AUTHORS: Michael J. Farias, BS and John D. Milner, MD and Manuel F. DaSilva, MD
Rickets is a result of deficient mineralization of osteoid matrix before closure of the epiphyseal plate causing softening and weakening of bones in infants and children. The mineralization impairment may be secondary to abnormal calcium, phosphorus, or vitamin D metabolism leading to accumulation of osteoid before epiphyseal closure, compromising bone stability at sites of rapid bone growth.1 When this occurs in adulthood after epiphyseal closure, it is referred to as osteomalacia. Renal osteodystrophy is a term used to describe a similar condition in patients with chronic kidney disease. Certain forms of the disorder may respond only to high doses of vitamin D and are referred to as vitamin D-resistant rickets (VDRR).2
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The classic clinical presentation of children with rickets includes:
The less pronounced clinical presentation of adults with osteomalacia includes:4
Figure E1 Rachitic rosary in a child with rickets.
Courtesy Dr. Thomas D. Thacher, Rochester, MN. In Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.
From Bullough PG: Orthopaedic pathology, ed 5, St Louis, 2010, Mosby, Fig 8-31. In Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.
Note the Bowing of the Femurs and Tibiae, Which May Result from Vitamin D Deficiency, Phosphate Deficiency, or Other Causes. (B) A Skeletal Radiograph of a Child with Rickets. Note that the Weight-Bearing Bones of the Lower Extremities are Bowed and that the Epiphyses are Open, Mottled, and Overgrown. (C) Looser Zones or Pseudofractures that are Characteristic of Osteomalacia or Rickets. Because the Epiphyses are Closed, the Patient is an Adult. This Radiograph is Diagnostic of Osteomalacia.
From Stewart A: Metabolic bone diseases. In Andreoli TE et al [eds]: Cecil essentials of medicine, ed 8, Philadelphia, 2010, Saunders.
TABLE E1 Clinical Features of Rickets
General | |||
Head | |||
Chest | |||
| |||
Back | |||
Extremities | |||
Hypocalcemic Symptoms | |||
∗These features are associated most frequently with vitamin D deficiency disorders.
These symptoms develop only in children with disorders that produce hypocalcemia.
The most common cause of rickets and osteomalacia is vitamin D deficiency. Insufficient calcium and phosphorus intake can also lead to rickets. Vitamin D and parathyroid hormone (PTH) play an important role in calcium homeostasis. Vitamin D is required for adequate calcium absorption in the gastrointestinal tract. Low vitamin D leads to reduced intestinal absorption of calcium, causing a compensatory increase in PTH and resorption of bone, leading to increased alkaline phosphatase levels.3 This may arise from various conditions including inadequate dietary intake, malabsorption, chronic parenteral nutrition, and the additional risk factors listed previously. Malabsorption that causes inefficient mineralization is observed in diseases such as cystic fibrosis, intestinal disorders such as celiac disease, and in many chronic illnesses, including severe liver disease.3
Chronic renal failure can produce bone mineralization deficiency due to electrolyte abnormalities causing hypocalcemia and renal osteodystrophy (renal rickets). This results in decreased excretion of phosphate, therefore elevating serum phosphorus, along with elevated PTH and low levels of 1,25-OH vitamin D.1
Other causes specifically include vitamin D-dependent rickets (VDDR type I and II) and VDRR, also known as hereditary hypophosphatemic rickets.4 (Table E2)
TABLE E2 Causes of Vitamin D-Deficiency Rickets or Osteomalacia, or Both
From Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.
TABLE E3 Causes of Hypophosphatemic Rickets or Osteomalacia, or Both
Genetic Autosomal dominant rickets Autosomal recessive rickets X-linked dominant rickets (X-linked hypophosphatemia) X-linked recessive Hypophosphatemic hypercalciuric hereditary rickets (or Dent disease) Neurofibromatosis Fibrous dysplasia Genetic Fanconi syndrome (may have renal failure) Acquired Tumor-induced osteomalacia (most common acquired cause) Renal tubular damage or nonfamilial Fanconi syndrome Drug induced |
From Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.
TABLE E4 Contrasting Features of Four Major Metabolic Bone Diseases
Variable | Rickets and Osteomalacia | Osteoporosis | Osteitis Fibrosa | Osteitis Deformans |
---|---|---|---|---|
Basic abnormality | Defective mineralization of cartilage and bone | Insufficient replacement of normal lamellar bone | Replacement by woven bone and fibrous tissue | Abnormal woven bone |
Prevalence | Second most common | Most common | Uncommon | Not uncommon |
Serum calcium | Normal/low | Normal | High/very high | Normal |
Serum phosphate | Normal/low/very low | Normal | Frequently low | Normal |
Alkaline phosphatase | High | Normal/high | High/very high | High |
Parathyroid hormone | High | Normal/high | High/very high | Normal |
25-Hydroxyvitamin D | Low/normal | Normal/low | Frequently low | Normal/low |
Cortical thinning | Yes, except in X-linked hypophosphatemia | Sometimes | Yes | No |
Vertebral deformities | Biconcave or cod fishlike | Wedged/compressed | Variable | Enlarged size |
Long bone deformities | Bowing and pseudofractures | None, except fragility fractures | Brown tumors | Bowing and stress fractures |
Analytes: Ca, Serum calcium; P, serum phosphate; 25-D, serum 25-hydroxyvitamin D; 1,25-D, 1,25-dihydroxyvitamin D; PTH, serum parathyroid hormone; TmP/GFR, tubular maximum for phosphate reabsorption/glomerular filtration rate; HVO I, hypovitaminosis D osteopathy stage I; TRP, tubular reabsorption of phosphate; AA, urine amino acid analysis; HCO3, urine bicarbonate excretion; Glu, urine glucose. Conditions: VDD, vitamin D deficiency; VDDR, vitamin D-dependent rickets; XLH, X-linked hypophosphatemic rickets and osteomalacia; TIO, tumor-induced osteomalacia; HHRH, hereditary hypophosphatemic rickets with hypercalciuria.
From Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.
Blood testing (Table E5) should include serum calcium, inorganic phosphorus (Pi), alkaline phosphate, PTH, 25-OH vitamin D, creatinine, and liver enzymes. Tables E6 and E7 summarize laboratory findings in various disorders that cause rickets and osteomalacia. Children may present solely with an elevated alkaline phosphatase level and characteristic physical findings.4
TABLE E5 Evaluation of Osteomalacia
From Firestein GS et al: Firestein & Kelleys textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.
TABLE E6 Relevant Abnormalities in Various Types of Vitamin D-Related Rickets and Osteomalacia
Variable | Vitamin D Deficiency | Vitamin D Dependency Type 1B | Vitamin D Dependency Type 1A | Vitamin D Dependency Type 2 | Hypophosphatemic Vitamin D Resistanta |
---|---|---|---|---|---|
Basic defect | Nutritional/malabsorption | 25-Hydroxylase defect | 1α-Hydroxylase defect | VDR defect | Excess FGF23 |
Gene locus | Not applicable | Chromosome 11p15.2 | Chromosome 12q13.1 | Chromosome 12q12-q14 | Xp22.11 |
Enzyme defect | Not applicable | CYP2R1 | CYP27B1 | Receptor defect | PHEX gene defect |
Serum calcium | Low/normal | Low | Low | Low | Normal/high |
Serum phosphate | Normal/low | Normal/low | Normal/low | Normal/low | Very low |
Alkaline phosphatase | High | High | High | High | High |
Parathyroid hormone | High | High | High | High | Normal/high |
25-Hydroxyvitamin D | Low | Low/very low | Normal | Normal | Normal |
1,25-Dihydroxyvitamin D | Variable | Low/low normal | Low | High | Low |
Urine calcium | Low | Low | Low | Low | Normal/high |
Vitamin D dose required to heal/cure ricketsb | 1,000-2,000 IU daily Few weeks to months | 10,000 IU daily Lifelong | 10,000 IU daily Lifelong | 100,000 units daily Lifelong | 100,000 units daily Lifelong |
Calcitriol dose required to heal/cure rickets | 0.04 μg/kg per day Few weeks to months | 0.04 μg/kg per day Lifelong | 0.04 μg/kg per day Lifelong | 1-2 μg/day Lifelong | 1-2 μg/day and oral phosphate Lifelong |
CYP, Cytochrome P-450; FGF23, fibroblast growth factor 23; PHEX, phosphate-regulating endopeptidase homolog, X-linked; VDR, vitamin D receptor.
a Previously referred to as vitamin D-resistant rickets because of the large doses of vitamin D required to heal rickets; the current name is X-linked hypophosphatemic rickets and osteomalacia.
b Shown only to illustrate comparative effective doses. Both calcitriol and alfacalcidol are now widely available and used to treat all vitamin D-dependent rickets and osteomalacia.
TABLE E7 Key Abnormalities in Various Types of Rickets and Osteomalacia
Variable | Vitamin D Deficiency | Vitamin D-Resistant Hypophosphatemic | Tumor-Induced Osteomalacia | Drug-Induced Osteomalacia |
---|---|---|---|---|
Basic defect | Nutritional/malabsorption | PHEX gene defect Defective catabolism of FGF23 | Ectopic production of FGF23 | Renal tubular damage Direct effect on bone mineralization |
FGF23 levels | Not applicable | Usually high | Almost always high | High/variable |
Serum calcium | Low/normal | Normal/high | Normal | Variable |
Serum phosphate | Normal/low | Very low | Low/very low | Variable |
Alkaline phosphatase | High | High | High | Variable |
Parathyroid hormone | High | Normal/high | Normal | Variable |
25-Hydroxyvitamin D | Low | Normal | Normal | Low/normal |
1,25-Dihydroxyvitamin D | Variable | Low | Low | Low/variable |
Bone mineral density | Low | Normal/high | Often low | Often low |
Therapeutic strategy | Vitamin D + calcium | Calcitriol and phosphate Burosumab | Resection of the tumor Other therapies (see text) | Discontinuation of offending drug |
FGF23, Fibroblast growth factor 23; PHEX, phosphate-regulating endopeptidase homolog, X-linked.
From Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.
Neurofibromatosis (Related Key Topic)
Osteoporosis (Related Key Topic)