Rickets
Updated: Sep 09, 2022
Author: Steven M Schwarz, MD, FAAP, FACN, AGAF; Chief Editor: Jatinder Bhatia, MBBS, FAAP
Overview
Practice Essentials
Rickets is a disease of growing bone that is unique to children and adolescents. It is caused by a failure of osteoid to calcify in a growing person. Failure of osteoid to calcify in adults is called osteomalacia. The image below illustrates findings in a patient with rickets.
Findings in patients with rickets.
See 23 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.
Vitamin D deficiency rickets occurs when the metabolites of vitamin D are deficient. Less commonly, a dietary deficiency of calcium or phosphorus may also produce rickets. Vitamin D-3 (cholecalciferol) is formed in the skin from a derivative of cholesterol under the stimulus of ultraviolet-B light. Ultraviolet light or cod liver oil was the only significant source of vitamin D until early in the 20th century when ergosterol (vitamin D-2) was synthesized from irradiated plant steroids.
During the Industrial Revolution, rickets appeared in epidemic form in temperate zones where the pollution from factories blocked the sun’s ultraviolet rays. Thus, rickets was probably the first childhood disease caused by environmental pollution. In the United Kingdom during the 17th century, an estimated 2-8% of deaths in urban areas were attributed to rickets, which became known as the “English disease.”[1]
Natural nutritional sources of vitamin D are limited primarily to fatty, ocean-going fish. In the United States, dairy milk is fortified with vitamin D (400 IU/L). Human milk contains little vitamin D, generally less than 20-40 IU/L. Therefore, infants who are breastfed are at risk for rickets, especially those who receive no oral supplementation and those who have darkly pigmented skin, which blocks penetration of ultraviolet light.
Rickets may lead to skeletal deformity and short stature. In females, pelvic distortion from rickets may cause problems with childbirth later in life. Severe rickets has been associated with respiratory failure in children.
Findings in rickets are illustrated in the image below.
Radiograph in a 4-year-old girl with rickets depicts bowing of the legs caused by loading.
Pathophysiology
Cholecalciferol (ie, vitamin D-3) is formed in the skin from 5-dihydrotachysterol. This steroid undergoes hydroxylation in 2 steps. The first hydroxylation occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which circulates in the plasma as the most abundant of the vitamin D metabolites and is thought to be a good indicator of overall vitamin D status.
The second hydroxylation step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol). This cholecalciferol, which circulates in the bloodstream in minute amounts, is not technically a vitamin but a hormone.
Calcitriol acts at 3 known sites to tightly regulate calcium metabolism: (1) it promotes absorption of calcium and phosphorus from the intestine; (2) it increases reabsorption of phosphate in the kidney; and, (3) it acts on bone to release calcium and phosphate. Calcitriol may also directly facilitate calcification. These actions result in an increase in the concentrations of calcium and phosphorus in extracellular fluid.
This increase of calcium and phosphorus in extracellular fluid, in turn, leads to the calcification of osteoid, primarily at the metaphyseal growing ends of bones but also throughout all osteoid in the skeleton. Parathyroid hormone facilitates the 1-hydroxylation step in vitamin D metabolism.
In the vitamin D deficiency state, hypocalcemia develops, which stimulates excess secretion of parathyroid hormone. In turn, renal phosphorus loss is enhanced, further reducing deposition of calcium in the bone.
Excess parathyroid hormone also produces changes in the bone similar to those occurring in hyperparathyroidism. Early in the course of rickets, the calcium concentration in the serum decreases. After the parathyroid response, the calcium concentration usually returns to the reference range, though phosphorus levels remain low. Alkaline phosphatase, which is produced by overactive osteoblast cells, leaks into the extracellular fluids, so that its concentration rises to anywhere from moderate elevation to very high levels.
Intestinal malabsorption of fat and diseases of the liver or kidney may produce the clinical and secondary biochemical picture of nutritional rickets. In such cases, disturbance in calcium homeostasis may be the consequence of renal excretion or may result from intestinal losses, as dietary calcium forms insoluble soaps with malabsorbed fats. Anticonvulsant drugs (eg, phenobarbital, phenytoin) accelerate metabolism of calcidiol, which may lead to insufficiency and rickets, particularly in children who have darkly pigmented skin and those who are kept primarily indoors (eg, children who are institutionalized).
Calcium and vitamin D intakes are low in infants who are fed vegan diets, particularly in those who are lactovegans, and monitoring of their vitamin D status is essential.[2]
Studies have noted that disorders of increased fibroblast growth factor 23 (FGF-23) function are associated with rickets.[3]
Epidemiology
United States statistics
In the United States, vitamin D deficiency rickets does not generally occur in infants fed proprietary infant formulas, because both formula and cow milk sold in the United States contain 400 IU of vitamin D per liter. Accordingly, except in pediatric patients with chronic malabsorption syndromes or end-stage renal disease, nearly all cases of rickets occur in breastfed infants who have dark skin and receive no vitamin D supplementation.
International statistics
The incidence of rickets in Europe is similar to that in the United States. In sunny areas, such as in the Middle East, rickets may occur when infants are bundled in clothing and are not exposed to sunlight. In some parts of Africa, deficiency of calcium, phosphorus, or both in the diet may also lead to rickets, especially in societies where corn is predominant in the diet.
The frequency of rickets has been increasing internationally. Possible reasons include recommendations for children to wear sunscreen while outdoors and a tendency for children to spend more time indoors, watching television or playing electronic games, instead of playing outdoors.[4]
Sodri et al reported the case of a 22-month-old girl in Malaysia with nutritional rickets, who presented with abnormal gait and bowing of the legs during the coronavirus disease 2019 (COVID-19) pandemic. Because of lockdowns related to COVID, she had minimal exposure to sunlight. In addition, her calcium intake was poor.[5]
Presentation
Physical Examination
Generalized muscular hypotonia of an unknown mechanism is observed in most patients with clinical (as opposed to biochemical and radiographic) signs of rickets. Craniotabes (areas of thinning and softening of bones of the skull) manifests early in infants with vitamin D deficiency, although this feature may not be present in infants, especially those born prematurely.
If rickets occurs at a later age, thickening of the skull develops. This produces frontal bossing and delays the closure of the anterior fontanelle. In the long bones, laying down of uncalcified osteoid at the metaphases leads to spreading of those areas, producing knobby deformity, which is visualized on radiography as cupping and flaring of the metaphyses.
Weight bearing produces deformities such as bowlegs and knock-knees.
In the chest, knobby deformities results in the so-called rachitic rosary along the costochondral junctions. The weakened ribs pulled by muscles also produce flaring over the diaphragm, which is known as Harrison groove. The sternum may be pulled into a pigeon-breast deformity.
In more severe instances in children older than 2 years, vertebral softening leads to kyphoscoliosis. The ends of the long bones demonstrate that same knobby thickening. At the ankle, palpation of the tibial malleolus gives the impression of a double epiphysis (Marfan sign). Because the softened long bones may bend, they may fracture on one side of the cortex (ie, greenstick fracture).[6]
Manifestations of rickets are illustrated in the image below.
Findings in patients with rickets.
DDx
Diagnostic Considerations
Rare metabolic bone diseases, including hypophosphatasia, have been confused with rickets in infancy. Jansen syndrome is a rare autosomal dominant form of short-limbed dwarfism in which infants present with metaphyseal chondroplasia. Hereditary disorders of vitamin D metabolism have also been described, such as hypophosphatemic vitamin D–resistant rickets.
Severe calcium deficiency can also cause a syndrome that is confused with vitamin D deficiency rickets. Premature infants who are breast fed and do not receive mineral supplements may develop severe phosphorus deficiency that presents as rickets.
Workup
Approach Considerations
Serum measurements in the workup for rickets may include the following:
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Calcium
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Phosphorus
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Alkaline phosphatase
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Parathyroid hormone
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25-hydroxy vitamin D
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1,25-dihydroxyvitamin D
Radiography is indicated in patients with rickets (see Rickets Imaging).
Serum Chemistry
Early on in the course of rickets, the calcium (ionized fraction) is low. However, this level is often within the reference range at the time of diagnosis, as a consequence of increased parathyroid hormone secretion.
Although calcidiol (25-hydroxy vitamin D) is low and parathyroid hormone is elevated, determining calcidiol and parathyroid hormone levels is typically not necessary in order to establish a diagnosis.
Calcitriol levels maybe normal or elevated because of increased parathyroid activity.
The phosphorus level is invariably low for age, unless recent partial treatment or recent exposure to sunlight has occurred. Alkaline phosphatase levels are uniformly elevated.
A generalized aminoaciduria occurs from the parathyroid activity. However, aminoaciduria does not occur in familial hypophosphatemia rickets (FHR).
Radiography
The best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.
The metaphyses exhibit widening and cupping because of their exaggerated normal concavity and irregular calcification. Because calcified osteoid is abundant, the provisional calcification zone of the metaphysis is much more distant from the calcification center of the epiphysis than is normal for age.
Along the shaft, the uncalcified osteoid causes the periosteum to appear separated from the diaphysis. Generalized osteomalacia occurs (observed as osteopenia), with visible coarsening of trabeculae in contrast to the ground-glass osteopenia of scurvy.
Examples of radiographic findings are shown in the images below.
Anteroposterior and lateral radiographs of the wrist of an 8-year-old boy with rickets demonstrates cupping and fraying of the metaphyseal region.
Radiographs of the knee of a 3.6-year-old girl with hypophosphatemia depict severe fraying of the metaphysis.
Treatment
Approach Considerations
Treatment for rickets may be administered gradually over several months or in a single-day dose of 15,000 mcg (600,000 U) of vitamin D.[7] If the gradual method is chosen, 125-250 mcg (5000-10,000 U) is given daily for 2-3 months until healing is well established and the alkaline phosphatase concentration is approaching the reference range. Because this method requires daily treatment, success depends on compliance.
If the vitamin D dose is administered in a single day, it is usually divided into 4 or 6 oral doses. An intramuscular injection is also available. Vitamin D (cholecalciferol) is well stored in the body and is gradually released over many weeks. Because both calcitriol and calcidiol have short half-lives, these agents are unsuitable for treatment, and they bypass the natural physiologic controls of vitamin D synthesis.
The single-day therapy avoids problems with compliance and may be helpful in differentiating nutritional rickets from familial hypophosphatemia rickets (FHR). In nutritional rickets, the phosphorus level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.
A study by Dabas et al compared the efficacy of daily versus weekly oral vitamin D3 therapy in the radiologic healing of nutritional rickets. Children who received daily supplementation had greater increases in their radiologic scores from baseline than those who received weekly therapy.[8]
A study by Thacher et al sought to determine the optimal dose of calcium for treatment of children with rickets. The authors reported that a daily calcium intake of 1000 mg or 2000 mg resulted in more rapid radiographic healing than 500 mg per day dosing. However no clinical or radiographic differences were found between daily calcium supplements of 2000 mg and 1000 mg. The study also found that complete healing of nutritional rickets may take some children longer than 24 weeks.[9]
If severe deformities have occurred, orthopedic correction may be required after healing. Most of the deformities correct with growth.
A consultation with a pediatric endocrinologist is recommended.
Deterrence/Prevention
Human milk contains little vitamin D and contains too little phosphorus for babies who weigh less than 1500 g. Infants weighing less than 1500 g need special supplementation (ie, vitamin D, calcium, phosphorus) if breast milk is their primary dietary source. Recommending a vitamin D supplement from the first week of life for susceptible infants who are breastfed is safe and effective and, therefore, should be considered.[10]
The United States Institute of Medicine recommends an upper level of intake of 1000 IU/d and 1500 IU/d in infants aged 0-6 months and 6-12 months, respectively. An adequate intake of 400 IU/d has been suggested for infants aged 0-12 months. The recommended daily allowance is 600 IU/d thereafter.[11] The US Endocrine Society’s Clinical Practice Guideline suggests 400-1000 IU/d may be needed for children younger than 1 year; they also recommend 600-1000 IU/d for children aged 1 year or older.[12] Internationally, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition also suggests an oral supplement of 400 IU/d until age 1 year.[13]
Adequate ultraviolet light or 10 mcg (400 IU) orally (PO) daily of a vitamin D preparation and an adequate dietary supply of calcium and phosphorus prevent rickets.[14, 15] As little as 20 min/d of ultraviolet light to the face of a light-skinned baby is sufficient; however, significantly longer periods of exposure are necessary for children with increased skin pigmentation.
Medication
Medication Summary
Treatment for rickets is with cholecalciferol, which may be gradually administered over several months or in a single-day dose.[7] The single-day therapy avoids problems with compliance and may be helpful in differentiating nutritional rickets from familial hypophosphatemia rickets (FHR). In nutritional rickets, the phosphorous level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.
Vitamin D is well stored in the body and is gradually released over many weeks. Because both calcitriol and calcidiol have short half-lives, they are unsuitable; they would bypass the natural physiologic controls of vitamin D synthesis.
Vitamin D
Class Summary
Vitamin D is a fat-soluble vitamin used to prevent or treat vitamin D deficiency.
Cholecalciferol (Vitamin D3, Ddrops Kids, Delta-D3)
For treatment of rickets, cholecalciferol can be given in a single-day dose of 15,000 mcg (600,000 U), which is usually divided into 4 or 6 oral doses. An intramuscular injection is also available.
An alternative regimen is to give 125-250 mcg (5000-10,000 U) daily for 2-3 months until healing is well established and the alkaline phosphatase concentration is approaching the reference range. Because this gradual method requires daily treatment, success depends on compliance.