (for nonparametric distribution). Correlations between baseline clinical and laboratory variables and BMD of patients with SCD were determined using Pearson's correlation coefficient. For all tests, significance was defined as P value of <0.05 with a confidence interval (CI) of 95%. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Mir Sadat-Ali*, Abdulmohsen Al-Elq , Haifa Al-Turki , Osama Sultan§, Amein Al-Ali¶, Fatma AlMulhim**, * Department of Orthopedic Surgery, College of Medicine, University of Dammam, King Fahd University Hospital, Alkhobar, Saudi Arabia, Departments of Endocrine and Internal Medicine, College of Medicine, University of Dammam, King Fahd University Hospital, Alkhobar, Saudi Arabia, Departments of Obstetrics and Gynecology, College of Medicine, University of Dammam, King Fahd University Hospital, Alkhobar, Saudi Arabia, § Departments of Internal Medicine and Hematology, College of Medicine, University of Dammam, King Fahd University Hospital, Alkhobar, Saudi Arabia, ¶ Department of Biochemistry, College of Medicine, University of Dammam, Alkhobar, Saudi Arabia, ** Department of Radiology, College of Medicine, University of Dammam, King Fahd University Hospital, Alkhobar, Saudi Arabia.

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