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MD Consult: Books: Goldman: Cecil Medicine: Chapter 265 – OSTEOMALACIA AND RICKETS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Marc K. Drezner


Rickets and osteomalacia are diseases characterized by defective bone and cartilage mineralization in children and bone mineralization in adults. The abnormal calcification of cartilage occurs at epiphyseal growth plates. Delayed maturation of the cartilage cellular sequence and disorganization of cell arrangement are also present. The resultant profusion of disorganized, nonmineralized, degenerating cartilage causes widening of the epiphyseal plates with flaring or cupping and irregularity of the epiphyseal-metaphyseal junctions. The abnormal calcification of bone is restricted to the organic matrix at the bone-osteoid interfaces of remodeling tissue. The insufficient mineralization of newly formed matrix paradoxically results in enhanced bone volume and increased susceptibility to fractures or bone deformities. The various disorders associated with rickets and osteomalacia identified and characterized to date are numerous ( Table 265-1 ). Although the phenotypic expression of the defective bone and cartilage mineralization is similar in each of these disorders, the associated biochemical abnormalities and the therapeutic approaches differ according to the pathogenetic defect. Therefore, when diagnosing rickets and/or osteomalacia, further systematic analysis is needed to determine the cause and appropriate therapy for the disorder.

TABLE 265-1   — 

   I.    Disorders of the vitamin D endocrine system

   A.    Decreased bioavailability of vitamin D

   1.    Deficient endogenous production

   a.    Inadequate sunlight exposure
   b.    Aging
   2.    Nutritional deficiency
   3.    Loss of vitamin D metabolites

   a.    Nephrotic syndrome
   b.    Peritoneal dialysis
   B.    Vitamin D malabsorption

   1.    Gastrointestinal disorders

   a.    Partial/total gastrectomy
   b.    Small bowel disease (e.g., celiac disease)
   c.    Intestinal bypass
   2.    Pancreatic insufficiency
   3.    Hepatobiliary disease

   a.    Biliary atresia
   b.    Biliary obstruction
   c.    Biliary fistula
   d.    Cirrhosis
   C.    Abnormal vitamin D metabolism

   1.    Impaired hepatic 25-hydroxylation of vitamin D

   a.    Liver disease
   b.    Anticonvulsant therapy
   2.    Impaired renal 1α-hydroxylation of 25-hydroxyvitamin D

   a.    Hereditary vitamin D–dependent rickets type 1 (pseudo–vitamin D deficiency)
   b.    Chronic renal failure
   c.    Pseudohypoparathyroidism
   D.    Target organ resistance to vitamin D and metabolites

   1.    Hereditary vitamin D–dependent rickets type 2

   a.    Hormone binding negative
   b.    Defect in hormone binding capacity
   c.    Defect in hormone binding affinity
   d.    Deficient hormone receptor nuclear localization
   e.    Decreased affinity of the hormone receptor complex
   II.  Disorders of phosphate homeostasis

   A.    Dietary

   1.    Low phosphate intake
   2.    Ingestion of phosphate-binding antacids
   B.    Impaired renal tubular phosphate reabsorption

   1.    Hereditary

   a.    X-linked hypophosphatemic rickets/osteomalacia
   b.    Hereditary hypophosphatemic rickets/osteomalacia with hypercalciuria
   c.    Autosomal dominant hypophosphatemic rickets
   d.    Hypophosphatemic bone disease (nonrachitic hypophosphatemic osteomalacia)
   e.    Adult-onset hypophosphatemic rickets
   f.     Autosomal recessive hypophosphatemic rickets (X-linked hypercalciuric nephrolithiasis)
   g.    X-linked recessive hypophosphatemic rickets (X-linked hypercalciuric nephrolithiasis)
   2.    Acquired

   a.    Tumor-induced osteomalacia (oncogenous osteomalacia)

   i.     Mesenchymal, epidermal, and endodermal tumors
   ii.  Fibrous dysplasia of bone
   iii.  Neurofibromatosis
   iv.  Linear nevus sebaceous syndrome
   v.    Light-chain nephropathy
   b.    Sporadic hypophosphatemic osteomalacia
   C.    General renal tubular disorders

   1.    Fanconi’s syndrome type 1

   a.    Hereditary

   i.     Familial idiopathic
   ii.  Cystinosis (Lignac-Fanconi syndrome)
   iii.  Hereditary fructose intolerance
   iv.  Tyrosinemia
   v.    Galactosemia
   vi.  Glycogen storage disease
   vii.  Wilson’s disease
   viii.  Oculocerebral renal syndrome (Lowe’s syndrome)
   b.    Acquired

   i.     Renal transplantation
   ii.  Multiple myeloma
   c.    Intoxication

   i.     Cadmium
   ii.  Lead
   iii.  Tetracycline (outdated)
   iv.  Antiretroviral drugs
   2.    Fanconi’s syndrome type 2
   III.  Metabolic acidosis

   A.    Distal renal tubular acidosis

   1.    Primary

   a.    Sporadic
   b.    Familial
   2.    Secondary

   a.    Galactosemia (after galactose ingestion)
   b.    Hereditary fructose intolerance with nephrocalcinosis (after chronic fructose ingestion)
   c.    Hypergammaglobulinemic states
   d.    Medullary sponge kidney
   3.    Acquired

   a.    Drug induced

   i.     Acetazolamide
   ii.  Ammonium chloride
   IV.  Disorders of calcium homeostasis

   A.    Dietary calcium deficiency
   V.    Abnormal bone matrix

   A.    Fibrogenesis imperfecta ossium
   B.    Axial osteomalacia
   VI.  Primary mineralization defects

   A.    Hereditary

   1.    Hypophosphatasia

   a.    Perinatal disease
   b.    Infantile disease
   c.    Childhood disease
   d.    Adult-onset disease
   e.    Pseudohypophosphatasia
   VII.  Mineralization inhibitors

   A.    Etidronate
   B.    Fluoride
   C.    Aluminum

Mineralization of cartilage and bone is a complex process in which the calcium-phosphorus inorganic mineral phase is deposited in an organic matrix in a highly ordered fashion. Such mineralization depends on the following: (1) the availability of sufficient calcium and phosphorus from the extracellular fluid; (2) adequate metabolic and transport function of chondrocytes and osteoblasts to regulate the concentration of calcium, phosphorus, and other ions at the mineralization sites; (3) the presence of collagen with unique type, number, and distribution of cross-links, remarkable patterns of hydroxylation and glycosylation, and abundant phosphate content, which collectively permit and facilitate deposition of mineral at gaps, in hole zones, and between the distal ends of two collagen molecules; (4) maintenance of an optimal pH (∼7.6) for deposition of calcium-phosphorus complexes; and (5) low concentration of calcification inhibitors (e.g., pyrophosphates, proteoglycans) in bone matrix.

Many of the disorders of mineralization occur secondary to known defects in these control steps. In this regard, most diseases resulting in rickets and/or osteomalacia stem from abnormalities in the vitamin D endocrine system. Traditionally, a direct role has been assumed for vitamin D or, more properly, its active metabolite, 1,25-dihydroxyvitamin D, for production of normal collagen matrix and regulation of bone mineralization. However, it is more likely that the abnormal mineralization in these disorders results from an associated calcium and phosphorus deficiency that diminishes the driving force for calcification. Primary disorders of phosphate homeostasis also underlie many of the rachitic/osteomalacic disorders. Diminished gastrointestinal absorption or renal wasting of phosphorus limits this essential mineral in such disorders. The isolated deficiency of phosphorus alone or in conjunction with a frequently occurring aberration in vitamin D metabolism is the basis for defective mineralization. In accord with the complex regulation of bone mineralization, however, decreases in calcium or phosphorus do not account for rickets and osteomalacia in all forms of the disease. Indeed, certain forms of rickets and osteomalacia occur in spite of a normal or even elevated calcium-phosphate product. In such diseases, altered pH, abnormal collagen matrix, or excessive concentration of calcification inhibitors underlie the abnormal mineralization. In other forms of the disease, the precise mechanism causing the defective mineralization remains unknown.

Inadequate mineralization in rickets occurs in the matrix of cartilage in the growing epiphyseal plate. These characteristic changes are confined to the maturation zone of the cartilage, whereas the resting and proliferative zones of the epiphyses exhibit normal histologic features. In the maturation zone, the height of the cell columns is increased, and the cells are closely packed and irregularly aligned. Moreover, calcification in the interstitial regions of this hypertrophic zone is defective.

In bone, the abnormal mineralization results in accumulation of excess osteoid, a sine qua non for the diagnosis of osteomalacia in most instances ( Fig. 265-1 ). A supranormal amount of osteoid may also occur in disease states associated with accelerated bone turnover, such as hyperparathyroidism, however. In addition, reduced mineralization activity may be observed without hyperosteoidosis in patients with osteoporosis. Establishing the histopathologic diagnosis of osteomalacia, therefore, requires documentation of abnormal mineralization with excess osteoid. These defects are manifest in bone by an increase in the bone-forming surface covered by incompletely mineralized osteoid, an increase in osteoid volume and thickness, and a decrease in the mineralization front (the percentage of osteoid-covered bone-forming surface undergoing calcification) or the mineral apposition rate. The amount of osteoid in bone and the mineralization dynamics are determined in 3- to 5-μm thick sections of decalcified bone by special stains and the fluorescence of previously ingested tetracycline that is deposited at calcification fronts.

FIGURE 265-1  A, Radiographic appearance of the lower extremities in a youth with rickets. The bowed femora are evident bilaterally. In addition, at the distal ends of the femora, the growth plates are wide and flared and display an irregular hazy appearance at the diaphyseal line secondary to uneven invasion of the recently calcified cartilage by adjacent bone tissue. B, Microscopic appearance of bone biopsy sections from a patient with osteomalacia. Stained sections exhibit mineralized bone (white arrow) covered by unmineralized osteoid seams (black arrow). Such observations are representative of the abnormal mineralization that characterizes the osteomalacic bone disorder.

Clinical Manifestations

The clinical features of rickets, although variable to some degree according to the underlying disorder, are primarily related to skeletal pain and deformity, bone fractures, slipped epiphyses, and abnormalities of growth. In addition, hypocalcemia, when present, may be severe enough to produce tetany, laryngeal spasm, and seizures.

In infants and young children, symptoms include listlessness, irritability, and, in some forms of metabolic rickets, profound hypotonia and proximal muscle weakness. Indeed, as the disease progresses and muscle weakness is present, delayed motor milestones are evident, children often are unable to walk without support, and lower respiratory infections become frequent. Throughout early life, classic skeletal deformities appear. By 6 months of age, frontal bossing with flattening at the back is evident. Later, a lateral collapse of both chest walls (Harrison’s sulcus) and a rachitic rosary may appear. When the condition is left untreated, progressive bony deformities result in bowing (see Fig. 265-1 ), particularly in the tibia, femur, radius, and ulna, and fractures. In addition, dental eruption may be delayed, and, in those forms of the disease with hypocalcemia or hereditary hypophosphatemia, enamel defects and inadequate dentin calcification occur, respectively.

In contrast, clinical signs of osteomalacia are nondescript. Indeed, the disease-specific abnormalities may be overlooked, and features of an underlying disorder (e.g., malabsorption) may predominate. Symptoms, when present, may include diffuse skeletal pain and muscular weakness. The pain, often described as dull and aching, is generally worsened by activity and prominent around the hips, with a resulting antalgic gait. The muscle weakness is primarily proximal and is frequently associated with wasting, hypotonia, and a waddling gait. This myopathy is seen in almost all forms of rickets and osteomalacia, with X-linked hypophosphatemic rickets (XLH) and osteomalacia the notable exceptions. Clinical improvement in the myopathy usually results from specific therapy, such as vitamin D repletion in patients with nutritional osteomalacia, phosphate supplementation in disorders marked by renal phosphate wasting, or correction of acidosis. Fractures of the ribs, vertebral bodies, and long bones may occur and may lead to progressive deformities as well as point tenderness on palpation.

The radiographic abnormalities in both rickets and osteomalacia reflect the histopathologic changes. In rickets, alterations are most evident at the growth plate, which is wide and flared and displays an irregular, hazy appearance at the diaphyseal line secondary to uneven invasion of the recently calcified cartilage by adjacent bone tissue (see Fig. 265-1 ). The trabecular pattern of the metaphyses is also abnormal, the cortices of the diaphyses are thinned, and the shafts frequently are bowed (see Fig. 265-1 ).

In osteomalacia, a moderate decrease in bone density is usually associated with coarsening of the trabeculae and blurring of their margins. When secondary hyperparathyroidism is present, subperiosteal resorption in the phalanges and metacarpals, erosion of the distal ends of the clavicles, and bone cysts may be observed. A more specific radiographic abnormality is the presence of Looser’s zones, also called pseudofractures or Milkman’s fractures, in the shafts of long bones. These are ribbon-like zones of rarefaction, ranging from a few millimeters to several centimeters in length and usually oriented perpendicular to the bone surface. Often, they occur symmetrically and most commonly are present at the medial aspect of the femora near the femoral heads, in the metatarsals, or in the pelvis. Long-standing osteomalacia may also result in additional characteristic radiographic abnormalities, including biconcave collapsed vertebrae and a trefoil (or triangular) pelvis.

In patients with renal tubular disorders ( Chapter 129 ), increased rather than decreased bone density may be present. Despite the increased bone mass, histopathologic evaluation of biopsies reveals an abundance of unmineralized osteoid, and bones remain subject to fracture. Thus, the increased density likely reflects replacement of marrow air space with osteoid.

Biochemical abnormalities in patients with rickets and osteomalacia vary with the cause of the disorder. However, the rachitic and osteomalacic syndromes may be divided into calcipenic and phosphopenic forms, as well as those in which mineral availability is apparently normal. In general, patients with the calcipenic diseases exhibit a low or marginally normal serum calcium level, a decreased serum phosphorus concentration, and (secondary) hyperparathyroidism. When vitamin D deficiency prevails, the serum 25-hydroxyvitamin D levels are characteristically low, generally less than 10 ng/mL but occasionally 10 to 20 ng/mL. In contrast, the serum 1,25-dihydroxyvitamin D concentration may not be overtly decreased secondary to the prevailing hyperparathyroidism. Alternatively, a defect in vitamin D metabolism often results in an isolated deficiency of 1,25-dihydroxyvitamin D, whereas end-organ resistance to this active vitamin D metabolite increases the circulating level of calcitriol.

A primary abnormality of transepithelial phosphate transport in the nephron, resulting in renal phosphate wasting, underlies most of the phosphopenic disorders. As a rule, patients with these disorders maintain a normal serum calcium concentration, whereas the serum phosphorus level is characteristically low. In contrast to the calcipenic forms of disease, the serum 25-hydroxyvitamin D and parathyroid hormone (PTH) levels are normal in patients with hypophosphatemic disease. Moreover, affected subjects commonly maintain a normal (or mildly decreased) serum 1,25-dihydroxyvitamin D level despite the prevailing hypophosphatemia, which should increase production of this active vitamin D metabolite. However, an elevated serum 1,25-dihydroxyvitamin D concentration has been reported in several rare genetic phosphopenic disorders, hereditary hypophosphatemic rickets with hypercalciuria (HHRH), Fanconi’s syndrome type 2, and X-linked recessive hypophosphatemic rickets. Whereas the elevated calcitriol level underlies increased gastrointestinal absorption of calcium and hypercalciuria in these diseases, the impact of abnormal vitamin D metabolism on the phenotypic expression of the phosphopenic disorders is less certain. In patients with those diseases with normal serum calcium and phosphorus concentrations, laboratory abnormalities are unique to each form of the disease. Nevertheless, alkaline phosphatase activity in plasma is generally elevated in all forms of rickets and osteomalacia. Even severe forms of disease, however, particularly those caused by renal tubular disorders, may be associated with normal or only marginally elevated enzyme activity.


Rickets and osteomalacia resulting from disorders of the vitamin D endocrine system are caused by a wide variety of calcipenic diseases. The variable biochemical abnormalities associated with these disparate disorders are summarized in Table 265-2 . Although many of these diseases are no longer common causes of rickets and osteomalacia, others are often hidden causes of bone disease in a varying population of patients.

TABLE 265-2   — 

Phosphorus N/⇓ N/⇓ N/⇓
Alkaline phosphatase N/⇑ N/⇑
Parathyroid hormone
25(OH)D N/⇓ N N N N
1,25(OH)2D N/⇑
Urinary phosphorus
Urinary calcium
Calcium absorption
Phosphorus absorption

1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; ⇓ = decreased; ⇑ = increased; CRF = chronic renal failure; HP = hypoparathyroidism; HVDDR 1 = hereditary vitamin D–dependent rickets type 1; HVDDR 2 = hereditary vitamin D–dependent rickets type 2; N = normal; N/⇓= normal or decreased; N/⇑= normal or increased; PSH = pseudohypoparathyroidism; VDDR = vitamin D–deficiency rickets (including sunlight or nutritional deficiency, vitamin D malabsorption, inhibition of 25-hydroxylation).

   Decreased Bioavailability of Vitamin D: Inadequate Sunlight and Nutritional Vitamin D Deficiency

Adequate exposure to sunlight and fortification of dairy products with vitamin D have eliminated vitamin D deficiency secondary to inadequate endogenous production or nutrition in the majority of countries. However, in several populations, such as Asian immigrants in Britain, rickets and osteomalacia secondary to vitamin D deficiency occur in neonates and infants, in adolescents during pubertal growth, and, less frequently, among adults. In addition, over the past 20 years, a resurgence of vitamin D deficiency rickets has been observed in North America and Europe. Insufficient vitamin D intake secondary to using unfortified foods, naturally dark pigmentation (which interferes with ultraviolet transmission through the skin), genetic factors, and social customs (such as avoiding sun exposure) contribute to the development of disease in these subjects. Moreover, occurrence of disease in neonates is virtually always the result of vitamin D deficiency in mothers with ethnocultural risk factors for such deficiency. In the United States and other developed countries, a surprisingly frequent occurrence of vitamin D deficiency osteomalacia has also been recognized recently in alcoholic patients, institutionalized patients, and elderly persons. Poor diet, in some cases including avoiding milk and milk products because of lactose intolerance, lack of sunlight exposure, and an age-related decline in the dermal synthesis of 7-dehydrocholesterol are among the factors predisposing to the vitamin D deficiency and consequent bone disease.

The clinical sequelae of decreased vitamin D bioavailability are generally preceded by a fall in circulating 25-hydroxyvitamin D levels and begin to occur in the first 18 months of life. Whereas such a deficiency is caused in most patients by inadequate circulating vitamin D, Asian Indians in the United States also manifest increased 25-hydroxyvitamin D-24-hydroxylase activity, which may limit circulating 25-hydroxyvitamin D levels. In any case, measurement of 25-hydroxyvitamin D serves to identify populations at risk for, and facilitates early detection of, vitamin D deficiency rickets and osteomalacia. However, it has become increasingly clear that nutritional rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Moreover, along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Thus, vitamin D supplementation alone may not prevent or treat rickets in populations with limited calcium intake.

Treating clinically evident vitamin D–deficient rickets and osteomalacia invariably results in healing of the bone disease. The disorder is best treated with vitamin D and restoration of normal dietary calcium and phosphorus intake. Ergocalciferol (vitamin D2) is preferred to calcitrol because it provides the missing substrate that submits to physiologic regulation of vitamin D metabolite production.

   Vitamin D Malabsorption

Gastrointestinal malabsorption associated with diseases of the small intestine, hepatobiliary tree, and pancreas may result in decreased absorption of vitamin D and/or depletion of endogenous 25-hydroxyvitamin D stores owing to abnormal enterohepatic circulation. In general, malabsorption of vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicron-facilitated absorption ( Chapter 143 ). Such abnormalities often are associated with rickets and/or osteomalacia. However, most affected patients are asymptomatic, and many exhibit only reduced bone volume rather than evidence of defective bone mineralization. Intestinal bypass surgery and adult celiac disease are common instances in which vitamin D malabsorption occurs and in which the suspicion for osteomalacia should remain high. In contrast, patients with cholestatic liver disease, extrahepatic biliary obstruction, and diseases of the distal portions of the small intestine, such as regional enteritis, may develop bone disease secondary not only to poor vitamin D absorption but also to disruption of enterohepatic circulation.

Osteomalacia may also develop in patients who have had partial or total gastrectomy for peptic ulcer disease or other indications. Loss of gastrointestinal acidity or malfunction of the proximal small bowel underlies the vitamin D malabsorption in such circumstances. The absence of sufficient absorbing surface or the failure of intestinal mucosal cells to respond to vitamin D or its metabolites may also cause vitamin D malabsorption and consequent bone disease. In addition, after bariatric surgery, malabsorption may result in vitamin D deficiency and abnormal calcium metabolism occur in up to 60% of untreated patients, whereas osteomalacia develops in a substantial subset of the affected subjects.

Treatment of established disease generally requires pharmacologic amounts of vitamin D or its metabolites to overcome the defective absorption and/or the aberrant enterohepatic circulation or to offset end-organ resistance at the intestinal mucosa. Most patients respond well to calcium supplements, 1 to 1.5 g/day, and ergocalciferol, 1250 to 5000 μg/day. If the severity of malabsorption makes oral vitamin D ineffective, parenteral ergocalciferol, 12,500 to 25,000 μg, given intramuscularly once a month, is a practical alternative. Because magnesium deficiency often coexists in patients with malabsorptive diseases and may slow healing of the osteomalacia, adjunctive therapy with magnesium oxide may facilitate bone mineralization.

   Abnormal Vitamin D Metabolism

   Liver Disease

Because vitamin D is hydroxylated in the liver to form 25-hydroxyvitamin D, patients with severe parenchymal or obstructive hepatic disease ( Chapter 154 ) may have reduced production of this metabolite. These patients, however, rarely manifest biochemical or histologic evidence of osteomalacia. Indeed, an overt decrease of 25-hydroxyvitamin D generally requires concomitant nutritional deficiency or interruption of the enterohepatic circulation. Consequently, therapy for biopsy-proven osteomalacia, when present, is similar to therapy for osteomalacia that is secondary to malabsorption of vitamin D.

   Drug-Induced Disease

Decreased circulating levels of 25-hydroxyvitamin D may also occur in patients treated with drugs such as phenytoin, phenobarbital, carbamazepine, and rifampin. This defect in vitamin D metabolism results from induction of hepatic microsomal enzymes that metabolize 25-hydroxyvitamin D to inactive metabolites. Evidence suggests that such drugs activate the orphan nuclear receptor, pregnane X receptor, with consequent transactivation of the CYP24 promoter, enhanced CYP24 expression, and increased 25-hydroxyvitamin D-24-hydroxylase activity. Such increased enzyme activity would be expected to decrease the serum 25-hydroxyvitamin D levels. Secondary to this abnormality and/or to the direct inhibitory effects of these drugs on intestinal calcium absorption and PTH-mediated calcium mobilization from bone, treated patients often exhibit a decreased level of ionized calcium. These multiple influences commonly result in a bone disorder that may be mild osteomalacia or hyperparathyroid bone disease. Treatment of the bone disease and of hypocalcemia generally requires modest vitamin D supplementation (150 to 400 μg/week).

   Vitamin D–Dependent Rickets Type 1 (Pseudovitamin D Deficiency)

Limited production of 1,25-dihydroxyvitamin D consequent to hereditary or acquired diseases represents another abnormality of vitamin D metabolism that invariably results in rickets or osteomalacia. Vitamin D–dependent rickets type 1 is such a genetic disorder, transmitted as an autosomal recessive trait and characterized by hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase activity. As a result of the hypocalcemia, PTH levels are elevated, and, consequently, urinary excretion of amino acids and phosphate is enhanced. In addition to these biochemical abnormalities, within the first year of life patients exhibit muscle weakness and hypotonia, motor retardation, and stunted growth. As the condition progresses, patients develop the classic radiographic signs of vitamin D–deficiency rickets and bone biopsy evidence of osteomalacia. Further, affected subjects generally have a decreased serum 1,25-dihydroxyvitamin D concentration, resulting from inactivating missense and null mutations in the 1α-hydroxylase gene, as well as deletions, duplications, and splice site mutations, which abolish enzyme activity and limit production of this active vitamin D metabolite. This abnormality has been substantiated by (1) experiments in humans that demonstrate that serum calcitriol levels do not increase in response to classic stimuli of enzyme activity, (2) the absence of enzyme activity in renal cortical homogenates from the porcine homologue of this disease, and (3) the development of classic disease in mice following targeted ablation of 25-hydroxyvitamin D–1α-hydroxylase activity. More recently, however, two mutations have been identified, which result in only partial inactivation of enzyme activity and produce a mild form of the disease with normal serum levels of calcium and calcitriol but elevated circulating concentrations of PTH.

A physiologic dose of calcitriol (1 μg/day) generally promotes complete healing of the bone disease and resolution of the biochemical abnormalities, whereas a pharmacologic dose of vitamin D (20,000 to 100,000 U/day) or 25-hydroxyvitamin D (0.1 to 1.0 mg/day) is required to achieve similar effects. Regardless of the therapy used, in the majority of affected patients, therapy with vitamin D or its metabolites must be continued for life to prevent relapse.

   Chronic Renal Failure

Osteomalacia is common in patients with chronic renal failure and often tends to be the predominant type of renal osteodystrophy in younger patients ( Chapter 132 ). The abnormal mineralization may be part of mixed uremic osteodystrophy, or it may exist in isolation as a low-turnover osteomalacia. In the latter, the defect in mineralization almost certainly results in part from a decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Such abnormal vitamin D metabolism occurs secondary to either insufficient viable renal cortical tissue or the inhibitory effects of hyperphosphatemia on renal 25-hydroxyvitamin D–1α-hydroxylase activity. In addition, in some patients aluminum accumulated in bone underlies the abnormal mineralization. Indeed, the presence of aluminum may render the bone abnormality resistant to vitamin D. Under such circumstances, treatment with deferoxamine may be necessary to mobilize the aluminum from bone and other tissues and to improve mineralization.


Osteomalacia only rarely occurs in patients with hypoparathyroidism ( Chapter 266 ). Hypocalcemia and low or low-normal serum 1,25-dihydroxyvitamin D are usually present and appear important in the pathogenesis of the bone disease. However, the underlying reason for the variable occurrence of bone disease remains uncertain. The low serum 1,25-dihydroxyvitamin D concentration results from the PTH deficiency. Bone pain suggests the diagnosis, and generally the diagnosis depends on histomorphometric analysis of a bone biopsy. Most patients respond well to treatment with vitamin D and calcium supplements, but for reasons that are not clear, some require therapy with 1,25-dihydroxyvitamin D.


In pseudohypoparathyroidism, apparent bone and kidney resistance to PTH results in hypocalcemia, retention of phosphate, and low serum 1,25-dihydroxyvitamin D levels ( Chapter 266 ). Surprisingly, however, affected patients often manifest bone disease marked by increased resorptive activity and osteomalacia. Indeed, severe demineralization, including frank osteitis fibrosa cystica and occasionally rickets or osteomalacia, has been observed in 24 patients with pseudohypoparathyroidism. More commonly, the bone disease is silent, and diagnosis often depends on histomorphometric analysis of a bone biopsy sample. Undoubtedly, hypocalcemia, secondary hyperparathyroidism, and low serum 1,25-dihydroxyvitamin D levels are important cofactors in the pathogenesis of the disease. Patients respond well to pharmacologic amounts of vitamin D or to replacement doses of 1,25-dihydroxyvitamin D.

   Target Organ Resistance to Calcitriol

   Vitamin D–Dependent Rickets Type 2

Patients with clinical and biochemical abnormalities similar to those of patients with vitamin D–dependent rickets type 1, but with elevated 1,25-dihydroxyvitamin D levels, have been described. They have not only calcipenic rickets and osteomalacia but also variably associated abnormalities, including alopecia (in 60% of patients) and, in a minority of subjects, additional ectodermal anomalies, such as multiple milia, epidermal cysts, and oligodontia. The disease is a rare autosomal recessive disorder caused by mutations in the DNA and ligand-binding domains of the vitamin D receptor, which results in a decreased target organ responsiveness to 1,25-dihydroxyvitamin D through heterogeneous mechanisms. The genetic defects identified to date consist largely of point mutations in the conserved zinc finger region that reduce or abolish the affinity of the receptor for the DNA response element and, less often, point mutations that introduce a premature stop codon in the hormone binding domain of the receptor, which limits binding of 1,25-dihydroxyvitamin D to the receptor. As a consequence, affected patients manifest (1) failure of 1,25-dihydroxyvitamin D binding to available receptors, (2) a reduction in 1,25-dihydroxyvitamin D receptor binding sites, (3) abnormal binding affinity of 1,25-dihydroxyvitamin D to receptor, (4) inadequate translocation of the 1,25-dihydroxyvitamin D receptor complex to the nucleus, and (5) diminished affinity of the 1,25-dihydroxyvitamin D receptor complex for the DNA binding domain secondary to changes in the structure of receptor zinc binding fingers. It appears that complete loss of vitamin D receptor function by DNA binding domain mutations generally causes the alopecia or hair loss, whereas patients with mild impairment of the vitamin D receptor function from ligand binding domain mutations do not develop alopecia.

The role of the vitamin D receptor in the pathogenesis of this disorder has been confirmed in mice by targeted ablation of the DNA binding domain of the receptor; this procedure caused hypocalcemia, hyperparathyroidism, and alopecia within the first month of life. Effective treatment of this disease likely depends on the nature of the underlying abnormality. Thus, patients with deficient affinity of 1,25-dihydroxyvitamin D to receptor and inadequate nuclear translocation respond to high-dose vitamin D or 1,25-dihydroxyvitamin D with complete clinical and biochemical remission. In contrast, patients with other forms of the disease generally remain refractory to treatment with vitamin D or its analogues. However, every patient should receive a 6-month trial of therapy with supplemental calcium (1 to 3 g/day) and vitamin D (400,000 to 1,200,000 U/day), 25-hydroxyvitamin D (0.05 to 1.5 mg/day), or, in more severe cases, 1,25-dihydroxyvitamin D (5 to 60 μg/day). If the abnormalities of the syndrome do not normalize in response to this treatment, clinical remission may be achieved by administering high-dose oral calcium or long-term intracaval infusion of calcium. In addition, studies indicate that phosphate restriction in vitamin D–resistant null mice, the murine homologue of the human disease, effects normal bone mineralization.


Rickets and osteomalacia occur in association with a variety of disorders in which phosphate depletion predominates ( Chapter 120 ). Most typically, these diseases have in common abnormal proximal renal tubular function, which results in an increased renal clearance of inorganic phosphorus and hypophosphatemia. However, the biochemical abnormalities characteristic of these disorders are quite variable ( Table 265-3 ).

TABLE 265-3   — 

Calcium N N N N N N N
Alkaline phosphatase N/⇑ N/⇑ N/⇑ N/⇑ N/⇑ N/⇑ N/⇑
Parathyroid hormone N N N N
25(OH)D N N N N N N N
1,25(OH)2D (⇓) (⇓) (⇓)
Urinary phosphorus
Urinary calcium
Calcium absorption
Phosphorus absorption

Adapted from Econs MJ, Drezner MK: Bone disease resulting from inherited disorders of renal tubule transport and vitamin D metabolism. In Coe FL, Favus MJ (eds): Disorders of Bone and Mineral Metabolism. New York, Raven Press, 1992, p 937.

1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; ⇓= decreased; ⇑= increased; (⇓) = decreased relative to the serum phosphorus concentration; ADHR = autosomal dominant hypophosphatemic rickets; FS 1 = Fanconi’s syndrome type 1; FS 2 = Fanconi’s syndrome type 2; HHRH = hereditary hypophosphatemic rickets with hypercalciuria; N = normal; N/⇑= normal or increased; TIO = tumor-induced osteomalacia; XLH = X-linked hypophosphatemic rickets; XRHR = X-linked recessive hypophosphatemic rickets.

   Impaired Renal Tubular Phosphate Reabsorption

   X-Linked Hypophosphatemic Rickets/Osteomalacia

XLH represents the prototypic phosphate-wasting disorder, characterized in general by progressively severe skeletal abnormalities, growth retardation, and X-linked dominant inheritance. However, the clinical expression of the disease varies widely. The mildest abnormality is hypophosphatemia without clinically evident bone disease, and the most common clinically evident manifestation is short stature. Nevertheless, most children with the disease exhibit enlargement of the wrists and/or knees secondary to rickets, as well as bowing of the lower extremities. Additional early signs of the disease may include late dentition, tooth abscesses secondary to poor mineralization of the interglobular dentine, and premature cranial synostosis. Despite marked variability in the clinical presentation, bone biopsies in affected children and adults invariably reveal osteomalacia, the severity of which has no relation to gender, the extent of the biochemical abnormalities, or the severity of the clinical disability. In untreated youths and adults, the serum 25-hydroxyvitamin D level is normal, and the concentration of 1,25-dihydroxyvitamin D is in the low-normal range. The paradoxical occurrence of hypophosphatemia and normal serum calcitriol levels results from aberrant regulation of renal 25-hydroxyvitamin D–1α-hydroxylase activity, caused by abnormal phosphate transport or a circulating factor central to the genesis of the disease (see later).

A primary inborn error that results in an expressed abnormality in the renal proximal tubule (and perhaps the intestine), which impairs phosphate reabsorption (and absorption), underlies the pathogenesis of XLH. Although controversy exists regarding the character of the inborn error, studies in Hyp mice suggest that elaboration of a humoral factor is the basis for the observed inhibition of phosphate transport in affected patients. In this regard, investigations resulted in the cloning and identification of the disease gene as PHEX, a phosphate-regulating gene with homologies to endopeptidases located on the X chromosome. Deactivating mutations of this gene, which alters a membrane localized protein, clearly underlie the phenotypic expression of XLH by a mechanism that is incompletely understood. However, recognition of a humoral factor as essential to the pathogenesis of the disease suggests that the PHEX gene product may function normally to inactivate phosphatonin, a presumed phosphaturic hormone. An excess of this hormone would occur secondary to PHEX protein dysfunction and would result in renal phosphate wasting and perhaps abnormal bone mineralization. Despite these apparent advances, further progress has been limited by the inability to identify physiologically relevant PHEX substrates, which may function as phosphatonins. The search for candidate substrates has been guided, in part, by the knowledge that related endopeptidases have substrates that are coexpressed in an organ/cell type–specific fashion. In this context, physiologically relevant PHEX substrate is likely produced in osteoblasts, the site of predominant PHEX expression. Indeed, genes regulating extracellular matrix production, bone mineralization, and renal P transport (i.e., stanniocalcin I) are co-localized to the osteoblast. However, efforts to date have not identified a PHEX/Phex substrate in osteoblasts that influences renal P transport or bone mineralization. Nevertheless, various studies have identified circulating proteins, including fibroblast growth factor-23 (FGF-23), matrix, extracellular phosphoglycoprotein (MEPE), and secreted frizzled-related protein 4 (sFRP-4), which have actions consistent with those of presumptive phosphatonins. Moreover, circulating levels of FGF-23 are elevated in affected subjects with XLH and the Hyp-mouse.

Current treatment strategies for children with the disease directly address the combined calcitriol and phosphorus deficiency. Generally, the regimen includes a period of titration to achieve a maximum dose of calcitriol, 40 to 60 ng/kg/day in two divided doses, and phosphorus, 1 to 2 g/day in four or five divided doses. Although youths occasionally prove refractory to such therapeutic intervention, combined therapy often improves growth velocity, normalizes lower extremity deformities, and induces healing of the attendant bone disease. Of course, treatment involves a significant risk of toxicity that is generally expressed as abnormalities of calcium homeostasis and/or detrimental effects on renal function. Therapy in adults is reserved for episodes of intractable bone pain and refractory nonunion bone fractures. The observations that long-term growth hormone administration in affected youths may benefit growth, phosphate retention, and bone density suggest that a subgroup of patients may benefit from adjunctive treatment with this hormone.

   Hereditary Hypophosphatemic Rickets with Hypercalciuria

This rare autosomal recessive genetic disease is marked by hypophosphatemic rickets with hypercalciuria. In contrast to other diseases in which renal phosphate transport is limited, patients with HHRH exhibit increased 1,25-dihydroxyvitamin D production. The resultant elevated serum calcitriol levels enhance the gastrointestinal calcium absorption, which, in turn, increases the filtered renal calcium load and inhibits PTH secretion. The clinical expression of the disease is heterogeneous, although initial symptoms generally consist of bone pain and/or deformities of the lower extremities. Additional features of the disease include short stature, muscle weakness, and radiographic signs of rickets/osteomalacia and/or osteopenia. The various symptoms and signs may exist separately or in combination and may be present in a mild or severe form. In general, the severity of the bone mineralization defect correlates inversely with the prevailing serum phosphorus concentration. Relatives of patients with evident HHRH may exhibit an additional mode of disease expression. These persons manifest hypercalciuria and hypophosphatemia, but the abnormalities are less marked and occur in the absence of discernible bone disease.

Studies have mapped the disease genetic locus to the end of the long arm of chromosome 9, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaPi-IIc, located in renal proximal tubule cells. Nucleotide sequence analysis in multiple families has revealed disease-associated mutations. In individuals homozygous for the mutation, loss of SLC34A3 function presumably ensues, resulting in a primary renal tubular defect, which is compatible with the HHRH phenotype. Individuals heterozygous for the SLC34A3 mutation manifest the hypercalciuria and mild hypophosphatemia observed in relatives of patients with evident HHRH.

Patients with HHRH have been treated successfully with high-dose phosphorus (1 to 2.5 g/day in five divided doses) alone. In response to therapy, bone pain disappears, and muscle strength improves substantially. Moreover, most treated patients exhibit accelerated linear growth, and radiologic signs of rickets are completely absent within 4 to 9 months. Despite this favorable response, limited studies indicate that such treatment does not completely heal the associated osteomalacia. Therefore, further studies are necessary to determine whether phosphorus treatment alone is truly sufficient for this disorder.

   Autosomal Dominant Hypophosphatemic Rickets

Not all familial renal phosphate wasting disorders are X-linked; several studies have documented an autosomal dominant inheritance of a hypophosphatemic disorder similar to XLH. The phenotypic manifestations of this disorder include the expected hypophosphatemia resulting from renal phosphate wasting, lower extremity deformities, and rickets/osteomalacia. Affected patients also demonstrate normal serum levels of PTH and 25-hydroxyvitamin D, while maintaining an inappropriate normal concentration of 1,25-dihydroxyvitamin D, in the presence of hypophosphatemia. Long-term studies indicate that a few of the affected female patients demonstrate delayed penetrance of clinically apparent disease and an increased tendency for bone fracture, which are uncommon occurrences in XLH. In addition, among patients who manifest disease in childhood, rare individuals lose the renal phosphate-wasting defect after puberty. Limited information is available regarding other aspects of the disease. However, recent studies have identified the gene locus for this disease on chromosome 12p13.3 in an 1.5-Mb region between the markers D12S1685 and D12S1594. Mutation screening of the genes in this region ensued and direct sequencing of FGF-23 exons from families affected by autosomal dominant hypophosphatemic rickets (ADHR) revealed three unique missense mutations, which were not found in 214 sequenced control alleles and more than 1400 control alleles evaluated by RFLP analysis. Moreover, mutations in FGF-23 have been discovered in patients with ADHR. These mutations protect the protein from proteolysis, thereby potentially elevating circulating levels of the FGF-23, which likely leads to P wasting. This discovery suggests that FGF-23 may function not only as a phosphaturic factor in ADHR but also as phosphatonin in XLH.

   X-Linked Recessive Hypophosphatemic Rickets (X-Linked Hypercalciuric Nephrolithiasis)

The initial description of X-linked recessive hypophosphatemic rickets involved a family in which male family members presented with rickets or osteomalacia, hypophosphatemia, and a reduced renal threshold for phosphate reabsorption. In contrast to patients with XLH, affected patients exhibited hypercalciuria, elevated serum 1,25-dihydroxyvitamin D levels, and proteinuria of up to 3 g/day. Patients also developed nephrolithiasis and nephrocalcinosis with progressive renal failure in early adulthood. Female carriers in the family were not hypophosphatemic and lacked any biochemical abnormalities other than hypercalciuria. Three related syndromes have been reported independently: X-linked recessive nephrolithiasis with renal failure, Dent’s disease, and low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis. These syndromes differ in degree from each other, but common themes include proximal tubular reabsorptive failure, nephrolithiasis, nephrocalcinosis, progressive renal insufficiency, and, in some cases, rickets or osteomalacia. Identification of mutations in a gene in all four syndromes, CLCN5, whose product is involved in chloride transport, has established that they are phenotypic variants of a single disease and are not separate entities. However, the varied manifestations that may be associated with mutations in this gene, particularly the presence of hypophosphatemia and rickets/osteomalacia, underscore that environmental differences, diet, and/or modifying genetic backgrounds may influence phenotypic expression of the disease.

   Tumor-Induced Osteomalacia (Oncogenous Osteomalacia)

Since the initial recognition of this disease, reports have been published of more than 125 patients in whom rickets and/or osteomalacia were associated with a coexisting tumor. The coexistent tumors were of mesenchymal origin in the majority of patients. The cardinal feature of this disease is remission of the unexplained bone disease after tumor resection. In general, affected patients present with bone and muscle pain, muscle weakness, and, occasionally, recurrent fractures of long bones. Biochemical abnormalities include renal phosphate wasting marked by an abnormally low renal tubular maximum for the reabsorption of phosphate, decreased gastrointestinal absorption of phosphate, and consequent hypophosphatemia. In general, serum 25-hydroxyvitamin D levels are normal, and serum calcitriol is profoundly decreased or is inappropriately normal relative to the hypophosphatemia. Generalized osteopenia, pseudofractures, and coarsened trabeculae, as well as widened epiphyseal plates in children, are the common radiographic abnormalities of the syndrome.

Most investigators agree that tumor production of a humoral factor or factors that may affect multiple functions of the proximal renal tubule, particularly phosphate reabsorption (resulting in hypophosphatemia), underlies the pathogenesis of this syndrome. This possibility is supported by (1) the presence of phosphaturic activity in tumor extracts in patients with tumor-induced osteomalacia, (2) the occurrence of hypophosphatemia and increased urinary phosphate excretion in heterotransplanted tumor-bearing athymic nude mice, and (3) the demonstration that extracts of the heterotransplanted tumor inhibit renal 25-hydroxyvitamin D–1α-hydroxylase activity in cultured kidney cells. Indeed, extensive analysis of tumors from patients with tumor-induced osteomalacia have revealed constitutively high expression of several genes that potentially are involved in the systemic regulation of inorganic phosphate and calcitriol levels, including FGF-23, MEPE, and sFRP-4 and excessive production of proteins with known functions related to regulation of renal phosphate excretion (FGF-23, sFRP-4). Although such evidence supports the existence of several circulating factors, or phosphatonins, that play a pathogenetic role in the regulation of inorganic phosphate and vitamin D homeostasis in tumor-induced osteomalacia, the interaction of these factors and the predominant or coincident roles that they play in generating the phenotype of this disease remain under active investigation.

Regardless, studies indicate that in many affected patients, the secretion of the phosphatonins may be modulated by somatostatin receptors. Hence, tumor identification is possible on octreotide scanning, and octreotide therapy (50 to 100 μg subcutaneously three times a day) may ameliorate the biochemical and perhaps bone abnormalities of the syndrome if tumor resection is not possible.

Adding to the complexity of the syndrome, patients with tumor-associated osteomalacia secondary to hematogenous malignancy exhibit abnormalities of the syndrome secondary to a distinctly different mechanism. In these subjects, the nephropathy associated with light-chain proteinuria results in decreased renal phosphate reabsorption and consequent hypophosphatemia. At least 15 patients with this form of the disorder have been reported.

The primary treatment of this disorder is complete resection of the associated tumor. However, recurrence or metastasis of tumors often precludes such definitive therapy. In such cases, calcitriol (1.5 to 3.0 μg/day) alone or combined with phosphorus supplementation (2 to 4 g/day) completely heals the attendant bone disease or significantly improves the biochemical and histologic abnormalities. Careful serial assessment of parathyroid function, serum and urinary calcium, and renal function are essential to ensure safe therapy in affected subjects.

   Fanconi’s Syndrome

Rickets and osteomalacia are frequently associated with Fanconi’s syndrome, a disorder characterized by phosphaturia and consequent hypophosphatemia, aminoaciduria, renal glycosuria, albuminuria, and proximal renal tubular acidosis ( Chapter 129 ). Although many diverse congenital and acquired diseases are associated with this syndrome (see Table 265-1 ), damage to the proximal renal tubule represents the common underlying mechanism of disease. Resultant dysfunction produces renal wasting of those substances primarily reabsorbed at the proximal tubule. The associated bone disease in this disorder is likely secondary to hypophosphatemia and/or acidosis, abnormalities that occur in association with aberrantly regulated (Fanconi’s syndrome type 1) or normally regulated (Fanconi’s syndrome type 2) vitamin D metabolism. Most recently, several investigators have recognized that antiretroviral therapeutic regimens in human immunodeficiency virus–positive patients cause Fanconi’s syndrome in a subset of the treated patients. Regardless of the underlying cause, patients with osteomalacia associated with adult-acquired Fanconi’s syndrome appear to respond well to treatment with phosphate alone or in combination with vitamin D replacement. In fact, these patients do not appear to require 1,25-dihydroxyvitamin D.


Intrinsic disorders of bone in which apparently abnormal matrix is produced but is not normally mineralized are extremely rare and are poorly understood. These diseases may result from presumed abnormalities of collagen or other proteins in the matrix or aberrant enzyme activity essential for normal mineralization.

   Abnormal Bone Matrix

   Fibrogenesis Imperfecta Ossium

Fibrogenesis imperfecta ossium is a rare, sporadically occurring disorder characterized by the gradual onset of intractable skeletal pain in middle-aged men and women. Pathologic fractures are a prominent clinical feature, and patients typically become bedridden. Although the serum calcium and phosphorus levels are normal, the alkaline phosphatase level is invariably elevated. The bones have a dense, amorphous, mottled appearance radiologically and a disorganized arrangement of collagen with decreased birefringence histologically. Most likely, the disorganized collagen matrix limits normal bone mineralization.

   Axial Osteomalacia

Axial osteomalacia is another unusual, sporadically occurring disorder that generally affects only middle-aged men. Most patients present with only vague, dull, chronic axial discomfort that typically affects the cervical region most severely. Abnormal radiographic findings are limited to the pelvis and spine, where the coarsened trabecular pattern is characteristic of osteomalacia. Although the alkaline phosphatase level may be increased, histopathologic studies reveal a normal lamellar pattern of collagen. However, the osteoblasts appear flat and inactive, a finding suggesting that an osteoblastic defect and perhaps an attendant abnormal matrix inhibit normal mineralization.

   Abnormal Enzyme Activity


Hypophosphatasia is a heritable disorder characterized by a deficiency of the tissue-nonspecific (liver, bone, kidney) isoenzyme of alkaline phosphatase, increased urinary excretion of phosphorylethanolamine, and skeletal disease that includes osteomalacia and rickets. The severity of clinical expression is remarkably variable and spans intrauterine death from profound skeletal hypomineralization at one extreme to lifelong absence of symptoms at the other. As a consequence, six clinical disease types are distinguished (see Table 265-1 ). The age at which skeletal disease is initially noted delineates, in large part, the perinatal (lethal), infantile, childhood, and adult variants of the disorder. However, affected children and adults may manifest only the unique dental abnormalities of the syndrome and, accordingly, are classified as having odontohypophosphatasia. Finally, patients with the rare variant, pseudohypophosphatasia, have the clinical, radiologic, and biochemical features of the classic disease without a decrease in the circulating levels of alkaline phosphatase. These individuals have defects in cellular localization and substrate specificity of the enzyme.

Affected infants exhibit hypercalcemia, hypercalciuria, enlarged sutures of the skull, craniosynostosis, delayed dentition, enlarged epiphyses, and prominent costochondral junctions. Genu valgum or genu varum may develop subsequently. In older children, disease may be limited to rickets. Surprisingly, the disorder in adults is mild despite the presence of osteopenia. Indeed, the disease may be limited to slowly healing metatarsal fractures or loss or fracture of teeth. Nevertheless, 50% of patients have a history of early exfoliation of deciduous teeth and/or rickets, and disease may reflect re-expression of the childhood disorder.

The perinatal and infantile forms of disease are inherited as autosomal recessive traits. The modes of inheritance for odontophosphatasia, adult hypophosphatasia, and childhood hypophosphatasia remain unclear, although an autosomal dominant disease transmission has been described in some kindreds with mild or severe disease. In many of these families, studies indicate that the existent mutations exhibit a negative dominant effect, thereby inhibiting the enzymatic activity of the heterodimer. The variability in disease apparently depends on the degree of heterodimeric inhibition with highly negative dominant effects associated with severe hypophosphatasia. The physiologic basis for the bone disease likely relates to the role of alkaline phosphatase in cleaving pyrophosphate, an inhibitor of bone mineralization. Failure to hydrolyze this physiologic substrate results in inorganic pyrophosphate elevated to levels sufficiently high to inhibit the mineralization process. The consequence of this pathophysiologic process is a block of the vectorial spread of mineral from initial nuclei within matrix vesicles outward into the matrix of growth cartilage and bone. Confirmation of this pathophysiologic mechanism has been obtained in mice with deletion of the tissue-nonspecific alkaline phosphatase gene. These animals have hypophosphatasia, elevated levels of pyrophosphate, and poorly mineralized bone, rescued by deletion of nucleotide pyrophosphatase phosphodiesterase 1, which generates pyrophosphate.

Therapy of this disease has been generally unrewarding. Thus, supportive treatment is important and may include craniotomy in children (to manage craniosynostosis) and, in adults, insertion of load-sharing intramedullary rods to treat fractures. Expert dental care is also crucial to minimize tooth loss and to prevent consequent malnutrition in youth.



Disturbances in mineralization may be seen in patients who consume etidronate daily at doses greater than 5 mg/kg of body weight. The etidronate is deposited at the bone surface and inhibits osteoblast function; it also directly inhibits calcium-phosphate crystallization.


Although multiple studies document that fluoride stimulates new bone formation, administering the drug in high doses without adequate calcium supplementation results in poorly mineralized bone, consistent with osteomalacia. The mechanisms by which fluoride alters osteoblast function and/or directly inhibits mineralization remains unknown.


Excess aluminum accumulation in bone inhibits mineralization and is a potential mechanism for the osteomalacia observed in patients with chronic renal failure, as discussed earlier. In addition, accumulation of aluminum in bone likely underlies the osteomalacia observed in patients treated with total parenteral nutrition. In such cases, aluminum contamination of casein hydrolysate, as well as albumin, phosphate, and calcium solutions, provides the major source of the mineral. Changing total parenteral nutrition solutions from those with casein hydrolysate to those with purified amino acids has markedly reduced the incidence of clinically evident bone disease.

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