Maya Rahme

Hypovitaminosis D in the Middle East and North Africa: Prevalence, risk factors and impact on outcomes

Background: The Middle East and North Africa (MENA) region registers some of the highest rates of hypovitaminosis D worldwide. Aim: We systematically reviewed the prevalence of hypovitaminosis D, rickets and osteomalacia, their predictors and impact on major outcomes, in the region. Methods: Medline, Pubmed and Embase search engines, entering keywords and concepts, combined with individual countries of interest, were used. Search was limited years 2000–2012; and review articles were used for the period preceding year 2000. Results: Rickets and osteomalacia still occur in this sunny region. Hypovitaminosis D prevails, with rates varying 30–90%, considering a desirable serum 25 hydroxy-vitamin D [25(OH)D] of 20 ng/ml. Advancing age, female gender, multi-parity, clothing style, season, socio-economic status and urban living are recognized predictors of hypovitaminosis D in adults. Prolonged breastfeeding without vitamin D supplementation and low dietary calcium intake are the recognized risk factors for rickets and hypovitaminosis D in children.. Associations with pain score and disease activity in rheumatologic disorders, viral load and interleukins in hepatitis C, BMI, lipids and insulin sensitivity, blood pressure, heart failure and mortality are described. Sun exposure in adults decreased prevalence of metabolic syndrome in one study. Few randomized vitamin D trials revealed that the majority of mothers or children failed to achieve a desirable 25(OH)D level, even with doses by far exceeding current recommendations. A trial in adolescent girls reveals substantial bone and lean mass increments. Conclusion: Hypovitaminosis D is prevalent in MENA. The lack of populations based studies, gaps in studies in infants, pre-pubertal children and pregnant women, hinder the development of region specific guidelines and constitute a major obstacle to impact this chronic and most often subclinical disease.

Cancer-associated bone disease

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.

Do Desirable Vitamin D Levels Vary Globally

Vitamin D insufficiency is a common problem worldwide, with a varying prevalence depending on the population of interest and cutoff used to define insufficiency. The medical literature has witnessed an explosion in the number of vitamin D publications over the last three decades, most convincingly supporting a beneficial effect of vitamin D on musculoskeletal parameters. This led the Institute of Medicine (IOM) to issue an update in 2011 with an increase in the recommended vitamin D intake across all age groups and to set the desirable level at 50 nmol/L. This compares modestly to the desirable level recommended by the Endocrine Society (ES) of 75 nmol/L, which is similar to that recommended by the International Osteoporosis Foundation for older individuals. While the IOM Committee focused on the population needs in North America, the Endocrine Society tried to target high-risk populations. Some of the lowest vitamin D levels are recorded in black subjects and in non-western populations, populations in whom data on fractures and falls are scarce. Information using surrogate markers for the beneficial effect of vitamin D action on musculoskeletal health has many limitations, even in Caucasian subjects where it is the most available. The calcium–vitamin D economy in blacks seems different, and the desirable vitamin D level to optimize musculoskeletal health may be lower than that of Caucasians. Furthermore, some evidence from association studies suggests an increase in the risk of fractures in blacks, and possibly Asians, at 25(OH)D levels exceeding the desirable level for Caucasians. In view of this apparent divergence, the lack of solid outcome data in other ethnic and racial groups, and the multitude of modulators that affect vitamin D metabolism and action, the notion of a global desirable vitamin D level to date is not tenable.

Impact of Calcium and Two Doses of Vitamin D on Bone Metabolism in the Elderly: A Randomized Controlled Trial

The optimal dose of vitamin D to optimize bone metabolism in the elderly is unclear. We tested the hypothesis that vitamin D, at a dose higher than recommended by the Institute of Medicine (IOM), has a beneficial effect on bone remodeling and mass. In this double‐blind trial we randomized 257 overweight elderly subjects to receive 1000 mg of elemental calcium citrate/day, and the daily equivalent of 3750 IU/day or 600 IU/day of vitamin D3 for 1 year. The subjects’ mean age was 71 ± 4 years, body mass index 30 ± 4 kg/m2, 55% were women, and 222 completed the 12‐month follow‐up. Mean serum 25 hydroxyvitamin D (25OHD) was 20 ng/mL, and rose to 26 ng/mL in the low‐dose arm, and 36 ng/mL in the high‐dose arm, at 1 year (p < 0.05). Plasma parathyroid hormone, osteocalcin, and C‐terminal telopeptide (Cross Laps) levels decreased significantly by 20% to 22% in both arms, but there were no differences between the two groups for any variable, at 6 or 12 months, with the exception of serum calcitriol, which was higher in the high‐dose group at 12 months. Bone mineral density (BMD) increased significantly at the total hip and lumbar spine, but not the femoral neck, in both study arms, whereas subtotal body BMD increased in the high‐dose group only, at 1 year. However, there were no significant differences in percent change BMD between the two study arms at any skeletal site. Subjects with serum 25OHD <20 ng/mL and PTH level >76 pg/mL showed a trend for higher BMD increments at all skeletal sites, in the high‐dose group, that reached significance at the hip. Adverse events were comparable in the two study arms. This controlled trial shows little additional benefit in vitamin D supplementation at a dose exceeding the IOM recommendation of 600 IU/day on BMD and bone markers, in overweight elderly individuals.

Effects of hormone therapy on blood pressure.

ObjectiveAlthough hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies. MethodsComprehensive Ovid MEDLINE searches were conducted for the terms “hypertension” and either of the following “hormone therapy and menopause” or “selective estrogen receptor modulator” from year 2000 to November 2013. ResultsIn vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women. ConclusionsLarge randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment.

Vitamin D Metabolism in Bariatric Surgery

Hypovitaminosis D is common in obese patients and persists after roux-en-Y gastric bypass and sleeve gastrectomy. Several societies recommend screening for vitamin D deficiency before bariatric surgery, and replacement doses of 3000 IU/d and up to 50,000 IU 1 to 3 times per week, in case of deficiency, with periodic monitoring. These regimens are mostly based on expert opinion. Large trials are needed to assess the vitamin D dose response, by type of bariatric surgery, and evaluate the effect on surrogate markers of skeletal outcomes. Such data are essential to derive desirable vitamin D levels in this population.

Limitations of platform assays to measure serum 25OHD level impact on guidelines and practice decision making

CONTEXT Liquid Chromatography Mass Spectroscopy (LC-MS/MS) is the preferred method to measure 25 hydroxyvitamin D (25OHD) levels, but laboratories are increasingly adopting automated platform assays. OBJECTIVE We assessed the performance of commonly used automated immunoassays, with that of LC-MS/MS, and the National Institute of Standards and Technology (NIST) reference values, to measure 25OHD levels. METHODS/SETTING We compared serum 25OHD levels obtained from 219 elderly subjects, enrolled in a vitamin D trial, using the Diasorin Liaison platform assay, and the tandem LC-MS/MS method. We also assessed the performance of the Diasorin and Roche automated assays, expressed as mean % bias from the NIST standards, based on the vitamin D External Quality Assessment Scheme (DEQAS) reports, from 2013 to 2017. RESULTS Serum 25OHD levels were significantly lower in the Diasorin compared to LC-MS/MS assay at baseline, 18.5 ± 7.8 vs 20.5 ± 7.6 ng/ml (p < 0.001), and all other time points. Diasorin (25OHD) = 0.76 × LC-MS/MS (25OHD) + 4.3, R2 = 0.596. The absolute bias was independent of 25OHD values, and the pattern unfit for any cross-calibration. The proportion of subjects considered for vitamin D treatment based on pre-set cut-offs differed significantly between the 2 assays. There also was wide variability in the performance of both automated assays, compared to NIST reference values. CONCLUSION The performance of most widely used automated assays is sub-optimal. Our findings underscore the pressing need to re-consider current practices with regard to 25OHD measurements, interpretation of results from research studies, meta-analyses, the development of vitamin D guidelines, and their relevance to optimizing health.

Vitamin D in the Middle East and North Africa

Purpose The Middle East and North Africa (MENA) region registers some of the lowest serum 25‑hydroxyvitamin D [25(OH)D] concentrations, worldwide. We describe the prevalence and the risk factors for hypovitaminosis D, completed and ongoing clinical trials, and available guidelines for vitamin D supplementation in this region. Methods This review is an update of previous reviews published by our group in 2013 for observational studies, and in 2015 for randomized controlled trials (RCTs) from the region. We conducted a comprehensive search in Medline, PubMed, and Embase, and the Cochrane Library, using MeSH terms and keywords relevant to vitamin D, vitamin D deficiency, and the MENA region, for the period 2012–2017 for observational studies, and 2015–2017 for RCTs. We included large cross-sectional studies with at least 100 subjects/study, and RCTs with at least 50 participants per arm. Results We identified 41 observational studies. The prevalence of hypovitaminosis D, defined as a 25‑hydroxyvitamin D [25(OH)D] level below the desirable level of 20 ng/ml, ranged between 12–96% in children and adolescents, and 54–90% in pregnant women. In adults, it ranged between 44 and 96%, and the mean 25(OH)D varied between 11 and 20 ng/ml. In general, significant predictors of low 25(OH)D levels were female gender, increasing age and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude. We retrieved 14 RCTs comparing supplementation to control or placebo, published during the period 2015-2017: 2 in children, 8 in adults, and 4 in pregnant women. In children and adolescents, a vitamin D dose of 1000–2000 IU/d was needed to maintain serum 25(OH)D level at target. In adults and pregnant women, the increment in 25(OH)D level was inversely proportional to the dose, ranging between 0.9 and 3 ng/ml per 100 IU/d for doses ≤2000 IU/d, and between 0.1 and 0.6 ng/ml per 100 IU/d for doses ≥3000 IU/d. While the effect of vitamin D supplementation on glycemic indices is still controversial in adults, vitamin D supplementation may be protective against gestational diabetes mellitus in pregnant women. In the only identified study in the elderly, there was no significant difference between 600 IU/day and 3750 IU/day doses on bone mineral density. We did not identify any fracture studies. The available vitamin D guidelines in the region are based on expert opinion, with recommended doses between 400 and 2000 IU/d, depending on the age category, and country. Conclusion Hypovitaminosis D is prevalent in the MENA region, and doses of 1000–2000 IU/d may be necessary to reach a desirable 25(OH)D level of 20 ng/ml. Studies assessing the effect of such doses of vitamin D on major outcomes, and confirming their long term safety, are needed.