Should We Prescribe Calcium Supplements For Osteoporosis Prevention?

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How well does calcium intake really protect your bones?

Ask anyone how to prevent bone fractures and they’re likely to answer, “Get more calcium.” Medical experts have tended to agree. For example, the Institute of Medicine advises a calcium intake of 1,000 to 1,200 milligrams (mg) a day for most adults. But in the last five years, we’ve also learned that calcium — at least, in the form of supplements — isn’t risk-free. An intake of 1,000 mg from supplements has been associated with an increased risk of heart attack, stroke, kidney stones, and gastrointestinal symptoms.

Now an analysis of reams of research concludes that consuming calcium at that level doesn’t even reduce fractures in people over 50. And a related analysis indicates that increasing calcium intake has only a modest effect on bone density in people that age. Both were published online this week in the medical journal BMJ.

These results may seem startling, but they aren’t a surprise to Dr. David Slovik, associate professor of medicine at Harvard Medical School and author of our Special Health Report Osteoporosis: A guide to prevention and treatment. “I don’t believe that we’ve ever thought that calcium per se reduces fractures; it’s one part of a larger picture,” he says. You really can’t say ‘Take enough calcium and you’ll be fine.'”

What the analyses found

The analyses were conducted by a team of New Zealand researchers led by Mark Bolland, who first identified the cardiovascular risk associated with calcium supplements. For the first analysis, they looked at more than 70 studies on the effects of dietary calcium and calcium supplements in preventing fractures. They considered both randomized clinical trials and observational studies, and the studies varied widely in terms of numbers of participants, calcium intake, vitamin D intake, and how fractures were reported. The researchers found that, over all, neither dietary calcium nor calcium supplements were associated with a reduction in fractures.

In the second analysis, the team reviewed 59 randomized controlled clinical trials that evaluated calcium intake and bone density. Fifteen of those studies involved dietary calcium, and 44 looked at calcium supplements. Over all, getting at least 800 mg of calcium a day from the diet or taking at least 1,000 mg of supplemental calcium a day increased bone density. But bone density only increased by about 0.6% to 1.8% — an amount too low to affect fracture risk.

It’s important to note that these studies included very few men. (Many people think that osteoporosis only affects women, but men can develop osteoporosis too.)

The study that started it all?

Bolland and colleagues pointed to one study that they think may be responsible for today’s calcium recommendations. This study was a randomized controlled trial conducted among 3,800 elderly French women (average age 84) in assisted living. The women initially had a low calcium intake (around 500 mg a day), low vitamin D levels, and low bone density. Those who received 1,200 mg of calcium and 800 international units (IU) of vitamin D supplements daily for three years had a 23% lower risk of hip fracture, and a 17% lower risk of fractures over all, than those taking placebos. The women who took calcium also built bone, while those on placebos continued to lose it. Those results — reported in 1992 and 1994 — are often cited by experts when drafting calcium recommendations for the general population. But Bolland argues that healthy, active people who don’t have a calcium or vitamin D deficiency aren’t likely to get the same protection from taking that much calcium.

What to do?

“The takeaway is that you shouldn’t be taking calcium with the idea that it will prevent bone fractures,” Dr. Slovik says. But he notes that adequate calcium and vitamin D intake is still essential for healthy bone. A deficiency of either can increase the risk of diseases like osteomalacia and rickets.

It’s impossible to determine how much calcium each of us, individually, needs. Try to get as much calcium as you can from food. If your doctor advises you to get 1,000 to 1,200 mg of calcium a day, you can safely add a daily calcium supplement of 500 or 600 mg without increasing your risk of heart attack or kidney stones. And don’t forget vitamin D. No one is challenging the recommendation for vitamin D — 600 to 800 IU a day from either food or supplements.

Possibilities of using calcium and vitamin D preparations for the prevention of osteoporosis in the work of a general practitioner, articles on treatment

Roitberg Grigory Efimovich, Dr. med. Sci., Professor, Academician of the Russian Academy of Sciences, Head of the Department of Therapy and Family Medicine, Russian National Research Medical University named after N. I. Pirogov of the Ministry of Health of Russia, President of JSC “Medicina”	Popova Inga Evgenievna, Ph.D. honey. Sci., Endocrinologist, JSC “Medicina”, Associate Professor of the Department of Therapy and Family Medicine, Professor of the Department of Therapy and Family Medicine, Federal State Educational Institution of Higher Professional Education, N.I. Pirogov” of the Ministry of Health of Russia

Article authors:
Roitberg Grigory Efimovich, Dr. med. Sci., Professor, Academician of the Russian Academy of Sciences, Head of the Department of Therapy and Family Medicine, Russian National Research Medical University named after N.I. Pirogova of the Ministry of Health of Russia, President of JSC “Medicina”

Popova Inga Evgenievna, Endocrinologist of the highest category, Candidate of Medical Sciences, Member of the European Diabetes Association

Summary. The article discusses the possibility of using calcium and vitamin D preparations for the prevention and treatment of osteoporosis at the outpatient stage. The material is presented from the standpoint of evidence-based medicine, the data presented allow the use of modern approaches to the management of patients with this pathology.

Key words: osteoporosis, calcium, vitamin D, prevention.

The World Health Organization has listed osteoporosis (OP) as one of the ten most important chronic diseases of mankind. In terms of socio-economic and medical significance, OP ranks fourth, second only to diabetes mellitus, cardiovascular and oncological diseases.

Epidemiological studies indicate that there are about 250 million people in the world suffering from OP. The consequences of OP – fractures of the vertebral bodies and bones of the peripheral skeleton – lead to large material costs in the field of healthcare and cause a high level of disability, including disability and mortality. It is predicted that by 2025 the number of hip fractures will be about 2.6 million cases, and the number of deaths after a hip fracture will be about 700 thousand per year.

One of the main ways to prevent osteoporosis and maintain bone density is to ensure adequate intake of calcium salts and vitamin D. With age, there is a decrease in calcium absorption and a decrease in its intake, which increases the risk of fractures. Vitamin D is essential for calcium absorption and bone health in both men and women. Vitamin D deficiency plays an important role in the pathogenesis of osteoporosis and many other important chronic diseases, including type 2 diabetes, some cancers, cardiovascular disease, autoimmune diseases, and infectious diseases. . Low vitamin D levels can lead to inadequate calcium absorption, secondary hyperparathyroidism, leading to increased bone turnover and increased risk of fractures, especially in the elderly.

Approximately 80% of vitamin D in the body is formed endogenously and about 20% comes from food. Vitamin D is synthesized in the skin as a result of the conversion of 7-dihydrocholesterol under the action of ultraviolet B-band light. After formation in the skin (or absorption in the gut from food), vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating metabolite of vitamin D and the most important indicator of vitamin D levels. Further, 25 (OH) D is metabolized in the kidneys to the active form of vitamin D-1,25-dihydroxyvitamin D [1,25 (OH) 2D]. The formation of 1,25-dihydroxyvitamin D [1,25 (OH) 2D] is increased by the action of parathyroid hormone (PTH), calcium and serum phosphate.

The active metabolite of vitamin D – 11.25 (OH) 2D, interacting with receptors located in the intestine, increases calcium absorption by up to 40%. There is evidence that vitamin D has an anabolic effect – 1,25 (OH) 2D stimulates the expression of growth factors (TGF and IGF), which increases the proliferation and differentiation of osteoblasts – cells that form bone tissue, and accelerates the synthesis of type I collagen and bone matrix proteins. Another metabolite 24,25 (OH) 2D is involved in the healing of microfractures. Vitamin D is also a regulator of PTH formation, and its deficiency leads to the development of secondary hyperparathyroidism, as a result, activation of osteoclastogenesis and bone loss. Thus, vitamin D deficiency is associated with a negative calcium balance and reduced bone mineralization, leading to osteopenia and an increased risk of fractures.

Another important function of vitamin D is to maintain muscle tone and balance. On the membranes of muscle cells there are 1,25 (OH) 2D receptors, due to which the regulation of calcium and phosphate transport occurs, these receptors are also in the cell nucleus, where they are involved in the production of energy for muscle contraction. Muscle cells have the ability to convert 25(OH)D to 1.25(OH)2D. The concentration of vitamin D receptors in muscle tissue decreases with age, which may also be the cause of weakened muscle strength and an increased tendency to fall. A number of clinical studies have found a positive correlation between muscle strength and blood levels of vitamin D. A meta-analysis of studies examining the effect of vitamin D supplementation on preventing the risk of falls confirmed the positive effect of vitamin D.

Vitamin D deficiency is usually the result of insufficient sun exposure or insufficient dietary intake. The list of foods containing vitamin D in the required amount is very limited, so getting this vitamin from food is difficult. Fatty fish (herring, mackerel, salmon) are the richest in vitamin D, and it is contained in small amounts in vegetable and dairy products, as well as in eggs. For example, one yolk contains 20 IU, 100 ml of milk – only 2 IU, 100 g of sour cream – 50 IU.

The prevalence of hypovitaminosis D does not depend on the geographical location of countries and the season. So, in the countries of Northern Europe, the frequency of hypovitaminosis is even lower than in countries located in southern Europe (Italy, Spain) and the Middle East (Turkey, Iran, Lebanon, etc.). In Moscow, 65% of postmenopausal women had deficiency and hypovitaminosis D, while the level of vitamin D significantly fluctuated depending on the season of blood sampling. Along with the global decline in B-band ultraviolet radiation at various latitudes, the fact that people have begun to work more indoors and do not have the opportunity to spend daily in sunlight and thus create a supply of vitamin D is discussed. Another factor is the decrease in the ability to synthesize vitamin D with age.

According to the recommendation of the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Diseases of the Musculoskeletal System ESCEO, the concentration of 25 (OH) D in the blood, which is one of the best clinical indicators of sufficient intake of vitamin D, should be at least 20 ng / ml ( 50 nmol / l), and with a high risk of fractures and falls, its level should not be lower than 30 ng / ml (75 nmol / l).

Calcium, having a weak antiresorptive effect, potentiates the effect of the main drugs for the treatment of osteoporosis, prevents hypocalcemia and is recommended for any therapeutic regimens and treatment regimens for OP.

A sufficient daily intake of calcium from food is considered to be the presence in the diet of at least three servings of dairy products per day. One serving can include 30 g of cheese, 100 g of cottage cheese, 150 g of yogurt, 200 ml of milk.

Generally accepted recommendations for optimal calcium intake for women who are menopausal or older than 50 years of age should consume 1000-1200 mg of calcium per day. However, studies show that the actual intake of calcium is significantly lower. A study of calcium consumption among residents of 6 regions of Russia (about 4500 respondents) over the age of 50 showed that on average, women receive 683 ± 231 mg of calcium from food, and men – 635 ± 276 mg of calcium per day. At the same time, it was found that more than 70% of the examined persons consumed with food daily less than half of the norm required by age, which is clearly not enough to maintain bone strength. In the USA, data were received, where 90% of postmenopausal women over the age of 50 consume less than 1200 mg of calcium per day.

Vitamin D supplementation is an integral part of the treatment of osteoporosis. The positive role of calcium and vitamin D supplementation in reducing the risk of fractures has been shown in several meta-analyses, which have shown that it is their combined intake that is most effective. As a result of the analysis of 7 randomized trials with a total number of participants of 68.5 thousand people, it was shown that the greatest success was achieved with the combined use of calcium and vitamin D supplements. %. However, vitamin D alone (400-800 IU) was not effective in preventing fractures.

Similar data were obtained in the study of the risk of falls. Meta-analysis conducted by Murad M.N. et al showed a 17% reduction in the risk of falls in the combination therapy group compared with placebo. In a meta-analysis of 17 studies lasting up to three years, more than 50,000 patients received calcium alone or in combination with vitamin D. As a result of calcium supplementation alone, a 12% reduction in the risk of fractures at various sites, including the vertebrae, femur, and forearm, was noted. The addition of vitamin D did not lead to a significant reduction in the risk of fractures: against the background of calcium intake, the risk was reduced by 10%, in combination with vitamin D – by 13%. Another pooled analysis of 68,500 patients treated with vitamin D alone showed no reduction in fracture risk. But the combination of calcium and vitamin D reduced the risk of all fractures by 12% (p = 0.025) and hip fractures by 26% (p = 0.005).

With all the undeniable evidence of the role of calcium supplementation in the prevention of osteoporosis, the debate about possible adverse events with additional calcium intake, especially from the cardiovascular system, does not subside. At the same time, there is data confirming an increased risk of developing arterial hypertension against the background of low calcium intake, which was presented in the AHRQ systematic review.

In 2008 Bolland M.J. et al. published data on an increased risk of myocardial infarction in healthy postmenopausal women who took calcium for 5 years, but this study did not find a significant increase in the risk of strokes and sudden death.

In 2010, the same authors presented a meta-analysis of 15 studies, which also found a 1.27-fold increase in the risk of myocardial infarction, but the increase in the risk of strokes, sudden death, and all cardiovascular events was not significant.

Also in 2010, another meta-analysis of 17 studies was published by Wang L. et al., which showed no increase in cardiovascular risk with an additional intake of 600-1200 mg of calcium per day for 2-5 years in addition to about 900 mg calcium from food.

The discussion about the cardiovascular safety of calcium intake was brought to a close by a prospective 5-year study of the effect of calcium supplementation on the risk of cardiovascular disease (CVD) followed by a 4.5-year follow-up after its completion, which demonstrated no increase in the risk of CVD and mortality when taking 1200 mg of calcium in elderly women.

Rejnmark L. et al conducted a meta-analysis of the effect of vitamin D and calcium supplements on mortality and found that in elderly patients, combination therapy with calcium and vitamin D was associated with a reduction in mortality, which was not observed with vitamin D monotherapy. Taking additional calcium in the form of pharmacological Supplementation is not associated with an increase in mortality rates unless it is given to individuals with a dietary calcium intake of more than 1400 mg per day. Currently, there is no data that would require a change in the tolerable upper intake level of calcium, which is 2500 mg per day.

Another fear of doctors is associated with the risk of developing urolithiasis when taking calcium supplements. In a systematic review of 14 studies published in 2008, it was shown that there is no risk of increased stone formation with high calcium intake, and in some studies there was even an inverse correlation between them.

In 2012, the conclusion of the EFSA (European Food Safety Authority) expert commission was published, which states that randomized trials, the purpose of which would be to study the effect of calcium supplementation on the risk of CVD, have not been conducted, and based on the results of large prospective cohort studies in In general, calcium intake up to 2000 mg per day from food and supplements is not associated with an increased risk of cardiovascular disease. According to experts, there was no association between long-term intake of calcium from food or in the form of drugs and an increased risk of nephrolithiasis, cardiovascular disease or prostate cancer.

Thus, an integral and safe component of the strategy for the prevention and treatment of osteoporosis in the work of a general practitioner should be recommendations on proper nutrition with the use of foods rich in calcium, additional intake of calcium and vitamin D supplements. This will increase the effectiveness of treatment by an average of 10%, and also reduce the risk of falls and fractures.

Scientific and practical journal for primary health care professionals “Reference book of a general practitioner”, No. 5, 2018. P. 50-56.

Benefits of a combination of calcium and vitamin D in the prevention and treatment of osteoporosis: a renaissance of the paradigm

Calcium and vitamin D deficiency is an urgent medical problem worldwide today: the international PubMed database offers 19,362 articles for the query “calcium deficiency”, the number of which increases every year. Much of the lively discussion of calcium and vitamin D deficiencies is associated with the role of these micronutrients in the pathogenesis of osteoporosis, a metabolic skeletal disease characterized by decreased bone strength and increased risk of fracture.

Osteoporosis and its prevention is the main indication for prescribing calcium and vitamin D supplements to slow down the inevitable bone loss in the elderly, as well as to prevent severe disabling fractures that occur against a background of low bone mineral density (BMD) [1]. Complications of osteoporosis, such as a hip fracture, compression fractures of the vertebrae, and posture disorders, significantly reduce the quality and life expectancy of patients, and also require huge financial costs for surgical interventions, drug treatment, and subsequent rehabilitation [2].

To date, calcium and vitamin D preparations are widely represented on the pharmaceutical market, are actively prescribed by doctors and used by the population. However, there are still many questions, uncertainty and doubts among doctors and patients regarding the benefits of these drugs, harm, rational combination and dosage.

Calcium and vitamin D intake by age

Calcium deficiency is formed when this mineral enters the body in a smaller dose than the established daily requirement. Most often, deficiency occurs during periods of physiologically increased need for calcium in adolescents, pregnant women, and the elderly. In adolescence (during the growth spurt, the formation of the skeleton and peak bone mass), up to 400–500 mg of calcium is deposited in the bones daily [3], during pregnancy, the fetus accumulates approximately 30 g of calcium from the maternal skeleton, and during lactation, the mother’s body daily with milk loses up to 150-300 mg of calcium [4]. Although adolescents and young women have fairly wide compensatory-adaptive reserves of the body to maintain phosphorus-calcium homeostasis, with an extremely low intake of dietary calcium, these reserves may not be enough even for a young body, which will require additional intake of calcium preparations.

An increased need for calcium is also characteristic of the postmenopausal period in women and the elderly, when bone remodeling is activated, the rate of BMD loss increases and the risk of fractures increases. Nevertheless, calcium intake in the population as a whole decreases with age: in all age groups of women over 40, a pronounced deficiency of calcium intake with food is revealed compared to the age norm, varying on average from 160 to 586 mg/day. The minimum figures for calcium intake are observed at the age of 70-79years and 80 years and older, which is associated with the highest risk of developing osteoporosis and associated fractures [5]. According to the results of the program “Osteoscreening, Russia”, which included more than 5000 patients, the daily intake of calcium by women averaged 683±231 mg, and by men – 635±276 mg. Thus, more than 70% of the examined daily consumed with food less than half of the amount of calcium required by their age [6].

To compensate for the nutritional deficiency of calcium, it is preferable to use its salts, characterized by the highest percentage of elemental calcium – carbonate, triphosphate or citrate. With a simultaneous intake of more than 600 mg of ionized calcium, its absorption is significantly reduced, so it is advisable to take a large dose in several doses. Quality, ease of use, cost, and good tolerability should serve as the basis for choosing a calcium preparation. The intake of calcium gluconate does not seem rational, since 1 g of salt contains only 89mg of elemental calcium [7].

Vitamin D significantly increases the absorption of calcium in the intestines, and therefore sufficient intake of this vitamin is of no small importance in replenishing calcium losses. A number of studies [8, 9] have shown that 50–70% of patients with postmenopausal osteoporosis complicated by vertebral fractures have reduced intestinal absorption of calcium, which is caused in most cases by an insufficient level of 25(OH)D in blood serum.

Vitamin D belongs to the group of fat-soluble vitamins and occurs in two forms. Vitamin D ₂ (ergocalciferol) enters the human body by absorption in the duodenum and small intestine from food. Such varieties of oily fish as salmon, herring and mackerel are especially rich in ergocalciferol [10]. Vitamin D ₃ (cholecalciferol) is formed in the skin from 7-dehydroxycholesterol under the influence of ultraviolet rays. Vitamin D production ₃ is associated with skin pigmentation, the latitude of the region, the duration of daylight hours, season, weather conditions and depends on the area of ​​the skin that is not covered by clothing [11, 12]. In countries located in northern latitudes (above the 35th parallel), where the entire territory of Russia falls, in winter, most of the ultraviolet radiation is absorbed by the atmosphere, and in the period from October to March, the synthesis of vitamin D ₃ is practically absent [13]. According to N.V. Toroptsova et al. [14], in the Moscow region, only 3% of postmenopausal women have a normal serum 25(OH)D level. A low level of vitamin D was also noted among residents of the Urals [15].

Natural vitamin D deficiency, like calcium deficiency, is exacerbated in women with the onset of menopause [2], as well as in old age. The elderly spend much less time in the sun, their skin loses the ability to synthesize vitamin D ₃ , the production of the active metabolite 1,25 (OH) ₂ D decreases in the kidneys – all this contributes to the widespread prevalence of vitamin D deficiency among older people [12 ].

Benefits of Combining Calcium Salts with Vitamin D

Some studies [16] note a positive effect of calcium salts on the risk of fractures and BMD, however, for the prevention or treatment of osteoporosis, monotherapy with calcium has a weaker clinical effect than its combination with vitamin D. The results of a meta-analysis demonstrate that calcium supplements do not prevent the development of hip fracture in either men or women [17]. Micronutrients from combined preparations are more completely absorbed in the intestine, and their use is associated with a more pronounced increase in BMD and a decrease in the risk of fractures compared with calcium monotherapy [18].

Recently, there has been a tendency to preferentially prescribe vitamin D monotherapy without concomitant intake of calcium salts in the prevention or complex treatment of osteoporosis. According to a meta-analysis, 9 randomized trials with a total of 53,260 patients, conducted by S. Boonen et al. [19], vitamin D monotherapy without calcium supplementation is ineffective in relation to the risk of fractures, and in particular, in relation to hip fractures. The results of this meta-analysis showed that the combined use of calcium and vitamin D reduced the risk of hip fracture by 25% more effectively (95% CI: 4–42), and the risk of all peripheral fractures was 23% (95% CI: 1–40) compared with vitamin D monotherapy. Another meta-analysis demonstrated that only the combined use of calcium and vitamin D, but not monotherapy with the latter, reduces the risk of fractures of all localizations and, in particular, fracture of the femur in the elderly [20].

Back in the 1990s, large-scale studies were carried out on the effectiveness of combination therapy with calcium and vitamin D on the incidence of fractures. M. Chapuy et al. [21] showed that in elderly women living in nursing homes, daily intake of 1200 mg of calcium from carbonate and 800 IU of vitamin D for 18 months reduces the risk of hip fracture by 43%, all peripheral fractures by 32%, increases BMD in the proximal femur by 2.7% versus a decrease of 4.6% in the placebo group ( p< 0.001). The administration of calcium in combination with vitamin D at a daily dose of 700-800 IU for 3 years in postmenopausal women leads to a reduction in the relative risk of hip fracture by an average of 27% (95% CI 0.23-0.99). It is important to note that this effect may be lost with further discontinuation of calcium and vitamin D intake [22, 23]. M. Chapuy calculated that in order to prevent one fracture of the femoral neck, it is necessary to prescribe a combined preparation of calcium and vitamin D to 45 patients (95% CI 28–114), and to prevent any peripheral fracture in 27 patients (95% CI 19–49) [21].

Later, these results were confirmed by meta-analyses, which showed a reduction in the incidence of new fractures in various parts of the skeleton when taking calcium in combination with vitamin D by up to 25-70% [24-26]. K. Salovaara et al. [27] concluded in their work that the combined intake of calcium at a dose of 1000 mg and vitamin D at a dose of 800 IU daily leads to a decrease in fractures of any localization by 17%, in particular, non-vertebral fractures by 13%, fractures of the upper limbs by 25% . Thus, the combination of calcium and vitamin D contained in many pharmacological preparations is clinically justified, since the combined administration of these micronutrients has a more pronounced clinical effect compared to their isolated use [18].

The risk of fractures in the elderly is largely associated with a high incidence of falls, which in most cases is due to muscle wasting and sarcopenia associated with vitamin D deficiency [28, 29]. Many studies [21, 23, 27] have shown that vitamin D therapy significantly reduces the risk of falls. This is because vitamin D has a direct effect on neuromuscular conduction, muscle strength [30, 31], balance and equilibrium [32]. According to a meta-analysis by H. Bischoff-Ferrari et al. [33], vitamin D supplementation in combination with calcium can reduce the risk of falls in elderly women living in residential institutions by more than 20%. However, there is no strong evidence of a positive effect of calcium and vitamin D therapy on the risk of falls in a continuum of postmenopausal women.

M. Kärkkäinen et al. [34] patients aged 65–71 years received cholecalciferol 800 IU and calcium carbonate 1000 mg daily, against which the frequency of falls in general and falls requiring medical attention was assessed. Despite no effect of therapy on overall incidence of falls, there was a 25% reduction in the likelihood of falls requiring medical intervention.

Osteoporosis is accompanied by increased bone turnover, reflected in an increase in the level of biochemical markers of resorption, which is a harbinger of disease progression and further loss of BMD. Many authors in their works [39, 42] presents data on slowing bone resorption while taking combined preparations of calcium and vitamin D at a dose of 400–800 IU/day, in particular, a significant decrease in the level of parathyroid hormone and biochemical markers of bone metabolism.

Calcium and vitamin D preparations are a mandatory addition to any pathogenetic therapy for osteoporosis – bisphosphonates, menopausal hormone therapy, denosumab or teriparatide [7]. In this aspect, it seems much more rational and cost-effective to use combined pharmacological preparations containing calcium and vitamin D salts in order to compensate for their deficiency, prevent and comprehensively treat osteoporosis [35–37].

At the same time, attention should be paid to the problem of low adherence in the process of treating osteoporosis, when up to 50% of patients can stop taking recommended drugs within a year, which in turn is associated with both an increase in the risk of fractures and an increase in the ratio of treatment costs to the quality indicator life. In a randomized clinical trial that assessed patient preferences for various prevention and treatment regimens for calcium deficiency, vitamin D deficiency, and osteoporosis, calcium-D supplementation ₃ Nycomed (1 tablet contains 500 mg of elemental calcium and 200 IU of cholecalciferol) and Calcium-D ₃ Nycomed Forte (1 tablet contains 500 mg of elemental calcium and 400 IU of cholecalciferol) proved to be significantly more preferable, from the point of view of patients, according to compared with other drugs containing calcium and cholecalciferol [38]. Thus, ease of administration and good organoleptic properties of preparations Calcium-D ₃ Nycomed and Calcium-D ₃ Nycomed Forte allow to achieve high adherence in long-term prevention or treatment of established osteoporosis.

Effective doses of calcium and vitamin D

There is an ongoing scientific debate regarding vitamin D and calcium dosages. Despite the cautious attitude towards the appointment of calcium supplements in the elderly (even those suffering from osteoporosis) in recent years, therapy with only vitamin D and / or minimal dosages of calcium salts is ineffective. This was also confirmed in the study by B. Ettinger et al. [39]: the positive effect of taking calcium and vitamin D supplements by women in the first 10-20 years after menopause is achieved only with the appointment of high doses of calcium. In women who received 1000 mg of calcium in early postmenopause with a moderate intake of calcium from food (650-850 mg/day), there was a positive dynamics of BMD in the radius, but not in the spine. Higher doses of calcium (1000–2000 mg) slowed down or prevented bone loss in all skeletal regions, including the femoral neck [40]. In another study [41], in women with low calcium intake (up to 650 mg/day), low doses of calcium (500 mg/day) did not lead to an increase in BMD in the spine, hip, and radius. In a meta-analysis by B. Shea et al. [42], which included 59publications have demonstrated the safety and efficacy of high doses of calcium up to 3000 mg/day.

There is evidence that vitamin D at a dose of 800 IU/day has a more pronounced effect on thigh BMD than at low doses (400 IU/day). Experience in prescribing Calcium-D ₃ Nycomed and Calcium-D ₃ Nycomed Forte at a dose of 2 tablets per day (which corresponds to taking 1000 mg of elemental calcium and 400 IU of cholecalciferol in the first case, and 1000 mg and 800 IU, respectively, in the second case ) in women with osteopenia in the postmenopausal period has shown that treatment with any of these agents can stop bone loss in the spine and hip, normalize calcium homeostasis and reduce the rate of bone remodeling. However, Calcium-D ₃ Nycomed Forte has a more powerful effect on bone mass and quickly eliminates the manifestations of secondary hyperparathyroidism caused by vitamin D deficiency [1].

There was no clear dose-dependent effect of cholecalciferol in preventing new fractures and falls. The efficacy of a vitamin D dosage of 400 IU/day has not been proven in this regard [23, 24, 43]. However, 24,000 IU of vitamin D ₃ per month (approximately 800 IU/day) is more effective in reducing the risk of falls than 60,000 IU per month (2000 IU/day) [44]. According to H. Bischoff-Ferrari et al. [45], the most effective doses of vitamin D for fracture prevention are 792-2000 IU / day. According to the results of a meta-analysis by B. Tang et al. [26], in the elderly, the most effective doses of calcium are at least 1200 mg/day and vitamin D at least 800 IU.

Extraskeletal effects of calcium and vitamin D

Treatment with high doses of calcium (greater than 1000 mg of elemental calcium per day) and vitamin D in elderly patients is believed to be associated with an increased risk of myocardial infarction and increased atherosclerotic plaque calcification. However, the authors of a meta-analysis of 18 randomized trials published in 2015 showed that calcium supplementation is not associated with an increased risk of coronary heart disease and mortality [46]. According to R. Bostick et al. [47], in women over the age of 55–69years, taking high doses of calcium (1425 mg / day), on the contrary, contributed to a decrease in mortality from coronary heart disease by 33%, compared with the group receiving low doses (700 mg / day). A large prospective study, Nurses’ Health Study [48], which included 85,764 women aged 39–59 years, found a reduction in the risk of stroke when taking calcium salts. Severe vitamin D deficiency at 25(OH)D levels below 15 ng/mL is also associated with a high risk of cardiovascular complications. Conversely, a normal serum 25(OH)D level (not lower than 30 ng/mL) reduces the relative risk of developing myocardial infarction and arterial hypertension [47, 48].

There is also evidence that the combination of vitamin D at a dose of 800 IU per day in combination with calcium is more effective in lowering systolic BP than calcium alone [49]. In addition, taking calcium supplements as part of complex therapy additionally helps to reduce the level of blood cholesterol, in particular, atherogenic fractions in both men and women [50, 51]. Finally, calcium and vitamin D therapy contributes to some reduction in body weight and visceral fat volume [52], which implies a reduction in the degree of cardiac risk.

Another common misconception is that there is an increased risk of developing urolithiasis when taking calcium supplements. The results of large randomized trials in which calcium salts were taken with food did not confirm these data [53]. In some studies, the risk of developing nephrocalcinosis even decreased [54], which is probably due to the binding of the calcium ion by oxalate. According to the decision of the EFSA (European Food Safety Authority) expert council, consumption of up to 2400 mg of elemental calcium per day from all sources is not associated with the development of chronic hypercalciuria, and up to 3000 mg is not accompanied by the development of urolithiasis [55].

Epidemiological reviews [56–58] have shown that mortality due to cancer, cardiovascular diseases, and diabetes mellitus increases with increasing latitude of residence, i.e., a decrease in the ultraviolet index, which can be corrected by prophylactic vitamin D supplementation. In a meta-analysis Eighteen randomized clinical trials with a total cohort of 57,311 patients showed that calcium supplementation in combination with vitamin D significantly reduced all-cause mortality, while vitamin D without concomitant calcium supplementation did not confirm the significance of such an association.

It should be taken into account that not all current data on the effectiveness of calcium and vitamin D in the prevention of extraskeletal diseases correspond to a high degree of evidence, and, of course, well-designed long-term studies are required to evaluate the association of vitamin D and calcium intake with these diseases acting in as endpoints. Although there is currently no reason to recommend the use of combined calcium and vitamin D preparations to reduce the risk of age-associated extraskeletal pathology, in the future, complex preventive therapy with calcium and vitamin D may probably become an important factor in active healthy longevity.

Combined preparations of calcium and vitamin D are currently of great importance for the prevention and complex treatment of osteoporosis, as well as for replenishing calcium deficiency in adolescence, in the elderly, during pregnancy and lactation. The combined intake of calcium and vitamin D significantly and more effectively than their monotherapy, slows down bone loss and reduces the risk of fractures, strengthens skeletal muscles and reduces the likelihood of falls. In addition to the effect on the musculoskeletal system, additional intake of calcium and vitamin D helps to reduce the risk of cardiovascular and oncological diseases and is well tolerated.

Calcium carbonate in combination with vitamin D is the most rational drug in terms of availability, good tolerability and cost-effectiveness. Calcium-D ₃ Nycomed and Calcium-D ₃ Nycomed Forte. These drugs are a time-tested optimal source of calcium and vitamin D. Their use for the prevention of calcium and vitamin D deficiency, as well as for the prevention and in the complex therapy of osteoporosis, is scientifically justified.