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Overview of rickets in children

Overview of rickets in children
Author:
Thomas Carpenter, MD
Section Editor:
Joseph I Wolfsdorf, MD, BCh
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Jul 2022. | This topic last updated: Nov 08, 2021.

INTRODUCTION — Normal bone growth and mineralization require adequate calcium and phosphate, the two major constituents of the crystalline component of bone. Deficient mineralization can result in rickets and/or osteomalacia. Rickets refers to deficient mineralization at the growth plate, as well as architectural disruption of this structure. Osteomalacia refers to impaired mineralization of the bone matrix. Rickets and osteomalacia usually occur together as long as the growth plates are open; only osteomalacia occurs after the growth plates have fused [1]. (See "Epidemiology and etiology of osteomalacia".)

An overview of the pathogenesis, clinical presentation, and the differential diagnosis of rickets is presented here. The etiology and treatment of calcipenic and phosphopenic rickets are discussed separately. (See "Etiology and treatment of calcipenic rickets in children" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

TYPES OF RICKETS — Mineralization defects are classified according to the predominant mineral deficiency:

Calcipenic rickets is caused by calcium deficiency, which usually is due to insufficient intake of vitamin D or failure to metabolize dietary vitamin D into its active form. In some cases, it is caused by insufficient intake or absorption of calcium in the setting of normal vitamin D levels. Calcipenic rickets may be associated with low serum calcium levels but also occurs in the setting of normocalcemia.

Phosphopenic rickets is characterized by low serum levels of phosphorus, usually caused by renal phosphate wasting and, less commonly, by nutritional phosphorus deficiency.

PATHOGENESIS — Growth plate thickness is determined by two opposing processes [1]:

Chondrocyte proliferation and hypertrophy

Calcification of growth plate cartilage with subsequent vascular invasion of the growth plate and conversion to primary bone spongiosa

Vascular invasion requires mineralization of the growth plate cartilage, which is delayed or prevented by deficiency of calcium or phosphorus [1-3]. In these circumstances, growth plate cartilage accumulates and the growth plate expands. In addition, the chondrocytes of the growth plate become disorganized, losing their columnar orientation [4-6] with characteristic expansion of the hypertrophic zone and impaired mineralization [7]. In the bone tissue below the growth plate (metaphysis), the mineralization defect leads to the accumulation of osteoid [8].

These abnormalities alter the overall geometry of the involved skeletal sites, leading to secondary increases in the diameters of the growth plate and metaphysis. These changes may be regarded as an attempt to compensate for decreased bone strength by increased bone size. Nonetheless, bone stability is compromised. If the underlying condition does not improve, bowing occurs.

CLINICAL MANIFESTATIONS — Calcipenic and phosphopenic rickets initially manifest at the distal forearm, knee, and costochondral junctions. These are the sites of rapid bone growth, where the demand for calcium and phosphorus accrual is greatest.

Skeletal findings — The skeletal findings are similar for calcipenic and phosphopenic rickets. The typical findings of advanced rickets include [9]:

Delayed closure of the fontanelles

Parietal and frontal bossing

Craniotabes (soft skull bones)

Enlargement of the costochondral junction visible as beading along the anterolateral aspects of the chest (the "rachitic rosary") (image 1)

Formation of Harrison sulcus (or groove) at the lower margin of the thorax caused by the inward pull by diaphragmatic attachments of the softened lower ribs

Widening of the wrist and bowing of the distal radius and ulna

Progressive lateral bowing of the femur and tibia (picture 1)

The site and type of deformity of the extremities depend upon the age of the child and the weight-bearing patterns in the limbs. Thus, deformities of the forearms and posterior bowing of the distal tibia are more common in infants, whereas an exaggeration of the normal physiologic bowing of the legs (genu varum) is a characteristic finding in the toddler who has started to walk (picture 1 and image 2). In the older child, valgus deformities of the legs ("knock-knees") or a windswept deformity (valgus deformity of one leg and varus deformity of the other) may be apparent. The type of deformity depends upon the biomechanical forces acting on the lower extremities at the time when the structural weakness develops. (See "Approach to the child with bow-legs", section on 'Rickets' and "Approach to the child with knock-knees", section on 'Other causes'.)

Radiographic findings — The changes of rickets are best visualized at the growth plates of rapidly growing bones, where mineral demand is greatest. Thus, in the upper limbs, the distal ulna is the site that best demonstrates the early signs of impaired mineralization (image 3). In the lower extremities, the metaphyses above and below the knees are the most useful sites.

Radiographic signs include:

Epiphyseal/metaphyseal interface – Early signs of rickets are widening of the epiphyseal plate and loss of definition of the zone of provisional calcification at the epiphyseal/metaphyseal interface (image 3). As the disease progresses, this region becomes more disorganized, with cupping, splaying, formation of cortical spurs, and stippling. The appearance of the epiphyseal bone centers may be delayed or they may be small, osteopenic, and ill defined [10].

Long bones – The shafts of the long bones are osteopenic, and the cortices may become thin. The trabecular pattern is reduced and becomes coarse. Deformities of the shafts of the long bones are often present.

Looser zones and fractures – In severe rickets, pathologic fractures and Looser zones (also known as Milkman pseudofractures or insufficiency fractures) may be noted [11]. Looser zones are pseudofractures, fissures, or narrow radiolucent lines 2 to 5 mm in width with sclerotic borders and are a characteristic radiologic finding in osteomalacia (image 4). They may be bilateral and usually symmetric and lie perpendicular to the cortical margins of bones. They usually are found at the femoral neck on the medial part of the femoral shaft, immediately under the lesser trochanter or a few centimeters beneath, or on the pubic and ischial rami. They also may occur in the ulna, scapula, clavicle, rib, and metatarsal bones. Pseudofractures also can be seen as hot spots on bone scans [12].

Extraskeletal findings — The extraskeletal manifestations of rickets vary depending upon the primary mineral deficiency. Hypoplasia of the dental enamel is a typical finding of calcipenic rickets, whereas dental abscesses occur more often in heritable forms of phosphopenic rickets. (See "Developmental defects of the teeth", section on 'Enamel defects'.)

Calcipenic rickets can affect the musculoskeletal system with decreased muscle tone, leading to delayed achievement of motor milestones [13-15]. Presentation with hypocalcemic seizures occurs most frequently in the first year of life [14]. Children with calcipenic rickets also are particularly prone to acquiring infectious diseases [16,17]. (See "Clinical manifestations of hypocalcemia".)

Laboratory findings — Biochemical findings vary depending upon the type of rickets (table 1) [18]:

Calcium – The serum calcium concentration may be either decreased or normal in calcipenic rickets, depending on the stage of rickets; serum calcium usually is normal in phosphopenic rickets.

Phosphorus – Serum phosphorus concentrations usually are low in both calcipenic and phosphopenic rickets.

Parathyroid hormone (PTH) – The serum concentration of PTH typically is elevated in calcipenic rickets. In contrast, PTH concentrations are usually normal or only modestly elevated in phosphopenic rickets. If phosphorus deficiency is nutritional or not mediated by fibroblast growth factor 23 (FGF23), PTH levels may be in the low-normal range.

Alkaline phosphatase – Serum alkaline phosphatase activity usually is increased markedly over the age-specific reference range in nutritional rickets, whereas the level is elevated to a lesser extent in the common form of heritable phosphopenic rickets (X-linked hypophosphatemia [XLH]). Alkaline phosphatase participates in the mineralization of bone and growth plate cartilage and is an excellent marker of disease activity [19]. In the heritable forms of phosphopenic rickets, the serum alkaline phosphatase activity tends to be moderately elevated (400 to 800 international units/L), whereas in calcipenic rickets, values often reach greater levels (often up to 2000 international units/L).

Vitamin D – Serum concentrations of 25-hydroxyvitamin D (25OHD) reflect the amount of vitamin D stored in the body and, consequently, are low in vitamin D deficiency. In calcipenic rickets, serum concentrations of 1,25-dihydroxyvitamin D (1,25[OH]2D) can be low, normal, or increased.

In some forms of phosphopenic rickets (those mediated by excess FGF23, such as XLH and tumor-induced osteomalacia [TIO]), serum concentrations of 1,25(OH)2D may be low or inappropriately normal (in view of the ambient hypophosphatemia, which should serve to increase production of the metabolite). In other forms of phosphopenic rickets (those not mediated by excess FGF23, such as hereditary hypophosphatemic rickets with hypercalciuria [HHRH]), the serum concentration of 1,25(OH)2D may be elevated. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

EVALUATION — The evaluation of a child with clinical signs of rickets should include a dietary history, with particular attention given to calcium and vitamin D intake, along with a medication history and a history of sun exposure. Radiographic evaluation of a child with rickets should include, at a minimum, plain films of the wrist and hand or knees to evaluate the growth plates. (See 'Radiographic findings' above.)

Initial classification — Serum parathyroid hormone (PTH), alkaline phosphatase, inorganic phosphorus, and calcium concentrations are used to determine the initial classification of rickets (algorithm 1). Rickets is an unlikely diagnosis if all of these values are normal. Serum creatinine and liver enzymes should be measured to screen for renal and liver disease, respectively. (See 'Rickets associated with chronic kidney disease' below and 'Disorders that mimic rickets' below.)

Calcipenic rickets – If the serum PTH is considerably elevated and phosphorus concentration is normal or low, then a provisional diagnosis of calcipenic rickets can be made. Serum calcium may be normal in calcipenic rickets or may be low in advanced disease. The diagnosis is confirmed if appropriate healing is observed on a radiograph during the course of therapy. (See 'Calcipenic rickets' below.)

Phosphopenic rickets – If the serum PTH is normal or mildly elevated and the phosphorus concentration is low, then phosphopenic rickets should be suspected. Demonstration of renal phosphate wasting will identify most forms of phosphopenic rickets, but in cases of inadequate supply of dietary phosphorus (albeit an uncommon event), enhanced renal conservation of phosphate will be evident. (See 'Phosphopenic rickets' below.)

Further evaluation — The causes of rickets include conditions that lead to hypocalcemia and/or hypophosphatemia as a result of decreased intake, malabsorption, and/or increased excretion of calcium, phosphate, or vitamin D (table 2). To determine the optimal treatment, the common nutritional causes of rickets must be distinguished from the forms caused by a gastrointestinal or renal disease or an inherited disorder.

Calcipenic rickets — If the serum PTH is considerably elevated and phosphorus concentration is low, then a provisional diagnosis of calcipenic rickets can be made. Most cases of acquired rickets are calcipenic.

Calcipenic rickets can be further divided into the following disorders, which can be distinguished by measuring serum levels of 25-hydroxyvitamin D (25OHD) and, if necessary, 1,25-dihydroxyvitamin D (1,25[OH]2D) (algorithm 2 and table 1):

Low serum 25OHD

Nutritional rickets – Calcipenic rickets is usually caused by dietary deficiency of vitamin D. Occasionally, nutritional rickets is caused by deficiency of dietary calcium or a mixed deficiency of both vitamin D and calcium. 25OHD levels are typically low, but they may be normal if calcium deficiency is the primary nutritional deficiency.

25-hydroxylase deficiency – 25-hydroxylase deficiency (MIM #600081) is caused by variants in CYP2R1, the gene encoding the enzyme that converts vitamin D to the major circulating vitamin D metabolite, 25OHD, thus limiting the biosynthesis of 25OHD [20]. Activating variants in the enzyme that enhances clearance of 25OHD have also been found in early presentations of rickets [21]. These disorders are exceedingly rare and may be suspected when pharmacologic doses of vitamin D used in the treatment of nutritional rickets do not result in appropriate correction of the serum level of 25OHD. The differential diagnosis includes poor compliance with medication or fat malabsorption.

Secondary defects in vitamin D metabolism or absorption of calcium or vitamin D – This can occur in extremely severe liver disease or in intestinal disorders such as celiac disease. The circulating 25OHD level may be low or normal, depending on whether the calcium malabsorption is mediated by vitamin D deficiency or another process.

Normal serum 25OHD

1-alpha-hydroxylase deficiency – 1-alpha-hydroxylase deficiency (MIM #264700) is a rare disorder caused by variants in CYP27B1, which encodes the vitamin D 1-alpha-hydroxylase enzyme that converts 25OHD into the active metabolite 1,25(OH)2D. Serum levels of 25OHD are normal, and 1,25(OH)2D levels are low. This was previously known as vitamin D-dependent rickets type I and is also known as pseudovitamin D deficiency because its clinical manifestations mimic those of vitamin D deficiency.

Hereditary resistance to vitamin D – Hereditary resistance to vitamin D (MIM #277440) is a rare form of calcipenic rickets that is usually caused by variants in the gene that encodes the vitamin D receptor (VDR) which leads to vitamin D resistance. 25OHD levels are normal, and 1,25(OH)2D levels are high or very high. It was previously known as vitamin D-dependent rickets type II.

The diagnosis and management of each of these disorders are discussed in a separate topic review. (See "Etiology and treatment of calcipenic rickets in children".)

For children with a provisional diagnosis of calcipenic rickets who do not heal appropriately during the course of therapy, an alternate diagnosis should be considered. Elevated PTH levels are occasionally observed at diagnosis in X-linked hypophosphatemia (XLH), which is the most common form of phosphopenic rickets.

Phosphopenic rickets — Phosphopenic rickets is characterized by low serum phosphorus concentration; PTH concentrations are usually normal, although levels may be slightly elevated at the time of presentation of XLH (table 1). Phosphopenic rickets in children and adolescents is almost always caused by renal phosphate wasting, which may be isolated or part of a generalized renal tubular disorder. Occasionally, it is caused by nutritional phosphate deficiency. The causes are outlined below.

The steps in the evaluation are:

Tubular reabsorption of phosphorus (TRP) and TmP/GFR – Perform a fasting urine collection (usually for two hours) and obtain a blood sample during the course of the urine collection with measurement of phosphorus and creatinine concentrations in both the blood and the urine samples. These values are then used to calculate the TRP, expressed as a percentage of filtrate, and maximal renal tubular threshold for phosphate, expressed per glomerular filtration rate (TmP/GFR). The finding of very low TmP/GFR confirms renal phosphate wasting. In contrast, very high TRP and TmP/GFR indicate renal conservation of phosphate, implicating compromised dietary supply or intestinal absorption.

Other urine studies – If renal phosphate wasting is present, perform a routine urinalysis to determine pH and glucose, and an assessment of urinary calcium excretion.

For screening purposes, we usually obtain a random spot urine specimen for calcium and creatinine and determine the ratio. It should be kept in mind that normative values differ when using SI units as compared with conventional (mass) units, even though a ratio is employed. A more precise evaluation in the older child can be performed by obtaining these measurements in a 24-hour urine collection. If renal loss of multiple solutes is suspected, obtain urinary amino acids to assess for renal Fanconi syndrome.

Serum 1,25(OH)2D – If renal phosphate wasting is present, measurement of serum 1,25(OH)2D will help to distinguish the causes that are mediated by fibroblast growth factor 23 (FGF23) from those that are not.

This evaluation will help to distinguish among the causes of phosphopenic rickets, as outlined below (algorithm 3):

Renal phosphate wasting (low TRP and TmP/GFR)

Renal tubular disorders – Renal tubular disorders such as Fanconi syndrome can cause rickets due to renal loss of phosphate. Fanconi syndrome is characterized by hypophosphatemia due to phosphaturia, renal glucosuria (glucosuria with a normal plasma glucose concentration), aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Fanconi syndrome'.)

FGF23-mediated disorders (normal or low serum 1,25[OH]2D and urinary calcium excretion) – Many forms of renal phosphate wasting are mediated by an excess of FGF23, which acts on the kidney to induce renal phosphate wasting:

-X-linked hypophosphatemic rickets (XLH) – XLH (MIM #307800) is the most common cause of isolated renal phosphate loss. It is a heritable disorder, caused by variants in the PHEX gene. Renal phosphate wasting is present from birth, but the disorder tends to become clinically apparent when the child begins to walk, causing bowing of the legs. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'X-linked hypophosphatemia'.)

Less common autosomal dominant and autosomal recessive forms of hypophosphatemic rickets also exist. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Autosomal dominant hypophosphatemia' and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Autosomal recessive hypophosphatemic rickets'.)

-Tumor-induced osteomalacia (TIO) – TIO also causes isolated phosphate loss. It is an acquired disorder associated with a tumor, which usually is benign. These tumors express a variety of factors, including FGF23. The treatment of choice is complete removal of the tumor, if possible, which will remove the source of FGF23, thereby curing the disorder. However, other measures may be required if the tumor is unable to be resected completely. TIO may present in late childhood and adolescence but more commonly in adulthood. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Tumor-induced osteomalacia'.)

-Other causes of excess FGF23 production – Phenotypes of FGF23-mediated renal phosphate loss and rachitic bone disease may be observed in other conditions, which generally occur in sporadic fashion. These disorders include cutaneous skeletal hypophosphatemia syndrome, also known as epidermal nevus syndrome [22], and fibrous dysplasia of bone, as occurs in McCune-Albright syndrome [23].

Not FGF23-mediated (increased serum 1,25[OH]2D and urinary calcium excretion):

-Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) – HHRH (MIM #241530) is an autosomal recessive disease and is another rare cause of phosphopenic rickets. This disorder is distinguished from the FGF23-mediated forms of hypophosphatemic rickets by an elevated serum 1,25(OH)2D concentration and increased urinary calcium excretion. Because the treatment for this disorder is distinct, it is important to evaluate for HHRH in every patient with phosphopenic rickets before initiating therapy by measuring serum 1,25(OH)2D and urinary calcium excretion. The disorder is due to loss of function variants in NPT2C (SLC34A3), a sodium-phosphate transporter expressed in renal tubules. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Hypophosphatemic rickets with hypercalciuria'.)

No renal phosphate wasting (high TRP and TmP/GFR)

Nutritional phosphate deficiency – Occasionally, hypophosphatemic rickets is caused by nutritional phosphate deficiency, which is characterized by very high TRP and TmP/GFR, indicating renal conservation of phosphate. This may occur in premature infants who receive breast milk as their sole source of nutrition and reflects the relatively low phosphate content of breast milk. It was also reported in several case series of young children with complex disease who were fed Neocate brand formula (an elemental formula designed for children with multiple food allergies), suggesting a problem with phosphate bioavailability compared with standard formulas [24-26]. Reformulated products designed to avoid this complication were subsequently introduced in North America and Europe, with expected replacement worldwide in 2022.

Rickets associated with chronic kidney disease — Renal dysfunction is an important cause of bone disease (renal osteodystrophy), which can include rickets. In children with suspected rickets, renal function should be evaluated by measuring serum creatinine.

Bone disease occurs in children with renal insufficiency for many reasons, including reduced formation of 1,25(OH)2D, metabolic acidosis, administration of aluminum, and secondary hyperparathyroidism. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

DISORDERS THAT MIMIC RICKETS — A variety of conditions cause signs or symptoms that resemble rickets:

Skeletal abnormalities or bowing

Skeletal dysplasias – Skeletal dysplasia (eg, achondroplasia, pseudoachondroplasia, metaphyseal chondrodysplasia) is another cause of bilateral, symmetric bowed legs. The radiographic features can be similar to those of rickets. However, serum inorganic phosphorus and parathyroid hormone (PTH) concentrations usually are normal in children with skeletal dysplasia. (See "Approach to the child with bow-legs", section on 'Skeletal dysplasia' and "Skeletal dysplasias: Approach to evaluation".)

Blount disease – Blount disease is a pathologic varus deformity of the knee that results from disruption of normal cartilage growth at the medial aspect of the proximal tibial physis. It can be distinguished from rickets by distinct radiographic findings and normal serum biochemistry values. (See "Approach to the child with bow-legs", section on 'Blount disease'.)

Laboratory abnormalities

Liver disease – Elevations of serum alkaline phosphatase activity is seen in rickets but also can be caused by liver disease. The possibility of liver disease can be further evaluated by measuring liver enzymes (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma-glutamyl transpeptidase [GGT]). (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase'.)

Transient hyperphosphatasemia – Children with isolated elevations of serum alkaline phosphatase but normal liver enzymes and no radiographic evidence of rickets may have transient hyperphosphatasemia of infancy and early childhood. This is usually a benign condition that arises after a minor infectious illness and spontaneously remits over a several-month period. (See "Transient hyperphosphatasemia of infancy and early childhood".)

Primary hypoparathyroidism – Primary hypoparathyroidism causes marked hypocalcemia but is usually not associated with rickets. This observation suggests that low serum phosphorus and/or PTH itself may play roles in mediating the growth plate lesion. (See "Etiology of hypocalcemia in infants and children", section on 'Hypocalcemia with low PTH (hypoparathyroidism)'.)

Hypophosphatasia – Hypophosphatasia is a rare genetic disorder of alkaline phosphatase activity [27]. Like rickets, it is characterized by bone demineralization. In contrast to rickets, serum alkaline phosphatase activity is very low. Childhood forms are characterized by premature loss of primary teeth. (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia' and "Periodontal disease in children: Associated systemic conditions", section on 'Hypophosphatasia'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin D deficiency" and "Society guideline links: Pediatric bone health".)

SUMMARY AND RECOMMENDATIONS

Definition – Rickets refers to the disorganized expansion and deficient mineralization of growth plate cartilage. Osteomalacia refers to impaired mineralization of bone and, in children, typically accompanies rickets. (See 'Introduction' above.)

Classification – Rickets is classified according to the predominant mineral deficiency. Phosphopenic rickets usually is caused by renal phosphate wasting. Serum calcium levels are often, but not always, decreased in calcipenic rickets. (See 'Types of rickets' above.)

Calcipenic rickets usually is caused by dietary deficiency of vitamin D and/or calcium; this is the most common cause of rickets worldwide. Rarely, it is caused by genetic defects in vitamin D metabolism or action leading to vitamin D resistance. (See 'Calcipenic rickets' above.)

Phosphopenic rickets in children and adolescents is almost always caused by renal phosphate wasting, which is usually an isolated phenomenon but may be part of a generalized tubular disorder such as Fanconi syndrome. Rarely, it may result from inadequate dietary phosphorus or intestinal malabsorption. Renal phosphate wasting syndromes can be fibroblast growth factor 23 (FGF23)-mediated or occur independent of FGF23 excess. (See 'Phosphopenic rickets' above.)

Skeletal findings – The skeletal findings are similar for calcipenic and phosphopenic rickets and may include delayed closure of the fontanelles, parietal and frontal bossing, enlargement of the costochondral junction ("rachitic rosary"), widening of the wrist, and lateral bowing of the femur and tibia (bow legs) (picture 1). (See 'Skeletal findings' above.)

Radiographic findings – Radiographic findings of rickets include expansion of the growth plate and loss of definition of the zone of provisional calcification at the epiphyseal/metaphyseal interface, progressing to disorganization of the growth plate with cupping, splaying, and formation of cortical spurs (image 3). The changes are best seen in the distal ulna and the metaphyses above and below the knee. (See 'Radiographic findings' above.)

Laboratory findings – Serum alkaline phosphatase activity is elevated in both types of rickets and is a good marker of disease severity in children. Other biochemical findings include hypocalcemia and hypophosphatemia, but the pattern varies depending on the type and severity of the rickets (table 1). Serum concentration of parathyroid hormone (PTH) typically is quite elevated in calcipenic rickets but not in phosphopenic rickets. (See 'Laboratory findings' above.)

Identifying the cause – Measurements of serum PTH and inorganic phosphorus serve to distinguish calcipenic from phosphopenic rickets (algorithm 1). (See 'Initial classification' above.)

Calcipenic rickets – For children with calcipenic rickets, measurements of serum 25-hydroxyvitamin D (25OHD) help to distinguish rickets caused by vitamin D deficiency (the most common form) from other causes of calcipenic rickets (algorithm 2). (See 'Calcipenic rickets' above and "Etiology and treatment of calcipenic rickets in children".)

Phosphopenic rickets – For children with phosphopenic rickets, an assessment of renal excretion of phosphate should be performed (as tubular reabsorption of phosphorus [TRP] or maximal renal tubular threshold for phosphate, expressed per glomerular filtration rate [TmP/GFR]) (algorithm 3).

-Low TRP or TmP/GFR suggests renal phosphate wasting. Causes of renal phosphate wasting should be investigated with assessment of serum 1,25-dihydroxyvitamin D (1,25[OH]2D), a routine urinalysis to determine pH and glucose, and an assessment of urinary calcium excretion.

-High TRP or TmP/GFR indicates renal conservation of phosphate and is consistent with nutritional phosphate deprivation. This may be due to insufficient phosphate content or decreased bioavailability in formula products and other nutritional supplements.

(See 'Phosphopenic rickets' above and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

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