Rickets is a condition associated with bone-deformity due to inadequate mineralization in growing bones [rx]. While some cases relate to hereditary syndromes, renal disease, or use of medication, rickets in the world mostly stems from nutritional insufficiency [rx]. Nutritional rickets is prevalent throughout much of the developing world and is again being increasingly seen in more affluent countries [rx].
Rickets is a condition that results in weak or soft bones in children.[rx] Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping.[rx][rx] Complications may include bone fractures, muscle spasms, an abnormally curved spine, or intellectual disability.[rx][rx]
Types of Rickets
- Calcipenic (hypocalcemic) rickets is characterized by a deficiency of calcium or more commonly vitamin D. In Indian children living in the UK, diets are typically low in calcium and high in phytate. The calcium content of common foodstuffs is given in [rx]. Rickets can occur despite adequate vitamin D levels if the calcium intake is very low. This problem generally does not occur unless calcium intake is very low because vitamin D increases intestinal calcium absorption. Most children with calcium deficiency rickets have normal serum 25-hydroxyVitamin D [25(OH)D] and high serum 1,25-dihydroxy vitamin D [1,25(OH)2] concentrations, indicating adequate intake of vitamin D.
- Phosphopenic rickets is commonly caused by renal phosphate wasting. This may be isolated or part of a generalized renal tubular disorder such as Fanconi syndrome or Dent disease.[rx] Isolated phosphate loss is seen in X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, tumor-induced osteomalacia, and hypophosphatemic rickets with hypercalciuria (autosomal recessive) disease. Nutritional deficiency is uncommon. These causes can be distinguished by measuring urinary amino acids, bicarbonate, glucose, calcium, and vitamin D concentrations.[rx]
Renal (kidney) rickets
- Similar to hypophosphatemic rickets, renal rickets is caused by a number of kidney disorders. Individuals suffering from kidney disease often have decreased the ability to regulate the amounts of electrolytes lost in the urine. This includes calcium and phosphate, and therefore the affected individuals develop symptoms almost identical to severe nutritional rickets. Treatment of the underlying kidney problem and nutritional supplementation are recommended for these patients.
Vitamin D-related rickets
- Vitamin D deficiency
- Vitamin D-dependent rickets[rx]
- Type 1 (25-Hydroxyvitamin D3 1-alpha-hydroxylase deficiency)
- Type 2 (calcitriol receptor mutation)
- Chronic renal failure (CKD-BMD)
- Hypophosphatemia (typically secondary to malabsorption)
- Fanconi’s syndrome
Secondary to other diseases
- Tumor-induced osteomalacia
- McCune-Albright syndrome
- Epidermal nevus syndrome
- Dent’s disease
Causes of Rickets
- Sun exposure –Dietary vitamin D deficiency can also occur in children, with differences among ethnic groups depending on skin pigmentation and varied ingestion of supplements.[rx] A Caucasian infant’s vitamin D requirements are met by exposure to sunlight for 30 minutes per week, clothed only in a diaper, or for 2 hours per week fully clothed with no hat. Asians require approximately threefold longer periods of sunlight exposure because of the protective pigmentation in their skin and Africans need six times the same exposure.[rx]
- Cold Climates – Vitamin D deficiency is also common at the end of the winter due to less sun exposure.[rx] Vitamin D deficiency has been reported in dark-skinned immigrants from warm climates to cold climates. Asian Indian immigrants to the United States may have vitamin D deficiency, even with adequate sun exposure.[rx]
- Extensive burns – In patients with a history of extensive burn injuries, vitamin D synthesis in the skin is below normal, even with sun exposure.[rx]
- Nutritional deficiency – Vitamin D deficiency can occur even with adequate sun exposure.[rx] It can occur in people who consume foods that are not fortified with vitamin D or if there is intestinal malabsorption of vitamin D. There are few foods that naturally contain vitamin D and because most of these are meat or fish based, they may not be acceptable to cultures that favor a vegetarian diet. Currently, few foods are fortified with vitamin D. Routine vitamin D fortification should be considered for milk and other food products.
- Elderly people – Cutaneous vitamin D production and vitamin D stores decline with age. vitamin D intake is often low in older subjects. Achlorhydria, which is common in the elderly, limits calcium absorption. Older persons, in addition, may also be confined indoors.[rx]
- Maternal vitamin D deficiency -Vitamin D is transferred from the mother to the fetus across the placenta, and reduced vitamin D stores in the mother are associated with lower vitamin D levels in the infant.[rx] Low vitamin D levels during pregnancy have been associated with intrauterine growth retardation, premature labor, and hypertension, all of which increase the risk of low birth weight.
- Prematurity – Vitamin D levels are low in premature infants, who have less time to accumulate vitamin D from the mother through transplacental transfer. The third trimester is a critical time for vitamin D transfer because this is when the fetal skeleton becomes calcified, requiring increased activation of 25(OH)D to 1,25(OH)2D in the maternal kidneys and placenta. vitamin D deficiency in the mother during this period can cause fetal vitamin D deficiency, and in severe cases, fetal rickets.[rx,rx] Premature infants are more likely to have enamel defects in both primary and permanent teeth because vitamin D sufficiency is necessary for normal fetal tooth development.
- Exclusive breastfeeding -The vitamin D content of breast milk is low (15–50 IU/L) even in a vitamin D replete mother.[rx] Exclusively breastfed infants consuming an average of 750 mL of breast milk daily thus ingest only 10–40 IU/day of vitamin D. Most breastfed infants need to be exposed to sunlight for at least 30 minutes/ week while wearing only a diaper in order to maintain 25(OH)D levels at >20 ng/mL. vitamin D deficiency is uncommon in formula-fed infants because of the fortification of infant formulas (400 IU/L). However, it can still occur if the infant had low vitamin D stores at birth because of maternal vitamin D deficiency and if the vitamin D content of the formula is insufficient.[rx]
- Obesity – 25(OH)D levels are low in obese individuals as vitamin D is sequestrated in fat. vitamin D requirements are thus higher in obese individuals.[rx]
- Hospitalized patients – Inadequate intake and lack of sun exposure cause vitamin D deficiency in this group of patients.[rx]
- Women treated for osteoporosis – Subclinical vitamin D deficiency is common in postmenopausal women on therapy for osteoporosis (bisphosphonates, raloxifene, calcitonin, or PTH).[rx]
- Chronic renal disease – In patients with chronic kidney disease, calcitriol [1,25(OH)2D] production is low due to diminished glomerular filtration, loss of the 1-α-hydroxylase enzyme secondary to structural renal damage, and suppression of enzyme activity secondary to hyperphosphatemia. This results in hypocalcemia, hyperparathyroidism, and bone disease.[rx] In addition to the deficiency of 1,25(OH)2D, recent studies have shown co-existence of 25(OH)D deficiency in pre-dialysis and dialysis patients, especially in female diabetics and patients on peritoneal dialysis.[rx] Whether improving 25(OH) D concentrations benefit these patients is controversial, but Kidney Dialysis Outcome Initiative (KDOQI) guidelines have recommended supplementation.
- Nephrotic syndrome – Most of the calcidiol in serum is bound to DBP. Patients with nephrotic syndrome lose DBP and may develop vitamin D deficiency.[rx,rx]
- Distal renal tubular acidosis -Hypocalcemia can occur in dRTA, along with acidosis, which causes rickets. The presence of dRTA is suspected in conditions of hypokalemia, hyperchloremia, and normal anion gap metabolic acidosis.[rx]
- Gastrointestinal disease – Malabsorption associated with diseases of the small intestine, a hepatobiliary tree with cholestatic liver disease, extrahepatic biliary obstruction, and diseases of the pancreas may result in decreased absorption of vitamin D and/or depletion of endogenous 25(OH)D stores due to abnormal enterohepatic circulation. Malabsorption of vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicron-mediated absorption. Patients may have rickets or osteomalacia or only low bone density. Common examples are celiac disease, inflammatory bowel disease, food allergies, cholestasis, and exocrine pancreatic insufficiency (as in cystic fibrosis).[rx]
- Gastric bypass – Patients with short-limb bypass have secondary hyperparathyroidism (SHPT) in spite of normal 25(OH)D concentrations, due to calcium malabsorption. vitamin D deficiency also occurs in patients with partial or total gastrectomy for peptic ulcer disease or bariatric surgery due to the loss of gastrointestinal acidity, malfunction of the proximal small bowel which leads to vitamin D malabsorption, the absence of adequate absorbing surface, or failure of intestinal mucosal cells to respond to vitamin D.[rx,rx]
- Liver disease – Vitamin D is hydroxylated in the liver to produce calcidiol [25(OH)D]. Hence, patients with significant parenchymal or obstructive liver disease have reduced 25(OH)D. These patients manifest biochemical or histological evidence of osteomalacia only in the presence of concomitant nutritional deficiency or interruption of the enterohepatic circulation.[rx,rx]
- Medications – Certain anticonvulsants and antiretroviral drugs used to treat HIV infection can precipitate vitamin D deficiency by enhancing catabolism of 25(OH)D and 1,25(OH)2D.[rx] decreased circulating levels of calcidiol occur in patients on phenytoin, phenobarbitone, carbamazepine, isoniazid, rifampicin, and theophylline due to induction of P-450 enzyme activity, which metabolizes calcidiol to inactive vitamin D metabolites. Tenofovir can cause rickets. Abnormalities in calcium concentration are seen with medications used in the treatment of the complications of HIV, such as foscarnet, pentamidine, and recombinant growth hormone. vitamin D requirements are higher in patients on glucocorticoids because they inhibit intestinal vitamin D dependent calcium absorption. Ketoconazole and some other antifungal agents increase vitamin D requirements because they block 1-hydroxylation. Supplementation with vitamin D (400–4000 IU/day) may be needed for these patients.[rx]
- Insufficient nutritional quantities or faulty metabolism of vitamin D or phosphorus
- Renal tubular acidosis
- Malnutrition during pregnancy
- Malabsorption syndrome
- Chronic kidney failure
- Tumor-induced osteomalacia (Oncogenic osteomalacia)
- Long-term anticonvulsant therapy[rx]
- Celiac disease[rx]
- Cadmium poisoning, iliac disease
- Breastfed infants whose mothers are not exposed to sunlight
- Breastfed babies who are exposed to little sunlight
- Adolescents, in particular when undergoing the pubertal growth spurt[rx]
- Any child whose diet does not contain enough vitamin D or calcium
- Diseases causing soft bones in infants, like hypophosphatasia or hypophosphatemia, can also lead to rickets.[rx]
Symptoms of Rickets
- Pain or tenderness in the bones of the arms, legs, pelvis, or spine.
- Stunted growth and short stature.
- Bone fractures.
- Muscle cramps.
- Teeth deformities, such as delayed tooth formation. holes in the enamel.
- Skeletal deformities, including an oddly shaped skull. bowlegs, or legs that bow out.
- Delayed growth
- Pain in the spine, pelvis, and legs
- Muscle weakness
- Diffuse joint and bone pain (especially of spine, pelvis, and legs)
- Difficulty walking, often with a waddling gait
- Hypocalcemia (positive Chvostek sign)
- Compressed vertebrae and diminished stature
- Pelvic flattening
- Weak, soft bones
- Easy fracturing
- Bowed legs or knock knees
- Thickened wrists and ankles
- Breastbone projection
- Spinal curvatures of kyphoscoliosis or lumbar lordosis may be present. The pelvic bones may be deformed. A condition known as rachitic rosary can result as the thickening caused by nodules forming on the costochondral joints.
- This appears as a visible bump in the middle of each rib in a line on each side of the body. This somewhat resembles a rosary, giving rise to its name. The deformity of a pigeon chest[rx] may result in the presence of Harrison’s groove.
Diagnosis of Rickets
Rickets may be diagnosed with the help of
- Blood tests – Serum calcium may show low levels of calcium, serum phosphorus may be low, and serum alkaline phosphatase may be high from bones or changes in the shape or structure of the bones. This can show enlarged limbs and joints.
- A bone density scan – may be undertaken.[rx]
- Radiography typically – shows widening of the zones of provisional calcification of the metaphyses secondary to unmineralized osteoid. Cupping, fraying, and splaying of metaphyses typically appears with growth and continued weight bearing.[rx] These changes are seen predominantly at sites of rapid growth, including the proximal humerus, distal radius, distal femur and both the proximal and the distal tibia. Therefore, a skeletal survey for rickets can be accomplished with anteroposterior radiographs of the knees, wrists, and ankles.[rx]
Biochemical features are similar to those of rickets. The major factor is an abnormally low vitamin D concentration in blood serum. Major typical biochemical findings include:[rx]
- Low serum and urinary calcium
- Low serum phosphate, except in cases of renal osteodystrophy
- Elevated serum alkaline phosphatase (due to an increase in compensatory osteoblast activity)
- Elevated parathyroid hormone (due to low calcium)
- The skeletal changes are similar in calcipenic and phosphonic rickets.[rx] The anterior fontanelle closes by 18 months and posterior by 3 months normally. However, in rickets, there is a delay in the closure of the fontanelles.
- There is parietal and frontal bossing, craniotabes (soft skull bones) with ping pong bones in infants, enlargement of the costochondral junction of ribs (the “rachitic rosary”), Harrison sulcus due to the muscular pull of the diaphragm on the lower ribs, widening of the wrist and bowing of the distal radius and ulna, and progressive lateral bowing of the femur and tibia.
- The child may be asymptomatic or may present with pain, irritability, delay in motor milestones, and poor growth.[rx] Visceroptosis leads to a pot belly. Children may have waddling gait (antalgic gait). Presentation with hypocalcemic seizures is frequent in the first year of life.[rx]
- Children with calcipenic rickets are prone to acquiring infectious diseases.[rx] There is hypoplasia of dental enamel. Increased sweating is a common finding in young infants with calcipenic rickets and may be caused by bone pain.
- In children, the changes of rickets can be seen at the growth plate of rapidly growing bones. Thus, in the upper limbs, the changes are most prominent at the distal ulna, while in lower limbs the changes are most prominent at the metaphyses above and below the knees.
- There is widening of the epiphyseal plate due to unmineralized osteoid and loss of definition of the zone of provisional calcification at the epiphyseal/metaphyseal junction.
- There is cupping and splaying of the epiphyseal end of metaphysics with the formation of cortical spurs and stippling. The appearance of the epiphyseal bone centers may be delayed, and these are small and osteopenic.[rx]
Bone mineral density
- Several studies have demonstrated markedly reduced spine, hip, and forearm bone density [as measured by dual-energy X-ray absorptiometry (DXA)] in patients with osteomalacia related to vitamin D deficiency.
- However, bone mineral density (BMD) is not required for the diagnosis of osteomalacia, and reduced BMD does not distinguish osteoporosis from osteomalacia. In contrast, BMD tends to be normal or increased (especially lumbar spine) in adults with XLH.
- Bone biopsy with tetracycline labeling is the most accurate way to diagnose osteomalacia/rickets. However, it is infrequently performed because it is invasive and the diagnosis can usually be made from a combination of clinical and laboratory findings.
- Prolonged mineralization lag time, widened osteoid seams, and increased osteoid volume. All of these features are necessary for the diagnosis because other disorders may show one of these findings. Wide osteoid seams reflecting high turnover can be seen with hyperthyroidism, Paget’s disease, and hyperparathyroidism. However, the mineral apposition rate is elevated in these disorders in contrast to osteomalacia.
Treatment of Rickets
American Academy of Pediatrics (AAP) introduced the protocol of 400 IU/day of vitamin D starting from the 2nd month of life for rickets prophylaxis [rx]. The latest recommendations by AAP about vitamin D supplementation was reported in 2008 [rx] as follows:
- A minimum of 400 IU/day vitamin D supplementation is recommended to prevent VDD and rickets in healthy infants, children, and adolescents.
- 400 IU/day vitamin D should be introduced to the diet of infants fed completely or partially by mother’s milk until they start receiving at least 1 liter of formula per day.
- 400 IU/day vitamin D should be provided to all infants fed with less than 1-liter formula per day and not receiving mother’s milk. Other sources of nutrition should be calculated individually for infants receiving this type of nutrition.
- 400 IU vitamin D should be provided to all adolescents not receiving 400 IU vitamin D from milk or other foods fortified with vitamin D.
- According to recent evidence, the level of serum 25(OH)D should be above 20 ng/mL, particularly in infants and children.
- 400 IU/day vitamin D should be continued in cases with chronic fat malabsorption, chronic anticonvulsant intake or similar conditions increasing the risk of VDD. Higher vitamin D supplementation may be necessary in these cases to maintain the normal serum level of vitamin D.
Low dosage and long−term vitamin D therapy
- There are different views about the dose and duration of vitamin D therapy. In this treatment model, depending on the age of the c h I l d, vitamin D is usually administered at a dose of 1000− 10 000 IU/day for 2−3 months. In this regimen, vitamin D can be given according to the infant’s age as follows: 1000 IU/day for infants under 1 month of age, 1000 to 5000 IU/ day for children 1 to 12 months old, and 5000 IU/day for children older than 12 months. Afterward, it is recommended to give maintenance therapy of 400 IU/ day.
- Levels of Ca and P are normalized in 6−10 days by this therapy, while it takes 1−2 months for PTH to reach normal levels. Depending on the severity of the disease, it may take 3 months for the normal serum ALP levels to be restored and the radiological findings of rickets to disappear. In this treatment model, lack of compliance is an important cause of lack of response [rx, rx, rx, rx, rx, rx].
- For patients who are suspected to have poor compliance, a high dose of vitamin D can be given orally or intramuscularly as a single dose of 100 000−600 000 IU after the first month of life [rx, rx, rx, rx]. Administration of 600 000 units of vitamin D in infantile rickets has been reported to cause hypercalcemia [rx]. Cesur et al [rx] reported that 150 000−300 000 units of vitamin D is an effective and safe method of treatment.
- A recent study also demonstrated that intramuscular administration of a single dose of 300 000 IU of vitamin D is effective in cases of malnutrition with rickets [rx]. Shah and Feinberg have successfully administrated 100 000 IU of vitamin D every two hours over a twelve−hour period [rx, rx]. This treatment evokes a rapid clinical response, resulting in a biochemical recovery in a few days and radiological recovery in 10−15 days.
Monitored Supplementation of Pregnant Women
- Low socioeconomic status, covered clothing and lack of supplementation contribute to the high prevalence of vitamin D deficiency in pregnancy [rx]. Congenital rickets and postnatal hypocalcaemic seizures are reported in risk groups in both developed and developing countries [rx , rx, rx]. Poor maternal vitamin D status affects the fetus and of the newborn. In a large Italian study, 76% of newborns of dark-skinned migrant women had 25OHD levels below 25 nmol/L (10 μg/L), compared to 38% of newborns of native Italian women [rx].
Universal Supplementation of Infants Regardless of Mode of Feeding
- The amount of vitamin D available in breast milk but also infant formula milk is insufficient to prevent NR; even formula-fed infants can present with the asymptomatic deficiency in the first few months of life [rx, rx, rx] if born to deficient mothers.
- In a recent survey of vitamin D supplementation policies across Europe, we found that universal supplementation, currently practiced by 79% (23/29) of countries was significantly (p = 0.007) associated with good adherence to supplements [rx]. The recommended dose of 400 IU/day (10 μg) is safe also in formula-fed infants. Toxicity is usually related to errors in manufacturing, formulation or prescription [rx, rx].
Supplementation Beyond the First Year of Life
- The duration of childhood supplementation varies widely across Europe [rx]. Assessment of daily intakes at 18 months and 3.5 years of age in 755 children in the UK showed low daily intakes of vitamin D and calcium [rx].
- The incidence of NR rises beyond the recommended age of infant supplementation [rx, rx, rx], especially in dark-skinned (immigrant or resident) individuals. Hence, national policies should ensure that the daily requirement of vitamin D beyond the first year of life is met through supplementation or fortification [rx].
Identifying Successful and Sustainable Implementation Strategies
- Although most developed countries have vitamin D supplementation policies in place, some countries lack successful implementation strategies. Recent studies from Canada and New Zealand reported that none of the individuals with NR had received vitamin D supplements for rickets prevention despite the presence of national recommendations [rx, rx].
- Similarly, 85% of British parents are unaware of the need for infant vitamin D supplementation for their baby despite existing policy [rx]. There is overwhelming evidence that infant vitamin D supplementation improves 25OHD concentrations [rx] and prevents NR [rx].
Food Fortification with Vitamin D or Calcium
- Health benefits of food fortification with micronutrients, including vitamin D, are well established [rx]. Currently, most European countries follow voluntary fortification [rx]; however, evidence from Canada and the USA suggests that mandatory fortification improves vitamin D uptake at the population level [rx].
- Fortification should not be restricted to dairy products due to its limited consumption in certain risk groups [rx]; fortification of a variety of food sources is more beneficial [rx]
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