Vitamin D Deficiency and Rickets: Clinical Guidelines

List of Abbreviations

ALT - alanine aminotransferase

AST - aspartate aminotransferase

BAD - dietary supplements

IBD - inflammatory bowel disease

HPP - hypophosphatasia

GIT - gastrointestinal tract

IIH - infantile hypercalcemia

CI - clinical studies

CS - craniosynostosis

CT — computed tomography

BMD - bone mineral density

OI - osteogenesis imperfecta

PTH - parathyroid hormone

RDI - recommended dietary intake

T1D/T2D - type 1 / type 2 diabetes mellitus

UV - ultraviolet

CKD - chronic kidney disease

ALP - alkaline phosphatase

VDBP - vitamin D-binding protein

VDR - vitamin D receptor

FGF23 - fibroblast growth factor 23

25(OH)D - 25-hydroxycholecalciferol (calcidiol)

1,25(OH)₂D - 1,25-dihydroxycholecalciferol (calcitriol)

...** - the drug is included in the list of vital and essential drugs (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On approval of the list of vital and essential drugs, as well as lists of drugs for medical use and the minimum assortment of drugs required for medical care") as amended at the time of approval of clinical guidelines

# - the use of a medicinal product in accordance with indicators (characteristics) not specified in the instructions for its use (off-label) is carried out by decision of the medical commission subject to a signed informed voluntary consent (in accordance with Federal Law No. 323-FZ of November 21, 2011, as amended)

Terms and Definitions

Upper tolerable intake level – the highest level of daily nutrient intake that poses no risk of adverse health effects in almost all individuals.

Upper limit of safe intake – the level of nutrient intake that is safe for the majority of healthy people and above which some people may develop side effects and symptoms of toxicity over time.

Hypervitaminosis D – a pathological condition caused by vitamin D intoxication, accompanied by hypercalcemia and calcium salt deposition in many tissues.

Therapeutic doses of a vitamin – doses significantly exceeding the recommended daily intake and intended for course use as prescribed and monitored by a physician.

Norms of physiological requirements for energy and nutrients – the level of daily nutrient intake sufficient to meet the physiological needs of at least 97.5 percent of the population, taking into account age, sex, physiological state, and physical activity.

Prophylactic doses – close to the physiological requirement or recommended daily intake and intended for continuous replenishment of insufficient vitamin content in the diet.

Recommended daily intake – the averaged value of the required nutrient intake ensuring the optimal implementation of physiological and biochemical processes.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Vitamin D insufficiency – a condition characterized by a decrease in serum 25(OH)D concentration below normal values, which can potentially lead to reduced intestinal calcium absorption, the development of secondary hyperparathyroidism, and an increased risk of fractures.

Serum 25(OH)D concentration characterizes vitamin D status (Table 1); however, the criteria for vitamin D insufficiency and deficiency remain debatable [116], and the thresholds used to define these conditions (Table 1) are based on the association of 25(OH)D concentrations with clinical signs of rickets and elevated levels of alkaline phosphatase and other bone metabolism markers (this information is detailed in Section 1.5). Vitamin D insufficiency and deficiency are associated with many chronic diseases and significantly increase the risk of infections.

Table 1. Interpretation of serum 25(OH)D concentrations [116].

Exceeding target vitamin D concentrations with concomitant hypercalciuria and decreased parathyroid hormone activity may be potentially toxic.

Hypervitaminosis D – a pathological condition caused by vitamin D intoxication, accompanied by hypercalcemia and calcium salt deposition in many tissues [42].

Rickets – a disease of infants and young children resulting from changes in calcium-phosphate homeostasis leading to impaired bone mineralization. The clinical presentation of rickets depends on the patient's age, disease duration, and the etiological cause of the pathological process.

Currently, more than 20 acquired or hereditary causes of rickets are known. The latter are caused by mutations in genes involved in vitamin D metabolism or action, renal phosphate reabsorption or synthesis, or degradation of fibroblast growth factor 23 (FGF23, or phosphaturic hormone) [1, 2, 123], while in some such conditions, serum 25(OH)D levels remain within the normal range [40].

Vitamin D-deficient (or nutritional, classical) rickets – caused by vitamin D deficiency and/or dietary calcium deficiency, is the most common cause of rickets. In 2016, the Global Consensus on Prevention and Management of Nutritional Rickets was adopted, defining rickets as a disorder of chondrocyte differentiation, mineralization of growth plates, and osteoid in children caused by vitamin D deficiency and/or insufficient calcium intake [3]. In 2022, a review on various types of rickets was published [93, 123]. Thus, vitamin D deficiency, calcium deficiency, phosphorus deficiency, and distal renal tubular acidosis are the main etiological causes of rickets [1]. The pathological process in rickets is localized mainly in the metaphyseal zones of bones; bone manifestations of rickets are most pronounced in children of the first 2–3 years of life.

Vitamin D deficiency causes rickets in infants and children, as well as osteomalacia in all age groups. It was previously thought that the risk of rickets is higher in socioeconomically disadvantaged regions. However, it is now proven that this condition can develop in any child if adequate vitamin D intake in the form of medicines, dietary supplements, or fortified foods is not ensured, especially in the presence of predisposing factors, including limited sunlight exposure and/or in children with chronic diseases.

Osteomalacia – impaired mineralization of the bone matrix in already mature bone tissue — although morphologically present in children with rickets, the term is usually used to describe a mineralization defect after bone growth has ceased.

The clinical consequences of vitamin D insufficiency are less studied, but consistently low vitamin concentrations negatively affect bone mineral density even in the absence of rickets.

These clinical guidelines discuss rickets resulting from insufficient dietary intake of vitamin D and calcium, or nutritional rickets.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Vitamin D exists in two forms – cholecalciferol and ergocalciferol, known as vitamin D₃ and vitamin D₂, which differ in side-chain structure; these differences do not affect metabolism, and both forms of vitamin D function as hormones. The absorption of vitamin D₃ and vitamin D₂ is virtually identical [4], but the transformation of ergocalciferol into active forms of vitamin D occurs more slowly, so vitamin D₂ is less commonly used to compensate for vitamin deficiency.

Cholecalciferol (vitamin D₃) is synthesized in the skin under the influence of ultraviolet (UV) rays and enters the body with food. During sun exposure, 7-dehydrocholesterol in the skin is converted into provitamin D and then transformed into vitamin D₃.

Ergocalciferol (vitamin D₂) is produced by fungi, found in yeast and bread, and enters the body solely through diet, including via foods fortified with vitamin D₂ or dietary supplements [1].

Most of Russia's territory is located in a low insolation zone, and the majority of populated areas are characterized by a small number of sunny days per year (40-70). In addition, vitamin D synthesis requires not just sunlight, but spectrum B UV radiation, which does not reach the Earth's surface in all regions of the country. When unfavorable factors are combined (insufficient intensity of spectrum B UV radiation, dark skin color, poor environmental conditions, use of sunscreens, physical inactivity, etc.), endogenous vitamin D synthesis decreases sharply [1].

Vitamin D becomes biologically active after undergoing stages of enzymatic conversion via hydroxylation. At the first stage of metabolism, vitamin D binds to plasma vitamin D-binding protein (VDBP), which interacts with albumin and is transported to the liver. In the Kupffer cells of the liver, under the action of the membrane-bound enzyme of the cytochrome P450 family 25-hydroxylase (CYP2R1), cholecalciferol is converted into the first active metabolite, 25-hydroxycholecalciferol [25(OH)D], or calcidiol. Cytochromes CYP2C9 and CYP2D6 are also involved in this reaction [5].

25(OH)D is the main form of vitamin D circulating in the blood. The production of 25(OH)D in the liver is feedback-regulated and maintained at a relatively constant level. The blood level of this metabolite can serve as a criterion for the body's vitamin D sufficiency [6].

The second stage of metabolism occurs in the kidneys with the help of the 1α-hydroxylase enzyme (CYP27B1), which converts 25(OH)D into the biologically active hormone calcitriol, 1,25-dihydroxycholecalciferol [1,25(OH)₂D]. It is precisely 1,25(OH)₂D, together with parathyroid hormone (PTH) and thyrocalcitonin, that ensures calcium-phosphate homeostasis, bone mineralization, and bone growth.

25(OH)D is also metabolized into 1,25(OH)₂D in various tissues and cells of the body, participating in the regulation of cell proliferation and differentiation, promoting the synthesis of interleukins and cytokines, including cathelicidin D—an antimicrobial polypeptide in macrophages—as well as providing other extra-skeletal effects of vitamin D [7, 8].

1,25(OH)₂D (calcitriol) binds to the receptor in target tissues. Calcitriol has a 100-fold higher affinity for the vitamin D receptor (VDR) than 25(OH)D. By binding to it, calcitriol induces genome-wide changes in transcription. To date, the expression of the VDR receptor gene has been established in virtually all human body tissues [10]. The molecular effects of the activated VDR include influence on the levels of hormones, growth factors and inflammation, proteins, and blood calcium levels [11]. The results of physiological studies, clinical observations, and randomized controlled trials indicate that vitamin D deficiency is a universal risk factor for various multifactorial diseases [12, 13, 14] (see Appendix A3.1).

Pharmacological and physicochemical studies have shown that vitamin D absorption in the small intestine occurs most completely from solutions of so-called micelles. Micelles are nanoparticles (10 – 1000 nm in diameter) with a "fat core" (containing vitamin D) and a hydrophilic shell that allows the nanoparticles to be evenly distributed throughout the aqueous solution. It is precisely due to the formation of micelles that the "solubilization" of vitamin D (i.e., its transition into a water-soluble form) occurs [15]. Normally, micelles containing vitamin D are formed during intestinal transit under the action of natural emulsifiers—bile and fatty acids. Due to the process of micelle formation (emulsification), not only vitamin D is absorbed in the small intestine, but also complex lipids (e.g., lecithin) and other fat-soluble vitamins (A, E, and K) [1].

Factors causing the development of rickets in children

1. High rates of growth and development in early childhood and increased demand for mineral components (Table 2), especially in preterm infants (see Section 5).

2. Dietary calcium and phosphorus deficiency associated with nutritional defects. The main pathogenetic cause of rickets is insufficient dietary intake of vitamin D, calcium, and phosphorus, which fails to meet the child's requirement for these nutrients.

Table 2 - Requirements for vitamin D, calcium, and phosphorus in infants and young children (according to MR 2.3.1.0253-21 Norms of physiological requirements for energy and nutrients for various population groups of the Russian Federation) [92].

Newborns and preterm infants are the population groups most vulnerable to vitamin D deficiency. The vitamin D status of a newborn, as well as of an infant during intrauterine development, directly depends on the mother's vitamin D status. The concentration of 25(OH)D in the child's cord blood is 50-80% of the maternal blood level, regardless of gestational age. Vitamin D deficiency is widespread among pregnant women, which explains the high rate of vitamin D deficiency in infants in the first month of life [16, 17, 18, 19]. Taking vitamin and mineral complexes (dietary supplements or medicinal products (ATC A11AA04 Multivitamins in combination with trace elements)) or micronutrient-fortified foods containing vitamin D during the pre-gravid period, pregnancy, and lactation leads to an improvement in the status of both the woman and her child.

It is known that vitamin D crosses the placenta, likely via passive or facilitated transport and predominantly in the form of 25(OH)D, and is subsequently metabolized into 1,25(OH)₂D in the newborn's kidneys. This ability is observed as early as the 24th week of gestation. It is believed that the main source of fetal 1,25(OH)₂D is the infant's kidneys during intrauterine development [16, 19, 20].

An important risk factor for vitamin D deficiency in infants is exclusive breastfeeding. The vitamin D content in breast milk is low (from 15 to 50 IU/L) even in mothers receiving adequate vitamin D. Exclusively breastfed infants consuming an average of 750 ml of breast milk per day receive from 10 to 40 IU per day (from 0.25 to 1 mcg/day) of vitamin D in the absence of sun exposure or vitamin D supplementation [21, 22]. The calcium content in breast milk ranges from 15 to 40 mg/dL; infants in the first months of life receive from 180 to 350 mg of calcium daily, compared to a requirement of 400 - 500 mg/day for infants in the first 6 months of life, 600 mg/day in the second half of life, and 800 mg/day in the 2nd year of life. The phosphorus content in breast milk ranges from 5 to 15 mg/dL; infants in the first months of life receive from 50 to 180 mg of phosphorus daily. For infants in the first half of life, the required amount of phosphorus is at least 300 mg [1, 23]. Prolonged breastfeeding combined with late introduction of complementary foods (at 7-8 months or later) can cause hypovitaminosis in the child even if the nursing mothers maintain a complete, balanced diet [24].

Vitamin D deficiency in formula-fed infants is less common, as adapted infant formulas are predominantly fortified. However, formula feeding also requires vitamin D supplementation. When introducing complementary foods, industrially produced cereals fortified with a vitamin and mineral complex (including calcium and vitamin D) serve as a source of vitamin D. Appendix A3.2 presents the main foods that serve as sources of vitamin D [25, 26]. The pathogenesis of rickets is proven to be negatively affected by dietary deficiencies of vitamins A, C, B vitamins (especially B1, B2, B6), folic acid, and trace elements such as zinc, copper, iron, magnesium, manganese, etc. Rickets occurs more frequently and runs a more severe course with the excessive consumption of monotonous foods, including flour products.

3. Impaired intestinal absorption of calcium and phosphates, increased urinary excretion, or impaired bone utilization due to the immaturity of transport systems in early childhood or diseases of the intestine, liver, and kidneys.

4. Decreased blood calcium and phosphate levels and impaired bone mineralization during prolonged alkalosis and trace element imbalances (zinc, magnesium, strontium, aluminum) caused by various factors.

5. Disruption of the physiological ratio of osteotropic hormones (parathyroid hormone and thyrocalcitonin) associated with decreased PTH production (most commonly hereditary hypoparathyroidism).

6. Exogenous or endogenous vitamin D deficiency, low levels of the vitamin D metabolite as a modulator of phosphate and calcium metabolism.

7. Reduced motor and weight-bearing activity (in various chronic diseases/conditions) and associated secondary disorders of calcium metabolism.

Increased skin pigmentation (including in black individuals) leads to lower 25(OH)D levels and, consequently, a high risk of vitamin D deficiency. However, due to the influence of vitamin D-binding protein polymorphism, black individuals exhibit higher bone mineral density and a lower risk of fractures compared to white individuals [9].

Clinical manifestation of rickets typically occurs in the spring and winter seasons, especially in children born between October and April who live in regions with insufficient insolation, frequent fogs, cloud cover, or in ecologically disadvantaged areas.

Thus, the main factors predisposing to the development of rickets are a high rate of child growth in the first months of life; the presence of protein-energy malnutrition, prematurity, intrauterine growth restriction, morphofunctional immaturity, and other pathological conditions (Table 3).

Table 3 - Risk groups for the development of nutritional rickets.

In low birth weight infants, the development of rickets is associated with phosphorus deficiency against the background of accelerated growth and a low amount of this element in food. Hypocalcemia, secondary hyperparathyroidism, low tubular reabsorption of phosphates, and subsequent hypophosphatemia may develop in malabsorption syndrome. Increased skin pigmentation leads to lower 25(OH)D levels and, consequently, a high risk of vitamin D deficiency. Nevertheless, individuals with dark skin tones exhibit higher bone mineral density and a lower risk of fractures compared to light-skinned individuals due to the influence of vitamin D-binding protein polymorphism [9].

Numerous epidemiological studies have investigated the possible association between vitamin D insufficiency and various pathological conditions, but no causal relationship has been established. Hypotheses have been described regarding associations with immunological disorders, such as multiple sclerosis [48], type 1 diabetes mellitus (T1DM) [49], rheumatoid arthritis [50], inflammatory bowel disease [51], as well as mental disorders [52, 53], cardiovascular diseases [54], and oncological pathology [55, 56, 57]. Low concentrations of 25(OH)D may be associated with arterial hypertension, hyperglycemia, metabolic syndrome (even after adjustment for race/ethnicity, body mass index, socioeconomic status, and physical activity) [58], upper respiratory tract infections [59, 60], food allergy, and bronchial asthma [61, 62, 63, 64, 65].

1.3 Epidemiology of the Disease or Condition

To date, there are no exact data on the prevalence and incidence of rickets in children.

The largest number of plasma vitamin D studies among the population has been conducted in the northern part of the Russian Federation due to the naturally low level of insolation. A study of vitamin D sufficiency in children and adolescents in the Amur Region revealed clinical markers of low vitamin D levels in 26.2% of examined children: vitamin D insufficiency in 16% of cases, deficiency in 9%; no cases of avitaminosis were detected [27]. An examination of children and adolescents in the Northwestern District revealed a high prevalence of vitamin D insufficiency across all age groups [28, 29]. In children aged 1 month to 3 years and schoolchildren in the Volga District during the winter period, the mean calcidiol level was 18.2 ± 1.0 ng/mL, and only 14.8% of patients showed 25(OH)D levels corresponding to normal sufficiency. Among schoolchildren, a sufficient level of vitamin D sufficiency was found in 11.2% of cases [30, 31].

According to a multicenter prospective cohort pharmacoepidemiological study evaluating vitamin D sufficiency in young children (RODNICHOK-1 study), 66% of children under 3 years of age in the Russian Federation have an inadequate vitamin D level. The results obtained during the study indicate a high frequency of vitamin D insufficiency and deficiency in various regions of the Russian Federation regardless of geographical location. Only 34% of young children have 25(OH)D levels above 30 ng/mL, 24% of children belong to the insufficient group, and 42% to the vitamin D deficient group [32, 33, 34]. The lowest prevalence of vitamin D insufficiency was registered in the Northwestern and Central regions. The lowest frequency of vitamin D deficiency (> 10 ng/mL) is observed in children in Moscow and Yekaterinburg, which is due to the highest frequency of dietary supplementation with cholecalciferol** preparations in young children living in these cities [34]. Conversely, low levels of vitamin D sufficiency were found in cities of the South of Russia and the Far East located below the 45th parallel of the Northern Hemisphere [33, 34].

The majority of older children (70.6%) have vitamin D deficiency, and only every twentieth adolescent has normal vitamin D sufficiency [35, 36]. In the Khabarovsk Territory, the difference in vitamin D sufficiency depends on living in one of the three geographical zones of the region: serum 25(OH)D concentrations in children of the northern geographical zone of the territory are significantly lower compared to their peers from the central and southern zones, whereas sufficient vitamin D sufficiency is more frequently detected in children in the southern zone [37].

In the USA, the overall prevalence of vitamin D insufficiency (defined as serum 25(OH)D concentration < 20 ng/mL) in childhood is approximately 15%, and a 25(OH)D level < 10 ng/mL is found in 1–2% of children [38, 39, 43, 44].

The frequency of vitamin D hypovitaminosis in pregnant women and newborns varies across different countries depending on race, lifestyle, season, and vitamin D intake during pregnancy. Thus, a blood 25(OH)D level of less than 20 ng/mL was observed in 18% of non-Hispanic white mothers in the USA, in 42–48% of pregnant women in Canada, Australia, and the UK, in 68–82% in Finland, India, New Zealand, and African-American mothers in the USA, and in 98% of women in the UAE [17].

According to a study conducted at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in 2015–2016, the majority of children in Russia, regardless of gestational age, are born with an inadequate vitamin D level. Median vitamin D values in the first week of life did not exceed 15 ng/mL; in 85% of newborns, the 25(OH)D level was below 20 ng/mL, and in 1/3 of children, below 10 ng/mL. In extremely premature newborns examined throughout the year, the lowest 25(OH)D level was detected in winter and the highest in summer: 8.1 ng/mL (3.3–14.5) and 17.9 (4.5–29.3), respectively [1].

1.4 Features of Coding the Disease or Condition

E55 – Vitamin D deficiency

E55.0 – Active rickets

E55.9 – Vitamin D deficiency, unspecified

1.5 Classification of the disease or condition

Currently, given modern concepts of phosphorus-calcium homeostasis and vitamin D metabolism, as well as from the standpoint of clinical feasibility, it is proposed to classify rickets in young children by severity [45]:

o Mild rickets – grade I;

o Moderate rickets – grade II;

o Severe rickets – grade III.

By disease period:

o Height (active phase);

o Convalescence;

o Residual effects.

The period of initial manifestations is currently not routinely distinguished due to the nonspecificity of manifestations, but attention should be paid to them starting from 3 months of age in premature infants and from 6 months in term infants.

By clinical course:

o Acute;

o Subacute.

Depending on the main cause of the rachitic process, three forms of the disease are distinguished [46, 47]:

Calcium-deficient (calcipenic) rickets – caused by calcium deficiency, usually resulting from insufficient dietary vitamin D intake or the inability to metabolize dietary vitamin D into its active form. In some cases, caused by insufficient intake or absorption of calcium with normal vitamin D levels.

Phosphate-deficient (phosphopenic) rickets – characterized by a low serum phosphorus level caused by renal phosphate wasting or, less commonly, insufficient phosphate intake (in prematurity), with an increased phosphate demand under conditions of rapid growth, impaired intestinal absorption, etc.

Vitamin D-deficiency rickets is frequently associated not only with vitamin D deficiency, but also with calcium and phosphorus metabolism disorders, which determine the clinical presentation of the disease (including laboratory and radiological changes).

1.6 Clinical presentation of the disease or condition

In the majority of patients, vitamin D deficiency is asymptomatic.

The timeframe from the development of vitamin D deficiency (a 25(OH)D level drop below 20 ng/mL or 50 nmol/L) to the onset of clinical manifestations of rickets has not been clearly established; therefore, it is critical to implement adequate prevention and treatment of vitamin D deficiency.

The clinical presentation of vitamin D-deficiency rickets is most commonly observed in infants and young (toddler) children, manifesting primarily as skeletal changes, occasionally accompanied by symptoms caused by hypophosphatemia and/or hypocalcemia.

Bone signs of rickets in young children are due to rapid growth rates, a high rate of bone remodeling, a deficiency of phosphates and calcium in the growing organism amidst imperfect pathways of their transport, metabolism, and utilization (maturation heterochronia). Signs and symptoms involving the skeleton may include:

• delayed closure of the anterior fontanelle (normally closes by 9–18 months, on average by 1.5 years);

• delayed tooth eruption (absence of incisors by 10 months, absence of molars by 18 months);

• lower limb deformities (bowlegs/knock-knees/windswept deformity);

• rachitic rosary (enlargement of the costochondral junctions: palpable on the anterior chest wall, lateral to the midclavicular line);

• frontal bossing;

• craniotabes (softening of the skull bones, usually detected by palpation of the frontal sutures in the first 3 months of life as the "felt hat" or "ping-pong ball" sign [indentation of the skull bone upon palpation with subsequent spring-back recovery]);

• osteoid hyperplasia (thickenings in the interphalangeal joints of the fingers ["string of pearls"], at the wrist ["rachitic bracelets"] and ankle joints, Harrison's sulcus – chest deformity with widening of the lower thoracic aperture and rib flaring);

• radiological signs (osteoporosis at sites of maximal bone growth, indistinctness of ossification centers, widening of growth plates [widening/flattening/cupping deformation], surface roughness and trabeculation of the metaphyses; thinning of the diaphyseal cortical layer, loss of distinct borders between the epiphysis and metaphysis);

• pelvic deformities, including narrowing of the pelvic outlet (risk of abnormal labor and mortality).

In severe cases – persistent and clinically significant deformities; pathologic fractures.

Extraskeletal manifestations of rickets develop alongside bone symptoms and include manifestations of hypocalcemia and hypophosphatemia: decreased muscle tone (including abdominal distension ["frog belly"], delayed acquisition of motor milestones, hyperreflexia, hypocalcemic seizures and tetany, laryngospasm, prolonged QT interval on the electrocardiogram, respiratory failure, erythrocyte and leukocyte dysfunction, signs of encephalopathy, restlessness and irritability, elevated intracranial pressure, delayed weight gain and linear growth. In severe cases – hypocalcemic dilated cardiomyopathy (heart failure, cardiac arrhythmias, cardiac arrest, death).

Complications of rickets include conditions associated with an increased risk of extremity fractures, spinal compression fractures, femoral neck fractures, severe radicular syndrome, and height reduction due to decreased vertebral body height in marked osteoporosis.

Stage I rickets is characterized by bone changes: compressibility of skull bones upon palpation, craniotabes, rib thickenings at the cartilage-to-bone transition sites ("rosary"), moderate muscle hypotonia. Detecting only symptoms of autonomic dysfunction (sweating, restlessness, irritability) is not sufficient for a diagnosis, contrary to previous practice.

Stage II (moderate) rickets is characterized by pronounced manifestations of osteomalacia and osteoid hyperplasia: frontal and parietal eminences, "rosary", Harrison's sulcus are noted; moderate, predominantly varus deformity of the lower extremities, as well as a "frog belly".

Stage III (severe) rickets is characterized by gross skull deformities (sinking of the nasal bridge, "olympian" forehead), chest deformities (pigeon chest/funnel chest), spinal deformities (rachitic kyphosis); thickening of the forearm bone epiphyses ("rachitic bracelets") and finger phalanges ("string of pearls"), lower extremities (valgus or varus); disruption of the timing and sequence of tooth eruption (absence of incisors by 10 months, absence of molars by 18 months), possible bone fractures, marked muscle hypotonia, "frog belly", delayed development of static functions.

During the acute phase of rickets, symptoms of bone involvement predominate, the severity of which depends on the degree and course of the process: osteomalacia, osteoid hyperplasia, bone hypoplasia, bone deformities, alterations in the muscular system, ligamentous apparatus, internal organs, and hematopoietic organs, corresponding to moderate and severe rickets.

During convalescence, symptoms of active rickets are resolved (bone deformity, muscle hypotonia, anemia, nervous system symptoms, restoration of the function of other organs and systems). In biochemical blood tests, phosphorus levels normalize, while mild hypocalcemia and elevated alkaline phosphatase activity may persist.

Residual manifestations of rickets may be observed in children over 2–3 years of age, when bone deformities persist as sequelae of stage II or III rickets. The child has normal serum calcium, phosphorus, and alkaline phosphatase levels. Deformity of the tubular bones disappears after 3 years as a result of bone remodeling, but changes in flat bones persist (enlargement of parietal and frontal eminences, flattening of the occiput, pelvic bone deformities), malocclusion, chest deformity.

The course of nutritional rickets can be acute or subacute. Acute course is detected in rapidly growing infants in the first six months of life and is characterized by the predominance of osteomalacia over osteoid hyperplasia processes, with an intense progression of symptoms. Subacute course is more frequently observed in children with intrauterine or postnatal malnutrition, premature infants, or infants receiving an inadequate dose of vitamin D; it is distinguished by a slower development of disease symptoms and the predominance of osteoid hyperplasia processes over osteomalacia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of "Vitamin D deficiency" is established based on medical history, physical examination data, and the results of biochemical studies (see sections 2.1, 2.2, 2.3, 2.4); the key diagnostic criterion for vitamin D deficiency is the blood level of vitamin D 25(OH)D (см. раздел 2.3) [3].

Thus, vitamin D-deficiency rickets includes a clinical and laboratory complex of disorders ― vitamin D deficiency, signs of osteomalacia and/or signs of osteoid hyperplasia, impaired phosphorus and calcium metabolism, mineralization of metaphyseal zones, and increased alkaline phosphatase activity.

The diagnosis of rickets should not be based solely on pathological symptoms such as delayed tooth eruption, delayed closure of the anterior fontanelle, and delayed static-motor development.

2.1 Complaints and Anamnesis

Comment: it should be noted that the listed clinical manifestations are not pathognomonic.

2.2 Physical Examination

• Upon physical examination, it is recommended to pay attention to the main clinical manifestations of rickets for diagnostic purposes:

  o enlargement of the skull (frontal eminences);

  o craniotabes;

  o enlargement of the costochondral junctions ("rachitic rosary");

  o chest deformity with widening of the lower aperture and rib flaring (Harrison's sulcus);

  o swelling/thickenings in the area of the wrist and ankle joints;

  o varus, less commonly valgus deformity of the lower extremities;

  o muscle hypotonia ("frog belly")

  (performed as part of the initial and follow-up examinations (evaluations, consultations) by a pediatrician, neonatologist, or general practitioner (family physician) (therapeutic visual inspection, therapeutic palpation, therapeutic auscultation, therapeutic percussion) [1].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

2.3 Laboratory Diagnostics

Comment: 25(OH)D (calcidiol) has a half-life of approximately 2-3 weeks. Biologically active calcitriol circulates in significantly smaller quantities (its concentrations are 1000 times lower), has a short half-life (4 hours), and does not reflect the body's vitamin D reserves. Calcitriol levels remain normal or may increase in vitamin D deficiency due to secondary hyperparathyroidism, and its determination is advisable only in the diagnosis of congenital or acquired disorders of vitamin D metabolism (e.g., in 24-hydroxylase deficiency) [72].

Criteria for determining vitamin D status in Table 1 (see section 1.1) [3, 66, 116]:

o Serum 25(OH)D concentration less than 20 ng/mL (50 nmol/L) corresponds to vitamin D deficiency;

o Serum 25(OH)D concentration in the range of ≥ 20 and < 30 ng/mL (≥ 50 and < 75 nmol/L) corresponds to vitamin D insufficiency.

• Routine screening for vitamin D deficiency (measurement of blood 25-OH D levels) in full-term newborns and preterm infants born after 31 weeks of gestation is not recommended due to the lack of evidence supporting the benefit of this approach and its high cost [3].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: screening for vitamin D deficiency should be performed in patients with risk factors for its development; indications for testing blood levels of 25-OH vitamin D include hypocalcemia, signs of congenital rickets, and metabolic bone disease.

Comment: in persistent cholestasis (more than 10 days) and exocrine pancreatic insufficiency, monitoring via blood 25-OH vitamin D levels and other fat-soluble vitamins is necessary [76].

Comment: calcium levels adjusted for albumin should be evaluated to exclude falsely elevated or falsely lowered calcemia values when plasma protein concentrations change, especially at albumin levels below 40 g/L and above 45 g/L.

Formulas for calculating albumin-corrected calcium:

o plasma total calcium (mmol/L) = measured plasma total calcium level (mmol/L) + 0.02 × (40 - measured blood albumin level (g/L));

o plasma total calcium (mg/dL) = measured plasma total calcium level (mg/dL) + 0.8 × (4 - measured plasma albumin level (g/dL));

o conversion factor: [calcium] mg/dL × 0.25 == > [calcium] mmol/L [124].

• In children receiving therapeutic doses of a vitamin D group drug (cholecalciferol**), it is recommended to assess vitamin D status (measurement of blood 25-OH vitamin D levels) for the timely diagnosis of hypervitaminosis and therapy adjustment [83].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: the timing and intensity of serum 25(OH)D monitoring depend on the severity of the initial deficiency/insufficiency [83].

Comment: hypercalcemia is most likely in individuals with inactivating mutations in the CYP24A1 gene. Testing is usually performed after one to two months [41].

Comment: this condition is characteristic of patients with mutations in the CYP24A1 or SLC34A1 genes responsible for the development of idiopathic infantile hypercalcemia (IIH) types 1 and 2, respectively [77, 78]. The CYP24A1 gene encodes the 24-hydroxylase enzyme involved in the inactivation of active vitamin D forms. CYP24A1 mutations lead to the accumulation of active vitamin D metabolites in the absence of 24-hydroxylase enzymatic activity, contributing to the development of hypercalcemia. The SLC34A1 gene encodes the type IIa Na-Pi cotransporter in the kidneys. Due to its impaired function, excessive renal phosphorus loss, hypophosphatemia, and accumulation of active vitamin D metabolites occur in the absence of the inhibitory effect of fibroblast growth factor 23 (FGF23) [78, 79]. IIH may manifest when prophylactic doses of drugs from the "vitamin D and its analogues" group (D3) are prescribed [80, 81].

• When 25-OH vitamin D deficiency is detected during adequate treatment, it is recommended to measure inorganic blood phosphorus, blood calcium and/or blood calcium, blood 25-OH vitamin D, blood alkaline phosphatase activity, and blood parathyroid hormone (PTH) to assess calcium-phosphorus metabolism (Appendix A3.3) [43, 82].

GCR BLEL 3Grade of Recommendation — B, Level of Evidence — 3

Comment: with increasing severity of vitamin D deficiency, the concentration of 1,25(OH)₂D decreases, while parathyroid hormone (PTH) and alkaline phosphatase levels increase. Elevated PTH mobilizes calcium from bones, and serum calcium concentration remains within the normal range or is moderately decreased in mild to moderate vitamin D deficiency, despite reduced intestinal calcium absorption. However, calcium concentration may be low in severe vitamin D deficiency. Decreased intestinal absorption and elevated PTH levels lead to a progressive decrease in phosphorus concentration [82]. Alkaline phosphatase activity in the blood is usually significantly higher than age-related norms in nutritional rickets, whereas the level is elevated to a lesser extent in the common form of hereditary phosphopenic rickets (X-linked hypophosphatemia). A marked increase in alkaline phosphatase activity is a marker of disease activity. In hereditary forms of phosphopenic rickets, blood alkaline phosphatase activity tends to be moderately elevated (from 400 to 800 IU/L), whereas in calcipenic rickets, values often reach higher levels (frequently up to 2000 IU/L) [83].

In certain forms of phosphopenic rickets (mediated by FGF23 excess, such as X-linked hypophosphatemia and tumor-induced osteomalacia), the blood concentration of 1,25(OH)₂D may be low or inappropriately normal (considering the concomitant hypophosphatemia, which should stimulate increased metabolite production). In other forms of phosphopenic rickets (not mediated by FGF23 excess, such as hereditary hypophosphatemic rickets with hypercalciuria), blood 1,25(OH)₂D concentrations may be elevated.

2.4 Instrumental Diagnostics

• To determine the spectrum and severity of bone abnormalities in patients with clinical signs of rickets or osteomalacia associated with vitamin D deficiency and impaired calcium-phosphorus metabolism, it is recommended to perform an X-ray assessment of structural skeletal changes, including radiography of the pelvis and/or radiography of the lower extremities and/or radiography of the upper extremities and/or targeted chest radiography [3].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: specific indications for radiography of a particular skeletal region in the diagnosis of rickets have not been established; therefore, the necessity and scope of X-ray examinations are determined on an individual basis.

The radiological presentation during the peak period is characterized by specific lesions of the epimetaphyseal zones of tubular bones, the so-called rachitic metaphysis—blurred zones of mineralization, widening of the metaphyseal zones, cupping deformity of the epimetaphyseal regions of the bones, and indistinct ossification centers; osteopenia and coarse trabecular pattern of the diaphyseal regions are identified. Widening of the growth plates, saucer-like deformation of the metaphyses, and irregularity and concavity of their margins are also observed.

2.5 Other Procedures

2.5.1 Specialist Consultations and Monitoring

Comment: the disease is characterized by involvement of multiple organs and systems, which dictates the need for collaborative patient management by specialists in various fields. Initial and follow-up appointments (examinations, consultations) are indicated with a geneticist, neurologist, neurosurgeon, pediatric endocrinologist, traumatologist-orthopedist, dentist, nephrologist, cardiologist, pulmonologist, otolaryngologist-audiologist, ophthalmologist, pediatrician/neonatologist/general practitioner (family physician), medical rehabilitation specialist (medical rehabilitation physician/physical and rehabilitation medicine physician/exercise therapy physician/physiotherapist, or others), as well as other specialists as indicated.

2.5.2 Differential Diagnosis

There is a wide range of diseases and pathological conditions presenting with rachitic syndrome [66, 67, 68]. When making a diagnosis of vitamin D-deficient rickets, hereditary forms of rickets—known as rickets-like disorders, genetically determined osteopathies, vitamin D-dependent or vitamin D-resistant forms of rickets (e.g., hereditary hypophosphatemic vitamin D-resistant rickets, renal tubular acidosis, De Toni-Debré-Fanconi syndrome, etc.)—should be excluded as part of the differential diagnosis (Appendix A3.4).

A resistant form of rickets should be suspected in the following cases:

• if there is a positive family history of similar disorders;

• the disease clinically progresses with the development of skeletal deformities (grade III rickets) despite dietary correction and the use of therapeutic doses of vitamin D group preparations and their analogues at recommended dosages for 1 month;

• the disease is accompanied by delayed physical development (primarily in height).

The corresponding differential diagnostic clinical and laboratory criteria are provided in Appendix A3.4.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The mainstay of therapy for vitamin D insufficiency/vitamin D deficiency/rickets in children is the administration of a preparation from the "Vitamin D and its analogues" group—cholecalciferol** in therapeutic doses [1, 72], followed by the continued use of prophylactic doses to maintain a sufficient serum 25(OH)D concentration [72, 84, 85, 116].

3.1 Conservative Treatment

3.1.1 Pathogenetic therapy

Table 4. Therapeutic doses of #cholecalciferol** for vitamin D insufficiency/vitamin D deficiency/rickets in children [1, 72, 116].

• 1 – after the therapeutic dose, once the target 25(OH)D level is reached, a prophylactic dose is prescribed [1, 72, 116].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: under close monitoring of clinical status and laboratory tests.

3.1.1.1 Treatment of Vitamin D Insufficiency

• For the treatment of vitamin D insufficiency in children with serum 25(OH)D levels ≥ 21 but < 30 ng/mL (≥ 50 but < 75 nmol/L), it is recommended to prescribe a vitamin D group preparation and its analogues (cholecalciferol**) at a therapeutic dose of 2000 IU/day under the control of blood 25-OH vitamin D levels, followed by the administration of a prophylactic dose to correct the insufficiency [1, 72, 69].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comments: when treating vitamin D insufficiency, preference is given to the D3 form (cholecalciferol**), which has a comparatively greater efficacy in achieving and maintaining target serum 25(OH)D values. Therapy is carried out for 1 month or until the target level (≥ 30 ng/mL or 75 nmol/L) is reached. Preparations of vitamin D and its analogues (cholecalciferol**) at a therapeutic dose may be prescribed when deficiency is confirmed, with regular monitoring of blood 25-OH vitamin D levels.

Monitoring for potential cholecalciferol** overdose should be performed by measuring calcium levels in 24-hour urine (no more than 2 mg/kg per day) (see Section 2.3).

An increase in blood 25(OH)D levels up to 50 – 60 ng/mL (or 125–150 nmol/L) is safe; exceeding this level does not imply hypervitaminosis, but requires adjustment of the cholecalciferol** dose. A potentially toxic level is a 25(OH)D concentration greater than 100 ng/mL (or greater than 250 nmol/L) [70, 89, 118].

Treatment of rickets with vitamin D group preparations and their analogues can be effective only if there is an adequate intake of calcium and phosphates into the child's body, taking into account their physiological requirements.

3.1.1.2 Treatment of Vitamin D Deficiency / Rickets

• For the treatment of vitamin D deficiency/rickets in children with serum 25(OH)D levels ≥ 11 and < 20 ng/mL (≥ 25 and < 50 nmol/L), it is recommended to use a vitamin D group preparation and its analogues (cholecalciferol**)* at a therapeutic dose of 3000 IU/day for 1 month, followed by monitoring of 25(OH)D and prescribing a prophylactic dose once a level of 30 ng/mL or more is reached [1, 72].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

• For the treatment of vitamin D deficiency/rickets in children with a decreased 25(OH)D level of 10 ng/mL (25 nmol/L) or less, it is recommended to use vitamin D preparations and their analogues (cholecalciferol**) at a therapeutic dose of 4000 IU/day for 1 month, followed by monitoring of blood 25-OH vitamin D levels and prescribing a prophylactic dose once a level of 30 ng/mL or more is reached (see Table 4) [1, 72].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

• If blood 25(OH)D levels remain below normal (less than 30 ng/mL) in children during a therapeutic course (1 month) of vitamin D group preparations and their analogues (cholecalciferol**) at a therapeutic dose, it is recommended to continue the therapeutic dosage based on the blood 25(OH)D level for an additional 15 days, with a follow-up assessment of blood 25-OH vitamin D (calcidiol) levels in order to achieve a normal 25(OH)D level [1, 72].

GCR CLEL 5Grade of Recommendation – C, Level of Evidence – 5

3.1.1 Symptomatic Therapy

• In case of hypocalcemia associated with vitamin D deficiency and/or insufficient dietary calcium intake, it is recommended to prescribe calcium-containing medicinal products, either as monotherapy or in combinations (e.g., calcium preparations combined with vitamin D and/or other medicinal products), including calcium carbonate + colecalciferol (in accordance with the instructions for medical use) to meet the daily requirement for this element [3, 91].

GPP BLOE 2Grade of recommendation – B, level of evidence – 2

Comment: calcium is a building block for bone tissue and a primary participant in calcium-phosphorus metabolism. Therefore, adequate calcium intake is essential for the full realization of vitamin D functions. Calcium is found in many food products (dairy products, including cottage cheese, etc.), and one should strive to maximally meet the daily calcium requirement through adequate dietary intake.

In accordance with current standards of physiological requirements for energy and nutrients [92] for children aged 0–6 months, the calcium requirement is 400–500 mg/day, in the second half of life – 600 mg/day, and in the second year of life, the normative intake of this macronutrient is 800 mg/day.

3.2 Surgical Treatment

Comments: following posture and gait analysis, the child is offered individualized kinesitherapy (general therapeutic exercises, therapeutic exercises for musculoskeletal disorders in children, general medical massage, therapeutic swimming in a pool, physical therapy in a pool, hydrokinesitherapy for joint diseases and injuries).

Physical therapy in the postoperative period is based on the same principles as non-surgical treatment. In the presence of rotational limb deformities, orthotics is added to physical exercises and massage as indicated. The use of orthopedic devices helps reduce pain and improve the quality of movement (for example, the use of special insoles and special footwear reduces discomfort in the feet, lower legs, and thighs).

The use of assistive mobility devices, including walkers and wheelchairs, is also necessary in the postoperative period.

Against the background of adequate rehabilitation, most rotational deformities resolve spontaneously by the age of eight [97].

3.3 Other Treatment

Medical Nutrition Therapy

Along with basic treatment, children with rickets are prescribed diet therapy balanced in Ca, P, protein, vitamins C, A, and B group. The ratio of proteins, fats, and carbohydrates should be 1:3:6, respectively. Maximum intestinal calcium absorption is observed when the Ca:P ratio in food products is 2:1, which occurs in breast milk.

The organization of dietary nutrition for patients receiving inpatient care in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition".

Pain Management

Pain management is performed as necessary in accordance with the underlying disease.

For analgesic purposes, methods such as ice (application of an ice pack, local contact hypothermia), heat (application of a heating pad), or taping (medical rehabilitation services for children with neuro-orthopedic pathology using therapeutic taping methods) can be used.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation methods and health-resort treatment options for patients with vitamin D deficiency and rickets currently lack a high level of evidence.

It should be noted that rehabilitation and health-resort treatment cannot replace adequate supplementation with "vitamin D and its analogues" group drugs

Rehabilitation of children with rickets

The main rehabilitation objectives in children with rickets during the height of the disease are: normalization of neuromuscular conduction, improvement of metabolism, restoration of impaired functions of the respiratory and circulatory systems, and prevention of potential musculoskeletal deformities [93, 94].

Rational nutrition, adequate exposure to fresh air, general medical massage, and therapeutic gymnastics (therapeutic gymnastics for musculoskeletal disorders in children) are of positive significance for the recovery of children after the correction of vitamin D deficiency [1, 95].

Comments: early rehabilitation is carried out simultaneously with treatment using a drug from the "vitamin D and its analogues" group (see Section 3).

The main ways to achieve rehabilitation goals are stroking massage (of the back, abdomen, extremities) and passive physical exercises performed after the massage in compliance with the necessary methodological rules (with warm hands, slowly, within the physiological range of motion in the joint). In the presence of unconditioned motor reflexes, reflex exercises can be used. To prevent musculoskeletal deformities, positioning on a flat mattress with mandatory frequent position changes is used.

Thus, in premature newborns, data have been obtained indicating the effectiveness of a daily passive mobilization exercise program with gentle joint pressure, lasting 10 to 15 minutes per day for 4 to 8 weeks, regarding bone mineralization as measured by ultrasound, densitometry, and bone formation biomarkers [94].

Rehabilitation during the convalescence period of rickets

The objectives of child rehabilitation during the convalescence period of rickets are: elimination of muscle hypotonia, correction of psychomotor development disorders, restoration of lost or delayed motor skills, prevention and correction of musculoskeletal deformities, since the majority of patients exhibit simultaneous hyperlaxity and increased elasticity of the skin and ligamentous apparatus.

Comments: individual therapeutic gymnastics sessions lasting 12-15 minutes are conducted with the child 2-3 times a day. During the sessions, massage with all techniques is used primarily for the most affected muscles (back, abdomen, buttocks). According to the child's existing motor skills, gymnastic exercises are prescribed. For the development of delayed motor skills – massage of the corresponding muscle groups, passive exercises, muscle stimulation. Exercises for the correction of skeletal deformities are performed.

Massage is used if the child is gaining weight. When the child is eating and not gaining weight, massage is better postponed.

Physical methods in complex treatment include general UVR (general long-wave ultraviolet therapy); salt-conifer baths are used starting from 6 months of age (after a course of UVR).

In addition to massage and physical therapy, which are prescribed 2 weeks after the initiation of drug therapy, children with rickets may undergo balneotherapy (coniferous, saline baths for a course of treatment of 10–15 baths). Balneotherapy is performed 2–3 times a year. Sea baths are conducted for 10–15 minutes, with a water temperature of +33...+35 °C. Swimming and water exercises, as well as walking exercises in the bath on a textured rubber mat, are desirable [96].

In the presence of secondary skeletal deformities, rehabilitation measures are aimed primarily at alleviating pain during active physical loads.

Rehabilitation measures for vitamin D deficiency:

Rehabilitation measures for vitamin D deficiency are comprehensive in nature, including:

- supplementation with «vitamin D and its analogues» preparations (see sections 3 and 5);

- diet correction including foods with a high content of vitamin D and calcium;

- spending time outdoors (excluding the risk of excessive sun exposure and in the absence of contraindications): 5–30 minutes (face, arms, hands, and legs without sunscreen) from 10:00 to 16:00 daily or at least twice a week [98, 99].

There are no direct physiotherapeutic interventions for vitamin D deficiency. There is evidence suggesting that physical exercise and the administration of «vitamin D and its analogues» preparations have a mutually potentiating effect [99, 100].

5. Prevention and Dispensary Observation

Sufficient evidence has been accumulated [1, 32, 33, 34, 116] indicating that sun exposure alone cannot provide adequate prevention of vitamin D insufficiency.

5.1 Prevention

5.1.1 Antenatal Prophylaxis

The administration of vitamins and micronutrients to pregnant women for antenatal prevention of vitamin D deficiency is carried out in accordance with the clinical guidelines «Normal Pregnancy».

5.1.2 Postnatal Prophylaxis

Postnatal prevention includes a balanced diet for the child, adherence to the daily routine (including spending time outdoors and sufficient physical activity), and supplementation with a vitamin D and its analogues preparation. The maximum permissible prophylactic doses of vitamin D and its analogues (cholecalciferol**) must be kept in mind (Table 5).

Table 5. Upper limits of daily intake of cholecalciferol** for the prevention of vitamin D deficiency (depending on age) [116, 121]

Comments: children should receive vitamin D regularly and continuously.

• Premature infants, regardless of the type of feeding and the use of human milk fortifiers, are recommended daily prophylactic supplementation with a vitamin D and its analogues preparation - #cholecalciferol** during the first 3–4 months of life at a dose of 500–1000 IU/day, with a maximum daily dose of no more than 1000 IU/day. The indicated prophylactic dosage corresponds to 300–525 IU/kg/day at a body weight of 750 g, 400–700 IU/kg/day at a body weight of 1000 g, and 600–1000 IU/kg/day at a body weight of 1500 g, with the aim of preventing the development of a vitamin D-deficient state [103, 126].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: supplementation is carried out at a dose of 500 IU/day until the age of 1 month. Children with a small fontanelle size do not have contraindications to prophylactic supplementation if they maintain age-appropriate head circumference growth rates [1, 103].

• Children aged 1–12 months are recommended prophylactic supplementation with a vitamin D and its analogues preparation (cholecalciferol**) at a dose of 500–1000 IU/day (according to the instructions) (for children in Northern Russia aged 6–12 months – #cholecalciferol** 1000–1500 IU/day) with the aim of preventing the development of a vitamin D-deficient state [1, 116, 119].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

• Children aged 12 months – 18 years are recommended prophylactic supplementation with a vitamin D preparation (cholecalciferol**) at a dose of 1000–2000 IU/day (according to the instructions) with the aim of preventing the development of a vitamin D-deficient state [1, 72, 116, 119].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

• As part of non-specific prevention, it is recommended to properly establish the child's daily routine, ensure sufficient time spent in the fresh air and physical activity, including wide swaddling of infants to ensure adequate motor activity [2].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

5.2 Dispensary monitoring

• Patients with vitamin D insufficiency and no biochemical changes or signs of rickets are not recommended intensive dynamic monitoring due to inexpediency [82, 116, 119].

GCR CLOE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C, Level of Evidence – 5

Comment: in medical practice, as a rule, in case of vitamin D insufficiency, the 25(OH)D level is evaluated after 2–3 months of therapy with vitamin D and its analogues preparations and further as clinically indicated.

A positive therapeutic effect is achieved only with a comprehensive approach: optimizing infant feeding, balanced intake of calcium and phosphorus salts, vitamin D therapy, and utilizing natural general health-improving measures.

Comment: the scope of medical services during dispensary follow-up of children with rickets is determined by the pediatrician or general practitioner (family physician) individually, depending on the severity of rickets and the presence of comorbid pathology (timing and number of laboratory, instrumental, and other studies; primary and follow-up appointments (examinations, consultations) with a trauma surgeon-orthopedist, neurologist, pediatric endocrinologist, and other specialized primary care physicians as needed).

Vaccination

Vitamin D insufficiency and rickets (after acute condition relief, in a stable course, i.e., in the absence of severe complications) are not a contraindication to vaccination using any type of vaccine [110, 111].

In conditions of unfavorable epidemiological situations, it is necessary to consider carrying out emergency vaccination or replacement immunoprophylaxis against the background of treatment for the underlying disease [112].

6. Organization of Medical Care

Medical care for patients with rickets or vitamin D deficiency/insufficiency is provided, as a rule, in outpatient and polyclinic settings. Some patients may be indicated for inpatient hospitalization regarding the underlying disease (see the section «Etiology and Pathogenesis») or complications.

Patients with rickets or vitamin D deficiency/insufficiency may, depending on necessity, be provided with any type, setting, and form of medical care stipulated by the legislation of the Russian Federation.

6.1 Indications for planned hospitalization

Carrying out diagnostics and treatment requiring prolonged (day or round-the-clock stay) medical observation and monitoring of clinical and laboratory parameters, as well as the absence of effect from previously administered therapy.

6.2 Indications for emergency/urgent hospitalization

Presence/risk of serious complications or life-threatening conditions requiring urgent treatment, including intensive care, as well as round-the-clock medical observation and special types of examinations and treatments – according to clinical manifestations and corresponding recommendations.

6.3 Indications for hospital discharge

1. Absence of a threat to the patient's life and the risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. Stabilization of the condition and basic clinical and laboratory parameters of the pathological process, absence of the need for prolonged medical observation (day or round-the-clock stay);

3. Fulfillment of the patient's examination and treatment plan in cases where the patient has been given recommendations for further monitoring and treatment.

4. The need to transfer the patient to another medical organization or social welfare institution.

7. Additional Information

7.1 Outcomes and prognosis

The prognosis for vitamin D insufficiency/deficiency, including vitamin D-deficient rickets, with adequate correction and absence of comorbid pathology, is favorable.

Relatively favorable prognosis in severe rickets and persistence of its residual effects.

Criteria for Evaluating the Quality of Medical Care

Table 6. Quality criteria for the provision of specialized medical care

References

Appendix A1. Working Group Composition

1. Alekseeva A.A., Candidate of Medical Sciences, Deputy Head of the Consultative and Diagnostic Center for Children - Pediatrician, Head of the Multidisciplinary Pediatric Day Hospital - Allergist-Immunologist, Leading Research Scientist at the Department of Clinical Immunology and Allergology, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery.

2. Anisimova I.V., – PhD in Medicine, Head of the Department of Medical Care Organization, Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists.

3. Baranov A.A., – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Professor at the Department of Pediatrics and Pediatric Rheumatology, N.F. Filatov Institute of Childhood, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Chief Freelance Pediatrician of the Russian Ministry of Health.

4. Batysheva T.T., – Professor, Doctor of Medical Sciences, President of the Association of Pediatric Rehabilitologists of Russia, Director of the Scientific and Practical Centre for Children's Psychoneurology of the Moscow Healthcare Department, Head of the Department of Neurology, Physical and Rehabilitation Medicine for Children, Faculty of Continuous Medical Education, RUDN University, Chief Freelance Pediatric Rehabilitologist of the Russian Ministry of Health, Honored Doctor of Russia.

5. Bezlepkina O.B., – Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Centre for Endocrinology of the Russian Ministry of Health — Director of the Institute of Pediatric Endocrinology.

6. Belyaeva I.A., – Doctor of Medical Sciences, Head of the Department of Preconceptional, Antenatal, and Neonatal Medicine, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia, Honorary Professor of the Russian Association of Perinatal Medicine Specialists.

7. Bombardirova E.P., – Doctor of Medical Sciences, Chief Researcher at the Department of Preconceptional, Antenatal, and Neonatal Medicine, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Neonatologist.

8. Bykova O.V., – Doctor of Medical Sciences, Head of the Research Department, Scientific and Practical Centre for Children's Psychoneurology of the Moscow Healthcare Department, Professor at the Department of Neurology, Physical and Rehabilitation Medicine for Children, Faculty of Continuous Medical Education, RUDN University, Moscow.

9. Zayachnikova T.E., – PhD in Medicine, Associate Professor at the Department of Pediatrics and Neonatology, Institute of Continuing Medical and Pharmaceutical Education, Volgograd State Medical University, Chief Freelance Neonatologist of the Healthcare Committee of Volgograd Region.

10. Ivardava M.I., – PhD in Medicine, Head of the General Pediatrics Department, Pediatrician, Head of the Department for the Development of Scientific Approaches to the Management of Children with Motor Disorders, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Member of the Union of Pediatrists of Russia.

11. Kaitukova E.V., – PhD in Medicine, Deputy Head for Medical Activities — Head of the Consultative and Diagnostic Centre for Children, Gastroenterologist, Leading Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

12. Karaseva M.S., – Junior Researcher, Pediatrician, Scientific and Practical Centre for Children's Psychoneurology of the Moscow Healthcare Department, Member of the Union of Pediatrists of Russia.

13. Klimov Yu.A., – PhD in Medicine, Deputy Director for Medical Work, Scientific and Practical Centre for Children's Psychoneurology of the Moscow Healthcare Department; Head of the Department of Neurology and Neurosurgery, Russian State Social University.

14. Kodentsova V.M., – Professor, Doctor of Biological Sciences, Chief Researcher, Federal Research Centre of Nutrition and Biotechnology.

15. Komarova E.V., – Doctor of Medical Sciences, Deputy Head for the Expertise of Innovative Treatment and Rehabilitation Methods, Gastroenterologist, Chief Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

16. Kutsev S.I., – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Association of Medical Geneticists (AMG), Director of the Research Centre for Medical Genetics named after Academician N.P. Bochkov of the Ministry of Science and Higher Education of Russia, Chief Freelance Medical Geneticist of the Russian Ministry of Health.

17. Margieva T.V., – PhD in Medicine, Chief Specialist of the Methodological Centre for Specialist Accreditation, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Nephrologist, Member of the Union of Pediatrists of Russia.

18. Namazova-Baranova L.S., – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, President of the Union of Pediatrists of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Head of the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Chief Freelance Children's Specialist in Preventive Medicine of the Russian Ministry of Health.

19. Peterkova V.A., – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Supervisor of the Institute of Pediatric Endocrinology, National Medical Research Centre for Endocrinology of the Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology, National Medical Research Centre for Endocrinology of the Russian Ministry of Health.

20. Petryaikina E.E., – Doctor of Medical Sciences, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Pirogov Russian National Research Medical University, Professor at the Department of Evidence-Based Medicine, Faculty of Continuous Medical Education, RUDN University, Chief Freelance Pediatric Endocrinologist of the Moscow Healthcare Department.

21. Privalova T.E., – PhD in Medicine, Associate Professor, Head of Academic Affairs at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Leading Researcher at the Department of Social Pediatrics and Organization of Multidisciplinary Care for Children, Head of Department / Pediatrician, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Member of the Union of Pediatrists of Russia.

22. Pyryeva E.A., – PhD in Medicine, Head of the Laboratory of Age-Related Nutraciology, Federal Research Centre of Nutrition and Biotechnology.

23. Selimzyanova L.R., – PhD in Medicine, Head of the Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

24. Tikhonov S.V., – PhD in Biology, Scientific Secretary, Scientific and Practical Centre for Children's Psychoneurology of the Moscow Healthcare Department, Associate Professor at the Department of Neurology, Physical and Rehabilitation Medicine, Faculty of Continuous Medical Education, RUDN University, Moscow.

25. Turti T.V., – Doctor of Medical Sciences, Chief Researcher at the Department of Preconceptional, Antenatal, and Neonatal Medicine, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

26. Fedoseenko M.V., – PhD in Medicine, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

27. Shishimorov I.N., – Head of the Department of Pediatrics and Neonatology, Institute of Continuing Medical and Pharmaceutical Education, Volgograd State Medical University of the Russian Ministry of Health, Doctor of Medical Sciences, President of the Volgograd Regional Branch of the Union of Pediatrists of Russia.

28. Shaposhnikova N.F., – PhD in Medicine, Associate Professor at the Department of Pediatrics and Neonatology, Institute of Continuing Medical and Pharmaceutical Education, Volgograd State Medical University of the Russian Ministry of Health.

29. Efendieva K.E., – PhD in Medicine, Executive Secretary of the Union of Pediatrists of Russia, Deputy Head for International Relations and Educational Activities, Leading Researcher, Allergist-Immunologist, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery (NCC № 2), Associate Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia.

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

These guidelines are intended for use by medical organizations and institutions of federal, territorial, and municipal healthcare management systems, compulsory and voluntary medical insurance systems, and other medical organizations of various legal forms engaged in the provision of medical care.

Clinical guidelines are based on a literature review and current international clinical guidelines for the diagnosis, treatment, and management of patients with metabolic disorders.

Target audience for these clinical guidelines:

1. General practitioners (family physicians);

2. Pediatricians;

3. General practitioners;

4. Obstetricians-gynecologists;

5. Medical geneticists;

6. Laboratory geneticists;

7. Neurologists;

8. Neurosurgeons;

9. Trauma surgeons and orthopedists;

10. Surgeons;

11. Pediatric surgeons;

12. Cardiologists;

13. Pediatric cardiologists;

14. Nephrologists;

15. Radiologists;

16. Ophthalmologists;

17. Functional diagnostics physicians;

18. Physical and rehabilitation medicine physicians;

19. Psychiatrists;

20. Otorhinolaryngologists;

21. Otorhinolaryngologist-audiologists;

22. Anesthesiologists-intensivists;

23. Rheumatologists;

24. Neonatologists;

25. Pulmonologists;

26. Endocrinologists;

27. Pediatric endocrinologists;

28. Dentists;

29. Pediatric dentists;

30. Medical psychologists;

31. Medical students;

32. Residents and postgraduate students.

Table 7. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 8. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 9. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Procedure for Providing Pediatric Care".

2. Order of the Russian Ministry of Health No. 1094n dated November 24, 2021, "On Approval of the Procedure for Prescribing Medicinal Products, Forms of Prescription Forms for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting and Storage, Forms of Prescriptions Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting and Storage, as Well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents".

3. Decree of the Government of the Russian Federation No. 3053-r dated December 31, 2018, "On Approval of Lists of Medical Devices Implantable into the Human Body When Providing Medical Care Within the Framework of the State Guarantee Program of Free Medical Care to Citizens and Dispensed by Prescription for Medical Devices Upon Provision of a Set of Social Services."

4. International Statistical Classification of Diseases and Related Health Problems (ICD-10).

5. Order of the Russian Ministry of Health No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers" (Registered with the Ministry of Justice of Russia on June 1, 2023, No. 73664)

6. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

7. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Legislation in the Russian Federation' Regarding Clinical Practice Guidelines."

8. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

9. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

10. Order of the Ministry of Health and Social Development of the Russian Federation "On the Procedure for the Use of Medicinal Products in Patients on Vital Indications" No. 494 dated August 9, 2005.

11. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

12. MR 2.3.1.0253-21 Norms of physiological requirements for energy and nutrients for various population groups of the Russian Federation.

Drug information: https://grls.rosminzdrav.ru/

Appendix A3.1 Physiological systems and processes responding to the hormonally active form of vitamin D

Table 10. Physiological systems and processes regulated by the active form of vitamin D [1].

Appendix A3.2 Main dietary sources of vitamin D

Table 11. Vitamin D content [25, 26] in certain food products.

tsp - teaspoon

Table 12. Cholecalciferol and 25(OH)D₃¹ content in certain food products [119].

Note:

^{1 -} The proportion of 25(OH)D3, whose vitamin activity is approximately 5 times higher than that of cholecalciferol, varies in animal-derived products and can reach 1/3-1/2 of the total content of this vitamin.

Appendix A3.3 Biochemical Parameters of Calcium-Phosphorus Metabolism in Vitamin D Deficiency

Table 13. Biochemical manifestations of various stages of vitamin D deficiency compared to calcium or phosphorus deficiency [82].

Notes: ALP – alkaline phosphatase; PTH – parathyroid hormone; 25(OH)D – calcidiol; 1,25-OH D – calcitriol; FGF23 – fibroblast growth factor 23.

Appendix A3.4 Differential Diagnosis of Various Forms of Rickets

Table 14. Laboratory parameters in rickets of various etiologies.

Table 15. Differential diagnosis of rickets [123].

Note:

N = normal; ↑ = increased; ↑↑ or ↑↑↑ = markedly increased; ↑ (↑↑) = may vary widely: Ca = serum calcium level; Pi = serum phosphate level; Alkaline phosphatase ALP; U_{Ca /crea} - urine calcium-to-creatinine ratio; U_{P / Crea} - urine phosphate-to-creatinine ratio; TmP / GFR = maximum tubular reabsorption rate of phosphate normalized to glomerular filtration rate; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone; 1,25 (OH)₂D = 1,25-dihydroxyvitamin; 25 (OH) D = calcidiol; NA = not applicable; ^a = cave: vitamin D deficiency prevalence has been reported to reach 50% in healthy children; ^b = normal after Pi replenishment, but falsely decreased prior to replenishment; ^c = PTH may be moderately elevated; ^d = decreased relative to serum phosphate concentration; ^e = depending on the stage in chronic kidney disease.

Table 16. Typical clinical features of certain hereditary diseases presenting with a rickets symptom complex [123].

Note:

¹ Nonspecific features that may be observed in various forms of rickets include: prominent frontal bones, dental anomalies, enamel hypoplasia, widening of the wrists and ankles (expanded metaphysis), prominent costochondral junctions (rachitic rosary), chest deformity, bowed legs, fractures, bone pain, muscle weakness, waddling gait, hypotonia, heart failure (tachycardia, tachypnea, hepatomegaly, and edema), growth retardation.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

All children, especially newborns and premature infants, require regular year-round vitamin D supplementation for normal bone growth and proper development. Children who do not receive sufficient vitamin D from dietary supplements may develop vitamin D insufficiency, and in more severe cases, rickets in children under the age of three.

Clinical manifestations of rickets include skeletal changes: compressibility of skull bones upon palpation, thickenings on the ribs at the chondrocostal junctions («rachitic rosary»), decreased muscle tone, prominent frontal and parietal bones, chest deformity with rib retraction («Harrison's sulcus»). In severe cases, gross skull deformities (sinking of the bridge of the nose, «olympian» forehead), chest deformities (pectus carinatum («pigeon chest»), pectus excavatum («funnel chest»)), and spinal deformities (rachitic kyphosis) may develop; timing and sequence of tooth eruption are disrupted, and bone fractures and psychomotor developmental delay are possible.

The risk of vitamin D insufficiency and rickets is particularly high in premature infants and exclusively breastfed infants, as breast milk contains low amounts of vitamin D. Consequently, it is necessary to administer additional prophylactic doses of vitamin D approved by the pediatric community.

Risk factors for vitamin D insufficiency include:

• poor nutrition or elimination diets leading to reduced intake of vitamin D and calcium;

• dark skin color;

• low sunlight exposure;

• use of certain medications;

• concomitant diseases impairing the intestinal absorption of vitamin D and calcium (cystic fibrosis, celiac disease, etc.).

Foods and beverages containing vitamin D:

• Fortified infant formulas, milk, fermented milk products;

• Fatty marine fish (salmon, mackerel, tuna);

• Vitamin D-fortified cereal products, etc.

In addition to dietary sources, active forms of vitamin D are synthesized in the skin under the influence of sunlight. However, direct UV exposure to the skin is required; clothing and sunscreens reduce incoming UV radiation, which is contraindicated due to the risk of skin burns and oncogenic skin diseases.

Unfortunately, living in countries with insufficient insolation is not the only factor leading to vitamin D deficiency; this is precisely why preventive vitamin supplementation is required for children year-round in all regions of the Russian Federation, including the southern ones.

Children who are at risk for vitamin D deficiency or present with overt clinical manifestations undergo blood testing to determine 25-OH vitamin D levels. Based on the results, the physician decides whether to prescribe therapeutic doses of vitamin D preparations and its analogues.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.