Block 2 Pathology Test 1 Chapter 8 Rickets and Osteomalacia

What are the two types of osteomalacia?

(a) hypocalcemic osteomalacia, caused by calcium deficiency, and (b) hypophosphatemic osteomalacia caused by phosphate deficiency. Hypophosphatemic osteomalacia/rickets may be secondary to a hereditary disease or caused by neoplasms and only rarely due to nutritional phosphate deficiency. Hypophosphatemic osteomalacia/rickets is commonly caused by impaired resorption of phosphate by the proximal renal tubules, with resulting renal phosphate wasting and hypophosphatemia. Hypophosphatemia is associated with inappropriately low levels of calcitriol. On the other hand, hypophosphatemia results in failure of calcification of osteoid.

What are the limb deformities associated with rickets?

- Rachitic children are short; the growth of children is stunted. During the ambulatory stage several bone deformations develop: - Exaggerated thoracic kyphosis, i.e. excessive convex kyphotic curvature of the spine as it occurs in the thoracic region. - Accentuated lumbar lordosis: anteriorly convex curvature of the lumbar segment of the vertebral column. - Genu varum: outward bowing of the legs while standing, giving them the appearance of a bow. - Genu valgum: inward slant of the thigh in which the knees are close together and the ankles far apart - Wrist widening is due to metaphyseal cartilage hyperplasia.

How is osteomalacia diagnosed?

1. Bone biopsy. The definitive diagnosis of osteomalacia is made by bone biopsy using decalcified sections. The histological parameters that are relevant to the diagnosis include: Osteoid seam thickness: osteoid seam width increases > 15 µm and mineralized bone fall dramatically. Osteoid volume: the normal osteoid volume is less than 5% of total bone volume; in osteomacia, the osteoid volume is typically 20% to 75%. 2. Mineralization lag time. Rates of bone mineralization can be assessed by giving two courses of tetracycline 10 days apart prior to a full-thickness undecalcified bone biopsy and tetracycline analysis with fluorescent microscope. This antibiotic has two properties useful to morphologic evaluation of bone metabolic bone disease. First, it fluoresces in ultraviolet light, and second, it absorbs onto newly formed calcium hydroxyapatite crystals. In osteomalacia, there may be no label, there may be only a single fluorescent line or there may be very close double lines indicating a decreased mineralization rate.

What are the radiological abnormalities of adults with osteomalacia?

1. Changes in vertebral bodies. Inadequate mineralization of osteoid and loss of trabeculae of the cancellous bone lead to a loss of radiologic distinctness of vertebral body trabeculae. With more advanced disease, softening leads to a concavity of the vertebral bodies called codfish vertebrae. The vertebral disks appear large and biconvex. There may be spinal compression fractures, but these are more common in osteoporosis. 2. Looser zones. Looser zones are wide radiolucent bands traversing part way through a bone, usually at right angles to the involved cortex. Looser zones, also called Looser pseudofractures, represent incomplete fractures that have been repaired by the laying down of inadequately mineralized osteoid. They often are bilateral and symmetric and usually found at the femoral neck, on the medial part of the femoral shaft, immediately under the lesser trochanter, and in the pubic and ischial rami. They may also occur at the ulna, scapula, clavicle, rib, and metatarsal bones. 3. Skeletal deformations. More severe osteomalacia can lead to shortening and bowing of the tibia, complete bone fractures without any identifiable trauma or following a minor injury, and coxa profunda hip deformity. Coxa profunda is radiologically defined as the acetabular fossa touching the ilioischial line. It means that the hip socket is too deep and can cause severe pain.

Describe the steps of development in renal osteodystrophy.

1. Chronic renal disease. The reduced glomerular filtration rate in chronic renal disease leads to retention of phosphate, thereby producing hyperphosphatemia. High serum phosphate levels drive down the serum calcium levels. 2. Vitamin D deficiency. Damaged kidneys display reduced 1α-hydroxylase activity. The conversion of the calcidiol (25OHD) to calcitriol [1,25(OH)2D] is reduced leading to calcitriol deficiency. 3. Hypocalcemia. Hypocalcemia develops as the levels of calcitriol fall secondary to reduced intestinal absorption of calcium. 4. Hyperparathyroidism. Hypocalcemia stimulates PTH production. In fact, most patients with ESRD have substantial hyperparathyroidism (which is termed secondary hyperparathyroidism). The increased PTH secretion hormone acts on bone to normalize serum calcium. Other direct effects of increased PTH secretion are (a) stimulation of vitamin D metabolism, which increases intestinal resorption of calcium; (b) increased resorption of calcium from the kidneys, and (c) increased renal excretion of phosphate. However, PTH does not effectively promote adequate vitamin D production. Therefore, the spectrum of clinical and radiographic findings in renal osteodystrophy may be a manifestation of both hypocalcemia and hyperparathyroidism.

What are complications of renal osteodystrophy?

1. Fractures. The most common complication of renal osteodystrophy is bone fracture. Bone fractures may be single but often they are multiple bilateral and symmetric. Typical sites include the concave surface of the femoral neck, axillary margin of the scapula, pubic rami, and ribs. 2. Skeletal deformities. An example of skeletal deformity is basilar invagination. It consists of invagination (infolding) of the base of the skull that occurs when the C2 vertebra migrates upward. 3. Metastatic calcification. Hyperphosphatemic patients may display metastatic calcification at various sites, including the eyes, skin, muscular tunica of arteries and arterioles, and periarticular soft tissues.

What are the three stages of osteomalacia and rickets?

1. In stage I, plasma levels of 25(OH)D decrease leading to reduction of calcium resorption from bone and absorption of calcium from intestine. Hypocalcemia is the end-result. 2. In stage II, secondary hyperparathyroidism develops in response to low plasma calcium levels. (i) Increased PTH secretion normalizes plasma calcium level by the following mechanisms: - In bone, PTH releases calcium by stimulating osteoclastic activity; - In kidney, PTH directly increases renal calcium reabsorption and phosphate excretion; - In kidney, PTH upregulates 1α-hydroxylase gene promoter to increase synthesis of 1,25(OH)2D. (ii) Elevated plasma alkaline phosphatase (ALP) and decreased plasma phosphate accompany secondary hyperparathyroidism. 3. Stage III is characterized by severe pathologic, clinical and radiologic features. (i) Secondary hyperparathyroidism is unable to keep plasma calcium within the normal range because of bone hyporesponsiveness. (ii) Hypocalcemia returns while hypophosphatemia persists.

What is osteitis fibrosa cystica (OFC)?

A metabolic bone disease caused by severe hyperparathyroidism (PHP). PHP is defined as overactivity of the parathyroid glands characterized by: (a) autonomous overproduction of parathyroid hormone (PTH); and (b) hypercalcemia, as a consequence of PTH overproduction. Hyperactivity of the parathyroid glands is usually triggered by parathyroid adenoma (and in this case is termed primary hyperparathyroidism).

Describe autosomal dominant hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia. Less than 100 cases have been described. The disease is caused by activating mutations in the FGF23 gene on chromosome 12p13, encoding fibroblast growth factor 23. These mutations render FGF23 resistant to degradation and thus cause an increase in serum FGF23 levels, which leads to reduced renal phosphate reabsorption, hypophosphatemia and bone demineralization.

What would imaging studies show in renal osteodystrophy?

Because of hyperphosphatemia, a substantial proportion of patients with ESRD have increased bone mass, i.e. osteosclerosis. Osteosclerosis is particularly prominent in vertebrae where, owing to alternating bands of radiopaque and normally dense bone, the lesion is named rugger jersey spine. Alternating parallel sclerotic and lucent bands are analogous to the stripes on an English rugby sweater. The rugger jersey spine sign is almost diagnostic of the osteosclerosis associated with chronic renal failure. The opaque sclerotic bands seen on the inferior and superior endplates of vertebral bodies represent accumulations of excess osteoid. Although they are deficiently mineralized, the areas of osteoid appear opaque at radiography because of their increased volume in comparison with that of normal bone.

What are the lab studies of patients with osteitis fibrosa cystica?

Characteristic findings include the following: elevated serum calcium, increased 24-hour urinary calcium concentration, decreased serum phosphate, elevated 1,25-dihydroxyvitamin D (1,25(OH)2D), and elevated alkaline phosphatase (ALP). Biochemical markers of bone formation and bone resorption in serum or urine are elevated.

How do renal disorders contribute to osteomalacia?

Disorders that decrease the kidney mass such as chronic kidney disease or chronic renal failure lead to a decrease in the ability of the kidney to produce calcitriol and osteomalacia.

What are the skull deformities of rickets?

During the nonambulatory stage of infancy, the head sustains the greatest deformities. In the first few months of life, craniotabes is characteristic. Craniotabes is defined as thinning and softening of the occipital and parietal bones associated with widen open sutures and delayed closure of anterior fontanelle. The softened occipital bones become flattened and the parietal bones can be buckled inward by pressing along the suture line. The prominence of the frontal bones and the major foramen results in 'frontal bossing' or a squared appearance of the head ('caput quadratum').

How does rickets affect growth plate thickness?

Growth plate thickness is determined by two opposing processes: chondrocyte proliferation and hypertrophy on the one hand, and vascular invasion of the growth plate followed by conversion into primary bone on the other. Vascular invasion requires mineralization of the growth plate cartilage and is delayed or prevented by deficiency of calcium or phosphorus. • In these circumstances, growth plate cartilage increases in width and thickens. In addition, the chondrocytes of the growth plate become disorganized, losing their columnar orientation with characteristic expansion of the hypertrophic zone. In the bone tissue below the growth plate (metaphysis), the mineralization defect leads to the accumulation of osteoid. • These abnormalities alter the overall geometry of the involved bones, 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.

What is the pathology of children with rickets?

Histologically rickets manifests most characteristically in the epiphyseal growth plates. Calcium is typically incorporated at the level of the zone of provisional calcification. Because of the lack of calcium, the zone of provisional calcification is all but absent, causing significant distortion of the zone of hypertrophy above it. Within the zone of hypertrophy, the cells become enormous, and their normal columnar arrangement becomes grossly distorted. There is persistence of epiphyseal cartilage that distorts the architecture within the other zones of the growth plate. Zone of hypertrophy consists of persistent tongues and islands of hypertrophic chondrocytes surrounded by a thick layer of osteoid. Similar disorganization results also in the zone of ossification below the zone of provisional calcification, where orderly primary cancellous bone is typically seen. The bony trabeculae which are laid down on the cartilage bars are rudimentary and cartilage persists as distorted, irregular masses.

What are the microscopic findings of osteomalacia?

Histopathologic hallmark of osteomalacia is presence of extraordinary wide osteoid seams. Osteoid seam is the narrow region of newly formed organic matrix not yet mineralized on the surface of a bone. The width of osteoid seams and the total osteoid volume is exaggerated in osteomalacia in up to the double or triple of the normal width. Osteoid seams reflect a time lag between the deposition of collagen and the appearance of the calcium salt. Although adults add 1 μ of new matrix to the surfaces of bones every day, it requires 10 days to mineralize this new bone. The normal thickness of osteoid seams therefore does not exceed 10-12 μ. The wide osteoid seams can be visualized in sections stained with H&E as wide, homogenous pale red bands arranged about the more basophilic normally mineralized trabeculae. In sections stained with Masson trichrome stain, osteoid seams appear as bright red, whereas bone matrix is green.

Describe hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited metabolic disease caused by mutations in the ALPL gene on chromosome 1p36.12, encoding tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is an ectoenzyme that resides on the cell surface of an osteoblast. TNSALP is also found in the liver and kidney. TNSALP is known to cleave the phosphate-containing substrates such as inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA) (which are all extracellular substrates) into inorganic phosphate to promote mineralization. PPi is a potent inhibitor of bone mineralization, When TNSALP activity is low, as in HPP, PPi levels increase, leading to inhibition of bone mineralization. Calcium and phosphorus cannot combine to form hydroxyapatite and serum calcium and phosphorus levels often rise. Bone mineralization decreases. The disease is highly variable in clinical expression, ranging from stillbirth without mineralized bone to pathologic fractures which develop only late in adulthood.

In OFC how does PTH affect osteoclast and osteoblast activity?

In OFC, excess PTH stimulates both osteoclasts and osteoblasts, which are increased in number. There is an accelerated bone resorption and bone formation, and increased bone remodeling. Increased PTH levels trigger the release of stored calcium through the dissolution of bone. Microscopically, tunneling cones of bone resorption of trabeculae and peritrabecular fibrosis are seen. Brown tumor, also known as osteoclastoma, is an exaggerated form of "local" OFC. Radiologically it is a round, radiolucent bone lesion formed as a consequence of intense bone resorption. Histologically, the bone defect is filled with fibrovascular stroma infiltrated by clusters of osteoclast-like giant cells in a background of mononuclear cells. The brown tumor derives its name from the deposition of hemosiderin that results from microhemorrhages and fractures, which gives the lesion its color. It is not a true neoplasm but a result of bony remodeling and repair.

How do GI and hepatic disorders contribute to osteomalacia?

In industrialized countries, diseases that are associated with intestinal malabsorption cause osteomalacia more often than does poor nutrition. Intrinsic diseases of the small intestine (celiac disease, Crohn disease, and scleroderma), biliary obstruction and chronic pancreatic insufficiency are associated with chronic diarrhea, and malabsorption of vitamin D and calcium.

What are the two main causes of rickets?

Inadequate vitamin D supply. Causes of inadequate vitamin D supply include inadequate dietary vitamin D, malabsorptive vitamin D deficiency, a defect of 1α-hydroxylase (vitamin D-dependent rickets type I), or dysfunction of the vitamin D receptor (hereditary vitamin D-resistant rickets). The main reasons for inadequate vitamin D supply in infants from Western countries are prolonged breastfeeding without vitamin D supplementation and concomitant avoidance of sun exposure. 2. Inadequate phosphate supply. Nutritional deficiency of phosphate is a rare cause of rickets. Phosphate is abundant in most diets. Phosphate-deficient rickets is almost always caused by renal phosphate wasting. Examples include X-linked hypophosphatemia and tumor-associated osteomalacia, both resulting from excessive blood levels of FGF-23.

What does imaging studies show in patients that have osteitis fibrosa cystica?

Increased osteoclastic activity results in generalized skeletal demineralization (diffuse osteopenia). Excessive bone resorption occurs in multiple skeletal locations. Subperiosteal resorption is virtually pathognomonic for hyperparathyroidism and is typically seen at the radial aspect of the middle phalanx of the index and middle fingers. It leads to cortical thinning, best seen in the proximal and middle phalanges of the 2nd and 3rd fingers. Spotty demineralization of the skull results in multiple tiny, well defined lucencies in the calvarium, known as salt and pepper sign, caused by resorption of bone. Single or multiple brown tumors of bone form cyst-like, well circumscribed lytic lesions. They most commonly occur in the jaw, pelvis, and metaphyses of long bones. A marked reduction in bone mass at all sites is seen by dual x-ray absorption (DEXA) with T-scores in the markedly osteoporotic range.

What are the lab findings of hypophosphatasia patients?

Laboratory findings include low activity of serum alkaline phosphatase (ALP) and elevated levels of substrates of ALP including PPi, PLP, and PEA.

What is the most common cause of osteomalacia in adults?

Nutritional vitamin D deficiency is the most common cause of osteomalacia in adults. Individuals with osteomalacia tend to be homebound elderly who have inadequate exposure to sunlight and insufficient dietary calcium and vitamin D, or women who have become depleted of calcium as a result of successive pregnancies and lactation.

What is osteomalacia?

Osteomalacia (soft bones) is a disorder of adults characterized by decreased mineralization of newly formed osteoid at sites of bone turnover.

How are osteomalacia and rickets different in regards to the population affected?

Osteomalacia and rickets can occur together in children (open growth plates), but only osteomalacia occurs in adults (fused growth plates). More than 40% of the adult population older than age 50 are vitamin D deficient, this being the most prominent cause of osteomalacia. Osteomalacia is more frequent in women than in men.

Where is osteomalacia localized in the body?

Osteomalacia is most pronounced in the stem skeleton (vertebral column, thorax, or pelvis) and femur, but may appear at any bone.

What are the 5 clinical forms of recognized hypophosphatasia?

Perinatal (lethal), infantile, childhood, adult and odontohypophosphatasia. The prevalence of perinatal, infantile, and childhood forms is estimated to be 1/300,000. The prevalence of the adult form, which is milder, is estimated to be about 1/6,370. Perinatal and infantile forms of HPP are transmitted as an autosomal recessive trait, while both autosomal recessive and autosomal dominant transmission have been shown in childhood and adult forms of HPP. Perinatal lethal HPP shows marked impaired mineralization of all bony structures in utero associated with hypoplastic lungs and respiratory insufficiency. Infantile HPP is characterized by rickets developing between birth and six months of age. Childhood-onset HPP features rickets leading to short stature, with delay in walking and a waddling gait, and bone and joint pain. The perinatal, infantile, and childhood forms are characterized by hypercalcemia hyperphosphatemia. Adult HPP involves osteomalacia, early loss of primary dentition and stress fractures of the lower extremities in middle age. Adult HPP is characterized by normal plasma levels of calcium and phosphate. Lastly, odontohypophosphatasia includes premature exfoliation of primary teeth and/or severe dental caries, in the absence of skeletal system abnormalities.

What would be the laboratory findings of a child with rickets?

Plasma 25(OH)D level is very low, while plasma PTH level is increased. Plasma calcium is decreased in stage I, is normal in stage II and is decreased in stage III. Plasma alkaline phosphatase (ALP) activity is markedly increased (often up to 2000 IU/L) and is an excellent marker of disease activity. Plasma phosphate is decreased. Plasma 1,25(OH)2D may be normal or elevated as PTH stimulates renal 1α-hydroxylase and is therefore not helpful in making the diagnosis.

Clinical presentation of renal osteodystrophy

Presentation varies markedly with age. Adults may present with findings of osteomalacia and osteitis fibrosa cystica (a skeletal manifestation of advanced hyperparathyroidism), while children typically show rickets and growth retardation. Clinically, renal osteodystrophy is subtle. Patients may exhibit no symptoms. When symptoms are present, they consist of nonspecific bone pain, joint pain (arthralgia), bone deformation and bone fracture. Fractures are most commonly localized in the arms, legs, or spine.

What are the chest deformities associated with rickets?

Rachitic rosary can be defined as enlargement of the ends of the ribs due to expansion of the costochondral junction in a 3- to 6-month-old child. Rachitic rosary is visible as beading along the anterolateral aspects of the chest. Harrison groove, also known as Harrison sulcus, is a horizontal groove along the lower border of the thorax corresponding to the insertion of the diaphragm to the lower ribs.

What is renal osteodystrophy?

Renal osteodystrophy is a complex metabolic bone disease that occurs in the context of chronic renal failure (end-stage renal disease or ESRD). Severe renal osteodystrophy is most common in patients maintained on long-term dialysis, because they live long enough to develop conspicuous bone disease. The term renal osteodystrophy is used to describe collectively five types of skeletal changes: (a) increased osteoclastic bone resorption mimicking osteitis fibrosa cystica, (b) delayed matrix mineralization (osteomalacia), (c) increased bone mass (osteosclerosis), and (d) rickets and growth retardation with decreased final adult height in children with ESRD. Osteoporosis, i.e., decreased bone mineral density measured by DEXA and renal osteodystrophy may coexist in elderly patients with ESRD. Over 485,000 persons in the United States are being treated with hemodialysis for ESRD. By the time dialysis is initiated, almost all patients are affected by renal osteodystrophy.

What is rickets?

Rickets is a disorder of defective mineralization of cartilage in the epiphyseal growth plates of children.

What are the dental abnormalities associated with rickets?

Rickets is associated with serious dental complications. There may be delayed eruption of permanent dentition, markedly hypoplastic enamel, large pulp chambers, short roots in all permanent teeth, periodontal disease and dental caries.

What is the definition of rickets?

Rickets is deficient mineralization at the growth plate, and architectural disruption of this structure.

What does severe and prolonged vitamin D deficiency result in?

Severe and prolonged vitamin D deficiency results in hypocalcemia, secondary hypophosphatemia, and osteomalacia. Hypocalcemia stimulates PTH production, which activates 1α-hydroxylase activity.

What is the role of parathyroid hormone?

The classical effects of PTH are elevation of serum calcium, increased urinary excretion of phosphate, and calcitriol synthesis. The main actions of PTH include the following: (a) PTH promotes release of calcium from the bone by stimulating osteoclasts to break down bone; (b) PTH increases the renal tubular reabsorption of calcium and reduces the reabsorption of phosphate; (c) PTH increases the conversion of 25-hydroxyvitamin D to its most active metabolite, 1,25-dihydroxyvitamin D by activation of the enzyme 1-hydroxylase in the proximal tubules of the kidney; (d) PTH augments gastrointestinal calcium absorption.

What is the clinical presentation of rickets?

The classical picture of rickets is severe bone pain, short stature, bone deformities, X-ray changes at the epiphyses and abnormal serum chemistry (increased alkaline phosphatase, hypocalcemia and hypophosphatemia).

What is the clinical presentation of osteomalacia?

The clinical diagnosis of osteomalacia is often difficult. Osteomalacia may be asymptomatic and present radiologically as osteopenia, which is bone loss that is not as severe as in osteoporosis. The most common clinical symptoms and signs of osteomalacia include: 1. Bone pain. Patients have diffuse bone aches and pains, aggravated by activity and weight bearing. 2. Osteomalacic myopathy. About 50% of patients have proximal muscle weakness associated with difficulties in walking and getting up from a chair. Muscle weakness is more severe in legs than in the arms. An aching sensation in fatigued muscles is also noted. 3. Bone fractures. Fractures may occur with little or no trauma, typically involving the ribs, vertebrae, femoral neck and pubic ramus. 4. Bowing of limbs. Bowing deformity of the long bones especially lower limbs is frequent. 5. Symptoms of hypocalcemia. Severe hypocalcemia presents with neuromuscular irritability (numbness, paresthesias, muscle spasms, laryngospasm, tetany, and seizures.

What is the clinical presentation of osteitis fibrosa cystica?

The clinical profile of severe OFC includes bone pain, increased susceptibility to pathologic fractures, muscle weakness and hyperreflexia. Nephrolithiasis (renal calculi) occurs in 15-20 % of patients with PHP. Nephrocalcinosis, diffuse deposition of calcium phosphate complexes in the renal tubules, occurs in most severe cases. Neuropsychiatric symptoms may be present.

What is the order of development of renal osteodystrophy?

The development of renal osteodystrophy may be summarized as follows: Chronic renal disease → Vitamin D deficiency → Hypocalcemia → Hyperparathyroidism.

What are the extraskeletal findings associated with rickets?

The muscle weakness associated with hypocalcemic rickets leads to the delayed achievement of motor milestones. Hypocalcemic seizures are frequent in stages I and II of rickets. Children are particularly prone to acquiring infections such as influenza during winter. Increased sweating is a common finding. Children with rickets are apathetic and irritable.

How is 1α-hydroxylase regulated in the kidney.

The principal regulators of 1α-hydroxylase activity in the kidney are parathyroid hormone (PTH), calcium, phosphate, and 1,25(OH)2D. • Hypocalcemia stimulates PTH secretion, which in turn upregulates the expression of 1α-hydroxylase, increasing the conversion of 25(OH)D into 1,25(OH)2D. • Hypophosphatemia also upregulates the expression of 1α-hydroxylase, increasing the production of 1,25(OH)2D.

What are the imaging results of children with rickets?

The specific radiographic features of rickets are best seen in the metaphysis of rapidly growing bones such as distal ulna, distal femur and proximal tibia. Widening of the epiphyseal plate and loss of definition of the zone of provisional calcification at the epiphyseal/metaphyseal interface are the early signs of rickets. As the disease progresses, disorganization of the growth plate becomes more apparent with cupping, splaying and stippling. The appearance of the epiphyseal bone centers may be delayed, or they may be small and ill-defined. The shafts of the long bones are osteopenic; the cortices are thin; the trabecular pattern is reduced. Deformities of the shafts of the long bones typically are present. In severe rickets, Looser zones and greenstick fractures may be noted. A greenstick fracture is an incomplete fracture that occurs typically in children: the bone cracks but doesn't break all the way through, one side of the bone is broken and the other only bent.

What is the best indicator of vitamin D supply in the body?

The total serum 25(OH)D level is currently considered the best indicator of vitamin D supply to the body from cutaneous synthesis and nutritional intake. The reference range of the 25(OH)D level is 25-80 ng/mL. Serum levels of <20 ng/mL constitute vitamin D deficiency.

Describe tumor associated osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by secretion of phosphatonins by the tumor. The tumors, typically benign, are of mesenchymal origin. The most common types are hemangiopericytomas (vascular neoplasms), hemangioma, osteoblastoma and giant cell tumors. Other types include fibromas, chondrosarcomas, neuroblastomas and prostate carcinoma. The phosphatonin implicated in TIO is FGF23. Patients are characterized by elevated levels of FGF23 and renal tubular phosphate wasting. TIO mimics the clinical phenotype of X-linked hypophosphatemia. Surgical removal of the tumor is often curative.

How is vitamin D deficiency/ rickets inherited?

Two autosomal recessive diseases associated with rickets are known as vitamin D-dependent rickets type 1 and 2. (A) Vitamin D-dependent rickets type 1 (VDDR1). VDDR-1 results from an inactivating mutation in the CYP27B1 gene encoding 1α-hydroxylase in proximal renal tubules. As a result, calcidiol is not hydroxylated to calcitriol in the kidney and calcium is not absorbed normally. (B) Vitamin D-dependent rickets type 2 (VDDR2). VDDR2 is also known as 'hereditary vitamin D-resistant rickets (HVDRR)'. VDDR2 is caused by inherited loss of function mutations of the vitamin D receptor which render end organs insensitive to 1,25(OH)2D.

What are the vitamin D precursors and how are they obtained?

Two chemically distinct forms of vitamin D precursors exist: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Ergocalciferol is ingested in food and absorbed in the jejunum. Cholecalciferol is synthesized in the skin from its precursor, 7-dehydrocholesterol, under the influence of the ultraviolet component of sunlight.

How is vitamin D transformed in the body?

Vitamins D2 and D3 have no significant biological activity. They must be metabolized to the hormonally active form known as 1,25-(OH)2D (dihydroxycholecalciferol or calcitriol). This transformation occurs in two steps. Hydroxylation of D2 and D3 by the enzyme 25-hydroxylase in hepatocytes yields 25-hydroxycholecalciferol or calcidiol [25(OH)D]. Hydroxylation of 25(OH)D by the enzyme 1α-hydroxylase in proximal renal tubules yields 1,25-dihydroxycholecalciferol, or calcitriol [1,25(OH)2D]. The 25-hydroxylase and 1α-hydroxylase are cytochrome P450 enzymes. Receptors for 1,25(OH)2D are present in classic targets, such as intestine, bone, and kidney but are also expressed in many cells. This steroid hormone is a general inducer of differentiation. Both 25(OH)D and 1,25(OH)2D are inactivated by the enzyme 24-hydroxylase (CYP24A1). CYP24A1 is a cytochrome P-450 enzyme present in skin, intestine, and kidney. Degradation products are 24,25-dihydrocholecalferol or 24,25(OH)2D, and calcitroic acid. Both are water-soluble and eliminated via biliary excretion.

Describe x-linked hypophosphatemia.

X-linked hypophosphatemia (XHL) is inherited as an X-linked dominant trait. XHL is associated with an inactivating mutation in the PHEX (phosphate regulating endopeptidase homolog, X-Linked) gene on chromosome Xp22.1. PHEX protein is involved in degradation of fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone (phosphatonin), which normally inhibits renal phosphate reabsorption. PHEX gene mutations cause FGF23 overactivity, which leads to renal phosphate wasting and hypophosphatemia.

What do lab studies show in patients with osteomalacia/rickets?

• Plasma 25(OH)D levels are decreased to less than 12 ng/dL (normal: 20-100 ng/dL) in all patients. Plasma 1,25(OH)2D may be normal or elevated as PTH stimulates renal 1α-hydroxylase and is therefore not helpful in making the diagnosis. • Plasma parathyroid hormone (PTH) levels are elevated in all patients. • Decreased plasma calcium of stage I returns to normal levels. • Plasma phosphate is markedly decreased (hypophosphatemia is related to elevated PTH). • Plasma alkaline phosphatase (ALP) is elevated (increased PTH increases plasma levels of ALP).