AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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. 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.

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.

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 is not technically a vitamin but a hormone.

Calcitriol acts at 3 known sites to tightly regulate calcium metabolism. Calcitriol promotes absorption of calcium and phosphorus from the intestine, increases reabsorption of phosphate in the kidney, and acts on bone to release calcium and phosphate. Calcitriol may also directly facilitate calcification. These actions increase the concentrations of calcium and phosphorus in extracellular fluid. The 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 parathyroid hormone, which stimulates renal phosphorus loss, 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 to 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. Anticonvulsant drugs (eg, phenobarbital, phenytoin) accelerate metabolism of calcidiol, which may lead to insufficiency and rickets, particularly in children who are kept indoors in institutions.

Calcium and vitamin D intakes are low in infants who are fed vegan diets, particularly lactovegans, and monitoring of their vitamin D status is essential.¹

Frequency

United States

In the United States, vitamin D deficiency rickets does not occur in formula-fed infants because formula and milk sold in the United States contains 400 IU of vitamin D per liter. 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

Incidence 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 were corn is predominant in the diet.

Mortality/Morbidity

Skeletal deformity and short stature may occur. Severe rickets has been associated with respiratory failure in children, and resulting pelvic distortion in females may lead to problems with vaginal delivery later in life.

Race

Individuals with dark skin are at increased risk for vitamin D deficiency rickets.

Sex

No sexual predilection is noted.

Age

By definition, rickets is observed only in growing children, although the effects may be observed later in life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Generalized muscular hypotonia of an unknown mechanism is observed in most patients with clinical (as opposed to biochemical and radiographic) signs of rickets.
• Craniotabes manifests early in infants with vitamin D deficiency, although this feature may be normal in infants, especially for 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 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 one side of the cortex (ie, greenstick fracture).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to Be Considered

• 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.
• Severe calcium deficiency can also cause a syndrome that is confused with vitamin D deficiency rickets. 
• In premature infants, severe phosphorus deficiency that occurs when human milk is used without mineral fortification presents with rickets. 
• Hereditary disorders of vitamin D metabolism have also been described, such as hypophosphatemic vitamin D–resistant rickets.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Early on in the disease course, the calcium (ionized fraction) is low; however it is often within the reference range at the time of diagnosis as parathyroid hormone levels increase.
• Calcidiol (25-hydroxy vitamin D) levels are low, and parathyroid hormone levels are elevated; however, determining calcidiol and parathyroid hormone levels is typically not necessary.
• 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 elevated.
• A generalized aminoaciduria occurs from the parathyroid activity; aminoaciduria does not occur in familial hypophosphatemia rickets (FHR).

Imaging Studies

• 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.

Other Tests

• Serum measurements include calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxy vitamin D, and 1,25-dihydroxyvitamin D.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Treatment for rickets may be gradually administered over several months or in a single-day dose of 15,000 mcg (600,000 U) of vitamin D.² 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 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. The single-day therapy avoids problems with compliance and may be helpful in differentiating nutritional rickets from FHR. In nutritional rickets, the phosphorous level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.
• If severe deformities have occurred, orthopedic correction may be required after healing. Most of the deformities correct with growth.

Medical Care

• 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.

Consultations

• A consultation with a pediatric endocrinologist is recommended.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Vitamin D

Fat-soluble vitamin used to treat vitamin D deficiency or for prophylaxis of deficiency.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Adequate ultraviolet light or 10 mcg (400 IU) PO daily of a vitamin D preparation and an adequate dietary supply of calcium and phosphorus prevent rickets.³
• 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Improper treatment that results in vitamin D poisoning
• Failure to supplement breastfed infants, which may lead to clinical rickets

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Zmora E, Gorodischer R, Bar-Ziv J. Multiple nutritional deficiencies in infants from a strict vegetarian community. Am J Dis Child. Feb 1979;133(2):141-4. [Medline].
2. Shah BR, Finberg L. Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method. J Pediatr. Sep 1994;125(3):487-90. [Medline].
3. Greer FR. Issues in establishing vitamin D recommendations for infants and children. Am J Clin Nutr. Dec 2004;80(6 Suppl):1759S-62S. [Medline].
4. Feldman D, Glorieux FH, Pike JW. Vitamin D. San Diego: Academic Press; 1997.
5. Harrison HE, Harrison HC. Disorders of calcium and phosphate metabolism in childhood and adolescence. Philadelphia: WB Saunders Co; 1979.
6. Price DI, Stanford LC Jr, Braden DS, Ebeid MR, Smith JC. Hypocalcemic rickets: an unusual cause of dilated cardiomyopathy. Pediatr Cardiol. Sep-Oct 2003;24(5):510-2. [Medline].

Article Last Updated: Jun 19, 2008