Журнал «Боль. Суставы. Позвоночник» 3 (23) 2016

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The first module of workshop covered the relationship of vitamin D status and various chronic diseases. 

Paula Freitas (Porto, Portugal) noted the link between vitamin D deficiency and diabetes mellitus (DM) and presented data of various studies on this topic. For example, in the Nurses’ Health Study (Pittas A.G. et al., 2006) a potential beneficial role for both vitamin D and calcium intake in reducing the risk of type 2 diabetes had been suggested. It had been estimated, that women, who consumed more than 800 IU per day of vitamin D had 23 % lower risk for developing incident type 2 DM in comparing with women who consumed less than 200 IU per day. Similarly, in the Women’s Health study (Liu S. et al., 2005) an intake of 511 IU per day or more of vitamin D had been associated with 27 % lower risk of developing type 2 DM compared with an intake of 159 IU per day or less. Y. Song at al. (2013) had included 21 prospective studies and a total of 76,220 participants and had calculated the risk of type 2 DM developing, according to 25(OH)D baseline level. There had been a 38 % lower risk of type 2 DM developing in the highest tertile of 25(OH)D compared with the lowest tertile with little he-terogeneity between studies. A linear analysis had shown that a 4 ng/ml increment in 25(OH)D levels was associated with 4 % lower risk of type 2 DM. The effect of vitamin D supplementation on glycemia or type 2 DM incident had been reported in several trials with mixed results. In trials that had been included participants with normal glucose tolerance at baseline, vitamin D supplementation had a neutral effect on measures of glycemia, including fasting plasma glucose and insulin resistance and no effect on incident type 2 DM. The potential effect of vitamin D supplementation was more prominent among people with high risk of DM (Pittas A.G. et al., 2007). However, M.B. Davidson et al. (2013) had found no effect of high-dose vitamin D supplementation on insulin secretion, insulin sensitivity or incident DM in population with impaired fasting glycemia or impaired glucose tolerance and low vitamin D levels. In recent double-blind randomized clinical trial (Al-Sofiani M.E., 2014) it had been estimated that vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved β-cell activity in vitamin D deficient type 2 DM with no significant changes in HbA1c or insulin sensitivity. 

Many effects of vitamin D on the pathophysiology of type 1 DM had been described, including changes in the immune-mediated destruction, but also the β-cell itself. It also had been reported that specific vitamin D polymorphism interacted with the HLADRB1 allele, which predisposed to type 1 DM. The prevalence of type 1 DM had been inversely correlated with ultraviolet radiation and altitude, suggesting that low vitamin D synthesis might be important in the pathogenesis of type 1 DM. Lack of vitamin D supplementation in infancy had been associated with increased risk of type 1 DM later in life. 

In the conclusion P. Freitas accented, that applying international guidelines on vitamin D supplementation using in small daily doses of vitamin D (500–1000 IU) might contribute to reduce the burden of diabetes by preventing vitamin D deficiency. 

The secretary of Ukrainian division of EVIDAS Natalyia Balatska (D.F. Chebotarev Institute of Gerontology NAMS of Ukraine, Ukrainian scientific center of osteoporosis, Kyiv, Ukraine) in her report emphasized that recent studies had proved the relationship between vitamin D deficiency and several autoimmune disorders, including rheumatoid arthritis (RA). N. Balatska presented data of studying the associations between serum level of 25(OH)D and disease activity in patients with rheumatoid arthritis. 93 patients aged 27 to 80 yrs with exacerbation of RA had been examined. Control group had consisted of 93 practically healthy persons. It had been estimated that only 7.6 % of patients with RA had normal blood level of vitamin D (30 ng/ml and over). Vitamin D insufficiency (21–29 ng/ml) had taken place in 37.6 %, vitamin D deficiency (lower than 20 ng/ml) — in 54.8 % of patients and 13.98 % subjects with RA had severe vitamin D deficiency. The risk of a high RA activity had significantly increased when the level of 25(OH)D had been lower than 20 ng/ml (OR = 3.00; 95% CI: 1.01–8.86; p < 0.05). Also 25(OH)D had been associated with erythrocyte sedimentation rate, C-reactive protein level, Hb level and DAS-28 index. So, vitamin D deficiency could be important factor in worsening of RA. And vitamin D supplementation might be useful for improving disease activity in patients with RA.

Association between subclinical and overt hyperthyroi-dism, vitamin D and bone mineral density (BMD) changes were in focus of report of Volodymyr Pankiv, Professor of Endocrinology at the Ukrainian Scientific Centre of Endocrine Surgery (Kyiv, Ukraine). Prof. V. Pankiv noted, that the severity of hyperthyroidism correlated with the decrease in BMD and the increase in fracture risk; women over 65 years old with a TSH < 0.1 had the greatest fracture risk. Nevertheless, normalizing thyroid function alone was able to effect some reversal of bone loss. Also Prof. V. Pankiv mentioned, that subclinical hyperthyroidism was surprisingly prevalent, and took place in up to 24 % of those over age 60 who received thyroxine replacement. Subclinical hyperthyroi-dism contributed to an estimated additional 1 % bone loss per year in those individuals. Patients with thyroid autoimmune diseases had lower blood level of vitamin D by comparison to a general population. However, there were few studies examining vitamin D status in patients with subclinical and overt hyperthyroidism. Prof. V. Pankiv presented study results of vitamin D blood level in 80 patients of reproductive age with subclinical and overt hyperthyroidism and its’ possible influence on disease progression. Vitamin D level (14.9 ± 1.8 ng/ml) had been significantly lower in patients with diffuse toxic goiter in the state of sub- and decompensation, comparatively with the group of women with diffuse toxic goiter in the state of stabile thyrotoxicosis compensation (21.2 ± 2.4 ng/ml) and control group (23.9 ± 2.7 ng/ml). The results of correlation analysis had testified the presence in patients with diffuse toxic goiter in the state of thyrotoxicosis sub- and decompensation significant negative connection between vitamin D range and level of thyrotropin receptor antibodies (r = –0.47; р < 0.05). Frequency of BMD disorders in patients with thyrotoxicosis syndrome had been 52.7 %, including osteopenia in 40 % and osteoporosis in 12.7 %. A basic factor that had resulted in the decline of BMD in patients with thyrotoxicosis syndrome had been excessive products of thyroid hormones, and also TSH-suppressive doses of levothyroxine. It was concluded, that the vitamin D blood level depended on the degree of thyrotoxicosis compensation. Significant association between 25(OH)D range and level of thyrotropin receptor antibodies had been established in the group of patients with an uncompensated thyrotoxicosis.

Manuel Bicho (Lisbon, Portugal) told about role of vitamin D deficiency in cardiovascular diseases. He emphasized, that normal vitamin D status played role in lowering of systolic blood pressure, vascular resistance, arterial intima thickness and total cholesterol level, in increasing of insulin secretion/sensitivity and in decreasing of inflammatory cytokines. Also M. Bicho characterized some potential mechanisms through which vitamin D deficiency might affect cardiovascular diseases. 

Luis Costa (Lisbon, Portugal) told about vitamin D deficiency in patients with cancer. He noted that vitamin D had potential anticancer effects mediated through the vitamin D receptor (VDR) by promotion of cell differentiation and apoptosis, inhibition of cellular proliferation, inhibition of angiogenesis and inhibition of tumor cell invasion. It had been proved that high VDR expression in prostate tumors was associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression (Hendrickson W. et al., 2011). A meta-analysis of published randomized controlled trials had shown that vitamin D supplementation consistently decreased total cancer mortality but not incidence (Keum N., 2014). That data suggested that vitamin D might be more relevant for survival. 

Volodymyr Novoshytskyy (Department of dentistry, Shupyk National Medical Academy of Postgraduate Education MH of Ukraine, Kyiv, Ukraine) presented study results of vitamin D level in patients with chronic periodontitis (CHP). Serum concentration of 25(OH)D had been examined in 198 patients with CHP. Tooth loss age depending on the level of vitamin D had been evaluated in patients with CHP. Deficiency and insufficiency of vitamin D had been found in 73.7 % patients with chronic periodontitis. No significant correlation between vitamin D levels in patients with severe and moderate periodontitis had been observed. The significant correlation between tooth loss and age in patients with CHP that had vitamin D deficiency and insufficiency had been estimated.

The prevalence of vitamin D deficiency and insufficiency in Ukrainian population was presented in the report of Prof. Vladyslav Povoroznyuk (D.F. Chebotarev Institute of Gerontology NAMS of Ukraine, Ukrainian scientific center of osteoporosis, Kyiv, Ukraine).The study of vitamin D status in Ukrainian population had consisted of two stages. On the first stage the 25(OH)D, iPHT levels and BMD had been examined in 1575 people from different regions of Ukraine. The vitamin D deficiency (lower than 20 ng/ml) was determined in 81.8 % of people, vitamin D insufficiency (21–29 ng/ml) — in 13.6 %. Normal blood level of vitamin D (30 ng/ml and over) had only 4.6 %. Secondary hyperthyroidism was determined in 11.9 % of population. The highest levels of vitamin D were in age group of 20–34 yrs, the lowest one — in age group of 35–44 yrs. In people aged over 50 yrs highest levels of vitamin D were in age group of 50–59 yrs and the lowest — in 80–89 yrs. The residents of southern region of Ukraine had the highest mean level of vitamin D, and the lowest one had been determined in people from western part of the country. On the second stage of the study 300 particularly healthy children aged 10–18 yrs from different regions of Ukraine had been observed during October and November (so, the influence of seasonal factors on 25(OH)D levels had been excluded). The prevalence of vitamin D deficiency was determined in 92.2 % of examined children, the vitamin D insufficiency — in 6.4 %. 1.4 % of children had the normal blood level of 25(OH)D. The highest prevalence of vitamin D deficiency in children (91.5 %) was determined in western part of Ukraine. Prof. V. Povoroznyuk concluded that high prevalence of vitamin D deficiency in Ukrainian population stimulated doctors to search for the effective methods of treatment and further prophylaxis of the disorder. And one of the way of the correction and prophylaxis of vitamin D deficiency and insufficiency was the using of fortified food, for example, the backing of high-fiber bread with a cholecalciferol concentration of 25 µg per 277 g had been developed. 

Skeletal muscle changes depending on vitamin D level in women of various ages was another highlight of the report. It had been noted that vitamin D deficiency and insufficiency was one of the factors that lead to sarcopenia — the geriatric syndrome characterized by the progressive and generalized loss of muscle mass, strength and performance. Vitamin D levels declined with age and cutaneous vitamin D levels were up to four times lower in older compared with younger individuals. An epidemiological study in 18 countries located at different latitudes had been evaluated 25(OH)D concentration in postmenopausal women and in result had been observed low concentrations almost throughout the planet. 64 % of the participants had inadequate concentrations (Hilger J. et al., 2014). Vitamin D supplementation alone in postmenopausal women was an expressive protective factor against the occurrence of sarcopenia, permitting an important increase in muscle strength and control of the progressive loss of lean mass (Cangussu L.M. et al., 2015). Prof. V. Povoroznyuk presented data of two Ukrainian studies — the evaluation of skeletal muscle and vitamin D level in women of various ages and the investigation of role of vitamin D and exercises in correction of age-related skeletal muscle changes in postmenopausal women. The first study had involved 122 healthy women aged 20–83 years. According to the gerontological classification, the examined women had been divided into groups: younger — up to 44 years (n = 35), middle — 45–59 years old (n = 26), older — 60–74 years (n = 44), senile age — 75–89 years (n = 17). Lean mass of the total body, upper and lower extremities, as well as strength of skeletal muscle, functional capacity of skeletal muscle and the level of 25(OH)D had been evaluated in all studying groups. A significant correlation between parameters of lean mass and the level of 25(OH)D in women of middle age had been determined. Also a significant correlation between the skeletal muscle functionality and level of 25(OH)D in women of older age had been found. The second study had involved 38 postmenopausal women aged 53–82 years (mean age — 67.00 ± 7.08 yrs; mean height — 160.31 ± 6.83 cm; mean weight — 63.25 ± 8.59 kg, body mass index — 24.62 ± 3.09 kg/m2), who were free of systemic disorders and did not take any medications known to affect skeletal and muscle metabolism. All women had been divided into the control group (n = 10), group of women who took an individually-targeted vitamin D therapy (n = 11) and group of women who took an individually-targeted vitamin D therapy and OTAGO Exercise Programme during 12 months (n = 17). It had been determined that using individually-targeted vitamin D therapy and OTAGO Exercise Programme during 12 months significantly improved daily activity, muscle strength, quality of life and reduced fall frequency in postmenopausal women. Further large randomized controlled trials were required with a longer follow-up period in order to assess the safety profile of vitamin D supplementation in younger and older people before it would be recommended as a treatment for sarcopenia in clinical practice.

Luis Raposo (Porto, Portugal) told about prevalence of hypovitaminosis D in Portugal (PORMETS study). He emphasized that hypovitaminosis D was very prevalent (85.6 %), and the prevalence was higher in overweight people with sedentary lifestyle, particularly in the period December — May. The correlation between PHT and 25(OH)D was weak and not statistical significant. Mean 25(OH)D level (14.11 ng/ml) was relatively low in comparing with other European and worldwide population. Although several European countries had adopted measures at national level to vitamin D supplementation and fortification, there was no legislation in Portugal about food fortification. Vitamin D supplementation (700–800 UI/day) in adults was only recommended in the elderly (over 65 yrs) and for subjects with osteoporosis, osteopenia or at major risk of osteoporosis. 

The correlation between vitamin D blood level, bone mineral density (BMD) and trabecular bone score (TBS) in men were in focus of the report of Prof. Mário Rui Mascarenhas (Medical Faculty of the University of Lisbon, Santa Maria Hospital, Lisbon, Portugal). 56 normal adult men without chronic diseases, influencing on the bone mass, had been included in the study. The measurement of the 25(OH)D, iPTH and osteocalcin blood levels had been conducted as well as BMD at the L1-L4, total fat and lean body masses had been determined by DXA and TBS at the L1-L4 had been evaluated. Vitamin D deficiency had been estimated in 55.3 % of men, vitamin D insufficiency took place in 30.4 %, and only 14.3 % had normal vitamin D status. Significant 25(OH)D serum levels correlations with weight, BMD, total fat body mass and TBS (L1-L4) had been found. Men with vitamin D deficiency had higher weight and lower TBS in comparison with groups of insufficiency and normal vitamin D status. It was concluded that blood level of 25(OH)D played an important role on the bone quality accessed by TBS, as normal men with low 25(OH)D might have worse bone quality and it was possible that PTH might also act negatively in the bone qua-lity. Prof. M.R. Mascarenhas noted that further studies were needed on a larger cohort and it might be worth to investigate also men with osteomalacia.

Prof. Ana Paula Barbosa (Endocrinology University Clinic of the University of Lisbon, Endocrinology, Diabetes and Metabolism Department, Santa Maria Hospital, Lisbon, Portugal) presented preliminary results of study the variation of vitamin D blood levels through summer and winter in a Portuguese young adult population. In 268 healthy adults (190 women, 78 men), aged 18 to 35 years, fasting blood had been taken to measure 25(OH)D, iPTH, calcium, phosphorus, liver and renal functions, TSH and other hormones, in summer and in winter. Significant variations summer/winter of both 25(OH)D and iPTH blood levels had been found. Also, the means of 25(OH)D had been relatively low, suggesting that many young adults had deficiency/insufficiency of vitamin D, such as it was described in other south European countries.

Natalyia Balatska (Kyiv, Ukraine) paid attention to the treatment of vitamin D status abnormalities. It had been noticed, that according to Practical guidelines for supplementation of vitamin D and treatment of deficits in Central Europe recommended vitamin D intakes in general population and groups being at risk of vitamin D deficiency were: 

— in case of vitamin D deficiency (25(OH)D level less than 20 ng/ml) — therapeutic doses;

— in case of suboptimal vitamin D level (21–29 ng/ml) — moderate increasing of vitamin D daily dose;

— in case of adequate vitamin D status (30–49 ng/ml) — the supplementation scheme and dose should be maintained;

— in case of high vitamin D supply (50–100 ng/ml) — the supplementation dose can be maintained for lower concentrations of this range or moderately decreased for higher concentrations;

— in case of risk for overall health outcomes (100–200 ng/ml) it was necessary to reduce of vitamin D supplementation until obtaining target 25(OH)D concentration;

— in case of toxic level of vitamin D (over 200 ng/ml) it was necessary to require cessation of vitamin D supplementation until obtaining target 25(OH)D concentration; such people might need specific medical intervention to correct toxic effects. 

Recommended therapeutic doses for patients with verified vitamin D deficiency were 7,000–10,000 IU/day (175–250 μg/day), depending on body weight, or 50,000 IU/week (1250 μg/week). Recommended treatment duration was 1–3 months. Recommended maintenance doses: 800–2,000 IU/day (20.0–50.0 μg/day), depending on body weight, was recommended between September and April; 800–2,000 IU/day (20.0–50.0 μg/day), depending on body weight, was recommended throughout the whole year, if sufficient skin synthesis of vitamin D was not ensured in the summer; the elderly (65 years and above) should be supplemented with 800–2,000 IU/day (20.0–50.0 μg/day) throughout the whole year, because of the reduced efficacy of vitamin D skin synthesis. It was reasonable to reevaluate 25(OH)D concentration after 3–4 months and then to monitor semi-annually, especially with the coincidence of exacerbating factors such as obesity that needs therapeutic doses covering the upper range of standard dosage. In cases with severe deficits, monitoring of serum calcium and phosphate concentrations, total alkaline phosphatase activity and calciuria rate in spot urine (Ca/CR ratio) might be desirable. 

The ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) recommended that 50 nmol/l (i.e. 20 ng/ml) should be the minimal serum 25(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Below that threshold, supplementation was recommended at 800 to 1000 IU/day. Vitamin D supplementation was safe up to 10,000 IU/day (upper limit of safety) resulting in an upper limit of adequacy of 125 nmol/l 25(OH)D. 

Daily consumption of calcium- and vitamin-D-fortified food products (e.g. yoghurt or milk) could help improve vitamin D intake. Above the threshold of 50 nmol/l, there was no clear evidence for additional benefits of supplementation. On the other hand, in fragile elderly subjects who were at elevated risk for falls and fracture, the ESCEO recommends a minimal serum 25(OH)D level of 75 nmol/l (i.e. 30 ng/mL), for the greatest impact on fracture. 

For patients with osteoporosis and osteoarthritis individual targeted therapy of vitamin D deficiency consisted of saturation period, the duration of which was calculated individually, and maintenance therapy period, during which patients took it constantly. Therapy in saturation period combined calcium (1000 mg of calcium and 800 IU of vitamin D) and 3000 IU of vitamin D per day. Maintenance therapy for patients with systemic osteoporosis consisted of combined calcium (1000 mg of calcium and 800 IU of vitamin D) and 1000 IU of vitamin D; for patients with osteoarthritis — 2000 IU of vitamin D. 

Effects of vitamin D supplementation in the glucose and lipid blood profiles in patients with type 2 diabetes mellitus were discussed in the report of David Barbosa (Lisbon, Portugal). It was mentioned, that according to results of some epidemiological studies about links between vitamin D level and type 2 DM, it might be suggested that supplementation with vitamin D could improve glycemic control and influence on lipid profile in type 2 DM patients. Although almost all interventional studies had not shown an effect of vitamin D supplementation on glycemic indices. To check those data the 21 women with type 2 DM had been evaluated before and one year after beginning of the vitamin D supplementation (cholecalciferol 750 IU/day + calcium phosphate 600 mg/day). It had been found, that mean 25(OH)D level was significantly higher as well as the total cholesterol level was significantly lower after one year of using vitamin D supplementation. However the decreasing of LDL- and HDL-cholesterol and triglycerides levels were statistically nonsignificant. No changes were observed in glycemia. So, the results of the study were consistent with data of recent studies in that area, that vitamin D was possible marker of the general health, but not a potential type 2 DM therapeutic target. 

To be concluded, all the aspects that were discussed during the workshop emphasized the commonality of problem of vitamin D of deficiency and insufficiency in Ukrainian and Portuguese population. The workshop has provided the brilliant opportunity to scientists of both countries to exchange their views as well as has let Portuguese and Ukrainian divisions of EVIDAS to share the results of their professional work.