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Vitamin D is converted in the liver by a vitamin D-25-hydroxylase (25-OHase) to form the major circulating form of vitamin D, 25-hydroxyvitamin D [25(OH)D]. There have been at least four differ-ent 25-OHases identified both in mitochrondia and in microsomes.1,2 25(OH)D is, however, biologically inert and requires hydroxylation in the kidneys on carbon 1 by the CYP27B mitrochondrial enzyme 25-hydroxyvitamin D-1α-hydroxylase (1-OHase). This results in the formation of 1α,25-dihydroxyvitamin D [1,25(OH)2D] which is the biologically active form of vitamin D responsible for regulating calcium and phosphorus homeostasis.1,2 1,25(OH)2D enters the circulation and is bound to the DBP and travels to its target tissues. In the small intestine, 1,25(OH)2D interacts with its vitamin D nuclear receptor (VDR) that results in the expression of several gene products including the epithelial calcium channel, calbindin9k, and a calcium dependent ATPase (see Figure 199-1).1,2,4 1,25(OH)2D increases the efficiency of intestinal calcium absorption. In a vitamin D deficient state, the small intestine is able to passively absorb about 10% to 15% of dietary calcium. Vitamin D sufficiency enhances the absorption of calcium in the small intestine to about 30% to 40%.1

1,25(OH)2D enhances the efficiency of intestinal calcium absorp-tion principally in the duodenum and to less of a degree in the jejunum and ileum. 1,25(OH)2D also stimulates phosphate absorption in the jejunum and ileum. The small intestine passively absorbs about 60% of dietary phosphate. 1,25(OH)2D enhances the efficiency of phosphate absorption by an additional 20% to about 80%.1 When there is adequate calcium and phosphate in the diet and vitamin D sufficiency is present, the serum calcium normal range is approximately 8.6 to 10.2 mg/dL (mg%) and the serum phosphate level is approximately 2.5 to 4.5 mg/dL. It is the calcium × phosphate product in the circulation and in the extravascular space that plays a major role in the normal mineraliza-tion of osteoid laid down by osteoblasts.

Vitamin D effect on bone metabolismIt is known that both in rodents and humans that vitamin D is not necessary for the mineralization of the osteoid matrix.5,6 This was demonstrated when vitamin D–deficient rats were either infused with calcium and phosphorus to maintain a normal calcium-phosphate product in the circulation or when they received a high-calcium lactose, high-phosphorus diet that maintained a normal serum calcium- phosphate product. In both circumstances, bone histology revealed that the mineralization occurred normally without any significant unmin-eralized osteoid. Vitamin D–resistant rickets patients have a mutation of their VDR and have severe rickets and osteomalacia. When these patients were infused with calcium and phosphorus to maintain a normal calcium-phosphate product, the unmineralized osteoid was mineralized.6

1,25(OH)2D interacts with its VDR in osteoblasts to increase the expression of alkaline phosphatase, osteocalcin, and receptor activator of NFκB ligand (RANKL).7 Alkaline phosphatase produced by osteo-blasts is important in bone mineralization because patients with a decrease in the bone-specific alkaline phosphatase known as hypophos-phatasia suffer from a mineralization defect of the osteoid.8,9 Osteocal-cin is the major noncollagenous protein in the skeleton. Although its function is not well understood, it appears to have a role in osteoclastic activity.10

RANKL, once expressed on the surface of an osteoblast, interacts with its receptor RANK on osteoclast precursors. This intimate interac-tion leads to signal transduction that results in the formation of mul-tinucleated mature osteoclasts (Fig. 199.2).1,7,10 These osteoclasts under the direction of a variety of cytokines10 increase the resorption of bone in the skeleton by releasing hydrochloric acid to dissolve the

Osteomalacia and rickets*Michael F. Holick

Rickets is a defect of mineralization affecting the growing skeleton, whereas osteomalacia is a defect of mineralization of the mature skeleton.

The most common causes of both conditions is vitamin D or calcium deficiency.

Other causes include hypophosphatemia, either inherited or acquired, renal tubular acidosis resulting in renal phosphate wasting, and inherited abnormalities of vitamin D metabolism.

The clinical features of rickets include growth failure, skeletal deformity, and proximal myopathy. In osteomalacia the main features are bone pain, fracture, and muscle weakness.

The radiologic appearance of rickets, with widening of the epiphyses and loss of distinction of the growth plate, is pathognomonic. In osteomalacia diagnosis may require bone biopsy, but the characteristic radiologic lesion is the Looser zone.

Treatment of vitamin D deficiency is based on replacement of physiologic amounts of native vitamin D. Hypophosphatemia requires the use of phosphate supplements with vitamin D supplementation and an active vitamin D. Osteomalacia due to systemic acidosis may respond to treatment of the underlying metabolic abnormality.

INTRODUCTIONOsteomalacia by definition means that osteoblasts have laid down a collagen matrix, but there is a defect in its ability to be mineralized. In children, a defect in the mineralization of the osteoid in the long bones and the failure or delay in the mineralization of endochrondal new bone formation at the growth plate leads to the classic skeletal deformities of rickets. However, in adults, the mineralization defect takes on a different character due to the failure of mineralization of newly formed osteoid at sites of bone turnover of periosteal or endosteal apposition. Several causes of poor or absent skeletal mineralization can lead to both rickets and osteomalacia, which are reviewed in this chapter.

CALCIUM, PHOSPHORUS, AND VITAMIN D METABOLISMThe major components of skeletal mineral are calcium and phosphate. Thus any alteration in the calcium-phosphate product in the circula-tion can result in a mineralization defect of the skeleton. Vitamin D plays a critical role in maintaining both serum calcium and phosphate concentrations.1 Vitamin D is obtained by exposure of the skin to sunlight resulting in the conversion of 7-dehydrocholesterol to previ-tamin D3 (Fig. 199.1). Previtamin D3 being thermodynamically unsta-ble is rapidly converted to vitamin D3. Once formed, vitamin D3 is ejected out of the epidermal cell into the extracellular space and, by diffusion, enters the circulation bound to the vitamin D binding protein (DBP).2 Vitamin D3 and vitamin D2 (D represents D2 or D3) in the diet are ingested, and the fat-soluble vitamins are incorporated into chylo-microns and absorbed into the lymphatics. The lymphatic drainage into the thoracic venous system permits the entrance of vitamin D into the circulation, where it is bound to the DBP and lipoproteins.2,3

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*This work was supported in part by National Institutes of Health grant 1UL1RR025771 and the UV Foundation.

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mineral matrix and collagenases and cathepsin K to dissolve the matrix.

Thus vitamin D’s effect on bone metabolism is to maintain a normal serum calcium and phosphorus levels. It accomplishes this by increasing intestinal calcium and phosphorus absorption and by mobi-lizing calcium and phosphorus from the skeleton.

CAUSES OF OSTEOMALACIA/RICKETSConsequences of vitamin D deficiency on bone mineralizationIt is usually assumed that when vitamin D deficiency occurs, it leads to hypocalcemia, which is therefore responsible for causing rickets in children and osteomalacia in adults. When a child or adult becomes vitamin D deficient, there is a decrease in the efficiency of intestinal calcium absorption that causes a transient decrease in the ionized calcium. This is recognized by the calcium sensor in the parathyroid glands, resulting in an increase in the expression and production of parathyroid hormone (PTH) (see Fig. 199.1).1,2,11 PTH conserves calcium by increasing tubular reabsorption of calcium throughout the proximal tubule and finely controls tubular reabsorption in the distal convoluted tubule.12,13 PTH stimulates the kidneys to produce 1,25(OH)2D, which in turn increases the efficiency of the intestinal calcium absorption.2,13 When these actions are inadequate to maintain the blood ionized calcium levels, the PTH and 1,25(OH)2D will inter-act with their receptors on osteoblasts to increase the expression of RANKL, which in turn mobilizes osteoclast precursors to become mature osteoclasts to remove calcium and phosphorus from the skel-eton (Fig. 199.3).1,2,12,13 Thus unless there are no longer any calcium deposits in the skeleton that can be mobilized to satisfy the body’s requirement, the blood level of calcium is usually normal or low normal in both vitamin D–deficient children and adults. Only when the adult

Solar UVBRadiation

7-DHC

Skin

PreD3

Vitamin D

Heat Inactivephotoproducts

D

Fat cellFish

MilkOJ

Supplement

Vitamin D2

Vitamin D3

Diet

SCHEMATIC REPRESENTATION OF THE SYNTHESIS AND METABOLISM OF VITAMIN D

Chylomicrons

1-OHase

25(OH)D

Major circulatingmetabolite

+

Pi, Ca, and otherfactors +/−

Preosteoclast RANKL

RANK

Osteoclast

ECaCCaBP

Kidneys

1,25(OH)2D

Osteoblast

Liver

24-OHase

1,25(OH)2D

−

−

Calcitroicacid

Bile

Excreted

Intestine

PTH

PTH

Parathyroidglands

BloodCalcium

Phosphorus

Ca2+ HPO42− Ca2+ HPO4

2−

AbsorptionCalcification

24-OHase

25-OHase

Fig. 199.1 Schematic representation of the synthesis and metabolism of vitamin D for regulating calcium, phosphorus, and bone metabolism. During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin is converted to previtamin D3 (preD3). PreD3 immediately converts by a heat-dependent process to vitamin D3. Excessive exposure to sunlight degrades previtamin D3 and vitamin D3 into inactive photoproducts. Vitamin D2 and vitamin D3 from dietary sources are incorporated into chylomicrons, transported by the lymphatic system into the venous circulation. Vitamin D (D represents D2 or D3) made in the skin or ingested in the diet can be stored in and then released from fat cells. Vitamin D in the circulation is bound to the vitamin D binding protein, which transports it to the liver, where vitamin D is converted by the vitamin D-25-hydroxylase (25-OHase) to 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form of vitamin D that is used by clinicians to measure vitamin D status (although most reference laboratories report the normal range to be 20 to 100 ng/mL, the preferred healthful range is 30 to 60 ng/mL). 25(OH)D is biologically inactive and must be converted in the kidneys by the 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to its biologically active form 1,25-dihydroxyvitamin D (1,25[OH]2D). Serum phosphorus, calcium, fibroblast growth factor (FGF-23), and other factors can either increase (+) or decrease (−) the renal production of 1,25(OH)2D. 1,25(OH)2D feedback regulates its own synthesis and decreases the synthesis and secretion of parathyroid hormone (PTH) in the parathyroid glands. 1,25(OH)2D increases the expression of the 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D and 25(OH)D to the water-soluble biologically inactive calcitroic acid, which is excreted in the bile. 1,25(OH)2D enhances intestinal calcium absorption in the small intestine by stimulating the expression of the epithelial calcium channel (ECaC, also known as transient receptor potential cation channel sub family V member 6 [TRPV6]) and the calbindin 9K (calcium-binding protein; CaBP). 1,25(OH)2D is recognized by its receptor in osteoblasts causing an increase in the expression of receptor activator of NFκB ligand (RANKL). Its receptor RANK on the preosteoclast binds RANKL, which induces the preosteoclast to become a mature osteoclast. The mature osteoclast removes calcium and phosphorus from the bone to maintain blood calcium and phosphorus levels. Adequate calcium and phosphorus levels promote the mineralization of the skeleton and maintain neuromuscular function. (From Holick MF. Copyright 2007. Reproduced with permission.)

VDR

PTHR

PTH

↑ RANKL

↑ RANK

Mature osteoclast

Bone

Bone resorption

OPG

Osteoclast precursor

1,25(OH)2D

1,25(OH)2D

PTH AND 1,25(OH)2D RECEPTOR INTERACTION

Ca+2 Ca+2

Ca+2

Fig. 199.2 Both PTH and 1,25(OH)2D interact with their receptors to increase the expression of RANKL. Once the RANK on the preosteoclast binds RANKL, signal transduction results in the formation of a mature osteoblast. (From Holick MF. Copyright 2006. Reproduced with permission.)

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blood chemistries show a low serum 25(OH)D (<20 ng/mL), elevated PTH, elevated or normal alkaline phosphatase level, and normal or low-normal serum calcium and phosphate levels. In young children with rickets due to vitamin D deficiency, they have 25(OH)D less than 20 ng/mL, elevated PTH, and alkaline phosphatase levels with low-normal or low serum calcium and phosphate (Table 199.1).8,14

Calcium deficiencyIt is well documented especially in Africa, where children are exposed to sunlight daily, that they develop rickets caused by calcium defi-ciency.15 A diet poor in calcium will result in an increase in PTH levels, which causes hyperphosphaturia. Thus children living in Africa, India, and Bangladesh who ingest approximately 200 mg of calcium daily and who have a diet high in phytates and oxalates, which irreversibly bind calcium in the gut, preventing its absorption, will develop rickets and osteomalacia.15-23 They are usually vitamin D sufficient due to ade-quate sun exposure.

Phosphate deficiency, heritable and acquired disordersNutritional phosphate deficiency is uncommon because our diet is rich in phosphate. Human breast milk, cow’s milk, and infant formulas have enough phosphate to satisfy an infant’s requirement. However, several acquired and inherited disorders cause phosphate wasting into the urine and can lead to severe hypophosphatemia resulting in rickets and osteomalacia.15

X-linked hypophosphatemic rickets and autosomal dominant phos-phatemic rickets are caused by either an increase in the production of fibroblast growth factor 23(FGF23) and other phosphatonins or a decrease in their catabolism resulting in severe phosphate wasting into the urine. FGF23 produced by osteocytes causes an internalization of the Na-Pi co-transporter and phosphaturia.14 In addition, the elevated blood level of FGF23/phosphatonins inhibits the renal production of 1,25(OH)2D, thus diminishing both the efficiency of intestinal calcium and phosphate absorption.14,24-27

Oncogenic osteomalacia is due to a benign or malignant tumor pro-duction of FGF23/phosphatonins.28 The result is increased phosphate wasting into the urine causing severe hypophosphatemia. Because this disease is often seen in adults, no overt clinical skeletal manifesta-tions of the osteomalacia occur other than the complaint of aches and pains in the bones and muscles and clinical observation of periosteal discomfort by applying pressure on the periosteum of sternum, radius, ulna, and anterior tibia. An x-ray of the skeleton may show osteope-nia, and low bone mineral density is often detected by bone densitometry.8,29

Fanconi syndrome and renal tubular acidosisFanconi syndrome is a disorder of the renal proximal tubules resulting in decreased reabsorption of phosphorus, glucose, and amino acids.30 These findings are accompanied by metabolic acidosis secondary to proximal tubular bicarbonate wasting (type II renal tubular acidosis).31 Typically these patients have hypophosphatemia, hyperphosphaturia, and a low tubular maximum for inorganic phosphate. In addition, they have glycosuria and generalized amino aciduria, hypobicarbonatemia, and excessive bicarbonate excretion in the urine. The serum calcium is usually normal with an elevated alkaline phosphatase and a normal PTH and 25(OH)D but an inappropriately low or low-normal serum 1,25(OH)2D (see Table 199.1).29,30-32 Children with Fanconi syndrome have classic x-ray evidence of rickets, whereas adults have radiographic changes consistent with osteomalacia.33

As noted in Box 199.1, a multitude of acquired and heritable disor-ders can cause Fanconi syndrome.30 Patients who have hypophospha-temia in a fasting blood specimen should be evaluated for Fanconi syndrome and the underlying cause identified and either appropriately treated or the offending agent removed.30

AluminumAluminum-containing antacids were routinely used to prevent phos-phate absorption in patients with chronic kidney disease. It was

Normal

Secondary hyperparathyroidism

Osteomalacia/rickets

Unmineralized matrix

a

b

c

Fig. 199.3 Bone histology demonstrating (a) increased osteoclastic bone resorption due to secondary hyperparathyroidism, (b) normal mineralized trabecular bone, and (c) osteomalacia with widened, unmineralized osteoid (lighter areas). (From Holick MF. Copyright 2009. Reproduced with permission.)

skeleton is completely depleted of calcium or the child has minimum calcium intake or absorption will hypocalcemia be observed.1,2,14

PTH has an additional effect on the kidneys. It causes the internal-ization of the sodium-dependent phosphate co-transporter (NaPi-2A) resulting in the loss of phosphate into the urine.1,2,12,13 This ultimately causes a lowering of the blood phosphorus level to a degree that the calcium-phosphate product is no longer adequate to mineralize the osteoid matrix (see Fig. 199.3).

Thus the major cause of osteomalacia is due to secondary hyper-parathyroidism and the low-normal or low serum phosphate level. In adults with osteomalacia due to vitamin D deficiency, their fasting

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TABLE 199.1 BIOCHEMISTRIES OF OSTEOMALACIA/RICKETS

Ca PO4 25(OH)D 1,25(OH)2D PTH Other

Deficiencies

Vitamin D deficiency ≈↓ or N ≈↓ or N ↓↓ ↑ or N ↑

Calcium-deficiency diet ↓ ↓ or N ↓ or N ↑ or N ↑ ↑Alk Phos

Kidney disease ↓ ↑ N or ↓ ↓ or N ↑ or N

1α hydroxylase deficiency pseudo vitamin D deficiency rickets ↓ ↓ N ↓↓ ↑ ↑Alk Phos

VDR defect vitamin D resistant rickets ↓ ↓ N ↑↑↑ ↑ ↑Alk Phos

Hypophosphatemia

X-linked hypophosphatemic rickets N ↓↓ N ↓ or low N N ↑FGF23/phosphatonins↑Urine phosphate

Autosomal-dominant hypophosphatemic rickets N ↓↓ N ↓or low N N ↑ FGF23/Phosphatonins↑Urine phosphate

Autosomal-recessive hypophosphatemic rickets N ↓↓ N ↓ or low N N ↑FGF23/ phosphatonins↑Urine phosphate

Oncogenic osteomalacia N ↓↓ N ↓ or low N N ↑FGF23/phosphatonins↑Urine phosphate

“Hereditary hypophosphatemic rickets with hypercalciuria,” NaPi2c mutation

N ↓↓ N ↑ or N N ↑Urine calcium↑Urine phosphate

Renal phosphate loss (including Fanconi syndrome, Dent disease, cadmium toxicity, heavy metal poisoning)

N ↓↓ N N or low N N ↑Urine phosphate↑Urine amino acids↑Urine bicarbonate↑Alk phos

Toxicities

Fluoride N N N N N ↑Fluoride bone bx

Etidronate N or low-N N N N N

Parenteral aluminum N N N N or ↓ N or ↑↓ Aluminum staining bone box

Hypophosphatasia N N N N N ↓↓Alk phos

Acidosis N N N N or low N Low N ↓Bicarbonate in urine

BOX 199.1 DISORDERS ASSOCIATED WITH FANCONI SYNDROME

AcquiredVitamin D deficiencyMultiple myelomaLymphomaLight chain nephropathyAmyloidosisSjögren syndromeNephrotic syndromeRenal transplantationBalkan nephropathyParoxysmal nocturnal hemoglobinuriaInterstitial nephritis/uveitis syndromeRenal vein thrombosis

HeritableX-linked hypophosphatemic ricketsAutosomal dominant hypophosphatemic ricketsCystinosisLowe syndromeHereditary fructose intoleranceTyrosinemiaGalactosemiaGlycogen storage diseaseWilson diseaseCytochrome oxidase deficiencySubacute necrotizing encephalomyelopathyAlport syndromeLeigh syndromeFranconi-Bickel syndrome

Dent diseaseGRACILE syndromeRod-cone dystrophy, sensorineural deafness, and renal dysfunctionPearson syndrome

DrugsIfosphamideMethy-3-chromone6-MercaptopurineGentamicinValproic acidStreptozocinIsophthalanilideCephalothinOutdated tetracycline

Heavy metalsCadmiumLeadMercuryUraniumPlatinumCopperBismuth

OtherParaquatLysolToluene inhalation

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Thus antiseizure medications, glucocorticoids, and other medications will enhance the destruction of 25(OH)D and 1,25(OH)2D, resulting in vitamin D deficiency and its consequences on skeletal mineralization.

Patients with Paget disease have an increase in bone remodeling activity (see Chapter 202). In the 1970s, a new class of drugs known as bisphosphonates were introduced as an effective treatment for Paget’s disease. The first bisphosphonate that was used was etidronate. The drug was typically given at a dose of 400 mg/day. Within a few months, there was a marked reduction in Pagetic bone activity, sug-gesting that this would be a safe and effective method for treating this metabolic bone disease. However, many patients who were on the medication for more than 6 months began developing bone pain. Bone biopsies revealed that they were suffering from osteomalacia.1,8,15,46 To prevent this complication, patients with Paget disease took the medica-tion for several months and then stopped the medication for several months and restarted it again to control the Paget’s disease but prevent the side effect of osteomalacia.8,15

When it was realized that bisphosphonates inhibited bone resorp-tion, several pharmaceutic companies began developing bisphospho-nate analogs that had much higher potency in inhibiting osteoclastic activity while having minimum negative effects on skeletal mineraliza-tion. As a result, the new class of bisphosphonates was effective in treating Paget’s disease when given either daily, weekly, or monthly without any evidence of osteomalacia on the basis of bone biopsies. These potent bisphosphonates are also used for the prevention and treatment of osteoporosis and do not cause osteomalacia.

Ifosfamide, a drug used to treat solid tumors, has been associated with renal Fanconi syndrome and hyperphosphaturia.15,30,47,48 Saccha-rated ferric oxide used intravenously can cause transient proximal renal tubular damage leading to phosphaturia.15,30,49 A wide variety of other drugs have been associated with hypophosphatemia, osteomalacia, and rickets (Boxes 199.1 and 199.2).8,15

observed in patients who were taking aluminum antacids or who were being dialyzed with water containing a high aluminum content that they developed osteomalacia.15, 34 Aluminum is a trivalent cation that in low concentrations stimulates osteoblastic activity. However, at higher concentrations, it will inhibit PTH release and 1-OHase activ-ity. It also inhibits osteoblastic activity at high concentrations and is deposited on the mineralizing surface of the skeleton, preventing further mineralization of osteoid. These patients often have little osteo-blastic or osteoclastic activity resulting in inactive bone remodeling or complete absence of bone remodeling known as adynamic bone disease (see Chapter 201). A bone biopsy that demonstrates stainable alumi-num on the mineralization surface helps to make the diagnosis of aluminum-induced osteomalacia.8,15,34

Patients who are on total parenteral nutrition (TPN) or hemodialy-sis where the water is not monitored for aluminum content are at high risk for this aluminum metabolic bone disease. In addition, patients on TPN have been exposed to high aluminum from casein hydrolysate solutions. As a result, hemodialysis baths are now free of aluminum contamination, as are TPN solutions. Aluminum-based phosphate binding agents for patients with chronic kidney disease have been replaced with either calcium carbonate or resins that bind phosphate.8,15,34

Heavy metalsSeveral heavy metals can cause phosphaturia.8,15,35,36 Cadmium exposure causes Itai-Itai disease (see http://www.kanazawa-med.ac.jp/~pubhealt/cadmium2/itaiitai-e/itai01.html accessed October 2, 2009). High cadmium exposure has wide-ranging pathologic effects on the body including the damage of the glomerulus and renal tubular function. Besides leading to renal failure, it initially causes proteinuria and phosphaturia.15

FluorideFluoride is well known to stimulate osteoblastic activity in low concentrations. Fluoride has been effective in preventing dental caries in part because the fluoride is incorporated into the dentin, reducing dental caries activity.15 At high concentrations, however, fluoride not only stimulates osteoblastic activity but gets incorporated into the skeleton as a calcium fluoride hydroxyapatite crystal. Because fluo-ride has a larger atomic weight than the OH that it replaces, the skel-eton appears on x-ray to be hyperdense and there is a substantial increase in bone mineral density on bone densitometry. It is well docu-mented that ingestion of food and water with a high fluoride content between 3 and 16 ppm is associated with increased bone mineral density that leads to stiffness, rigidity, and limitation of movement at the spine and can also lead to skeletal deformities and fractures (Fig. 199.4).8,15,37-39

Certain populations including children in India who are exposed to high dietary fluoride and are on a low-calcium diet can develop severe skeletal deformities.15,40-42 These children have classic features of rickets at their epiphyseal plates and osteomalacia with Looser zones. Histologically, the bone biopsy shows widened osteoid seams, poorly mineralized new bone formation, and areas of hypermineralization.15

DrugsA wide variety of drugs can cause rickets and osteomalacia.1,8,15 Chil-dren and adults who are institutionalized and on several antiseizure medications often develop rickets/osteomalacia.1,14,15,43,44,45 It is now recognized that not only antiseizure medications but glucocorticoids, medications used to treat infection with human immunodeficiency virus (HIV), and even St. Johns Wort can cause vitamin D deficiency and resulting rickets and osteomalacia. It has been demonstrated that antiseizure medications, HIV medications, glucocorticoids, and other drugs interact with the steroid xenobiotic receptor, which binds to retinoic acid X receptor. This complex is recognized by the vitamin D responsive element for the 25-hydroxyvitamin D-24 hydroxylase [24-OHase]. The 24-OHase introduces a hydroxyl group on carbons 23 and 24, resulting in cleavage at carbon 23 to form a water-soluble inac-tive vitamin D metabolite for both 25(OH)D and 1,25(OH)2D.1,14,45

a

b

c

Fig. 199.4 This child has fluorosis with classic skeletal (a), dental (b), and radiologic (c) abnormalities. (From Holick MF, Harayan. Copyright 2009. Reproduced with permission.)

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Fig. 199.5 Radiograph of the femur demonstrating a radiolucent line perpendicular to the shaft known as a Looser zone.

a

b

c

Fig. 199.6 Radiographs of a child with vitamin D deficiency rickets demonstrating bowing of the femurs and tibias (a) and widened, frayed, demineralized epiphyseal plates (b and c).

BOX 199.2 CAUSES OF OSTEOMALACIA/RICKETSVitamin D deficiencyCalcium deficiencyHypophosphatemiaFanconi syndromePseudovitamin D–deficiency rickets, vitamin D–dependent rickets type 1Vitamin D–resistant rickets, vitamin D–dependent rickets type 2X-linked hypophosphatemic ricketsAutosomal dominant hypophosphatemic ricketsOncogenic osteomalaciaHypophosphatasiaMalabsorption syndromeHypokalemic distal renal tubular acidosisWilson diseaseRentan failure, chronicCystinosisPhenytoinGlucocorticoidsHAARTEtidronateGlutethimideHeavy metalsCancer drugs

X-RAY AND BIOCHEMICAL MANIFESTATIONS OF OSTEOMALACIA AND RICKETSIt is not possible to distinguish osteomalacia from osteopenia and osteoporosis either by x-ray examination or by bone densitometry. The only exception is if the x-ray examination reveals Looser zones (Fig. 199.5). These are radiolucent lines that are often penetrating through the cortex perpendicular to the shaft and are most often seen in the medial cortices of the femurs and in the pelvis and ribs. In children, rickets/osteomalacia is easily detected because the epiphyseal plates have not closed. There is widening of the physis with fraying, cupping, and splaying of the metaphases (Fig. 199.6). The diaphyses of the long bones often appear to be less dense (i.e., osteopenic and show thinning of the cortices with periosteal new bone formation).8,15

Rickets and osteomalacia are associated with a variety of abnormali-ties on blood biochemistries. However, it is often the presenting symp-toms or manifestations of osteomalacia that will prompt the diagnosis

before the biochemical abnormalities are appreciated. The reason for this is that depending on the cause, the abnormal biochemistries can vary. For example, in children with severe vitamin D deficiency, there will be a low-normal or low serum calcium with a low-normal or low fasting serum phosphorus with an elevated alkaline phosphatase and a 25(OH)D less than 15 ng/mL. If the child has been vitamin D defi-cient for a prolonged period of time or there is little calcium intake, then the biochemical presentation is often hypocalcemia associated with all of the other biochemical abnormalities. An adult with vitamin D deficiency will present with a normal or low-normal serum calcium, a low-normal or low serum fasting phosphorus, a normal alkaline phosphatase, an elevated PTH, and a 25(OH)D less than 20 ng/mL. However, if the cause is due to an acquired disorder that causes severe

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phosphate wasting in the urine, these patients present with a normal or low-normal serum calcium, elevated PTH, low serum phosphorus, elevated alkaline phosphatase, and a normal 25(OH)D. The distin-guishing features of the various causes of osteomalacia based on bio-chemistries are summarized in Table 199.1.1,8,15

Clinical findingsChildren with rickets often have skeletal abnormalities including a rachitic rosary, bowed or knocked knees, frontal bossing, soft fontanels, delayed tooth eruption, dental caries, and severe muscle weakness (Fig. 199.7). The more serious consequences include grand mal seizures, carpal pedal spasms (Fig. 199.8), and upper respiratory tract infec-tions.14 Often children with rickets have other subtle symptoms as noted in Box 199.3.

In adults, osteomalacia does not present with any overt skeletal signs. However, patients with osteomalacia complain of throbbing, aching bone discomfort. They often note that the bone discomfort is worse when sitting or lying in bed. They also have proximal muscle weakness and aching in their muscles.1,8,15,29,50 To make the diagnosis, pressing with thumb or forefinger with some force on the sternum, radius, ulna, or anterior tibia will often result in wincing bone discom-fort. Often physicians conclude that pressing on the skeleton resulting in discomfort is consistent with a trigger point leading to the diagnosis of fibromyalgia. In many cases these patients are suffering from peri-osteal bone discomfort consistent with osteomalacia.50

Although the exact cause of the muscle weakness and bone discom-fort is not fully understood, it is believed that because the major cause of osteomalacia is vitamin D deficiency and because skeletal muscle has a VDR, the lack of 1,25(OH)2D interacting with the skeletal muscle VDR increases muscle weakness.1,2 Osteoblasts laying down the col-lagen matrix on the periosteal surface with no mineralization provides little structural support for the periosteal covering that is heavily inner-vated with sensory fibers. Thus pressing on the periosteal covering causing deformation leads to immediate bone discomfort. In addition, the collagen matrix acts like JELL-O and, once hydrated, expands. As a result, the outward pressure on the periosteal covering gives the sensation of throbbing, aching bone discomfort.50

Fig. 199.7 Child with vitamin D deficiency rickets with muscle weakness.

Fig. 199.8 Sister (left) and brother (right) ages 10 months and 2.5 years with the enlargement of the ends of the bones at the wrist, carpopedal spasm, and a typical “tailorwise” posture of rickets. (From Holick MF. Copyright 2006. Reproduced with permission.)

BOX 199.3 CLINICAL MANIFESTATIONS OF RICKETSRestlessness/irritabilityHead sweatingSkeletal signs approximately 6 to 9 monthsHead somewhat squareFontanels openedFrontal bossingOsseous borders soft (craniotabes)Teething delayedEnlargement of costochondral junctionsMuscles flabbyUpper respiratory tract infectionsAnemia (Von Jacksch–Luzet syndrome)Carpal pedal spasmsSeizure

STRATEGIES FOR THE TREATMENT AND PREVENTION OF OSTEOMALACIA/RICKETSThe major cause of osteomalacia/rickets is vitamin D deficiency. Vitamin D deficiency is defined as a serum 25(OH)D less than 20 ng/mL. However, to maximize intestinal calcium absorption and to mini-mize circulating PTH levels, it is desirable to maintain a 25(OH)D greater than 30 ng/mL.1,51 To achieve this, at least 1000 to 2000 IU of vitamin D daily or its equivalent is necessary.1 For every 100 IU of vitamin D2 or vitamin D3 ingested, the blood level of 25(OH)D increases by 1 ng/mL.52 Healthy adults at the end of the winter in Boston receiv-ing 1000 of vitamin D2 or 1000 IU of vitamin D3 per day or 500 IU vitamin D2 and 500 IU vitamin D3 per day were unable to achieve a sustained blood level of 25(OH)D greater than 30 ng/mL (Fig. 199.9). Most children and adults have a circulating blood level of 25(OH)D between 15 and 25 ng/mL.1 Thus to achieve a blood level of 25(OH)D greater than 30 ng/mL, it has been recommended that both children and adults take at least 1000 IU of vitamin D daily along with a mul-tivitamin containing 400 IU of vitamin D. For obese children and adults, the amount of vitamin D ingested should be increased by two- to threefold because body fat will sequester vitamin D and obese chil-dren and adults need at least two times more vitamin D to sustain their blood level of 25(OH)D greater than 30 ng/mL.1,2

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To treat vitamin D deficiency, 50,000 IU of vitamin D2 once a week for 8 weeks will often fill the empty vitamin D tank and raise the blood level above 30 ng/mL.53 Patients who are severely vitamin D deficient with a 25(OH)D less than 10 ng/mL or who are on medications that would enhance vitamin D destruction or obese may require an addi-tional 8 weeks of therapy with 50,000 IU of vitamin D2. Once the blood level of 25(OH)D is above 30 ng/mL, vitamin D sufficiency can be maintained by giving patients 50,000 IU of vitamin D once every 2 weeks. In our clinic, we have found over a 5-year period that the blood levels are sustained between 40 and 50 ng/mL on this regimen. Alternatively, to treat vitamin D deficiency with vitamin D supplemen-tation, 5000 IU of vitamin D daily for 2 months followed by 2000 IU of vitamin D daily will treat vitamin D deficiency and maintain vitamin D sufficiency in most adults.

The American Academy of Pediatrics recommends that all infants and children receive 400 IU of vitamin D per day.54 This will prevent rickets in children.

Children and adults who have calcium-induced rickets/osteomalacia should be treated with the adequate intake recommendation for calcium, which is 800 milligrams per day for children younger than the age of 12 years, 1300 milligrams per day for teenagers, 1000 mil-ligrams for adults aged 19 to 50 years, and 1200 milligrams per day for adults older than the age of 50.55 They should also be taking an adequate amount of vitamin D to maximize the benefit of the calcium.

Patients with phosphate wasting need to take either Neutra-Phos or sodium phosphate in amounts of 250 mg to 500 mg 3 to 5 times a day along with 1,25(OH)2D3 (calcitriol) 0.5 to 1.0 mg twice a day.1,15,24 It should be noted that the more frequent dosing of phosphate at lower doses to help maintain the serum levels of phosphate is desirable for two reasons. The first is that maintaining a more normal calcium-phosphate product will help in the mineralization of osteoid. Secondly, taking large amounts of phosphate orally results in a transient decrease in serum ionized calcium, which stimulates the parathyroid glands to produce and secret PTH. The chronic stimulation of the parathyroid glands by transient hypocalcemia can result in tertiary hyperparathyroidism.56

MEAN (± SEM) SERUM 25-HYDROXYVITAMIN D LEVELS AFTER ORALADMINISTRATION OF VITAMIN D2 AND/OR VITAMIN D3

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Fig. 199.9 Mean (±SEM) serum 25-hydroxyvitamin D levels after oral administration of vitamin D2 and/or vitamin D3. Healthy adults recruited at the end of the winter received either placebo ([n = 14; ···•···]), 1000 IU of vitamin D3 (D3, n = 20; [--]), 1000 IU of vitamin D2 (D2, n = 16; [--]), or 500 IU of vitamin D2 and 500 IU of vitamin D3 (D2 and D3, n = 18; [-♦-]) daily for 11 weeks. The total 25-hydroxyvitamin D levels are demonstrated over time. *P = 0.027 comparing 25(OH)D over time between vitamin D3 and placebo. †P = 0.041 comparing 25(OH)D over time between 500 IU vitamin D3 + 500 IU vitamin D2 and placebo. ‡P = 0.023 comparing 25(OH)D over time between vitamin D2 and placebo. (From Holick MF. Copyright 2008. Reproduced with permission.)

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REFERENCESFull references for this chapter can be found on www.expertconsult.com.