AUTHOR INFORMATION

Section 1 of 11

Authored by Laurence Finberg, MD, Clinical Professor, Department of Pediatrics, University of California at San Francisco and Stanford University

Laurence Finberg, MD, is a member of the following medical societies: American Medical Association

Edited by Steven M Schwarz, MD, FAAP, FACN, Chair, Department of Pediatrics, Long Island College Hospital; Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Jatinder Bhatia, MD, Professor of Pediatrics, Chief, Section of Neonatology, Vice Chairman for Clinical Research, Department of Pediatrics, Medical College of Georgia; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Jatinder Bhatia, MD, Professor of Pediatrics, Chief, Section of Neonatology, Vice Chairman for Clinical Research, Department of Pediatrics, Medical College of Georgia

Author's Email:	Laurence Finberg, MD
Editor's Email:	Steven M Schwarz, MD, FAAP, FACN

eMedicine Journal, April 25 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 11

Background: Rickets is defined as the failure of osteoid to calcify in a growing person or animal. Failure of osteoid to calcify in the adult is called osteomalacia. Rickets occurs when the metabolites of vitamin D are deficient. Less commonly, dietary deficiency of calcium or phosphorus may produce rickets. Vitamin D (cholecalciferol [vitamin D-3], a steroid compound) is formed in the skin under the stimulus of ultraviolet light. Ultraviolet light was the only significant source of vitamin D until early in the 20th century when ergosterol (vitamin D-2), contained in fish liver oil or as an irradiated plant steroid, was discovered. Ergosterol can be taken orally with good effect.

Rickets appeared in epidemic form in temperate zones when the factories of the Industrial Revolution produced so much smoke that ultraviolet rays were blocked. Rickets was probably the first childhood disease caused by environmental pollution. At that point in history, the deficiency of sunlight could be said to have caused the rickets epidemic in industrial areas.

Human milk provides little vitamin D because of evolutionary forces not producing a need for vitamin D in tropical and other sunny climates. Infants and children at risk for rickets are those who are breastfed, those who receive no oral supplementation, and those with darkly pigmented skin, which blocks penetration of light. Living in an inner-city area also is a risk factor for rickets because of the presence of smog, which reduces the amount of ultraviolet radiation that reaches the residents.

Pathophysiology: Cholecalciferol (ie, vitamin D-3) is formed in the skin from 5-dihydrotachysterol. Alternatively, vitamin D-3 or vitamin D-2 may be ingested as fish liver oil or irradiated ergosterol from plant sources. This steroid undergoes hydroxylation in 2 steps. The first step occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which is the circulating reserve compound. The second step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol), a hormone.

Calcitriol acts at 3 known sites. Calcitriol promotes absorption of calcium and phosphorous 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 phosphate in extracellular fluid. The increase of calcium and phosphate 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 and, along with calcitriol and calcitonin, plays a role in calcium regulation.

When calcitriol levels are low, hypocalcemia develops, which stimulates parathyroid hormone excess. Excess parathyroid hormone, in turn, produces renal phosphate loss, further reducing calcification potential. 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 returns to the reference range, with a very low phosphate level. Alkaline phosphatase, which is produced by very active osteoblast cells, leaks to the extracellular fluids so that its concentration rises to anywhere from moderate elevation to very high levels.

Severe intestinal malabsorption and diseases of the liver or kidney may produce the clinical and secondary biochemical picture of nutritional rickets. The anticonvulsant drugs phenobarbital and 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 macrobiotic diets, and rickets often has been reported.

Frequency:

• In the US: In the United States, severe nutritional rickets has become rare, although the mild disorder continues in the high-risk population (eg, individuals with dark skin, persons who live in inner-city areas). Breastfed infants who receive no vitamin D supplementation also are at risk. All infant formula, evaporated milks, and almost all whole milk sold in the United States contain 400 U (10 mcg) of vitamin D per quart.

• Internationally: 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 and/or phosphorous in the diet may lead to rickets.

Mortality/Morbidity: Skeletal deformity and short stature may occur. Severe rickets causing pelvic distortion in women may preclude vaginal delivery.

Age: By definition, rickets is observed only during growth, although the effects may be observed later.

CLINICAL

Section 3 of 11

History:

• Generalized muscular hypotonia of unknown mechanism is observed in most patients with clinical (as opposed to biochemical and radiographic) signs of rickets.



• Craniotabes manifests early in infants. Although this feature may normally be found in infants born prematurely, particularly along suture lines, craniotabes also is pronounced when rickets is present.



• If rickets progresses at a later stage, thickening of the skull develops. This produces frontal bossing, and the closing of the anterior fontanelle is delayed. The laying down of uncalcified osteoid at the metaphases leads to spreading of those areas, producing knobby deformity.



• In the chest, knobby deformity results in the rachitic rosary. 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).



• Weight bearing produces deformities such as bowlegs and knock-knees.



• Some deformity occurs before weight bearing from strong dorsal muscle pull.



• Acute infection or fever, producing catabolic release of phosphate from cells, occasionally precipitates hypocalcemia and tetany as a presenting manifestation.



• In the United States, infants with rickets usually are otherwise well nourished; rickets also may occur as part of general malnutrition, although some of its features are less obvious because of slower skeletal growth.

Causes: Rickets is caused by the failure of osteoid to calcify in the growing person or animal. Failure of osteoid to calcify in the adult is called osteomalacia. Rickets occurs when the metabolites of vitamin D are deficient. Less commonly, dietary deficiency of calcium or phosphorus may produce rickets. Vitamin D (cholecalciferol [vitamin D-3], a steroid compound) is formed in the skin under the stimulus of ultraviolet light. Ultraviolet light was the only significant source of vitamin D until early in the twentieth century, when ergosterol (vitamin D-2), which is contained in fish liver oil or as an irradiated plant steroid, was discovered. Ergosterol can be taken orally with good effect.

DIFFERENTIALS

Section 4 of 11

[Metabolic Bone Disease]

WORKUP

Section 5 of 11

Lab Studies:

• Early on in the disease course, the calcium (ionized fraction) is low; however it often is within the reference range at the time of diagnosis.



• The phosphorus level is invariably low for age unless recent partial treatment or recent exposure to sunlight has occurred.



• Alkaline phosphatase levels are elevated.



• Calcidiol levels are low, and parathyroid hormone levels are elevated; however, determining calcidiol and parathyroid hormone levels typically is not necessary.



• A generalized aminoaciduria occurs from the parathyroid activity; aminoaciduria does not occur in familial hypophosphatemia rickets (FHR).



• In some circumstances, calcitriol levels are normal or high because of parathyroid activity.

Imaging Studies:

• Radiographic changes: The best single radiogram for infants and children younger than 3 years is an anterior view of the knee showing the metaphyseal ends and epiphyses of the femurs and tibiae.


• • This site is best because growth is most rapid there, which accentuates the changes.
  
  
  
  • The metaphyses show 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.
  
  
  

TREATMENT

Section 6 of 11

Medical Care: Adequate ultraviolet light or 10 mcg (400 U) PO daily of a vitamin D preparation and an adequate dietary supply of calcium and phosphorus prevent rickets. 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 melanotic skin.

• Human milk contains little vitamin D, and, for babies weighing less than 1500 g, it also contains too little phosphate. Babies weighing less than 1500 g need special supplementation (vitamin D, calcium, phosphate) 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, effective, and, therefore, should be considered.



• A recent study suggests that vitamin D supplementation in infancy may be associated with increased bone density in adult women (which may, in turn, prevent osteoporosis).



• Vitamin D supplementation is critically important for infants living in an inner-city area and those with increased skin pigmentation.



• Treatment for rickets may be administered gradually over several months or in a single day’s dose with 15,000 mcg (600,000 U) of vitamin D. 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.



• An alternative and recommended therapy is to administer the vitamin D in a single day, usually divided into 4 or 6 oral doses. An intramuscular injection also is available. Vitamin D is well stored in the body and released gradually over many weeks. Neither calcitriol nor calcidiol with their short half-lives are suitable. The single-day therapy avoids problems with compliance and, on occasion, is helpful in differentiating nutritional rickets from FHR.



• In nutritional rickets, the phosphate level rises in 96 hours and radiographic healing is visible in 6-7 days. Neither happens with FHR.

• One must be careful in the single-day regimen not to use a preparation of vitamin D suspended in propylene glycol. At this dosage, the vehicle is toxic. One may use 50,000-U capsules of ergosterol that are softened in water and fed with a blended food, such as applesauce.

• If severe deformities have occurred, orthopedic correction may be required after healing. Most of the deformities correct with growth. Severe rickets, similar to that which once was observed in China, may cause pelvis deformation, which can prevent vaginal childbirth.

MEDICATION

Section 7 of 11

Drug Category: Vitamin D -- Fat-soluble vitamin used to treat vitamin D deficiency or for prophylaxis of deficiency.

Drug Name	Cholecalciferol (Delta-D) -- Vitamin D-3. 1 mg provides 40,000 IU vitamin D activity.
Pediatric Dose	Single-day dose method: 15,000 mcg (600,000 U) PO qd divided in 4-6 doses for 1 d Gradual method: 125-250 mcg (5000-10,000 U) qd for 2-3 mo
Contraindications	Documented hypersensitivity; hypercalcemia; malabsorption syndrome; decreased renal function
Interactions	Cholestyramine and colestipol decrease absorption of calcitriol; magnesium-containing antacids and thiazide diuretics can increase effects; poor absorption of vitamin D (and all fat-soluble vitamins) may be associated with administration of mineral oil–containing laxatives
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adequate response depends on adequate dietary calcium intake; maintain adequate fluid intake

FOLLOW-UP

Section 8 of 11

Complications:

• Short stature, pelvic deformation, and abnormal gait are potential serious outcomes of severe rickets, which is rarely observed today.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Improper treatment leading to vitamin D poisoning

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which if the following is the active metabolite of vitamin D?

A: Cholecalciferol
B: Dihydrotachysterol
C: Calcitriol
D: Calcidiol
E: 7-Dehyrocholesterol

The correct answer is C: Calcitriol is the active metabolite and the hormone derived from cholecalciferol by 2 oxidation steps. Some of the intermediates and molecules of further oxidation have less activity.

CME Question 2: Which of the following tissues is not involved in vitamin D metabolism?

A: Liver
B: Skin
C: Kidney
D: Thyroid
E: Parathyroid

The correct answer is D: Each of the organs except the thyroid participates in producing the active metabolite. Cholecalciferol (ie, vitamin D-3) is formed in the skin from 5-dihydrotachysterol. Alternatively, vitamin D-3 or vitamin D-2 may be ingested as fish liver oil or irradiated ergosterol from plant sources. This steroid undergoes hydroxylation in 2 steps. The first step occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which is the circulating reserve compound. The second step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol), a hormone. When calcitriol levels are low, hypocalcemia develops, which stimulates parathyroid hormone excess.

Pearl Question 1 (T/F): Human milk from a well-nourished woman has adequate vitamin D.

The correct answer is False: Human milk (and animal milk in general) contains only minute amounts of vitamin D because of evolutionary forces not producing a need for vitamin D in tropical and other sunny climates. Infants and children at risk for rickets are those who are breastfed, those who receive no oral supplement, and those with darkly pigmented skin, which blocks penetration of ultraviolet light (a significant source of vitamin D). Living in an inner-city area also is a risk factor for rickets because of the presence of smog, which reduces the amount of ultraviolet radiation that reaches the residents.

Pearl Question 2 (T/F): Vitamin D is converted to its active metabolite in the intestine.

The correct answer is False: Conversion occurs in 2 steps. The first step occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which is the circulating reserve compound. The second step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol), a hormone.

Pearl Question 3 (T/F): Living in an inner-city area increases an infant’s risk of rickets.

The correct answer is True: The smog, which is characteristic of urban areas, reduces ultraviolet radiation to residents. Vitamin D supplementation is critically important for infants living in an inner-city area.

Pearl Question 4 (T/F): A physical sign of rickets is the sensation of a double malleolus on palpation.

The correct answer is True: This also is known as the Marfan sign. Because the softened long bones may bend, they may fracture one side of the cortex (ie, greenstick fracture).

BIBLIOGRAPHY

Section 11 of 11

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

eMedicine Journals > Pediatrics > Nutrition > Rickets

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Bibliography