eMedicine Specialties > Pediatrics: General Medicine > Nutrition
Disorders of Bone Mineralization
Updated: Aug 21, 2008
Introduction
Several diseases can result in defective mineralization of bone in children, including the following:
- Rickets
- Nutritional rickets
- Congenital rickets
- Rickets of prematurity
- Vitamin D resistance (type I and type II)
- Neoplastic rickets
- Hypophosphatemic rickets
- Drug-induced rickets
- Renal causes - Renal osteodystrophy, Fanconi syndrome
- Tumor-induced osteomalacia
- Other causes
- Hypophosphatasia
- McCune-Albright syndrome
- Osteogenesis imperfecta with mineralization defect (a syndrome resembling osteogenesis imperfecta)
The disorders listed above may result in failure of osteoid calcification (rickets) in children because of a disruption in the pathway of either vitamin D or phosphate metabolism. Defective mineralization in bone causes osteomalacia, which can occur in both children and adults. Rickets, once thought defeated, is reappearing and remains a major health problem in many developing and developed countries.
The primary absorption site for vitamin D is the jejunum. The 2 main sources of vitamin D in humans are vitamin D3 (cholecalciferol), produced by the skin after UV radiation (290-320 nm)–dependent conversion of 7-dehydrocholesterol, and dietary intake of either vitamin D2 (ergocalciferol) or vitamin D3. Both have identical biological actions.
The initial step in the metabolic activation process is the introduction of a hydroxyl group at the side chain at C-25 by the hepatic enzyme, CYP 27 (a vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D2 and 25-(OH)D3, respectively. Further hydroxylation of these metabolites occurs in the mitochondria of kidney tissue, catalyzed by renal 25-hydroxyvitamin D-1α-hydroxylase to produce 1α,25-(OH)2 D2 (activated vitamin D2 or 1,25[OH]2 D2), the primary biologically active form of vitamin D2, and 1α,25-(OH)2 D3 (calcitriol or 1,25[OH]2 D3), the biologically active form of vitamin D3.
Of note, the kidney generates at least 30 other vitamin D metabolites, but their biological significance is not clear. The pathophysiology of rickets is not completely understood, nor is the role of the many vitamin D metabolites. Calcitriol levels may be normal in patients with rickets, suggesting that it is not the only active form of the vitamin.
Causes of rickets related to phosphate deficiency are discussed in the article Hypophosphatemic Rickets, and those related to Osteogenesis Imperfecta and related syndromes are discussed in the specific article.
Pathophysiology
Calcification of osteoid depends on adequate levels of ionized calcium and phosphate in the extracellular fluid. Vitamin D influences these levels after its dihydroxylation into calcitriol (at the 25 position in the liver and the 1 position in the kidney). If the enzyme that controls either of these steps is deficient because of a mutation, vitamin D function is less than normal. In addition, a renal tubular defect that reduces reabsorption may alter phosphate metabolism. Finally, a genetic absence of the receptor for calcitriol results in deficient calcification.
X-linked hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets are the result of mutations in PHEX (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome) and dentin matrix protein 1 (DMP1), respectively. Degradation of matrix extracellular phosphoglycoprotein (MEPE) and DMP-1 and release of acidic serine-rich and aspartate-rich MEPE-associated motif (ASARM) peptides are chiefly responsible for the hypophosphatemic rickets mineralization defect and changes in osteoblast-osteoclast differentiation.1 In patients with oncogenic osteomalacia, intact and C-terminal Fibroblast growth factor-23 (FGF-23) levels are elevated, and the tumors responsible for this disease show increased expression of FGF-23 messenger RNA (mRNA).
Clinical and laboratory findings
Clinical results and laboratory examination findings vary with each disorder. Low phosphate and high alkaline phosphatase levels characterize most of the disorders. Exceptions are noted in the discussion of each disorder.
Rickets
Nutritional rickets
A recommended daily allowance (RDA) for vitamin D has not been defined.2 Because no strong data support an RDA, recommendations for vitamin D intake are actually referred to as "adequate intake." Dietary rickets can be a consequence of inadequate intake of calcium, vitamin D, phosphate, or a combination of these. Infants fed exclusively with mother's milk can develop nutritional rickets because of the low content of vitamin D in breast milk (4-100 IU/L). In premature infants, insufficient amounts of both calcium and phosphorus may cause nutritional rickets. Furthermore, reserves of vitamin D in the neonate highly depend on the mother's vitamin D status. Infants with low or no sun exposure may develop rickets, particularly if they have dark skin, because of decreased vitamin D production by the skin after exposure to UV light. Maternal hypovitaminosis D may cause congenital rickets in infants.
In infants, clinical features of hypocalcemia and hyperphosphatemia include seizures, apnea, and tetany. In children clinical features of rickets include delayed motor milestones, hypotonia, enlargement of wrists, progressive bowing of long bones, rachitic rosary, Harrison sulcus, violin case deformity of the chest, late closure of anterior fontanelle, parietal and frontal bossing, craniotabes, craniosynostosis, delay in teeth eruption, enamel hypoplasia, decreased bone mineral density, myopathy with normal deep tendon reflexes, and propensity for infections (as a consequence of impaired phagocytosis and neutrophil motility).
Radiologic features include widening of the epiphysial plate, cupping, and deformities in the shaft of long bones. Of note, radiographs of the costochondral junction are not useful in the diagnosis of rickets. The healing process is characterized by broadened bands of increased density.
Different treatment modalities are available for nutritional rickets. Oral doses of 5,000-15,000 IU/day of vitamin D for 4 weeks are generally safe and effective. If compliance cannot be assured, 100,000-500,000 IU can be given orally or intramuscularly every 6 months or 600,000 IU may be given in a single intramuscular dose. Calcium intake must be optimized at the same time. Calcium, phosphorus, and parathyroid hormone concentrations should normalize within 1-3 weeks. Radiologic lesions and clinical symptoms improve rapidly with treatment, although alkaline phosphatase levels may remain elevated for several months after radiologic resolution.
Vitamin D–dependent rickets (type I)
Also known as vitamin D pseudodeficiency (PDDR), this disorder results from a genetic deficiency in the enzyme that converts calcidiol to calcitriol in the kidney. Inheritance is autosomal recessive, and the gene is located in band 12q13.3. Clinical and laboratory examination findings are similar to those associated with nutritional rickets, with low levels of 1,25(OH) 2 vitamin D. levels of 1,25(OH) 2 vitamin D may be normal but inadequately low for the levels of calcium, phosphorus, and parathyroid hormone. These patients develop rickets despite receiving vitamin D at the recommended preventive doses.
Medical treatment consists of oral calcitriol (0.5-1.5 mcg/d). These patients may also respond to pharmacologic doses of vitamin D (5,000-10,000 U/d).
Receptor defect rickets (type II vitamin D–dependent rickets)
Receptor defect rickets (hereditary 1,25-dihydroxyvitamin D–resistant rickets [HVDRR]) results from a recessively inherited abnormality in the calcitriol receptor, causing an end-organ resistance to the vitamin. The clinical picture is evident early in life, and consists of rickets with very severe hypocalcemia and alopecia, although a variant without alopecia has been reported. Patients without alopecia appear to respond better to treatment with vitamin D metabolites. Serum levels of 1,25(OH) 2 vitamin D 3 are typically elevated. HVDRR can be lethal in the perinatal period. Because calciferol receptors are in many tissues, other, more subtle, dysfunctions may occur. Patients are hypocalcemic and usually normophosphatemic.
Several mutant forms of receptor defect rickets are recognized, with a wide range of severity and response to calcitriol therapy. Some patients are totally resistant to therapy. Patients without alopecia appear to respond better to treatment with vitamin D metabolites. Some patients have benefited from intravenous calcium (400-1400 mg/m2/d) followed by oral therapy with high doses of calcium (with secondary risk of nephrocalcinosis, hypercalciuria, nephrolithiasis, and cardiac arrhythmias). Patients with mutations in the ligand-binding domain (LBD) region of the receptor are more likely to respond to high-dose vitamin D treatment than patients with mutations in the DNA-binding domain (DBD) region of the receptor.
Defective 25-hydroxylase
Two cases of 25-hydroxylase deficiency have been reported, one involving a family in the United States and the other involving a family in Germany. Inheritance is likely autosomal recessive. The clinical picture resembles that observed in nutritional rickets, with a later age of onset.
Treatment with calcidiol in physiologic amounts is sufficient for this condition. Calcidiol is a natural metabolite of vitamin D. Calcidiol is hydroxylated once at the 25 position and is the circulating form for vitamin D in plasma.
Familial hypophosphatemia
Several different familial and acquired conditions may lead to hypophosphatemia in children. In familial hypophosphatemia, the kidneys fail to reabsorb sufficient phosphate, leading to low levels of serum phosphate. This is usually evident only after age 6-10 months. Prior to this occurrence, the glomerular filtration rate is low, which sustains an adequate phosphate level. Once renal maturity is reached, phosphate levels are usually less than 3.5 mg/dL and are often less than 2.5 mg/dL. Levels of 1,25(OH) 2 vitamin D are normal in these patients, which is actually an abnormal response to hypophosphatemia, in which levels of 1,25(OH) 2 vitamin D should increase.
Mutations in PHEX and DMP1 result in X-linked hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets, respectively. PHEX codes for a protease, which is an enzyme that catalyzes the hydrolysis of a protein. Degradation of MEPE and DMP-1 and release of ASARM peptides are chiefly responsible for the hypophosphatemic rickets mineralization defect and changes in osteoblast-osteoclast differentiation.
Most families of patients with familial hypophosphatemia exhibit an X-linked dominant inheritance. FGF-23 has been implicated in the renal phosphate wasting in tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets. Mutations in the gene that codes for the main renal sodium-phosphate cotransporter (NPT2a) have been reported in some patients with familial renal calcium stones and hypophosphatemia due to a decrease in renal phosphate reabsorption. These patients have hypercalciuria and elevated levels of 1,25(OH) 2 vitamin D 3 .
Both autosomal recessive and autosomal dominant inheritance have been found and have been associated with the same clinical phenotype. In approximately one third of patients, the disease appears to occur as a consequence of a new mutation. Clinical findings are similar to those of nutritional rickets, but without proximal myopathy. These patients usually have high bone density. As hypophosphatemia is usually clinically evident at a later age, infantile skull defects are not apparent. Because calcium levels remain normal, neither tetany nor secondary hyperparathyroidism are present.
Optimal therapy consists of oral phosphate to provide 1-3 g of elemental phosphate per day in 5 divided doses plus oral calcitriol (0.5-1.5 mcg/d). Calcitriol (Rocaltrol) prevents increases in parathyroid hormone caused by phosphate therapy. The phosphate mixture contains mineral salts of phosphoric acid. Raising the concentration of plasma phosphate facilitates calcification of osteoid. Of note, phosphate half-life in serum is short, which usually causes low phosphate levels in fasting serum samples, despite proper therapy. Efficacy is reflected by proper linear growth.
Minor changes in calcitriol dose may produce hypercalcemia and renal damage. The calcium-creatinine (mg/mg) ratio in urine must be closely monitored at first and then every 3-6 months.
An elevated phosphate intake may produce secondary hyperparathyroidism. Therefore, only experienced practitioners should treat these patients.
Drug-induced rickets
Chronic anticonvulsant therapy (particularly with phenobarbital and phenytoin) may cause rickets, regardless of appropriate vitamin D intake. The main mechanism is related to induction of hepatic cytochrome P-450 hydroxylation, generating inactive metabolites. Levels of 25-hydroxyvitamin D 3 were reported to be low in children on long-term anticonvulsant therapy.
In one institution, fractures were found to be associated with the use of anticonvulsants in patients with cerebral palsy,3 although a different study did not find a relationship between serum 25(OH) vitamin D3 levels and the use of anticonvulsants in a similar patient population.4
Conversely, calcitriol levels in plasma are reportedly not low in patients taking medication for seizures. Different medications may affect bone in different ways. The dose of vitamin D required to prevent this type of rickets is unclear. Supplementation may not be needed. Approximately 800-1000 IU/d, plus good calcium intake, may be sufficient.
Renal Causes
Fanconi syndrome
Fanconi syndrome is a disorder of proximal renal tubular transport. Phosphate, amino acids, glucose, bicarbonate, and uric acid wasting characterize this disorder. Dysfunctions in tubular phosphate reabsorption via the sodium-phosphate cotransporter, endocytotic reabsorption of vitamin D–vitamin D–binding protein complex mediated by megalin and cubilin, and acid-base regulation are most important factors that cause bone mineralization defects in these patients.5
Lowe disease and Dent disease are familial forms of Fanconi. Two different genes have identified to be involved in the development of Dent disease. CLCN5 is affected in Dent disease type 1 and OCRL1 is affected in Dent disease type 2. Other genes may also be involved because mutations in CLCN5 and OCRL1 are not found in some patients. In this group of disorders, which includes cystinosis and tyrosinemia, renal phosphate wasting may occur, along with aminoaciduria and glycosuria. The causes may be genetic (as in the disorders described above) or may be acquired from various toxins, including heavy metals (eg, mercury, lead) and drugs. The clinical picture varies with age and cause and includes severe hypophosphatemic rickets, failure to thrive, and metabolic acidosis.
A potential drug-induced Fanconi syndrome has been noticed in children treated with ifosfamide, a derivative of cyclophosphamide. The syndrome presents with radiologic changes compatible with rickets. Most patients respond to a combination of managing the underlying cause when possible and vitamin D therapy. These patients do not necessarily appear to require treatment with calcitriol. Renal tubular acidosis, through phosphate wasting, may also cause rickets.
Renal osteodystrophy
In end-stage renal disease, renal 1-hydroxylase is diminished or lost, and excretion of phosphate is defective. This leads to low levels of 1,25(OH) 2 vitamin D, hypocalcemia, and failure of osteoid calcification. Osteodystrophy (ie, renal rickets) is the only type of rickets with a high serum phosphate level. It can be adynamic (a reduction in osteoblastic activity) or hyperdynamic (increased bone turnover).
Recently, calcium receptors (CaRs) have been discovered in bone, kidney, and intestine and also in organs not directly related to calcium regulation. Mutations that cause loss of function in the CaRs result in familial benign hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Familial benign hypocalciuric hypercalcemia is usually associated with heterozygous inactivating mutations of the CAR gene, whereas neonatal severe hyperparathyroidism is usually due to homozygous inactivation of the CAR gene. Familial benign hypocalciuric hypercalcemia is generally asymptomatic and is characterized by mild-to-moderate lifelong hypercalcemia, relative hypocalciuria, and normal intact parathyroid hormone. Individuals with neonatal severe hyperparathyroidism frequently develop life-threatening hypercalcemia.
Treatment of these patients includes phosphate binders, a low phosphate intake, and calcitriol and other vitamin D analogs.
Tumor-Induced Osteomalacia
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome with hypophosphatemia secondary to decreased renal phosphate reabsorption, normal or low serum 1,25-dihydroxyvitamin D concentration, osteomalacia, and myopathy. Several mesenchymal tumors of bone or connective tissue (including those termed nonossifying fibromas, fibroangioma, giant cell tumors) secrete a phosphaturic substance (parathyroidlike protein) that results in rickets. The age of onset has been late childhood, adolescence, or young adulthood. The clinical characteristics are similar to those associated with familial hypophosphatemia. FGF-23 causes renal phosphate wasting in tumor-induced osteomalacia. Treatment is surgical removal of the tumor (if it can be located), with excellent results.
Other Causes
Hypophosphatasia
This autosomal recessive condition resulting in low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) causes rickets without disturbance of calcium and phosphate metabolism. Levels of TNSALP substrates, namely pyridoxal-5'-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine (PEA) in serum and urine, are increased. Clinical severity widely varies, ranging from death in utero to pathologic fractures first presenting only in adulthood.
Six clinical forms of hypophosphatasia have been distinguished, although form assignment may be challenging in some cases. This classification is based on the age when skeletal lesions are discovered: perinatal (lethal), infantile, childhood, and adult. Two particular forms include odontohypophosphatasia (only biochemical and dental manifestations are present, with no clinical changes in long bones) and pseudohypophosphatasia.
No useful treatment is currently available. The effects of bone marrow transplant in hypophosphatasia are transient, and bone lesions may recur 6 months after the transplant. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used in patients with childhood hypophosphatasia with some clinical improvement.
McCune-Albright syndrome
Patients with McCune-Albright syndrome may have hypophosphatemia secondary to urinary phosphate leak, which may cause osteomalacia. Fasting phosphate levels should always be monitored in these patients, and phosphate supplements prescribed when indicated.
Syndrome resembling osteogenesis imperfecta
Syndrome resembling osteogenesis imperfecta (SROI) with mineralization defect is clinically indistinguishable from moderate-to-severe osteogenesis imperfecta.6 This rare form has been termed type VI osteogenesis imperfecta. It can only be diagnosed with bone biopsy, in which a mineralization defect that affects the bone matrix and sparing growth cartilage are evident. These patients have neither dentinogenesis imperfecta nor Wormian bones. Despite the histologic mineralization defect, no radiologic signs of growth plate involvement are seen.
The pattern of inheritance is not clear, but a case of two siblings from healthy consanguineous parents has been described, suggesting gonadal mosaicism or a somatic recessive trait. No mutations of COL1A1 and COL1A2 genes have been found in these patients, and collagen structure appears to be normal. This form shares several characteristics with fibrogenesis imperfecta ossium. A mild, rare form of this condition may occur (3 patients in a series of 128 bone biopsies performed to assess bone fragility). These patients do not appear to respond well to treatment with intravenous bisphosphonates.
Keywords
disorders of bone mineralization, rickets, metabolic bone disease, familial hypophosphatemia, vitamin D–resistant rickets, vitamin D–dependent rickets type I, receptor defect rickets, vitamin D–dependent rickets type II, defective 25-hydroxylase, Fanconi syndrome, oncogenous osteomalacia, osteodystrophy, renal rickets, hypophosphatasia, nutritional rickets, congenital rickets, rickets of prematurity, vitamin D intake, hypocalcemia, vitamin D pseudodeficiency, PDDR, hereditary 1,25-dihydroxyvitamin D–resistant rickets, HVDRR, cystinosis, tyrosinemia, aminoaciduria, glycosuria, failure to thrive, metabolic acidosis, end-stage renal disease
More on Disorders of Bone Mineralization |
| References |
References
Martin A, David V, Laurence JS, et al. Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology. Apr 2008;149(4):1757-72. [Medline].
Vieth R, Fraser D. Vitamin D insufficiency: no recommended dietary allowance exists for this nutrient. CMAJ. Jun 11 2002;166(12):1541-2. [Medline].
Henderson RC, Lin PP, Greene WB. Bone-mineral density in children and adolescents who have spastic cerebral palsy. J Bone Joint Surg Am. Nov 1995;77(11):1671-81. [Medline].
Ala-Houhala M, Korpela R, Koivikko M, et al. Long-term anticonvulsant therapy and vitamin D metabolism in ambulatory pubertal children. Neuropediatrics. Nov 1986;17(4):212-6. [Medline].
Prie D, Huart V, Bakouh N, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. Sep 26 2002;347(13):983-91. [Medline].
Plotkin H. Syndromes with congenital brittle bones. BMC Pediatr. Aug 31 2004;4:16. [Medline].
ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. Nov 2000;26(3):345-8. [Medline].
Anatoliotaki M, Tsilimigaki A, Tsekoura T, et al. Congenital rickets due to maternal vitamin D deficiency in a sunny island of Greece. Acta Paediatr. 2003;92(3):389-91. [Medline].
Chesney RW, Zimmerman J, Hamstra A, et al. Vitamin D metabolite concentrations in vitamin D deficiency. Are calcitriol levels normal. Am J Dis Child. Nov 1981;135(11):1025-8. [Medline].
Intakes SCotSEoDR. Dietary reference intakes: calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997.
Juppner, H. Novel regulators of phosphate homeostasis and bone metabolism. Ther Apher Dial. 2007;11:S3-S22. [Medline].
Plotkin H, Lifshitz F. Rickets and osteoporosis. In: Lifshitz F, ed. Pediatric Endocrinology. 5th ed. 2006.
Further Reading
Keywords
disorders of bone mineralization, rickets, metabolic bone disease, familial hypophosphatemia, vitamin D–resistant rickets, vitamin D–dependent rickets type I, receptor defect rickets, vitamin D–dependent rickets type II, defective 25-hydroxylase, Fanconi syndrome, oncogenous osteomalacia, osteodystrophy, renal rickets, hypophosphatasia, nutritional rickets, congenital rickets, rickets of prematurity, vitamin D intake, hypocalcemia, vitamin D pseudodeficiency, PDDR, hereditary 1,25-dihydroxyvitamin D–resistant rickets, HVDRR, cystinosis, tyrosinemia, aminoaciduria, glycosuria, failure to thrive, metabolic acidosis, end-stage renal disease
