Etiology and treatment of calcipenic rickets in children
- Thomas Carpenter, MD
Thomas Carpenter, MD
- Professor of Pediatrics (Endocrinology)
- Professor of Orthopaedics and Rehabilitation Yale University School of Medicine
- Section Editors
- Marc K Drezner, MD
Marc K Drezner, MD
- Section Editor — Bone Disease
- Professor of Medicine
- University of Wisconsin Medical School
- Joseph I Wolfsdorf, MB, BCh
Joseph I Wolfsdorf, MB, BCh
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Harvard Medical School
Calcipenic rickets comprises a group of disorders in which supply of calcium or its intestinal absorption is too low to match the calcium demands imposed by bone growth.
The most common cause of calcipenic rickets is dietary deficiency of vitamin D and/or calcium, which leads to insufficient intestinal absorption of calcium. Alternatively, calcipenic rickets may be caused by decreased vitamin D activity (eg, lack of conversion to the active metabolite or resistance to the active metabolite). Patients with calcipenic rickets have secondary hyperparathyroidism and characteristic changes of the growth plates and metaphyseal bone.
The clinical features of rickets and diagnostic evaluation to determine the cause of rickets are discussed in a separate topic review. (See "Overview of rickets in children".)
In brief, patients with calcipenic rickets are identified by elevated parathyroid hormone (PTH) and normal or low serum inorganic phosphorus (algorithm 1). Serum calcium levels are usually low in calcipenic rickets, but may be normal in some stages of the disease due to a compensatory increase in PTH. Measurement of serum 25-hydroxyvitamin D (25OHD) helps to categorize the disorder into one of the following subcategories, which are discussed in detail in this topic review (algorithm 2):
●Dietary vitamin D deficiency (the "classical" form of rickets)
- Fischer PR, Thacher TD, Pettifor JM. Pediatric vitamin D and calcium nutrition in developing countries. Rev Endocr Metab Disord 2008; 9:181.
- Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 1997; 349:1801.
- Holland PC, Wilkinson AR, Diez J, Lindsell DR. Prenatal deficiency of phosphate, phosphate supplementation, and rickets in very-low-birthweight infants. Lancet 1990; 335:697.
- Gonzalez Ballesteros LF, Ma N, Ward L, Backeljauw P, Wasserman H, Weber D, DiMeglio L, Gagne J, Stein R, Cody D, Simmons K, Zimakas P, Swartz Topor L, Agrawal S, Gordon R, Tebben P, Faircloth R, Casey L, Imel E, Carpenter TO. Hypophosphatemia associated with elemental formula use in children with feeding problems. Annual Meeting of the Pediatric Academic Societies, Baltimore, MD. May, 2016. Abstract #3853. Available at: https://www.aps-spr.org/regions/ESPR/meetings/2016_ESPR_Platforms_Sunday_AM_Endocrinology.pdf (Accessed on August 01, 2016).
- Misra M, Pacaud D, Petryk A, et al. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008; 122:398.
- Thandrayen K, Pettifor JM. Maternal vitamin D status: implications for the development of infantile nutritional rickets. Endocrinol Metab Clin North Am 2010; 39:303.
- Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. CMAJ 2007; 177:161.
- Robinson PD, Högler W, Craig ME, et al. The re-emerging burden of rickets: a decade of experience from Sydney. Arch Dis Child 2006; 91:564.
- Beck-Nielsen SS, Jensen TK, Gram J, et al. Nutritional rickets in Denmark: a retrospective review of children's medical records from 1985 to 2005. Eur J Pediatr 2009; 168:941.
- Hatun S, Ozkan B, Orbak Z, et al. Vitamin D deficiency in early infancy. J Nutr 2005; 135:279.
- Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96:53.
- Reeve LE, Chesney RW, DeLuca HF. Vitamin D of human milk: identification of biologically active forms. Am J Clin Nutr 1982; 36:122.
- Specker BL, Tsang RC, Hollis BW. Effect of race and diet on human-milk vitamin D and 25-hydroxyvitamin D. Am J Dis Child 1985; 139:1134.
- Hollis BW, Roos BA, Draper HH, Lambert PW. Vitamin D and its metabolites in human and bovine milk. J Nutr 1981; 111:1240.
- Hollis BW, Wagner CL. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr 2004; 80:1752S.
- Wagner CL, Hulsey TC, Fanning D, et al. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeed Med 2006; 1:59.
- Nozza JM, Rodda CP. Vitamin D deficiency in mothers of infants with rickets. Med J Aust 2001; 175:253.
- Dawodu A, Agarwal M, Sankarankutty M, et al. Higher prevalence of vitamin D deficiency in mothers of rachitic than nonrachitic children. J Pediatr 2005; 147:109.
- Nutrition During Infancy: Principles and Practice, 2nd ed, Tsang RC, Zlotkin SH, Nichols BL, Hansen JW (Eds), Digital Education Publishing, Cincinnati, OH 1997. p.467.
- Fraser D, Kooh SW, Scriver CR. Hyperparathyroidism as the cause of hyperaminoaciduria and phosphaturia in human vitamin D deficiency. Pediatr Res 1967; 1:425.
- Kruse K. Pathophysiology of calcium metabolism in children with vitamin D-deficiency rickets. J Pediatr 1995; 126:736.
- Vanstone MB, Oberfield SE, Shader L, et al. Hypercalcemia in children receiving pharmacologic doses of vitamin D. Pediatrics 2012; 129:e1060.
- Shah BR, Finberg L. Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method. J Pediatr 1994; 125:487.
- Munns C, Zacharin MR, Rodda CP, et al. Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a consensus statement. Med J Aust 2006; 185:268.
- Cesur Y, Caksen H, Gündem A, et al. Comparison of low and high dose of vitamin D treatment in nutritional vitamin D deficiency rickets. J Pediatr Endocrinol Metab 2003; 16:1105.
- Pfitzner MA, Thacher TD, Pettifor JM, et al. Absence of vitamin D deficiency in young Nigerian children. J Pediatr 1998; 133:740.
- DeLucia MC, Mitnick ME, Carpenter TO. Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants. J Clin Endocrinol Metab 2003; 88:3539.
- Thacher TD, Fischer PR, Isichei CO, Pettifor JM. Early response to vitamin D2 in children with calcium deficiency rickets. J Pediatr 2006; 149:840.
- Thacher TD, Fischer PR, Pettifor JM. Vitamin D treatment in calcium-deficiency rickets: a randomised controlled trial. Arch Dis Child 2014; 99:807.
- Thacher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med 1999; 341:563.
- Thacher TD, Fischer PR, Pettifor JM, et al. Case-control study of factors associated with nutritional rickets in Nigerian children. J Pediatr 2000; 137:367.
- Bergstrom WH. When you see rickets, consider calcium deficiency. J Pediatr 1998; 133:722.
- Maltz HE, Fish MB, Holliday MA. Calcium deficiency rickets and the renal response to calcium infusion. Pediatrics 1970; 46:865.
- Kooh SW, Fraser D, Reilly BJ, et al. Rickets due to calcium deficiency. N Engl J Med 1977; 297:1264.
- Scriver CR, Reade TM, DeLuca HF, Hamstra AJ. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N Engl J Med 1978; 299:976.
- PRADER A, ILLIG R, HEIERLI E. [An unusual form of primary vitamin D-resistant rickets with hypocalcemia and autosomal-dominant hereditary transmission: hereditary pseudo-deficiency rickets]. Helv Paediatr Acta 1961; 16:452.
- Fraser D, Kooh SW, Kind HP, et al. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med 1973; 289:817.
- Kitanaka S, Takeyama K, Murayama A, et al. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 1998; 338:653.
- Kim CJ, Kaplan LE, Perwad F, et al. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 2007; 92:3177.
- Edouard T, Alos N, Chabot G, et al. Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J Clin Endocrinol Metab 2011; 96:82.
- Dardenne O, Prud'homme J, Arabian A, et al. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology 2001; 142:3135.
- Panda DK, Miao D, Tremblay ML, et al. Targeted ablation of the 25-hydroxyvitamin D 1alpha -hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci U S A 2001; 98:7498.
- Thacher TD, Fischer PR, Singh RJ, et al. CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency. J Clin Endocrinol Metab 2015; 100:E1005.
- Cheng JB, Levine MA, Bell NH, et al. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A 2004; 101:7711.
- Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin North Am 2010; 39:333.
- Sakai Y, Kishimoto J, Demay MB. Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice. J Clin Invest 2001; 107:961.
- Chen CH, Sakai Y, Demay MB. Targeting expression of the human vitamin D receptor to the keratinocytes of vitamin D receptor null mice prevents alopecia. Endocrinology 2001; 142:5386.
- Balsan S, Garabédian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J Clin Invest 1986; 77:1661.
- Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J Pediatr 1992; 121:803.
- NUTRITIONAL RICKETS
- Vitamin D deficiency
- - Etiology
- - Prevention
- - Clinical course
- - Treatment
- - Monitoring
- Calcium deficiency
- - Etiology
- - Treatment
- VITAMIN D "DEPENDENT" RICKETS
- 1-alpha-hydroxylase deficiency
- - Etiology
- - Treatment
- - Monitoring
- 25-hydroxylase deficiency
- Hereditary resistance to vitamin D
- - Etiology
- - Clinical features
- - Treatment
- - Monitoring
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS