Vitamin D status correction in Saudi Arabia: an experts’ consensus under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases (ESCEO)

During the last decade, no other micronutrient has gained and sustained massive interest in the fields of health and biomedical research community as much as vitamin D. As a very active research area, many of the physiologic effects of vitamin D in both mineral metabolism and extra-skeletal effects have already been covered, but not without its own share of controversies, reinforcing the need for further (despite an abundance of) investigations. Among the roster of widely debated areas in vitamin D, the cutoff used for defining vitamin D deficiency, the methods used for measuring vitamin D status and for medical practitioners as well as the informed general public, and the right treatment for vitamin D deficiency are included.

Given that the management for vitamin D deficiency remains an evolving focus in biomedical research, several well-recognized international organizations have created their own evidence-based guidelines and consensuses for the general public [1, 2], including recommendations based on harder outcomes such as the preservation of bone health [3], prevention of fractures [4], and of nutritional rickets [5]. One possible caveat from the widely used guidelines is that they were tailored mostly for the European and North American populations whose geographical location, climate conditions, culture of outdoor social activities, not to mention the ethnicity itself, vary widely from other populations. The differences in the factors mentioned, which are considered major determinants of vitamin D status, therefore cast doubt on the suitability of some international recommendations to populations coming from other regions in the world. For instance, the global consensus defines vitamin D deficiency as serum 25(OH)D < 30 nmol/l [5], while the guidelines and position statements adopted in the USA, central Europe, South America, and Korea define “deficiency” as <50 nmol/l as the more appropriate cutoff for use in their populations [6‐8], twice the level adopted by the International Osteoporosis Foundation (IOF), which is <25 nmol/l [9]. The disparities in vitamin D cutoffs, not to mention the inconsistencies in terms such as deficiency, “insufficiency,” “hypovitaminosis D,” and “inadequacy,” among experts, are just a small fraction in the litany of other valid arguments (i.e., candidates for vitamin D screening and supplementation and type of 25(OH)D metabolite to measure using what method), making this seemingly straightforward, easy to treat micronutrient deficiency much more complicated. It is not surprising therefore that some national/regional societies find it most optimal to tailor the management for vitamin D deficiency in accordance to what they deem fit for their population [10, 11].

There is a wealth of epidemiologic evidence that vitamin D deficiency and its concomitant risk factors in the Middle Eastern region, and the Kingdom of Saudi Arabia (KSA) in particular, are very common in both children and adults [12‐14]. Despite the overwhelming data, little has been done to address this epidemic on a clinical setting. Different vitamin D guidelines from other parts of the world have been produced, most of which are dependent on the target disease (osteoporosis, osteomalacia, falls, etc.) [3‐6, 15‐17]. The present consensus guidelines are tailored to geographical location and known risk factors common to the Saudi general population. Recommendations for the Gulf countries including Saudi Arabia, with the exception of UAE [18], are still lacking. These countries are highly reliant on other existing guidelines, which may prove to be inapplicable to regional settings. Hence, a task force was created to address the vitamin D deficiency pandemic in the country with the objective of generating a unified and tailored consensus for KSA residents and citizens.

The Prince Mutaib Chair for Biomarkers of Osteoporosis (PMCO) in King Saud University (KSU), Riyadh, KSA, assembled local 12 local experts in the fields of endocrinology, clinical biochemistry, and clinical nutrition and invited two advisers from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), who are experts in bone diseases, health economics, and epidemiology. The selection of local and international experts commenced during the 2nd International Vitamin D Symposium conducted in Riyadh, Saudi Arabia, last January 20–21, 2016. Time frame and draft outline were discussed.

A survey was also circulated among experts to determine the experts’ consensus on the most suitable diagnostic cutoff of vitamin D deficiency to be used in Saudi Arabia, the group of populations most eligible for screening, method of measurement and type, dose and duration of supplementation depending on vitamin D deficiency severity, and other accompanying risk factors.

The most common definitions used for the diagnosis of vitamin D statuses are described in Table 1. While the cutoffs vary with respect to who is vitamin D deficient, most of the major international institutions that have endorsed them are in agreement that patients whose serum 25(OH)D levels fall below 50 nmol/l (20 ng/ml) require correction [1‐5, 9]. Hence, the consensus of local experts is to adapt the following cutoffs on the basis of impact on bone health:

The recommended cutoff for vitamin D sufficiency that is much lower than the one advocated by the US Endocrine Society [25(OH)D > 75 nmol/l (>30 ng/ml)] was also based on several local observational studies that noted normal levels of PTH despite severely low levels of circulating 25(OH)D [19], lack of association between intact PTH and 25(OH)D [20], and the absence of 25(OH)D threshold at which PTH level suppression is evident [21]. This apparent confusion is also related to the target, i.e., the general population or frail, osteoporosis, possibly undernourished elderly. Nevertheless, elevated PTH levels in response to low 25(OH)D among healthy Saudis were observed only at the “insufficient” cutoff (<50 nmol/l or 20 ng/ml), although inconsistent and at varying degrees, depending on the method used [22]. This threshold for insufficiency reinforces an earlier large-scale study which was also done in the Middle-East last 2011, that a 25(OH)D threshold of 50 nmol/l is enough for PTH suppression, at least among subjects with normal renal function, for the prevention of secondary hyperparathyroidism [23]. These more recent findings supersede the earlier consensus of using 25(OH)D < 37.5 nmol/l (15 ng/ml) for the MENA region (2007) [24] and <70 nmol (28 ng/ml) (for KSA (2011) [25] as cutoffs for vitamin D insufficiency.

Despite overwhelming evidence that vitamin D deficiency is common in the Saudi community across all age groups, vitamin D testing for the general population is not justified and practical in economic terms. Hence, the task force does not endorse population-based screening and recommends limited vitamin D testing for selected populations at highest risk for vitamin D deficiency and who will benefit the most from vitamin D status correction.

High-risk minority groups mentioned above with a confirmed diagnosis of vitamin D deficiency should receive higher than normal doses than the general population. While other non-skeletal metabolic abnormalities linked to vitamin D deficiency in the Saudi population such as obesity [26], metabolic syndrome [27], type 2 diabetes mellitus [28], and auto-immune diseases [29] may benefit from vitamin D status correction, mandatory screening is not recommended unless the patient has other risk factors and clinical features consistent with the ones mentioned above.

It has been established that circulating total 25(OH)D (including both D₂ and D₃ forms) is the best marker for vitamin D status as compared to other metabolites. Nonetheless, with the increase in the possible number of methods to assess vitamin D status, discrepancies in the validity and reliability of results were inevitable and still exist despite efforts for standardization, making reported prevalence in a given cohort largely dependent on the method used [30‐32]. Currently, the liquid chromatography–tandem mass spectrometry (LC-MS/MS) is the gold standard for measuring total 25(OH)D and other vitamin D metabolites for its high sensitivity and selectivity [33]. In major tertiary hospitals in KSA however, automated immunometric assays are preferred and major differences in results have been confirmed in local studies, mostly by Sadat and colleagues [22, 34, 35]. Well-known standardization systems include the Vitamin D External Quality Assessment Scheme (DEQAS) [36], of which PMCO in KSU is an accredited partner. The task force recommends caution in the interpretation and treatment of patient’s vitamin D status in cases where the reliability of method used is questionable, especially in the absence of other clinical features and risk factors consistent with the skeletal effects of chronic vitamin D deficiency. The task force also recommends standardization of serum 25(OH)D tests and other vitamin D metabolites in all clinical laboratories in Saudi Arabia from internationally recognized accreditation agencies such as College of American Pathologists (CAP) and DEQAS, among others.

The PMCO task force in cooperation with the ESCEO working group has addressed all the major aspects of vitamin D deficiency management in the Saudi population and endorses its consensus statements for general clinical practice not only in Saudi Arabia but in the Middle East in general. Vitamin D supplementation/correction is advised in all persons whose serum 25(OH)D falls below 50 nmol/l (20 ng/ml), and achieving a target of 75 nmol/l (30 ng/ml) is particularly suited for frail, osteoporotic, and older patients. The group also encourages conducting well-designed clinical trials in the region that will address risks and benefits, economic implications of vitamin D status correction and investigations on the treatment persistence, and compliance to vitamin D treatment in the region. The final recommendations assigned were based on the best available evidence at the time of submission of these guidelines to the journal.