Clinical Features of Rickets and Osteomalacia

The clinical manifestations of rickets are mainly related to skeletal pain and deformity, slippage of epiphyses, disturbances in growth, and fracture of the osteomalacic bones. Hypocalcemia, when it occurs, may be symptomatic. Depending on the degree of hypophosphatemia, muscular weakness and hypotonia may be prominent features. Dent and Stamp³¹ have indicated nine factors that underlie the clinical manifestations of rickets and osteomalacia, modified here as follows:

In infants and young children, especially in severe, classic rickets, listlessness and irritability are common. In infants, myopathy is characteristic and is manifested by hypotonia. In older children, the weakness may present as a proximal myopathy similar to that observed in the adult. Other findings in infants include parietal flattening or frontal bossing, softening of the calvarium (craniotabes), and widening of the sutures. The thickened growth plates may be evident clinically as the rachitic rosary at the rib ends and may even simulate juvenile rheumatoid arthritis when areas such as the wrists are involved. Indentation of the lower ribs at the site of attachment of the diaphragm is known as Harrison’s groove or sulcus. Pelvic deformities also occur, and the skeleton is more prone to fractures. Pain, when present, is greater at the knees and other weight-bearing joints. Dental eruption may be delayed, and enamel defects are common.

In contrast, osteomalacia in adults may be difficult to detect on clinical grounds alone. Diffuse skeletal pain and muscular weakness may be present. Pain, often prominent about the hips and in association with hypophosphatemic myopathy, may produce a waddling or antalgic gait. Fractures may occur in the ribs and vertebral bodies, as well as in long bones, leading to progressive deformities. Affected individuals may also have localized pain and swelling in one or more joints. Synovial fluid is noninflammatory and free of crystals. Symmetric polyarthralgias resembling those of rheumatoid arthritis or polymyalgia rheumatica may also be observed.³² Muscular weakness is quite common,^33,34 is primarily proximal in distribution (which contributes to the waddling gait), and is often associated with wasting and hypotonia with preservation of brisk reflexes.³⁵ This is thought to be a consequence of hypophosphatemia and responds to phosphate repletion.³⁶ The molecular basis remains elusive, with no difference observed in the relative concentrations of skeletal muscle phosphocreatine, adenosine triphosphate, or inorganic phosphate estimated by phosphorus nuclear magnetic resonance spectroscopy.³⁷ Although the etiology of the neuromuscular features of osteomalacia is not clearly defined, therapy of the underlying disorder, such as vitamin D in nutritional osteomalacia, alkalinization in acidosis, and phosphate repletion in hypophosphatemic osteomalacia, results in resolution of these features. The role of hypophosphatemia per se in muscular weakness is discussed in Chapter 61.

Radiologic Features

Radiologic features of rickets and osteomalacia reflect the histopathologic changes. In rickets, the alterations are most evident at the epiphyseal growth plate, which is increased in thickness, cupped, and reveals haziness at the diaphyseal border due to decreased mineralization of the hypertrophic zone and inadequate mineralization of the primary spongiosa (Fig. 70-3). Variation in the pattern of rachitic changes is influenced by differences in the rates of growth of individual bones. The trabecular pattern of the metaphyses is abnormal, the cortices of the diaphyses may be thinned, and bowing of the shafts may be present.

FIGURE 70-3. A, Rickets in a child with Fanconi’s syndrome, showing typical cupping of distal femoral epiphyses. B, Osteomalacia in an 80-year-old woman who had a history compatible with hypophosphatemic rickets dating to early childhood. Note multiple pseudofractures (arrows).

Osteomalacia is due to decreased mineralization and is therefore associated with a decrease in bone density, loss of trabecular patterning, and variable degrees of thinning of the cortices.^38,39 In some patients, radiologic changes are indistinguishable from those seen in osteoporosis. The characteristic finding that specifically suggests osteomalacia is the presence of radiolucent bands known as pseudofractures, Looser’s zones, or umbauzonen, ranging from a few millimeters to several centimeters in length and usually oriented perpendicularly to the surface of the bone. (Fig. 70-4). They tend to occur symmetrically and are particularly common at the inner aspects of the femur near the femoral neck, in the pelvis, in the outer edge of the scapula, in the upper fibula, and in the metatarsals.

FIGURE 70-4. Radiograph of the pelvis and proximal femora in an adult with renal phosphate wasting. Note pseudofractures, also known as Looser’s zones (arrows).

(From Case 2 in Jaworski ZFG, Kloswvych S, Cameron E: Proceedings of the First Workshop on Bone Morphometry. Ottawa: University of Ottawa Press, 1973.)

Pseudofractures are most often seen at sites where major arteries cross the bones. Arteriography in some^36,40,41 but not all cases⁴² suggests that the origins of the pseudofractures correspond to the locations of major arteries (Fig. 70-5). Trauma of some sort, whether related to arterial pulsation or other factors (e.g., weight-bearing stress), is likely responsible for the symmetry of the lesions and their predilection for the described sites. Pseudofractures are often multiple, occasionally occurring at 10 to 15 sites in a single individual; such multiple symmetric pseudofractures in osteomalacic individuals have been referred to as Milkman’s syndrome.^43–46 The abnormalities in Milkman’s original case were also considered by Albright and Reifenstein⁴³ to be manifestations of osteomalacia. The histopathology of Looser’s zones is that of premalacic lamellar bone, some of which is surrounded by lamellar osteoid at the edge of the defect.⁴⁷ In addition, there are foci of woven bone, some of which is mineralized and some not. This accounts for the lower radiologic mineral density of the pseudofracture compared with the surrounding bone. Subperiosteal erosions along the diaphyseal cortices extending to the metaphyses may be seen when secondary hyperparathyroidism is present. Widening (or pseudowidening) of the sacroiliac joints and the appearance of hazy margins has also been observed, sometimes suggesting ankylosing spondylitis, which osteomalacia may mimic clinically.³⁶

FIGURE 70-5. Radiograph (r) and corresponding arteriograms (a) of a patient with adult-onset renal phosphate wasting. A, Pelvis. B, Femur. Note that the origin of Looser’s zones (arrows) corresponds with crossing of major vessels.

(From Case 2 in Jaworski ZFG, Kloswvych S, Cameron E: Proceedings of the First Workshop on Bone Morphometry. Ottawa: University of Ottawa Press, 1973.)

In some patients with osteomalacia, increased rather than decreased radiologic density of bones may be observed.⁴⁸ This is seen particularly in patients with renal tubular phosphate leaks, as opposed to vitamin D deficiency (Fig. 70-6). In such patients, there may be a striking degree of thickening of the cortices and trabeculae of the spongy bone, at times associated with exostotic spurs. This hyperostosis has been noted in untreated patients. It is not usually observed in patients with generalized defects in proximal renal tubular reabsorption. Despite the increase in mass of bone per unit volume, microscopically the trabeculae are covered with abnormally thickened osteoid seams typical of osteomalacia. Similar findings may be noted in patients with chronic renal failure. The reason for the hyperostosis is unknown; the bone is still architecturally abnormal and subject to fracture with relatively minimal trauma.

FIGURE 70-6. Increased bone mass in patients with osteomalacia. A, Radiographs of femora of a 15-year-old boy with X-linked hypophosphatemia. Note the thick tibial cortex (c) and Looser’s zone (arrow). B, Radiograph of pelvis and femora of a 38-year-old woman with hypophosphatemia present since childhood. Note Looser’s zones (arrows).

In patients with X-linked hypophosphatemic osteomalacia and rickets, an additional finding has been the presence of a generalized involvement of the entheses, with exuberant calcification (more likely ossification) of tendon and ligament insertions.^49,50 The absence of inflammatory cells, as well as other clinical features, differentiates this disorder from degenerative joint disease and the seronegative spondyloarthropathies. A comprehensive classification of rickets and osteomalacia is shown in Table 70-2. A detailed discussion of all these conditions is not included here because selected areas are covered in other chapters.

Table 70-2. Classification of Rickets and Osteomalacia

Nutritional Osteomalacia and Rickets

In 17th century Scotland and England, the association of poverty and malnutrition with the occurrence of infantile rickets was vividly documented. The widespread prevalence of infantile rickets in the industrialized regions of Britain was further documented in reports from Glasgow in the late 1800s and early 1900s. The link between rickets, dietary deficiency of vitamin D, and correction of vitamin D deficiency by solar radiation was finally established in 1923 by the work of the Vienna Council. Following this discovery, fortification of certain foods with vitamin D reduced the incidence of nutritional rickets in Europe and the United States to negligible levels, and by the 1940s, vitamin D deficiency was no longer regarded as an important cause of osteomalacia and rickets.⁴³ Vitamin D metabolism and the role of specific metabolites in bone development, mineralization, and remodeling are discussed elsewhere (see Chapter 58). Nevertheless, the role of vitamin D in the prevention of osteomalacia and rickets is relevant to the discussion in this chapter.

Studies in Glasgow^51–53 and London⁵⁴ documented the reappearance of nutritional osteomalacia and rickets as a public health problem in the United Kingdom. Since the 1950s, the population at risk primarily involves East Asian immigrants whose unique dietary and social customs have led to the development of osteomalacia and rickets.^52,54–58 Other groups at risk include housebound and elderly subjects and food faddists, especially those on vegetarian or fat-free diets.^52,54–58 An unexpectedly high prevalence of osteomalacia was also observed in elderly women with rheumatoid arthritis who were housebound and had poor nutritional status.⁵⁹

Gastrointestinal and Hepatic Diseases

Another population at risk for development of nutritional osteomalacia are morbidly obese individuals⁶⁰ and those who have undergone intestinal bypass surgery for treatment of severe obesity.^61–63 In one bypass surgery series, iliac bone biopsies revealed the presence of osteomalacia in nearly a third of 21 patients studied.⁶³ Treatment with vitamin D₂ (36,000 IU/day), as well as supplemental calcium (27 mmol/day), was required to promote a more positive calcium balance in some individuals.⁶¹ An increased frequency of osteomalacia also was observed in patients after gastrectomy,^64–66 the severity of the mineralization defect being positively correlated with serum 25-hydroxyvitamin D [25(OH)D] but not with serum 1,25-dihydroxyvitamin D [1,25(OH)₂D].

Malabsorption associated with diseases of the small intestine, hepatobiliary tree, and pancreas is the most common cause of severe vitamin D deficiency in the United States. Disorders of the small intestine causing malabsorption of vitamin D and resultant osteomalacia include celiac disease or sprue, regional enteritis, scleroderma, multiple jejunal diverticula, and blind-loop syndrome. Impaired absorption of calcium in association with, or as a consequence of, vitamin D malabsorption contributes to the development of osteomalacia.

Rickets occurs in infants and children with cholestatic liver disease.⁶⁷ Children with biliary atresia develop biliary cirrhosis, jaundice, and ascites. Intestinal absorption of vitamin D is markedly impaired, and serum values are low. Bone disease has been attributed to vitamin D deficiency, and pharmacologic doses of 1,25(OH)₂D₃ are required for treatment of the bone disease.⁶⁸

Low-birthweight infants are at risk for rickets, with the reported incidence ranging from 13% to 32%. Insufficient intake of calcium, phosphorus, and vitamin D have been implicated. The condition should be detected early, since prompt nutritional supplementation is required.⁶⁹ Infants of vitamin D–deficient mothers are at greatest risk for neonatal rickets,⁷⁰ which can be averted by maternal vitamin D supplementation during pregnancy. Special consideration should be given to screening for vitamin D deficiency during pregnancy in women whose social and dietary history reveal inadequate sun exposure and food sources of vitamin D. Infants who are entirely breastfed and have inadequate exposure to sunlight are also at risk for rickets, because the amount of vitamin D and 25(OH)D in human milk is inadequate.⁷¹

Vitamin D sources include dietary supplementation with ergocalciferol (vitamin D₂), an irradiation product obtained from plants, and cholecalciferol (vitamin D₃), produced in human skin by the action of ultraviolet light on the physiologic precursor, 7-dehydrocholesterol. Because most foods (with the exception of fatty fish) contain only small amounts of vitamin D₃, individuals must rely on either adequate sunlight exposure or dietary supplements to avoid vitamin D deficiency. There is marked seasonal variation in plasma 25(OH)D, independent of age and sex.^72–74 These variations parallel changes in duration and intensity of sun exposure, with higher values in late summer months in the northern hemisphere. Plasma 25(OH)D is almost twice as high in American women of Caucasian descent than in those of African descent during winter months, and the increment during summer months is also greater.⁷⁵ Plasma 25(OH)D and parathyroid hormone (PTH) are inversely correlated, implying that the changes in circulating 25(OH)D are metabolically significant.⁷⁶ In a study of patients who were hospitalized in a general medical ward, plasma 25(OH)D was low in over half of the subjects, consistent with a high prevalence of vitamin D deficiency.⁷⁷ Thus, adequate vitamin D supplementation is essential when exposure to sunlight is marginal.

Vitamin D requirements are greater in the elderly than in young adults. This difference is attributed to an age-related decline in dermal production of 7-dehydrocholesterol, the precursor for vitamin D₃,⁷⁸ diminished renal production of 1,25(OH)₂D,⁷⁹ and diminished intestinal absorption of calcium caused by lower levels of the vitamin D receptor in the intestine.⁸⁰ Other contributing factors include previous gastric surgery and occult malabsorption in addition to altered vitamin D metabolism. To determine optimal plasma 25(OH)D and how much vitamin D is required to achieve optimal values, Vieth,⁸¹ in an exhaustive review, and Heaney in another⁸² concluded that total daily intake and production of vitamin D of 2.5 to 5.0 mg (100 to 200 IU) and plasma 25(OH)D values greater than 20 to 25 nmol/L are sufficient to prevent clinical rickets or osteomalacia. Higher intakes or production of vitamin D would be necessary, however, to prevent secondary hyperparathyroidism, bone loss, and subclinical osteomalacia. Therefore, it may be necessary to maintain serum 25(OH)D levels of 100 nmol/L or greater to avoid bone loss, subclinical osteomalacia, and osteoporosis. The amount of vitamin D supplementation necessary to attain these levels varies widely, based on dietary factors and solar exposure.

In the East Asian immigrant populations of Britain, rickets and osteomalacia secondary to vitamin D deficiency are seen most commonly in neonates, infants, and adolescents during pubertal growth and less frequently among adults.^51,83–85 Multiple factors have been implicated in the development of bone disease, including insufficient intake of calcium and vitamin D, skin pigmentation,⁸⁶ which attenuates ultraviolet transmission through the epidermis, genetic factors,^87–89 and social customs, such as avoidance of sun exposure and consumption of chapati, a dietary staple flatbread high in phytate, which binds calcium in the gut and interferes with its absorption.⁹⁰ Furthermore, studies in rats demonstrated that the rate of inactivation of vitamin D in the liver was increased by a calcium-restricted diet.

Studies by Dent and colleagues⁹¹ strongly suggest that insufficient sunlight exposure plays a pivotal role in the development of nutritional rickets and osteomalacia, in addition to the rickets and osteomalacia observed in patients on long-term anticonvulsant therapy.⁹² In two carefully studied individuals, they demonstrated healing of rickets and positive calcium balance following therapy with ultraviolet light, despite a vitamin D–deficient, high-phytate diet. Substitution of a low-phytate diet did not affect the plasma biochemical abnormalities or the calcium balance.⁹¹

Scriver⁹³ divides the evolution of vitamin D deficiency in infancy into three stages. In stage 1, serum calcium tends to be low, serum phosphorus normal, and aminoaciduria absent. Without treatment, stage 2 develops, and aminoaciduria and hypophosphatemia appear as a consequence of diminished tubular reabsorption. In this stage, serum calcium tends to return to normal, and serum alkaline phosphatase increases, presumably related to the increased PTH and resultant increase in bone turnover. Renal tubular dysfunction (aminoaciduria, phosphaturia) has, at least in part, been attributed to the increased PTH.^94,95 Stage 3 is characterized by the return of hypocalcemia. The effect of lowered concentrations of serum phosphorus in stage 2 and lowered concentrations of serum calcium and serum phosphorus in stage 3 presumably account for development of the mineralization defect.

Rao et al.⁹⁶ reviewed the histomorphometric findings in a series of 65 patients with vitamin D depletion diagnosed on the basis of plasma levels of 25(OH)D less than 10 ng/mL. They found that in early vitamin D depletion, the effects on bone are manifested principally by the occurrence of secondary hyperparathyroidism. With increasing severity or duration of the vitamin D deficiency, the mineralization process becomes progressively impaired, bone formation rates decline, and osteoid surface and thickness increase.

In summary, rickets and osteomalacia are being recognized with increasing frequency in selected populations. Serum 1,25(OH)₂D is not a reliable indicator of vitamin D nutrition, since values may be normal in individuals with vitamin D deficiency.^97,98 The availability of serum 25(OH)D assays has also permitted detection of those at risk, prior to the development of overt clinical disease.

Acidosis and Osteomalacia

Acidosis resulting from a number of different causes has been associated with osteomalacia. The mechanism of bone loss and the mineralization defects are complex and not completely understood. Albright and Reifenstein⁴³ originally suggested that acidosis produces slow dissolution of the mineral phase of bone in an attempt to buffer retained hydrogen ion. This process is associated with hypercalciuria. Support for this suggestion has been obtained in studies of patients with renal tubular acidosis in whom retention of hydrogen ion is greater than that theoretically required to produce the observed decrease in plasma bicarbonate concentrations.⁹⁹ On the basis of measurements in normal subjects in whom metabolic acidosis is induced, it has been proposed that excess retained hydrogen ion is balanced by bone buffering and loss of bone calcium in the urine.^100–102 Since the hypercalciuria and increased bone resorption that accompany most acidotic states do not directly result in osteomalacia, other mechanisms must be invoked to explain the occurrence of clinically significant skeletal mineralization defects. Osteoclasts function optimally at a pH of approximately 6.9 and are inactive at a pH greater than 7.3; therefore, it is probable that the calcium release from bone induced by acidosis can be ascribed to increased osteoclast activity rather than to simple physicochemical buffering.¹⁰³ Chronic acidosis activates vacuolar hydrogen ion pumps in isolated osteoclasts and stimulates osteoclastic bone resorption.¹⁰⁴ In addition, activation of the voltage-gated H⁺ channel through protein kinase C in osteoclasts can sense changes in pH.¹⁰⁵

In parallel, metabolic acidosis inhibits the function of osteoblasts: in osteoblast culture systems, lowering pH to 6.9 decreases formation of mineralized nodules.¹⁰⁶ Acidosis increases expression of osteoblastic RANK-L via a cyclooxygenase-dependent mechanism, leading to enhanced osteoclastogenesis.¹⁰⁷ Another potential proton-sensing mechanism in the osteoblast is G protein–coupled receptors OGR1 and OGR2.¹⁰⁸ OGR1 is inactive at pH 7.8 and fully activated at pH 6.8, signals through the phosphoinositol pathway, and is expressed in osteosarcoma lines and primary osteoblasts. OGR2 signals through the cyclic adenosine monophosphate (cAMP) pathway but has not yet been shown to be expressed in bone cells. Maintenance of pH within a critical range is thus essential for bone-cell function and for mineralization to proceed normally.

Acidosis can also affect phosphate metabolism by altering renal tubular handling of the anion. In patients with chronic acidosis, treatment with alkali to correct the acidosis can normalize serum phosphate by increasing renal tubular phosphate reabsorption and phosphate maximal tubular excretory capacity.^109,110 Secondary hyperparathyroidism may be another factor involved in the altered phosphate handling in systemic acidosis,¹⁰⁹ and acidosis can impair intestinal calcium absorption in response to exogenous vitamin D,¹⁰⁶ as well as activation of 25(OH)D.¹¹¹ Rickets and osteomalacia secondary to acidosis are most frequently a complication of inherited distal renal tubular acidosis (RTA).¹¹² Clinical manifestations vary widely in type as well as severity. Autosomal-dominant as well as autosomal-recessive forms have been described. As a rule, the dominant form is usually recognized in adults who present with relatively mild disease characterized by nephrolithiasis and acidosis. Osteomalacia occurs infrequently. In contrast, the autosomal-recessive form is recognized in infancy or early childhood, is usually severe, and rickets is common. In dominant RTA, the causal mutation is in the SLC4A1:AE1 gene that encodes the heterotopic Cl⁻/HCO₃⁻ exchanger located in the α-intercalated cells of the distal tubules. In recessive RTA, the causal mutations are in the B1 or A4 subunits of the H⁺/ATPase encoded by ATP6V1B1 and ATP6V0A4 genes, respectively. Rarely, mutations in the SLC4A1:AE1 gene occur in recessive RTA as well. In most of the cases described in early reports,^113–115 healing of the bone disease resulted from correction of the acidosis with sodium bicarbonate alone (5 to 10 g/day). Nevertheless, healing is slow, and the response may be hastened by the addition of vitamin D or 1,25(OH)₂D₃. Occasionally, vitamin D toxicity can develop unexpectedly, so patients must be monitored carefully. Although chronic treatment with vitamin D is not necessary once the osteomalacia is cured, continued use of vitamin D may be required to complete healing in those individuals in whom the glomerular filtration rate is low.^115,116

Another form of inherited mixed distal/proximal RTA is associated with osteopetrosis and cerebral calcifications. The osteopetrosis, due to inadequate osteoclast function secondary to defects in acidification in the extracellular space adjacent to the ruffled border, is caused by mutations in the gene that encodes carbonic anhydrase II (CAII).^117–119 This RTA is characterized by defective urinary acidification and bicarbonate wasting, and the syndrome is explained by the fact that CAII is expressed not only in osteoclasts but in both proximal and distal segments of the nephron. It is of interest that bone marrow transplantation does not affect the acidosis but reverses the osteopetrosis (by radiologic and histologic criteria), since osteoclasts are of hematopoietic origin.¹²⁰

In several of the syndromes associated with more widespread renal tubular reabsorptive defects, systemic acidosis may contribute to the pathogenesis of osteomalacia. Some of these are inherited, such as various forms of Fanconi’s syndrome and Lowe’s syndrome (oculocerebrorenal syndrome). Some patients with renal tubular phosphate leaks may also have mild acidosis.^121–125 Other aspects of these syndromes are considered elsewhere in this chapter.

Osteomalacia may also be a complication of the acidosis produced by ureterosigmoidostomy, a procedure formerly used in the treatment of patients with carcinoma of the bladder. Reabsorption of chloride and hydrogen ions from urine in the colon is responsible for the acidosis. Keeping the rectosigmoid empty by frequent drainage corrects the acidosis and thus prevents the development of osteomalacia. Typical osteomalacia has also been observed in a patient with acidosis presumably resulting from chronic acetazolamide therapy. This patient was receiving phenobarbital, as well as phenytoin, for a severe seizure disorder, but when the acetazolamide alone was discontinued and the plasma bicarbonate increased, radiologic and clinical healing of osteomalacia was observed. Acetazolamide has direct inhibitory effects on bone resorption in animals independent of pH, and carbonic anhydrase inhibitors do prevent bone loss in humans.^126,127

Dietary Phosphate Depletion

In humans, phosphate depletion and resultant hypophosphatemia may lead to the development of rickets or osteomalacia by mechanisms that were discussed earlier. It is difficult to produce selective deficiency of phosphorus by dietary means alone, because most foods contain this element in concentrations that are sufficient to prevent hypophosphatemia and bone disease (see Chapter 61). However, hypophosphatemia has been reported in patients who ingest large quantities of nonabsorbable antacids, usually as a form of self-medication for dyspepsia.^128–132 This is accompanied by a marked increase in fecal phosphorus content, presumably related to binding of dietary phosphate by the antacid, resulting in a complex that is poorly absorbed from the gastrointestinal tract. In addition to the changes in phosphorus handling, these individuals also develop hypercalciuria. Most of the affected individuals show no evidence of increased bone resorption, although a small increase in osteoclastic surface and number of osteoclasts has been reported in one patient studied.¹³³ It is more likely that the rise in urinary calcium excretion is related primarily to impaired bone mineralization, a concept that is supported by the association of this syndrome with osteomalacia. Elevated levels of serum 1,25(OH)₂D are observed in patients with antacid-induced osteomalacia, a normal response to hypophosphatemia. Clinically significant bone disease is rare, suggesting that an ample supply of dietary phosphorus compensates for the absorptive defect. A similar syndrome of phosphate depletion has been described in patients with renal failure receiving large quantities of aluminum hydroxide gel, but osteomalacia in these patients may be related to aluminum intoxication and/or renal insufficiency.

Hypophosphatemia has also been observed in both chronic and acute alcoholism (see Chapter 61).^134,135 Bone densitometric studies and tetracycline-labeled bone biopsies obtained from chronic alcoholic patients have revealed an increased frequency of bone disease compared to sex- and race-matched controls.¹³⁶ Bone abnormalities include changes consistent with mixtures of osteoporosis, osteomalacia, and osteitis fibrosa. Multiple factors, including hypomagnesemia, metabolic alkalosis or acidosis, and renal tubular phosphate wasting contribute to the hypophosphatemia and bone disease.¹³⁷ Bone disease in alcoholism may be part of the generalized skeletal disorder associated with chronic liver disease of diverse origin, which has been termed hepatic osteodystrophy.¹³⁷ The syndrome comprises osteomalacia, osteitis fibrosa, osteoporosis, and periosteal new bone formation in the presence of chronic liver disease. Osteomalacia is most common in patients with cholestasis (particularly primary biliary cirrhosis) but is also observed in patients with alcoholic liver disease and other forms of cirrhosis. In most patients, the serum levels of 25(OH)D are low, ascribable to impaired intestinal absorption of vitamin D, but reduced exposure to ultraviolet light and reduced dietary intake also contribute.¹³⁸ Treatment with vitamin D metabolites can heal hepatic osteomalacia.

Dietary Calcium Deficiency

Nutritional rickets caused by calcium deficiency was first reported in 1978 by Pettifor and co-workers,¹³⁹ who described findings in nine rural South African children. Although they had spent extensive time outdoors, the children showed obvious clinical features of rickets, including progressive bone deformities, decreased growth, and typical radiographic changes. Four of the children had hypocalcemia, and all of them had normal serum 25(OH)D values but increased serum alkaline phosphatase and serum 1,25(OH)₂D values. Calcium-balance studies showed that calcium absorption was not impaired. The biochemical and radiographic changes of rickets were entirely corrected by treatment with calcium alone.

In a prospective, randomized, double-blind study of 123 Nigerian children with nutritional rickets, Thacher et al.¹⁴⁰ compared treatment with calcium alone, vitamin D alone, and the combination of calcium and vitamin D together. Treatment with calcium alone or calcium and vitamin D together was more effective than treatment with vitamin D alone. Baseline calcium intake was similar in patients and in a control group. It was concluded that although calcium deficiency was an important contributor to nutritional rickets, other unidentified factors might have been involved. Calcium deficiency is also prevalent in North American children and can contribute to nutritional rickets. Review of the records of 43 infants and toddlers who presented with rickets in New Haven, Connecticut (86% of whom were of African, Hispanic, or Middle Eastern descent and more than 93% of whom had been breastfed), revealed serum 25(OH)D levels less than 15 ng/mL in only 22%. However, 86% of those with a food history had been weaned to diets with minimal calcium content.¹⁴¹

Impaired Renal Tubular Phosphate Reabsorption

In 1937, Albright and co-workers¹⁴² reported their studies of a 16-year-old boy with longstanding rickets in whom standard doses of vitamin D failed to produce clinical improvement. Healing of the bone disease eventually occurred, but only after administration of extremely high doses of vitamin D. The results of their studies led to the introduction of the concept of “vitamin D resistance” in certain types of rickets. Since this initial report, so-called vitamin D–resistant rickets has been classified into several clinical and biochemical subtypes, the most common of which is the X-linked, dominantly inherited form discussed in detail in Chapter 66. Affected individuals usually present with clinical and radiographic evidence of rickets within the second or third year of life. The cardinal biochemical disturbance is hypophosphatemia due to renal phosphate wasting, associated with elevated levels of fibroblast growth factor (FGF-23).¹⁴³ Other causes of osteomalacia (see Table 70-2) must be excluded, particularly primary vitamin D deficiency, malabsorption, renal insufficiency, generalized renal tubular disorders, and the presence of certain mesenchymal tumors.

The mode of presentation of patients with adult hypophosphatemic osteomalacia or phosphate diabetes, as it has occasionally been termed, is characteristic. In contrast to individuals with the X-linked form, patients with the sporadic disease often develop prominent myopathy similar to that seen in other forms of rickets or osteomalacia. Deformities of the limbs are usually absent (possibly indicating normophosphatemia during the growth period), but these patients experience severe bone pain related to vertebral body collapse or femoral neck fractures. As in other forms of osteomalacia, radiographs commonly reveal extensive pseudofractures. Some subjects may also have isolated renal hyperglycinuria and occasionally renal glycosuria in addition to the hypophosphatemia. Generalized aminoaciduria or acidification defects are not seen in these individuals. Evaluation of patients with possible adult-onset hypophosphatemic osteomalacia should include general tests of renal function (creatinine clearance, acidification, concentrating ability, and analysis of urinary amino acid excretion), evaluation for malabsorption, and a search for the presence of occult tumors.

A positional cloning approach was utilized by a consortium of investigators to identify the gene for X-linked hypophosphatemia.¹⁴⁴ The gene was structurally similar to a group of membrane-bound metalloendopeptidases and was termed PEX, but renamed PHEX to avoid confusion with other genes. Several inactivating mutations have been shown in the PHEX genes of patients with X-linked hypophosphatemia as well as in the murine Phex gene in the Hyp mouse.^145–148 It is still not clear how the mutations in the PHEX gene account for the excessive renal tubular phosphate losses, but it has been suggested that PHEX might function to directly or indirectly degrade FGF-23 or regulate its expression.

Another disorder with isolated renal tubular phosphate wasting and inappropriately normal plasma 1,25(OH)₂D levels has been termed autosomal-dominant hypophosphatemic rickets (ADHR). In contrast to X-linked hypophosphatemia, ADHR displays variable and incomplete penetrance, as well as other clinical manifestations.^149–151 Positional cloning was used to identify FGF-23 as the abnormal gene associated with ADHR.¹⁵² In individuals with ADHR, mutations in FGF-23 that are localized to a subtilisin-like proprotein convertase cleavage site lead to elevated levels of FGF-23, which results in increased renal phosphate clearance.

A mutation in the phosphate transporter SLC34A3 (NptIIc) is the genetic basis for hereditary hypophosphatemic rickets with hypercalciuria (HHRH). This disorder is due to hypophosphatemia secondary to renal phosphate wasting and presents with rickets, muscle weakness and bone pain. Hypercalciuria, secondary to increased 1,25(OH)₂D (which leads to increased intestinal calcium absorption), distinguishes it from other forms of hypophosphatemic rickets.¹⁵³

In patients with X-linked hypophosphatemia, serum levels of 25(OH)D are normal, whereas the levels of 1,25(OH)₂D are in the low-normal range, inappropriately low for the level of serum phosphorus. Treatment of affected patients with 1,25(OH)₂D₃ and oral phosphate (1 to 2 g/day phosphorus equivalent) results in healing of rickets and osteomalacia; however, hypercalcemia and hypercalciuria may complicate therapy.^154,155 Of note is that heterozygous girls appear to respond better to therapy than hemizygous boys.¹⁵⁶ A variety of neutral phosphate salts are available for oral supplementation, including sodium and potassium salts or mixtures of the two. Greater elevations in serum phosphorus levels are observed with the potassium salt, likely related to the effects of the sodium ion on increasing renal phosphate clearance.¹⁵⁷ The precise amount of phosphate must be individualized for each patient. In individuals with severe renal phosphate leaks, as much as 1000 mg of elemental phosphorus is required every 4 to 6 hours to effect sustained elevations of serum phosphorus levels. The rise in serum phosphorus level after a single oral dose of phosphate is transient, so phosphate supplements must be administered at frequent intervals. The efficacy of therapy cannot be assessed with a single fasting determination of serum phosphate; multiple measurements of serum levels at various times after each dose are required. Emptying the capsules and dissolving the salt in water or other liquid may improve intestinal absorption and enhance serum phosphorus levels. Most patients experience some degree of gastrointestinal distress, such as cramps and diarrhea, when therapy is initiated; therefore, initial doses should be low and increments gradually introduced as tolerated. Simultaneous use of phosphate and vitamin D has resulted in accelerated healing in children with the X-linked form of hypophosphatemic osteomalacia.¹⁵⁸ Vitamin D itself or various analogues have a “phosphate-sparing” effect, allowing the use of lower doses of oral phosphate supplements. Whether the improved serum phosphorus levels seen with vitamin D or 1,25(OH)₂D₃ are accounted for by increased intestinal absorption of phosphate or decreased renal loss (due to decreased secondary hyperparathyroidism) has not been established. After fusion of the growth plates, patients are no longer at risk for rickets or growth retardation, raising the question as to whether treatment should be continued in affected adults. Healing of osteomalacia with therapy has been documented in adults, but close monitoring is required to avert the potential development of parathyroid hyperplasia and hypercalcemia resulting in nephrocalcinosis and renal insufficiency.^159,160