Rickets, historically known as the “English disease”, is a common disease. Vitamin D deficiency due to insufficient light or intake leads to impaired mineralization of long bone growth plates and phosphorus deficiency on the surface of bone minerals, which is the main cause of rickets. The pathogenesis of hereditary hypophosphatemic rickets is more complex.
The current dose of vitamin D supplementation required for children needs further clarification, the existing guidelines are one-sided and may even be contradictory between guidelines, and treatment following these guidelines does not eradicate rickets.
The historical background, pathophysiological mechanisms, classification and definition of vitamin D deficiency, monitoring, epidemiology, characteristics of supplementation and prevention in different populations of rickets were examined by Professor Bishop et al. at the University of Sheffield, UK, and the article was published in the May 10, 2014 issue of The Lancet.
More than 100 years ago in the United Kingdom, about 25% or more of children had rickets. Today, rickets remains one of the most common non-communicable diseases in children in developing countries and the incidence of this disease shows an upward trend in the UK, despite the lack of data on this.
The typical manifestations of rickets are skeletal deformities and growth disturbances. The main deformities are lower limb deformities such as bowed legs, inversion of the knee and fracture changes, all of which can cause disability. If a girl develops pelvic deformities, this may lead to death during childbirth. Prolonged reduction in bone volume may have adverse effects on the skeleton, such as osteoporotic fractures that can occur in later life.
The pathology of rickets is defined as impaired new bone mineralization, which means that the formed osteoid does not mineralize (osteochondrosis) and the growth plate cartilage fails to calcify or calcification is diminished, which may be combined with growth plate deformities. In most patients, these characteristic changes are due to vitamin D deficiency, mostly with a clear medical history and with typical biochemical and imaging characteristic changes.
Whether there is a vitamin D threshold below which rickets occurs, for example, is unclear. However, there is a subset of patients in whom the total amount of calcium entering the bones is low, even though the vitamin D level is within the normal range and the body has a high capacity for calcium absorption.
Some rare cases, in which factors causing impaired phosphate metabolism or abnormal bone tissue mineralization may be the main cause of skeletal deformities. Further understanding of the complex homeostatic balance of phosphorus metabolism in vivo is needed. This article focuses on this issue, taking into account other controversial areas, including the role of low levels of vitamin D in early childhood fractures.
Historical Background
Early descriptions of rickets were mainly attributed to Professors Whistle and Glisson, both of whom were practicing medicine in England in the mid-1700s. The origin of rickets itself is not clear, and may be related to the German word “wricken,” which means distorted. glisson accurately distinguished rickets (chondromalacia) from hemorrhagic rickets by autopsy, although he had suggested that the treatment of rickets by wrapping wool around the legs was clearly wrong.
In 1861-1862, Professor Trousseau found that insufficient light and malnutrition could be the cause of rickets and gave a rational treatment plan that included cod liver oil treatment. 1890, Professor Palm concluded that increased latitude (reduced light exposure) was associated with the development of rickets.
In 1916, Professors Hess and Unger conducted a randomized controlled trial in the Columbia, New York community and found a definite effect of cod liver oil in the treatment of clinical rickets. This study brought to the forefront the classic work of Professor Mellanby, who first put cod liver oil in porridge and fed it to dogs with rickets that developed from lack of light, and this method cured these dogs of rickets. Professors Hess and Unger cured rickets by exposing children with rickets to sunlight.
Prof. Daniels and colleagues found that infants who received additional cod liver oil grew faster than those who were given only a normal diet.
In 1932, Windaus synthesized vitamin D2 and vitamin D3 chemically, and subsequently Professors Jeans and Stearns conducted a clinical study in an American orphanage in which children who received breast milk, received different doses of vitamin D2 and vitamin D3, respectively.
The conversion factors for vitamin D treatment and monitoring doses are presented in Figure 1. Children who received low doses of vitamin D along with sunlight exposure grew 2 cm taller on average at 1 year of age compared to those who received 1.5-3.4ug (60-135 IU) per day, and those who received high doses of vitamin D without sunlight exposure grew faster.
A follow-up study found that height growth slowed at doses higher than 45ug (1800 IU) of vitamin D daily and improved again when the daily dose was reduced to 10-15ug (400-600 IU). Recent studies have not found that high-dose vitamin D treatment can cause slow growth. The recommended daily dose of vitamin D in the UK is now largely consistent with the initial recommended dose.
Vitamin D metabolism and action
Vitamin D2 (ergocalciferol) can only be taken up from food, but vitamin D3 (cholecalciferol) is found in cod liver oil and fatty fish and can be synthesized through the skin. Sunlight exposure, especially ultraviolet B (UVB) at wavelengths of 290-315 nm, converts 7-dehydrocholestrol to pro-vitamin D3. pro-vitamin D3 isomerizes to vitamin D3 after several hours of dermal heating at normal skin temperature.
Despite the desire for increasing activity of vitamin D in its natural form (vitamin D3), in 1932, Professors Jeans and Stearns added two forms of vitamin D to milk and found that they had the same effect in preventing rickets and improving linear growth, while both were able to raise serum 25-hydroxyvitamin D (ossification diol) levels.
Vitamin D binds to vitamin D-binding protein and is then transported to the liver for 25-hydroxylation (the main enzyme is CYP2R1) and later to the kidney. The vitamin D-binding protein-25OHD complex is secreted into the renal tubules, reabsorbed via endocytosis of megalin and cubilin receptors in the proximal tubular epithelium, and converted to the active metabolite 1,25(OH)2D (osteotriol) by the action of mitochondrial 25-hydroxyD-1α-hydroxylase (1α-OHase) in the proximal tubular epithelium.
CYP27B1 enzyme deficiency leads to the development of vitamin D-dependent rickets type 1A, and treatment requires supplementation with either osteotriol or 1α-ossifying diol.
The vitamin D receptor is a heterodimer of the retinoic acid receptor, and 1,25(OH)2D and the vitamin D receptor bind to form a ligand-receptor complex that initiates a gene-specific response element. Mutations in the gene in the ligand-binding region of the vitamin D receptor result in remission of some children with rickets by supplementation with high doses of osteotrienols, but not all patients with mutations in the DNA-binding region respond to this treatment.
In infants and children with mutations in this region, severe hypocalcemia and rickets can occur, which may be accompanied by typical hair loss. Such children require daily high-dose intravenous calcium supplementation until the age of 2 years, followed by oral high-dose calcium preparations. Very few cases have intact vitamin D receptors but have abnormal protein interactions, which inhibit or attenuate the transcriptional process.
Both 1,25(OH)2D and 25OHD are degraded by vitamin D24-hydroxylase, an enzyme encoded by the CYP24A1 gene, and if this gene is deficient, idiopathic infantile hypercalcemia can occur. Figure 2 shows the vitamin D metabolic pathway.
The main function of 1,25(OH)2D is to increase intestinal calcium absorption by upregulating the calcium channel TRPV6, the calcium-binding protein D intracellular transporter, and the calcium pump PMCA1b, leading to calcium transport from the intestine to the blood against a concentration gradient. Calcium absorption can be reduced by 70-75% in animals due to the lack of vitamin D receptors, however, it is not well understood whether there is a cut-off point for serum concentrations of 25OHD and 1,25(OH)2D below which calcium absorption is significantly reduced.
At low levels of 25OHD (25C50 nmol/L), the calcium absorption fraction in children is 0.34, and at high levels of 25OHD (50C80
nmol/L) calcium absorption fraction was 0.28, meaning that more calcium is absorbed into the bloodstream from food at lower levels of 25OHD compared to high levels of 25OHD.
Professor Need and colleagues recorded data on calcium absorption and bone profiles in 319 cases in adults and found that calcium absorption did not decline until 25OHD levels were below 10 nmol/l. However, no similar work was done in the pediatric population, and the inference that calcium requirements are lower in adults than in children is not definitive for growing children. In addition, 1,25(OH)2D and osteoblast-derived factors are consistent in that they both increase bone resorption by osteoclasts.
Thus, the role of vitamin D in maintaining bone homeostasis in vivo is primarily to maintain blood calcium concentrations and to avoid manifestations of abnormal neuromuscular excitability.
Pathophysiology
Phosphorus deficiency leading to characteristic alterations in the growth plate can be seen in patients with rickets.Professor Sabbagh and colleagues studied different mouse models (phosphorus-free diet, X-linked hypophosphatemia model and vitamin D receptor knockout model), which resulted in a uniform appearance of impaired apoptosis of mast chondrocytes, an apoptotic process dependent on the internal caspase-9 of mast chondrocytes phosphorylation.
In vitamin D deficiency, blood calcium levels decrease, stimulating increased secretion of parathyroid hormone hormones, leading to phosphorus loss from the kidneys and lower serum phosphorus levels.
Some patients with genetically inherited hypophosphatemic rickets have a loss of phosphorus from the kidneys due to inhibition of renal sodium-phosphorus co-transport protein function. In patients with these types of rickets, serum levels of fibroblast growth factor 23 (FGF23), a type of endogenous fibroblast growth factor without a heparan sulfate binding region, are elevated, so FGF23 is not only present in the extracellular matrix.
The binding of FGF23 and fibroblast growth factor receptors requires the presence of α-klotho. Deficiency of either α-klotho or FGF23 results in hyperphosphatemia and ectopic calcification. Several studies have shown that increased phosphorus intake, 1,25(OH)2D and parathyroid hormone all stimulate increased FGF23 secretion. Conversely, FGF23 is able to downregulate the renal CYP27b1 enzyme, which promotes 1,25(OH)2D synthesis, and the upregulated 24-hydroxylase enzyme, which destroys 1,25(OH)2D in serum.
Although phosphorus is required for growth plate healing, however, the treatment of children with hypophosphatemic rickets in which osteochondrosis and long bone bowing deformities occur requires 1,25(OH)2D supplementation.
In the bone remodeling unit (i.e., the site where new bone replaces old bone) and the periosteal bone surface, if phosphorus deficiency is present, there is impaired mineralization of the fibrillar components of bone and osteoid. Inhibitors of bone mineralization homeostasis, such as pyrophosphates and phosphates, the period of initiation and dissemination of crystalline mineral deposits in the bone matrix is locally controlled.
Members of the SIBLING family of proteins, including dentin matrix protein 1 (small N-terminal linkage integrated glycoproteins), whose primary role is to regulate mineralization of bone tissue by regulating the balance between phosphate and mineral inhibitors on the bone surface. Mutations in the dentin matrix protein 1 gene result in autosomal recessive hypophosphatemic rickets type 1. However, with the exception of dentin matrix protein, mutations in the SIBLING protein in the male population do not cause rickets.
All SIBLING proteins contain an acidic serine-aspartic acid-rich extracellular matrix phosphoglycoprotein-associated motif (ASARM) or a divisibility peptide motif. the ASARM peptide is tightly linked to hydroxyapatite, which directly inhibits bone mineralization and inhibits the renal sodium-phosphate cotransporter leading to hypophosphatemia, and may also be the cause of PHEX (phosphate regulatory The X-linked hypophosphatemic enzyme is a substrate for PHEX (phosphate-regulating gene neutral peptide chain endonuclease).
The X-linked hypophosphatemic rickets has a similar clinical presentation and biochemical phenotype to autosomal recessive hypophosphatemic rickets type I, suggesting that both PHEX and dentin matrix protein 1 regulate FGF23 expression and that they act in a common pathway. Dentin matrix protein 1 and FGF23 are mainly expressed on the surface of osteoblasts embedded in the interior of bone tissue, whereas PHEX is expressed on osteoblasts on the bone surface.
The process of osteoid mineralization can affect the depression of osteoblasts and thus their formation of osteocytes. The processes underpinning this interaction constitute a complex mechanism in space and time that may also affect other bone structures.
Notably, skeletal imaging in patients with hereditary hypophosphatase rickets frequently shows osteosclerosis rather than the typical osteopenic manifestations caused by abnormalities in the vitamin D pathway.
Infantile hypophosphatasia, with no or severe deficiency of nonspecific alkaline phosphatase, leads to impaired clearance of pyrophosphates and other mineralization inhibitors, resulting in a severe rickets phenotype in the first days or months of life, with a perinatal and infant mortality rate of more than 50%. A role for recombinant bone targeting enzyme replacement therapy has been reported.
Rickets in preterm infants
Rickets is repeatedly seen in preterm infants. Obviously, mineral deficiency is the underlying cause, not vitamin D deficiency. Most infants with rickets are born earlier than expected or have hypercalcemia due to other causes of delayed enteral feeding or even some chronic lung disease that necessitates the use of steroidal hormonal drugs and diuretics.
If the affected infants have a history of these conditions, especially those with elevated conjugated bilirubin, then these infants are at increased risk for fracture. The risk of fracture in these children is further increased by periods of restricted activity, especially when hospitalized for these conditions.
Rib fractures are less common and are mostly due to physical therapy. The prevalence of these rib fractures at the time of hospital discharge is not known. However, recent data suggest that approximately 2% of infants will have a rib fracture within 1 year of birth.
Rickets, decreased vitamin D levels, and fractures in full-term infants
It is not clear to what extent reduced bone mineralization can cause a decrease in bone strength in the early stages of rickets. Some fracture events have been reported in infants and children. In infancy, no correlation has been found between low levels of vitamin D and increasing risk of fracture in children with non-rickets disease. Information on infants with rickets due to vitamin D deficiency complicated by hypocalcemia is sparse, and there is no follow-up information on fracture risk.
Further clarification is needed as to what advice should be given to parents during feeding of infants at potential fracture risk and what biochemical tests, such as serum 25OHD levels, should be performed if an infant is suspected to be at increased risk for fracture.
Definition of vitamin D deficiency
It is generally accepted that serum circulating vitamin D has the longest half-life and that serum 25OHD is the best indicator of vitamin D nutritional status. However, the question of how to define 25OHD levels in the presence of vitamin D adequacy or deficiency remains controversial.
Whether or not vitamin D is at normal levels is largely dependent on the clinical endpoint event, and the currently suggested cut points for 25OHD range from 25-100 nmol/l. The cut points have been developed primarily with the ability to maintain optimal health and good bone health or to prevent the development of rickets and osteochondrosis.
Most studies have been conducted to find optimal vitamin D levels to maintain good bone health, and these studies have been conducted in adults, and cut points in pediatric populations may vary with age. We are not yet clear on the exact 25OHD levels that are needed to maintain good health and bone health in children.
What is clearer is that the incidence of rickets tends to increase with decreasing vitamin D levels, although there are cases where there are no clinical signs of rickets, even though 25OHD levels are very low.
The general consensus among pediatricians in the UK is that serum 25OHD levels below 25 nmol/l represent vitamin D deficiency and an increased risk of rickets, while 25OHD levels below 50 nmol/l represent vitamin D insufficiency. The diagnostic cut point of elevated 25OHD is currently supported globally, but different organizations support different diagnostic cut points.
The 2011 American College of Endocrinology Clinical Practice Guidelines define 72.5 nmol/l as the optimal cut point, below 50 nmol/l as vitamin D deficiency, and in between as vitamin D insufficiency.
The Institute of Medicine defines 25OHD below 30nmol/l as vitamin D deficiency, and the US and Canadian governments support this cut point, and the Lawson Wilkins Pediatric Endocrine Society definition, which is now the Pediatric Endocrine Society, defines a similar cut point, with 25OHD levels below 37.5nmol/l defined as deficient and between 37.5-50nmol/l deficiency is defined.
Some internists point out that the purpose of defining the cut point for 25OHD should be to predict an increased risk of adverse events and not to define vitamin D deficiency status. There is no consensus on the importance of factors that can influence bone health and general health status in children, such as calcium intake, and there is a lack of large controlled studies on vitamin D therapy, whether it is targeted to children of different ages whose bone health or general health status can benefit from it.
Causes of vitamin D deficiency rickets
The entire fetal supply of vitamin D is from the mother, and fetal vitamin D levels depend on the vitamin D status of the mother, which is generally low in women of childbearing age. Maternal 25OHD is converted to 1,25(OH)2D as it passes through the placenta. at birth, the level of 25OHD in the umbilical cord blood is very strongly correlated with maternal levels, approximately 68-108%.
Pregnant women who are vitamin D rich also deliver children who are vitamin D rich, but mothers with osteomalacia are less likely to give birth to children with congenital rickets.
The amount of vitamin D in breast milk is very low, less than 1.5ug/L (60IU/L), unless the mother takes a daily vitamin D supplement close to the pharmacological dose of 100ug (4000IU) per day. Children born to pregnant women with relatively adequate vitamin D supplementation will have infant serum vitamin D level levels after 8 weeks of exclusive breastfeeding.
As latitude increases, the amount of light received is decreasing, because in winter, when latitude is higher than 350 in the northern hemisphere and 320 in the southern hemisphere, the vitamin D synthesized by the action of light is almost negligible. Taking into account religious or cultural practices, as well as the UV protection measures taken by people, these factors largely reduce the amount of UV light received by the skin, just as if sunscreen were used.
Industrialized countries, where atmospheric pollution is rapidly occurring, are in danger of repeating the fate of the United Kingdom a century ago. Compared to light-skinned races, people of color need more light to synthesize the same amount of vitamin D.
The pathophysiological mechanisms of rickets are so well defined that the corresponding clinical manifestations are easier to detect, occurring mostly during the growth spurt, especially in the first 2 years of life, but also in adulthood. The typical manifestations of rickets in children are due to a variety of factors, insufficient vitamin D levels during pregnancy due to a mother of color, inadequate vitamin D supplementation during pregnancy, or prolonged breastfeeding but no supplementation to give the child vitamin D.
Hypocalcemia and vitamin D deficiency
Neonatal hypocalcemia (early onset in the first week of life and late onset in the second to fourth weeks) is characterized by the earliest signs of neuroleptic arousal or progression to severe convulsions. 16 cases of neonatal hypocalcemia were reported by Prof. Maiya and colleagues, all 16 of which presented with life-threatening heart failure due to hypocalcemia, presumably with vitamin D deficiency (<50 nmol/L). .
In Australia, a retrospective study of 126 cases of 11-year-old children with either vitamin D deficiency or rickets conducted at the Sydney Pediatric Centre found that hypocalcemic episodes were the most common clinical manifestation in these children, occurring in approximately 1/3 of patients. In the West Midlands, UK, Professors Callaghan and Colleagues reported that although bowleggedness was common (46%), approximately 1/4 of patients with symptomatic vitamin D deficiency presented with hypocalcemic convulsions.
Determination of vitamin D
Although 1,25(OH)2D is the active product of vitamin D synthesis, it is somewhat difficult to quantify because the 1,25(OH)2D that can be monitored is at the pmol level (nmol for 25OHD) and the half-life of 1,25(OH)2D is shorter than that of 25OHD.
In addition, as a rate-limiting step in vitamin D synthesis, if factors affecting serum 1,25(OH)2D levels are present, there is a significant decrease in 25OHD levels at this time, but due to the effects of secondary hyperparathyroidism, serum serum 1,25(OH)2D levels are then mistakenly considered to be at normal, or even high, levels.
The method for measuring 25OHD is quite challenging. Up to now, no control method or standard has been established either, thus leading to a high variability of results between laboratories. Today, the gold standard for the determination of vitamin D status is isotope dilution liquid chromatographyCmass spectrometry (liquid chromatographyCmass spectrometry).
chromatographyCmass spectrometry (LCCMS/MS) for the determination of total 25OHD, 25OHD2 and 25OHD3, respectively.
LCCMS/MS is not without drawbacks. Different laboratories use different assay methods, resulting in high variability in the results between laboratories, and data from the international external quality assurance system for vitamin D suggest that these results either overestimate or underestimate true vitamin D levels.
In addition, the extraction techniques currently available do not remove 3′-25OHD (which is usually not detected by immunoassays), and initially it was thought that 3′-25OHD was present in only 22.7% of infant and child cases (approximately 8.7-61.1% of total 25OHD).
Recently, however, an increasing number of studies have reported that 3′-25OHD was present in 99% of subjects and that it accounted for 5% (0-25%) of total 25OHD levels. The biological activity of 3′-25OHD is currently not well defined.
Incidence and prevalence
There is no way to accurately assess the incidence and prevalence of rickets due to the lack of robust screening tools, the lack of global consensus on the cut-off point for vitamin D deficiency, and the confusing distinction between vitamin D deficiency and rickets.
Worldwide, the incidence of rickets appears to be on the rise, although there are no recent and definitive data. Previously published prevalence rates for rickets were 70% in Mongolia, 42% in Ethiopia Wie, 9% in Nigeria, 3.3% in The Gambia, and 2.2% in Monga. The country of Latin America was 2.2%. Northwest England, mostly Asian population, about 1.6% were rickets patients.
Hokkaido, located in northern Japan, had a prevalence of rickets in children under 4 years of age of about 9 per 100,000 during 1999-2004. In Denmark, the average prevalence of rickets in children was 2.9 per 100,000 over a 20-year period, and the average prevalence in children younger than 3 years of age was 5.8 per 10,000. In eastern Turkey, the prevalence of rickets in children attending pediatric clinics was 0.1%.
An Australian surveillance study estimated the overall prevalence of vitamin D deficiency and rickets to be approximately 4.9 per 100,000 children younger than 15 years of age, 98% of whom were of color.
The 2011 UK National Diet and Nutrition Survey measured serum 25OHD in people aged 11-18 years and showed mean 25OHD levels of 44.6 nmol/l in boys and 42.2 nmol/l in girls, with results indicating widespread vitamin D insufficiency or even deficiency in this age group of the adolescent population.
Rickets is increasing significantly worldwide. In the tropics, vitamin D deficiency rickets is also seen, probably related to their high phytate, low calcium diet recommendations, and the religious and cultural practices in these regions that prevent them from receiving adequate light.
A recent case-control study conducted in India found no statistical difference in 25OHD levels between the two groups, but subjects in the rickets group had lower serum calcium levels and higher dietary phytic acid levels. The study also found lower levels of calcium ions in the breast milk of mothers of young children with rickets.
Children with hypocalcemia only but not with vitamin D deficiency (>25 nmol/L), treated with calcium supplementation, show rapid improvement in the imaging and biochemical indices of rickets better than vitamin D supplementation alone, although the combination of the two is the most effective.
The reason for the increase in rickets in developed countries may be related to the migration of people of color to more temperate climates, as Afro-Caribbean, Asian populations in Europe and African Americans living in North America have typically been cited in published cases. Migration to the United Kingdom continues to increase, with 2011 census data showing that 13% of Britons are newcomers, mostly from India, Poland, and Pakistan.
Treatment
Figure 3 shows the flow chart for the treatment of rickets. Treatment of rickets due to vitamin D deficiency is relatively simple and cost-effective, and oral vitamin D and calcium preparations are usually sufficient for malnourished children or those with hypocalcemia.
The choice of vitamin D preparation, whether it should be vitamin D2 or vitamin D3, and how much supplementation is needed, has been controversial. In contrast to vitamin D3, there is increasing interest in the role of vitamin D2, which both raises serum levels of 25OHD and decreases rapidly after the end of treatment.
Some studies have shown that the two agents are comparable in their ability to elevate 25OHD levels, including two studies in pediatric populations. Most consensus and supplemental or treatment guidelines do not strongly recommend one agent to the exclusion of the other. There are no studies comparing the efficacy of the two agents, except for the study conducted by Professors Jeans and Stearns in a population of 80-year-olds.
The British National Formulary for Children states that regardless of the form of vitamin D2 given, it is recommended that a therapeutic dose of 8-12 weeks be given followed by a supplemental dose until the linear growth process has been completed. In practice, patients with vitamin D deficiency usually require longer periods of vitamin D supplementation so that the vitamin D deficiency can be corrected; therefore, it is recommended that the duration of vitamin D therapy take into account age-related changes in body composition and growth rate.
Supplementary rather than therapeutic doses are usually recommended in cases of vitamin D insufficiency (<50l="">25 nmol/L). The British National Formulary for Children recommends that all patients treated with pharmacological doses of vitamin D who develop nausea and vomiting have their serum calcium concentration measured 1-2 times per week initially. For asymptomatic patients our recommendation is not to monitor blood calcium and to monitor bone metabolic markers and 25OHD shortly after the end of treatment.
In the United States, for such an ethnically diverse country, the Endocrine Society Clinical Practice Guidelines recommend a dose of 2000 IU/day or 50,000 IU/week of vitamin D2 or vitamin D3 for infants and children 0-1 year of age for 6 weeks, followed by 400 IU/day, and this regimen is also recommended for children 1-18 years of age, but at a maintenance dose of 600 IU/day.
We do not recommend intramuscular vitamin D injections as a routine treatment in the pediatric population. Vitamin D shock therapy at 600,000 IU per dose may lead to hypercalcemia and renal calcinosis.
The use of 1α-hydroxy preparations, such as alfacalcidol and osteotriol, is not routinely recommended for the treatment of rickets caused by vitamin D deficiency. These drugs are mainly used to treat hypophosphatemic rickets with elevated FGF23 and some rare vitamin D pathway defects, and these drugs are also used to treat acute hypocalcemia cardiomyopathy.
Treatment of hypophosphatemic rickets
Hypophosphatemic rickets is often associated with elevated serum FGF23 levels, and supplementation with phosphorus along with osteotriol or osteodiol is required. The clinical work of a pediatric bone metabolism specialist usually involves monitoring the child’s growth, the degree of skeletal deformities, the complications arising from these disorders and how they are treated, including the causes of abscesses, premature closure of cranial sutures, renal calcinosis and parathyroid hyperplasia. Maintaining the balance of phosphorus and osteodiol intake is very difficult, especially during the rapid growth phase.
Arch deformity causing inversion of the knee may require surgical intervention if the distance between the ankle prominences is greater than 12 cm, and only if the bone metabolic disease is under control.
A good clinical guideline was published in 2010. The guideline evaluated the efficacy of anti-FGF23 antibodies in treating an X-linked hypophosphatemic rickets mouse model (HPY mice) and showed that this therapy not only corrected hypophosphatemia, but also restored the 25OHD to 1,25(OH)2D conversion function, while restoring the tendency for longitudinal bone growth and improving bone softening. Phase 1 trials of this drug, which focused on increasing the single dose in adults, have been completed, but no study results have been reported.
Prevention
In short, the prevention of rickets is the practice of adequate light exposure and adequate food intake. However, high-profile public health campaigns such as the recommended reduction in light exposure, the need for culturally sensitive strategies in populations at risk, and the diversity of international guidelines for daily doses of vitamin D intake make these approaches relatively difficult to implement.
Performing population screening is not a feasible approach because of the lack of an accepted diagnostic cut point, the absence of a test with appropriate specificity and sensitivity for diagnosis, and the lack of data on long-term follow-up of low levels of serum 25OHD.
Proposals for skin exposure to adequate light also failed because the side from the opposite culture was in the advantageous position to argue that skin exposure to light can lead to an increased risk of skin cancer, either due to dimensionality or seasonality, and therefore they were opposed. Epidemiological evidence strongly supports a correlation between light exposure and skin cancer, so the American Academy of Pediatrics supports the proposal in the guidelines to limit the amount of time children receive light, while proposing vitamin D supplementation throughout childhood.
A study of adults living in the northwest of England (latitude: 53.50N) showed that receiving the guideline-recommended level of light exposure (3 light exposures per week for 15 min with at least 35% skin exposure) was sufficient for Caucasians and elevated serum 25OHD levels, but South Asians (n=15) among the subjects still had vitamin D deficiency (<50 nmol/L).
Only a quarter of the South Asian population met vitamin D levels after a 3-fold increase in light exposure, suggesting that recommendations for receiving light exposure should be tailored to different skin color races; otherwise, there is the potential for a large group of people to exhibit vitamin D deficiency. Improve air quality to expose the skin to more UV light.
The British Atmospheric Protection Act, passed in 1956, is thought to have played a role in reducing the incidence of rickets in the UK to some extent, and similar government interventions introduced in industrial countries since then may have improved the levels of 25OHD in the population.
Differences in recommended doses of vitamin D during pregnancy are found in global guidelines (Table 5). Recommended supplementation doses range from 5-100ug/day (200-4000/day), and recently many information agencies have increased from the classical recommended dose of 5-10ug/day (200-400/day) because this dose has been shown to be insufficient to achieve optimal 25OHD levels of 80nmol/L (32ng/mL) during pregnancy.
Researchers believe that the recommended upper dose is very safe for women during pregnancy and lactation because a large randomized controlled study conducted in Europe in which 100ug (4000 IU) of vitamin D was supplemented daily found that this dose was the most effective dose for achieving serum vitamin D levels without any adverse effects.
The upper limit of daily intake recommended by the American Medical Association is also essentially 100ug (4000 IU). Randomized controlled studies with higher supplemental doses are currently underway (NCT01060735). The long-term effects of this dose on the fetal skeleton remain to be determined. Although poor adherence to this supplementation regimen remains a problem, the incidence of rickets and symptomatic vitamin D deficiency has decreased significantly with this targeted and universal approach to supplementation.
WHO recommends that infants be breastfed until at least 6 months of age. A 3.5 kg infant receiving 150 ml/kg of breast milk per day would have a daily intake of approximately 0.75ug (30 IU) of vitamin D, a dose that is insufficient to maintain normal linear growth.
The study by Prof. Jeans and Prof. Stearns concluded that 1.5-3.4ug (60C135 IU) of vitamin D per day is not sufficient to maintain normal linear growth, and that supplementation with 8.5-15ug (340C600
IU) per day to achieve this effect. In order to increase the vitamin D content in breast milk, mothers need to supplement with 100-160ug (4000C6400
IU) of vitamin D, but these studies are still in the experimental stage and therefore recommend vitamin D supplementation for breastfed infants.
In 2012, a letter from the UK Chief Medical Officer to family doctors, health visitors, pharmacists and clinical nurses stated that babies born to mothers who did not take vitamin D supplements throughout pregnancy need to be supplemented from 1 month of age. Vitamin D drops are required from 1 month of age.
In the absence of adequate light for the mother and without vitamin D supplementation, the infant does not receive adequate vitamin D through breastfeeding alone, so the recommended dose is inconsistent with the original published data. What is more confusing to health care practitioners is whether excessive vitamin D supplementation can cause hypercalcemia and renal calcium deposits.
Serum calcium levels rise with 25OHD levels and hypercalcemia can occur when 25OHD levels exceed 200 nmol/L. In the UK, the maximum permitted supplemental dose of vitamin D for infants and children under 10 years of age is 25ug/day (1000 IU/day).
The European Food Safety Authority recently revised their maximum recommended dose of vitamin D to 25ug (1000 IU) per day for infants and 50ug (4000 IU) per day for children under 10 years of age. In North America, the maximum recommended dose is similar for infants under 6 months of age, 37.5ug (1500 IU) per day from 6 months to 1 year, 62.5ug (2500 IU) per day from 1 year to 3 years, 75ug (3000 IU) per day from 4 years to 8 years, and 100ug (4000 IU) per day from 8 years and older.
In most countries, the concentration of vitamin D in infant formula is increased to 10ug/l (400IU/L). In the United States, breakfast is milk and cereal, while in Canada, it is milk and butter. Since the deaths of infants and children from idiopathic hypercalcemia in the United Kingdom in 1950, the Department of Health has declared that fortification of foods for infants and children is prohibited, except for butter, cereals and formula.
Bread flour, which is relatively low in vitamin D, is considered effective in Asia and the UK, but is not promoted for use, although flour fortification is feasible.
Summing up
Rickets is a preventable disease, and its prevention should begin during pregnancy. The simplest prevention is to receive adequate sunlight, and if this condition cannot be met it should be based on vitamin D supplementation, the dosage of which is not yet internationally standardized. Current guidelines from the UK health sector are confusing in this regard.
In general, 400 IU of vitamin D per day will adequately maintain body levels of vitamin D and will generally not cause adverse skeletal changes, suggesting that this dose is adequate for normal skeletal growth when factors such as skin color, latitude, sunlight, pollution, social and cultural stress are excluded. We recommend the use of 10 μg (400 IU) vitamin D daily as a supplemental dose until children stop growing (except for contraindications such as hypercalcemia and sarcoidosis), which we believe may reduce the incidence of rickets to some extent.