4.10 Rickets and osteomalacia (acquired and heritable forms) and skeletal dysplasias

Mineralization of newly formed organic matrix of bone is a complex and highly ordered process. The requirements include adequate extracellular concentrations of calcium (Ca²⁺) and phosphorous, as inorganic phosphate (Pi), and normal function of bone-forming cells. Disturbances in either requirement can lead to a stereotypic response of impaired skeletal mineralization (1).

Rickets describes the clinical consequences of diminished mineralization of matrix throughout a growing skeleton. Infants, children, and adolescents can be affected. Osteomalacia results from the same disturbance after growth plates fuse. However, neither term denotes a specific disease. Each is a generic label for the signs and symptoms that follow perturbations that disrupt the orderly deposition of hydroxyapatite crystals into skeletal tissue. Nevertheless, in nearly all patients, there are low extracellular levels of Ca²⁺ and/or Pi. Often, diminished stores or impaired bioactivation of vitamin D are involved and cause hypocalcaemia, secondary hyperparathyroidism, and hypophosphataemia (1). Occasionally, it is kidney tubule dysfunction that results directly in urinary Pi wasting and leads to hypophosphataemia, sometimes associated with impaired bioactivation of vitamin D. Rarely, disturbances involving chondrocytes and osteoblasts, defective bone matrix, or other disruptions interfere with Ca²⁺ and Pi deposition into the skeleton. The number of conditions that cause rickets and osteomalacia is considerable—some are acquired and some are inherited (Box 4.10.1).

Successful medical therapy for rickets or osteomalacia must address the specific disturbance(s) leading to aberrant mineral homoeostasis. It may be possible to correct the fundamental disorder, or it may be necessary to circumvent it. Except for dosage, pharmacological regimens for specific conditions will generally be the same regardless of patient age. However, distinctive disease manifestations trouble paediatric compared to adult patients, and the goals for treatment and follow-up differ.

In rickets, all three processes of skeletal formation are adversely affected (1):

Rickets features short stature (physeal disturbances), skeletal distortions (modelling defects), as well as fractures (impaired remodelling). Osteomalacia is usually not deforming (unless there are fractures) because growth plates are fused and modelling has essentially ceased; only remodelling is deranged. Accordingly, impaired mineralization of skeletal matrix is less apparent clinically and less distinctive radiographically in osteomalacia. In both conditions, however, defective bone remodelling (turnover) can appear on radiographs as generalized osteopenia or, occasionally, as osteosclerosis (coarse trabecular bone).

Alternatively, some refer to rickets as the disturbance in endochondral bone growth and modelling, and to osteomalacia as the disturbance in bone remodelling. In this context, osteomalacia is also present in paediatric patients.

Most of the clinical, radiological, and histological features of rickets and/or osteomalacia are the same and independent of the primary disorder. Thus, bone matrix mineralization can be impaired from: (1) primary Ca²⁺ deficiency (i.e. nutritional deficiency of the element, or more commonly from disruption of vitamin D metabolism) and called hypocalcaemic rickets and/or osteomalacia; (2) primary phosphorous deficiency (e.g. increased renal Pi clearance as in X-linked hypophosphataemia) and called hypophosphataemic rickets and/or osteomalacia; and (3) primary defects in local bone processes (e.g. hypophosphatasia due to alkaline phosphatase (ALP) deficiency) causing rickets and/or osteomalacia with normal or increased extracellular levels of mineral (1).

Much is now known about the biosynthesis, bioactivation, and physiological actions of vitamin D (2, 3) and the control of mineral homoeostasis (4). Despite fortification of foods with vitamin D in several countries (e.g. 400 IU per quart of milk or infant formula in the USA) or use of vitamin supplements, most antirachitic activity in healthy people comes from cutaneous synthesis of vitamin D (5). In the skin, 7-dehydrocholesterol is converted by 290–310 nm ultraviolet (UV) light to cholecalciferol (vitamin D₃). Age, skin pigmentation, and clothing as well as duration, angle, and intensity of UV light exposure all condition how much vitamin D₃ is made (5). Ergocalciferol (vitamin D₂) is the product of UV irradiation of ergosterol extracted from animal or plant tissues, and is used as a supplement or as a drug (2, 3).

Both vitamin D₂ and D₃ are prohormones, which are transported in the circulation by a high-affinity binding protein to muscle or fat for storage, or to the liver and subsequently to the kidney for bioactivation (2, 3). First, with little regulation, vitamin D is hydroxylated in hepatocyte mitochondria by the enzyme P450c25 to form the 25-hydroxyvitamin D metabolite called calcidiol. Then, with precise control mediated by Ca²⁺, Pi, and parathyroid hormone (PTH), 25-hydroxyvitamin D is further hydroxylated in kidney proximal convoluted tubule cells by mitochondrial P450c1α, more commonly referred to as 25-hydroxyvitamin D,1α−hydroxylase (or 1α−hydroxylase) to 1,25-dihydroxyvitamin D, also called calcitriol (6, 7, 8). Other cells can have 1α-hydroxylase activity: placental decidual cells, keratinocytes, macrophages from various origins, and some tumour cells (7, 8). However, the role of extrarenal production of 1,25-dihydroxyvitamin D is unknown, and under physiological conditions does not significantly add to circulating levels of this hormone. Hydroxylation at carbon 24 to produce 24,25-dihydroxyvitamin D, or 1,24,25-trihydroxyvitamin D, occurs in a wide range of normal tissues and is considered important for deactivation and removal of vitamin D metabolites. All of these enzymes are mitochondrial mixed function oxidases containing cytochrome P450 with ferredoxin and haem-binding domains. Vitamin D₂ and D₃ seem equally susceptible to these hydroxylations, and their bioactivated forms are essentially equipotent in influencing mineral homoeostasis (2, 3). However, there is some evidence that suggests vitamin D₂ is less effective than vitamin D₃ in humans. Rightfully, vitamin D is regarded as a steroid hormone, not as a nutrient, because cholecalciferol undergoes this series of bioactivation steps, and then circulates as 1,25-dihydroxyvitamin D to target organs where it binds to the vitamin D receptor (VDR) (6, 7, 8).

In target tissues, there are genomic and nongenomic actions of 1,25-dihydroxyvitamin D (9). 1,25-dihydroxyvitamin D couples to the VDR encoded by a gene of the nuclear hormone receptor superfamily. The VDR has both 1,25-dihydroxyvitamin D-binding and DNA-binding domains. After also combining with a retinoid X receptor heterodimeric partner, this VDR complex activates transcription of genes in bone, kidney, and enterocytes to assure adequate extracellular concentrations of minerals (9). 1,25-dihydroxyvitamin D is the active metabolite of vitamin D assessed by its potency and rapidity of action to augment gut absorption of Ca²⁺. Urinary Ca²⁺ reclamation by the kidneys and bone resorption are also increased. Furthermore, 1,25-dihydroxyvitamin D suppresses PTH synthesis (2, 3). The nomenclature of vitamin D and its activated forms emphasizes the hormonal nature of these secosterols (Table 4.10.1).

Extracellular concentrations of Ca²⁺ and Pi are maintained by three organs: intestine (mainly by absorption), bone (principally by in and out fluxes, as well as by resorption and formation), and kidney (by ultrafiltration and tubular reabsorption) (4). At least three hormones interact and control this homoeostatic mechanism. PTH activates bone cells, increases renal tubular reabsorption of Ca²⁺ while causing phosphaturia, and promotes 1,25-dihydroxyvitamin D production in the proximal renal tubule. Vitamin D (1,25-dihydroxyvitamin D) promotes Ca²⁺ absorption from the gut, probably affects osteoblasts, and controls the synthesis of PTH and a phosphatonin, fibroblast growth factor-23 (FGF-23) (10). FGF-23, produced by cells of the osteoblast lineage, diminishes renal tubular reabsorption of Pi and production of 1,25-dihydroxyvitamin D (7). The interplay of these hormones on net fluxes and each other creates a precise mechanism for controlling mineral homoeostasis; circulating levels of Ca²⁺ being more tightly controlled than Pi concentrations (4). Increments in extracellular Ca²⁺ reflect direct actions of PTH on the skeleton and kidneys to augment bone turnover and reclaim filtered Ca²⁺, respectively, but an indirect action on the gut mediated by the enhanced 1,25-dihydroxyvitamin D production (2, 3). Extracellular Pi levels are regulated primarily by the kidney (11). Although PTH is known to cause phosphaturia, how other factors control Pi homoeostasis remains incompletely understood, but now importantly includes the action of a variety of phosphatonins, such as FGF-23 (10).

Depending on the patient’s age, disturbances in vitamin D and mineral homoeostasis can engender a considerable variety of signs and symptoms. They can be metabolic or skeletal in origin (Box 4.10.2), and are likely to be severe when extracellular Ca²⁺ levels are low (Box 4.10.3). Furthermore, many somatic changes may manifest (Boxes 4.10.2 and 4.10.3). Reduced levels or ineffective action of vitamin D can be particularly harmful for infants and children. In osteomalacia in adults, there may be axial skeleton pain with focal areas of discomfort due to fractures or pseudofractures, but other symptoms can be vague. The importance of the medical history to capture this information for diagnosing and treating metabolic bone disease has been emphasized and reviewed (12).

Rickets affects especially the most rapidly growing bones (13, 14). Thus, the location and severity of the clinical features will depend on the age of onset. Children with hereditary disorders will usually appear normal at birth because Ca²⁺ and Pi levels in fetal plasma are unregulated and sustained by placental transport from maternal plasma. These patients usually develop the characteristic features of rickets within the first 2 years of life. During infancy, this includes the cranium, wrist, and ribs. Rickets at this time will lead to widened cranial sutures, frontal bossing, posterior flattening of the skull (craniotabes), widening of the wrists, bulging of costochondral junction (rachitic rosary), and indentation of the ribs at the diaphragmatic insertion (Harrison’s groove). The rib cage may be so deformed that it contributes to recurrent pneumonia and respiratory failure. Dental eruption is delayed, and teeth can show enamel hypoplasia. After infancy, with standing and rapid linear growth, deformities are most severe in the legs. Bow legs (genu varum) or knock-knee (genu valgum) deformities of variable severity develop as well as widening of the ends of long bones from metaphyseal expansion. If, however, soft bones develop later in childhood or during the adolescent growth spurt, knock-knee deformity can occur. Occasionally, the lower limbs curve in the same direction (‘windswept’ legs) (13). However, deformity may not manifest if the child cannot bear weight or is not growing. If not treated, rickets may cause severe lasting deformities, compromise adult height, and increase susceptibility to pathological fractures. Bone pain and tenderness can reflect fracture or deformity. In osteomalacia, compression of the ribs or sternum, percussion of the vertebrae, and squeezing of long bones may elicit tenderness.

In infants with deranged vitamin D homoeostasis and hypocalcaemia, floppiness and hypotonia are common. They are often listless and irritable (13). Symptoms of latent or overt tetany may be elicited during the medical history, but signs appear during the physical examination (Box 4.10.3). Such abnormalities are particularly striking with severe and/or rapid reductions in circulating Ca²⁺ levels. Hypocalcaemia enhances neuromuscular excitability (4). Depending on the severity, patients can experience paresthesias of the lips and fingertips and spontaneous muscle contractions in the limbs, face, or elsewhere. Carpopedal spasm manifests with thumb adduction, metacarpophalangeal joint flexion, and interphalangeal joint extension. Latent tetany is unmasked by Chvostek’s or Trousseau’s sign, yet both signs can be negative despite severe hypocalcaemia. Profound hypocalcaemia can also cause mental status changes, epileptic seizures, lethal stridor from laryngeal muscle spasm, and cardiomyopathy (Box 4.10.3) (4).

Additional problems include a ‘metabolic myopathy’ with reduced muscle tone and strength as well as a waddling gait, but no (or nonspecific) changes on electromyography (13). Myopathy is a prominent feature of vitamin D deficiency and tumour-induced rickets or osteomalacia. Proximal muscle weakness is suspected because of difficulty negotiating stairs, combing hair, or rising from a sitting position. Gower’s sign detects this problem when patients must push with their hands on their thighs to stand. Routine assessments of muscle strength should be performed, before and after treatment.

Skull shape and size can be distorted. Premature fusion of the sagittal suture often causes dolichocephaly in X-linked hypophosphataemia, but usually this is only a cosmetic difficulty. In hypophosphatasia, functional or true premature fusion of cranial sutures can lead to a scafalocephalic skull, sometimes with raised intracranial pressure (15).

Total alopecia is a distinctive finding in some patients with hereditary resistance to 1,25-dihydroxyvitamin D (6, 7). There can also be lax ligaments, pectus excavatum from diaphragmatic and intercostal muscle traction, delayed eruption of permanent teeth, and obvious enamel defects (13, 14).

Dystocia (narrowed birth canal) resulting from childhood vitamin D deficiency was a major cause of puerperal mortality at the turn of the past century (14). This deformity should be considered for women with a history of rickets.

In oncogenic (tumour-induced) rickets or osteomalacia, the causal neoplasm may be visible, if not palpable, although some lesions are no more than pea-size. Typically, they are found subcutaneously, but can be anywhere. Some have occurred intravaginally or in the nasopharynx, and some are discovered in the skeleton. Because extirpation of these tumours is curative, thorough physical examination is essential. If the neoplasm is also elusive on radiological studies, patients should conduct self-examination periodically for subcutaneous masses. Lesions grow slowly and may gradually manifest.

For rickets, an anteroposterior radiograph of a knee and a posteroanterior radiograph of a wrist best document the severity of physeal and metaphyseal distortion, and are used for diagnosis and to judge response to therapy (16). Rickets initially widens growth plates uniformly (Fig. 4.10.1a and b). However, chronic disease with skeletal deformity alters mechanical forces acting on lower limb physes, which can become asymmetrically broad in the knees (Fig. 4.10.1c). Typically, metaphyses are splayed and appear ragged and concave with epiphyses seemingly held within a cup (Fig. 4.10.1b). For a few years after the major growth plates fuse, indistinct apophyses can still be seen in the ischium and ilium (16). Long cassette films of the lower limbs, taken while the patient stands, help to explain and to quantify bowing or knock-knee deformity.

Radiographs can also provide clues to the aetiology or pathogenesis of rickets (12, 16). Disturbances in vitamin D homoeostasis, which result in secondary hyperparathyroidism, often lead to osteopenia and sometimes subperiosteal bone resorption. Conversely, X-linked hypophosphataemia features normal or sometimes increased radiodensity, and changes of hyperparathyroidism are generally absent. In hypophosphatasia, peculiar ‘tongues’ of radiolucency project from physes into metaphyses where there can be paradoxical areas of osteosclerosis (Fig. 4.10.2) (15). However, not all disorders that cause growth plate distortions and limb bowing are forms of rickets (16). Epiphyseal and metaphyseal dysplasias or Blount’s disease may mimic rickets, but they do not alter vitamin D homoeostasis and rarely produce overt abnormalities in mineral metabolism (4).

Radiographic signs of secondary hyperparathyroidism are seen best as subperiosteal erosions involving the radial border of the middle phalanx of the index finger, and erosion of the distal ends of the clavicles and symphysis pubis (16). The vertebrae may develop a ‘rugger-jersey’ appearance. In osteomalacia, pseudofractures (Looser’s zones) can occur anywhere except in the skull, and most often affect the pubic and ischial rami, ribs, scapulae, and the medial cortex of the proximal femora (Fig. 4.10.3). Intervertebral discs may compress softened endplates causing biconcave (‘cod fish’) vertebrae (16).

In addition, the rapidity of response to therapy may be of diagnostic significance for rickets. In primary vitamin D deficiency, radiographic improvement occurs just several weeks after a single large oral dose of vitamin D and correction of circulating 25-hydroxyvitamin D levels (13). Other forms of rickets, especially those due to renal Pi wasting, often take months to improve with current medical treatments (11).

Bone scintigraphy is useful for uncovering abnormalities in the skeleton, but does not provide a diagnosis. Enhanced radioisotope uptake in bone occurs where there is osteoidosis; hence, rickets or osteomalacia can produce a ‘superscan’ featuring also no apparent renal uptake of radioisotope. This procedure is usually unnecessary in children with rickets. However, when physical examination fails to disclose the cause of tumoral rickets or osteomalacia, bone scanning helps detect skeletal sources. In adults, this procedure also discloses complications of osteomalacia, such as fractures and pseudofractures.

Bone densitometry, especially by dual-energy X-ray absorptiometry, can be imprecise in rickets or osteomalacia because of short stature, bone deformities, and osteoid accumulation.

Measurements of serum Ca²⁺, Pi, PTH, and bone-specific ALP are essential to differentiate among the three principal aetiologies of rickets and/or osteomalacia; 24-hour urinary Ca²⁺ excretion and serum 1,25-dihydroxyvitamin D levels help differentiate among aetiological groups of primary hypophosphataemic rickets and/or osteomalacia due to defects in renal tubular Pi reabsorption.

Hypocalcaemia is usually more severe in vitamin D-deficiency rickets versus osteomalacia, and sometimes paradoxically results in hyperphosphataemia due to a direct disturbance in the kidney tubule (13). Secondary hyperparathyroidism causes a mild hyperchloraemic metabolic acidosis, reflecting enhanced renal excretion of bicarbonate. Significant acidosis, however, suggests Fanconi’s syndrome (11).

Although quantitation of circulating vitamin D₂ and D₃ levels directly assesses vitamin D status, assays for these prohormones are not readily available (2, 3). Fortunately, measuring serum 25-hydroxyvitamin D is an excellent surrogate. 25-hydroxyvitamin D assays are generally offered by reference laboratories and detect both 25-hydroxyvitamin D₂ and 25-hydroxyvitamin D₃ together. Assays for serum 1,25-dihydroxyvitamin D are also obtained commercially, but their utility is limited because levels can be high, normal, or low in vitamin D deficiency, depending upon the degree of secondary hyperparathyroidism and how much 25-hydroxyvitamin D substrate remains for 1,25-dihydroxyvitamin D production (13, 14). Quantitation of these two vitamin D compounds is, however, essential to differentiate among the various disturbances in vitamin D action: vitamin D deficiency, 1,25-dihydroxyvitamin D deficiency, and resistance to 1,25-dihydroxyvitamin D (Table 4.10.2).

Serum ALP activity (bone isoform) from osteoblasts is elevated in nearly all patients with rickets or osteomalacia. The exception is hypophosphatasia, which features hypophosphatasaemia (15). Levels of other markers of skeletal turnover can be altered, but are sometimes confusing in rickets or osteomalacia and need not be measured routinely.

Although the patient’s medical history, physical findings, and routine biochemical and radiographic abnormalities usually suffice to diagnose and to treat rickets or osteomalacia, histopathological studies showing defective mineralization of bone tissue provide the definitive evidence for these disturbances (1).

Because in clinical practice bone biopsy specimens are routinely acquired only from the iliac crest, the histological picture obtained is osteomalacia, not rickets. Osteomalacia is defined as excess osteoid (hyperosteoidosis) together with quantitative and dynamic proof of defective bone matrix mineralization using time-spaced tetracycline labelling (17).

Transiliac bone biopsy is taken at a standard location: 2 cm behind the anterosuperior iliac spine and just below the crest, using a trephine of 5.0 or 7.5 mm inner diameter for adults, or 5 mm diameter for children. The specimen should contain the inner and outer cortex and intervening trabeculae. Two 3-day courses of oxytetracycline or demeclocycline hydrochloride (20 mg/kg body weight per day in divided doses) are given (separated by a 2-week interval) for in vivo tetracycline labelling of mineralizing bone surfaces. The final dose is swallowed several days before the biopsy. The core is sectioned undecalcified and used unstained, or with different stains and techniques to assess qualitative and quantitative histomorphometric parameters (Fig. 4.10.4).

In rickets or osteomalacia, properly stained, nondecalcified sections will reveal increased quantities of unmineralized osteoid (width and extent) covering bone surfaces (Fig. 4.10.4a), and fluorescence microscopy will fail to show two discrete tetracycline ‘labels’ produced by ongoing mineralization (Fig. 4.10.4b). Instead, absent or smeared fluorescence is noted. Commonly used histomorphometric parameters (17) include trabecular bone volume, osteoid volume, osteoid surface, osteoid thickness, osteoblast surface, osteoclast surface, osteoclast number, double labelled surface, mineral appositional rate, bone formation rate, and mineralization lag time. Although bone biopsy is not required routinely for rickets, which is defined radiographically, bone histology in osteomalacia is useful because radiographic studies are less helpful (16).

Most forms of rickets or osteomalacia can be treated with considerable success. However, an accurate diagnosis and appropriate follow-up are essential for a favourable clinical outcome, while avoiding intoxication with vitamin D or mineral supplements. Ideally, the primary pathological process is corrected (Box 4.10.1). However, this may not be possible, and pharmacological doses of vitamin D (or an active metabolite), sometimes with mineral supplementation, will be necessary. Currently, five sterols with vitamin D activity are available as pharmaceuticals: vitamin D₂ or D₃, 25-hydroxyvitamin D₃, 1,25-dihydroxyvitamin D₃, alfacalcidiol (1α-hydroxyvitamin D₃), and dihydrotachysterol. They differ importantly in potency and biological half-life (Table 4.10.3).

Wisely chosen, medical therapy for rickets or osteomalacia can be rewarding for patient and physician. Given sufficient time before growth plate closure, the three disturbances of skeletal development can be corrected (1). Reversal of short stature and deformity are major goals of treatment of rickets. Relief from bone pain and fracture prevention also follow effective management of osteomalacia.

Physical examination provides critical information. Linear growth rates are important parameters to monitor in infants, children, and especially adolescents. Height is determined best with a wall-mounted stadiometer. Rapid increases in body size during the pubertal growth spurt can significantly augment dose requirements for chronic forms of rickets. Furthermore, inordinate weight gain in girls can accelerate puberty and the growth spurt can increase limb deformity and compromise final height. When growth is complete, dosage requirements may unexpectedly diminish.

Measurements of arm span and height as well as upper and lower segment lengths will help to quantify skeletal distortion. With chronic forms of rickets, treatment may be necessary throughout growth, and some time can pass before control is achieved. It may be the individual who sees the patient only every 6 months who best appreciates changes in deformities. Accordingly, clinical photography, gait analysis, and even videotaping can help to document gradual alterations. Radiographic changes, such as widening of the growth plates and metaphyseal irregularity, are essential not only for diagnosis but also to assess for follow-up. Pseudofractures can heal with treatment. Osteopenia and coarsening of trabecular bone are observed in only some patients (16). Other radiographic findings are less helpful.

The most useful biochemical parameters are serum Ca²⁺ and Pi concentrations, ALP, and PTH levels. Depending on the aetiology and pathogenesis of the rickets or osteomalacia, serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations may be helpful. Ca²⁺ excretion in 24-h urine collections (corrected for creatinine content) guides therapy, and helps monitor for drug toxicity. Maintenance of normal urinary levels of Ca²⁺ often indicates that treatment is effective. If, however, incomplete healing of rickets or osteomalacia is suspected, nondecalcified iliac crest histomorphometry is definitive (1).

The causes of rickets and osteomalacia are numerous (Box 4.10.1). Successful treatment will depend upon a correct diagnosis and understanding of the mechanism for the aberration in vitamin D stores or bioactivation and/or the changes in mineral homoeostasis. The optimum regimen will correct or circumvent the defect, but a range of effective doses should be anticipated among patients. Significant adverse consequences (failed treatment, hypercalcaemia, kidney stones, secondary or tertiary hyperparathyroidism, or renal damage) may result from an incorrect diagnosis or excessive therapy.

Treatment with active metabolites of vitamin D can circumvent defective bioactivation of vitamin D (7), and also be useful for hereditary defects in the VDR (see below) (7). These drugs are more potent than vitamin D₂ or D₃, have more rapid onset of action, and have shorter biological half-lives (Table 4.10.3). Thus, toxicity can be corrected rapidly (7). Unfortunately, they do not replete deficient stores of vitamin D, if present. Many preparations are available for Ca²⁺ and Pi supplementation (17). Ca²⁺ dose will be dependent on the primary disturbance, and Ca²⁺ salt on the individual patient. CaCO₃ given orally is least expensive, but Ca²⁺ citrate is better absorbed under certain conditions. Ca²⁺ gluconate is especially costly. Tablets rather than liquid preparations for Pi supplementation are more convenient, taste better, and seem less prone to cause diarrhoea. Those with high amounts of sodium should be avoided.

Follow-up clinic visits are essential for all types of rickets and osteomalacia, but the interval should reflect the specific diagnosis as well as the formulation and track record of therapy. Because rickets and osteomalacia reflect correctable deficiencies in skeletal mineral content, decreases in dose might be necessary when healing is complete. Satiation of ‘hungry bones’ may abruptly increase urinary Ca²⁺ excretion because the skeleton no longer acts avidly as a sump for mineral deposition. Correction of previously abnormal biochemical findings should herald hypercalciuria. Lower doses or cessation of vitamin D and mineral supplements may then be needed. Unless there is renal failure or fixed elevation in circulating PTH levels (reclaiming Ca²⁺ from the glomerular filtrate), hypercalciuria generally precedes hypercalcaemia. Thus, 24-h urine collections, not random specimens, assayed for Ca²⁺ and creatinine are especially important for follow-up. Because hypocalciuria characterizes most forms of rickets or osteomalacia, rising urinary Ca²⁺ levels will also indicate effective therapy.

Consultation and follow-up with the orthopaedic surgeon is often important for treating rickets. Leg bracing, physeal stapling (epiphysiodesis), or osteotomy may be helpful. Straight lower limbs when growth ceases, with alignment of physes parallel to the ground, helps prevent osteoarthritis. Intramedullary rodding may be necessary to heal pseudofractures or to prevent fractures for some patients with osteomalacia (18).

Pharmacological regimens for specific types of rickets or osteomalacia are outlined in the following sections, representing the different aetiologies; i.e. hypocalcaemic, hypophosphataemic, and with no abnormalities in mineral homoeostasis.

Vitamin D deficiency can be caused by decreased acquisition and/or increased clearance. Primary (‘nutritional’) rickets or osteomalacia is a man-made disorder involving social, economic, and/or cultural factors that prevent sufficient exposure to sunlight and insufficient photosynthesis of vitamin D₃ in the skin. Decreased input may be exacerbated by diminished intake from dietary (nutritional) deficiency or intestinal malabsorption. Increased vitamin D clearance could result from accelerated catabolism, mainly in the liver, or increased loss via the kidneys or intestine.

Vitamin D content of various unfortified food substances is very low, with the exception of fatty fish such as herring and mackerel, or cod liver oil. It is estimated that during unfortified food consumption less than 20% of total circulating 25-hydroxyvitamin D is contributed by nutritional vitamin D. However, in some countries, dietary vitamin D is enhanced by supplementation of certain food products. In the USA, milk is fortified with 400 IU per quart. Greater vitamin D intake could also result from habitual use of multivitamins, which usually contain 400 IU per tablet, or some Ca²⁺ salt preparations that also contain vitamin D. These supplements will increase the relative contribution of dietary vitamin D to the total body pool, and be beneficial especially when cutaneous production is limited. Now in the USA, substantially higher doses of vitamin D can be purchased over-the-counter.

Vitamin D synthesis in the skin requires UV light with a maximal effective wave length between 290 and 310 nm, and is affected by the intensity, surface area of the skin exposed, and intrinsic properties of the epidermis (5). In northern latitudes during winter, almost no UV light reaches the ground. In the north of the USA, Canada, and North-western Europe very little or practically no vitamin D is produced in exposed skin between October and March. Clothing, glass, plastic, and sunscreens effectively block UV radiation and prevent cutaneous vitamin D synthesis. Furthermore, vitamin D production is lower in dark skin (because melanin absorbs UV radiation), and in the elderly. Even in the elderly, however, dermal vitamin D production persists (5). It has been estimated that, in summer, a 20-min exposure three times weekly of the skin of the head and arms prevents vitamin D deficiency in the elderly.

Vitamin D deficiency is diagnosed by a low serum concentration of 25-hydroxyvitamin D, which is a reliable measure of vitamin D status in almost all clinically relevant situations. All additional biochemical parameters, as well as clinical signs and symptoms, reflect the subsequent perturbations in bone and mineral metabolism, and are shared by all disorders in vitamin D action and Ca²⁺ deficiency (Tables 4.10.2 and 4.10.4). Included are low to low-normal serum Ca²⁺ levels, hypocalciuria, secondary hyperparathyroidism, hypophosphataemia, increased levels of biochemical markers of bone turnover (e.g. bone-specific ALP and osteocalcin). Therefore, these parameters can support (but not establish) the diagnosis of rickets and/or osteomalacia, and help assess the relative severity of the vitamin D deficiency and the response to treatment. Importantly, circulating levels of 1,25-dihydroxyvitamin D can vary from low to elevated (Table 4.10.4), and thus are unhelpful for this diagnosis.

Population-based reference values for serum 25-hydroxyvitamin D levels were, for a considerable time, debatable and uncertain. They differ according to age, geography, season, dress habits, confinement to bed or home (affecting sunshine exposure and thus vitamin D synthesis) as well as eating habits, local regulation on food fortification, and customs of vitamin supplementation (affecting vitamin D intake). A better alternative, however, is to define health-based parameters, i.e. serum 25-hydroxyvitamin D levels below which adverse health outcomes may occur. Actually, this represents an intervention threshold below which therapy may prevent detrimental effects on the skeleton, including milder vitamin D deficiency states which may not compromise matrix mineralization but, via disruption of mineral homoeostasis, cause secondary hyperparathyroidism, increased bone turnover, and bone loss (19). The relationship between serum 25-hydroxyvitamin D and PTH levels has been analysed in multiple studies to define serum 25-hydroxyvitamin D concentrations below which serum PTH levels increase, or baseline 25-hydroxyvitamin D levels above which vitamin D supplementation significantly decreased serum PTH concentrations (19). Both approaches yielded similar functional thresholds. Accordingly, diagnostic staging of vitamin D states, based on serum 25-hydroxyvitamin D levels and secondary perturbations in mineral and bone metabolism, has been proposed. Vitamin D ‘adequacy’ is serum 25-hydroxyvitamin D at or above 30 ng/ml (75 nmol/l). This is accepted by most clinicians, though not by all, and some argue that the threshold level is instead somewhere between 50–75 nmol/l (20 and 30 ng/ml). However, there is no debate that serum 25-hydroxyvitamin D below 50 nmol/l (20 ng/ml) is inadequate. Vitamin D ‘inadequacy’ is subdivided into vitamin D ‘insufficiency’ levels between 25 nmol/l (10 ng/ml) and the threshold value, and vitamin D ‘deficiency’ below 25 nmol/l (10 ng/ml). Vitamin D deficiency represents a state in which Ca²⁺ homoeostasis begins to fail, i.e. a decrease in serum Ca²⁺ (up to overt hypocalcaemia) despite markedly increased serum PTH concentrations, with the high risk of developing rickets and/or osteomalacia. The same threshold of approximately 75 nmol/l (30 ng/ml) was observed in studies that correlated serum 25-hydroxyvitamin D levels to additional physiological variables, such as intestinal Ca²⁺ absorption, changes in bone mineral density, and lower extremity physical performance (20). Further support for this threshold was obtained by a meta-analysis of intervention studies with vitamin D. Reduction of falls and fractures was positively correlated to the doses of vitamin D and serum 25-hydroxyvitamin D levels (up to a certain threshold) (21).

Although we understand the biosynthetic and bioactivation pathways for vitamin D, primary deficiency is still common worldwide (14, 22). In the UK, the condition resurged in the 1970s within the immigrant Asian community (13). Because vitamin D status depends upon both cutaneous photosynthesis and dietary intake, serum 25-hydroxyvitamin D levels vary widely depending on latitude, season, urban living, clothing, skin pigmentation, use of sunscreens, age, gender, etc., and local rules and customs concerning vitamin D supplementation. The most vulnerable are those who cannot move freely, and therefore are at the beginning or end of life. However, any age can be affected, especially those with physical or mental handicaps. Limited sunshine exposure due to cultural practices and prolonged breastfeeding without vitamin D supplementation contributes considerably to vitamin D deficiency in some regions worldwide (5). Now, use of sunscreens may also block skin access to UV light (5). Additionally, a ‘safety-net’ created by fortifying certain foods with vitamin D may not be provided (13, 22). Among adults, institutionalized or housebound individuals, the poor, the elderly, food faddists, and some religious groups (because of diet and dress) are at greater risk. Infants who breast feed beyond 6 months of age or drink nonfortified milk or formula are also susceptible (13). In some populations, low dietary Ca²⁺ intake can be an important exacerbating factor (22).

In 1998, investigation of patients on a general medicine ward in Boston, Massachusetts revealed that secondary hyperparathyroidism was common when serum 25-hydroxyvitamin D levels were at or below 15 ng/ml (23), and led to subsequent studies which have redefined vitamin D insufficiency and deficiency.

In postmenopausal women treated for osteoporosis in various parts of the world, vitamin D inadequacy, serum 25-hydroxyvitamin levels below 75 nmol/l (30 ng/ml), was observed in 52% of those in North America, 58% in Europe, 53% in Latin America, 71% in Asia, and 82% in the Middle East (24). Pronounced variability was observed among countries, ranging from 30% in Sweden in the summer to approximately 90% in Japan and South Korea in the winter and summer. Deficiency, however, was much less common; approximately 1% in North America, and approximately 6% and 8% in Latin America and the Middle East, respectively.

Furthermore, serum levels below 50 nmol/l (20 ng/ml) were observed in 78% of healthy hospital staff in India, and 90% of young women in Beijing and Hong Kong. Values below 25 nmol/l (10 ng/ml) were reported in about 40% of those tested in Sri Lanka and Beijing, and 18% in Hong Kong (25).

An additional concern is the high prevalence, in some regions, of vitamin D deficiency in pregnant women, their children, adolescent girls, and the elderly. Maternal serum 25-hydroxyvitamin D levels correlate negatively with PTH, and positively with 25-hydroxyvitamin D levels in cord blood. Of pregnant women in India, 84% had serum 25-hydroxyvitamin D levels less than 20 ng/ml. In Saudi Arabia, Israel, Kuwait, the United Arab Emirates, and Iran 10–60% of mothers and 40–80% of their neonates had levels at or below 25 nmol/l (10 ng/ml) at delivery (25).In adolescent girls, 70% in Iran, 80% in Saudi Arabia, and 32% in Lebanon had serum 25-hydroxyvitamin D levels below 25 nmol/l (10 ng/ml); 91% of healthy school girls from Northern India and 89% of adolescent girls from North China had levels below 20 ng/ml (50 nmol/l).In multiple studies worldwide, vitamin D deficiency was detected in 35 to 65% of the elderly; more so in institutionalized individuals (26). In patients hospitalized for an osteoporotic fracture, deficiency was recorded in 20–68%; only 1–3% had levels above 75 nmol/l (30 ng/ml).

Fortunately, the prevalence of osteomalacia is lower, but depends on the criteria for diagnosis, i.e. clinical, biochemical, or bone histology or histomorphometry. In a review of multiple publications describing histomorphometry of the femoral head or iliac crest in approximately 1400 patients with hip facture, osteomalacia ranged from none to over 30% of patients. Perhaps this reflects separate populations and different magnitudes and durations of vitamin D deficiency, but also the histological criteria used to define osteomalacia. Nevertheless, the high prevalence of vitamin D deficiency in patients with hip fractures supports the hypothesis that this event is a complication of frank osteomalacia as well as secondary hyperparathyroidism and the consequent acceleration in bone turnover. In fact, there is a positive relationship between serum 25-hydroxyvitamin D levels (below a certain threshold) and hip bone mineral density, and a negative correlation between hip density and serum PTH. Moreover, vitamin D plus Ca²⁺ supplementation reduced the incidence of hip and other nonvertebral fractures in several studies of vitamin D deficiency.

Although patient or parent education and correction of adverse socioeconomic factors would be optimal for preventing and treating primary vitamin D deficiency, this is often difficult to achieve. Fortunately, pharmacological or supplementation therapy is inexpensive, effective, and works rapidly. Vitamin D deficiency should be treated using vitamin D₂ or D₃. Although 25-hydroxyvitamin D₃, 1α-hydroxyvitamin D₃, and 1,25-dihydroxyvitamin D₃ may be more potent and act more rapidly, none corrects depleted stores of vitamin D, and the therapeutic window is narrow.

Adequate vitamin D intake was recommended recently by the National Osteoporosis Foundation of the USA to be 800–1000 IU/day in adults age 50 years or older (27). Also, the recommendation for infants was increased to 400 IU/day of vitamin D₃. It will probably become routine to recommend the adult dose for adolescents and older children. However, these intakes are usually unachievable unless additional foods are fortified with vitamin D. Thus, the population at large, and the elderly in particular, are dependent upon both cutaneous vitamin D synthesis and vitamin D supplementation.

Treatment must be targeted to those at greatest risk. Vitamin D supplementation for infants up to 1 year of age is mandatory in many, but not all, countries. Unfortunately, this is not routine for the elderly. Nursing home residents, institutionalized and hospitalized elderly, patients with hip fractures, and those with neurological disorders are among those most in jeopardy (26). Thus, it may be necessary to treat with recommended doses of vitamin D and Ca²⁺ (see below) even before biochemical confirmation because of the high incidence of deficiency in this population, and the fact that tight physiological control of serum 1,25-dihydroxyvitamin D production makes toxicity unlikely.

It is important to remember that, together with vitamin D treatment, the recommended daily Ca²⁺ allowance must be achieved, often by Ca²⁺ salt supplementation. Low Ca²⁺ intake, common in some regions of Africa and North China, may also cause or exacerbate rickets.

The typical oral maintenance dose of vitamin D is 800 to 1000 IU daily. In severe vitamin D deficiency, 4000–8000 IU daily could be given for the first 4–6 weeks. Alternatively, 50 000 IU of vitamin D could be given two or three times a week for the first 2 weeks, followed by lower doses. Because vitamin D is stored in fat and released slowly, and the serum half-life of 25-hydroxyvitamin D is 2–3 weeks, dosing can be once weekly, monthly, or every 3–6 months. An oral dose of 100 000 IU every 4 months for 5 years increased serum 25-hydroxyvitamin D to adequate levels. This approach can improve compliance, both in independent elderly and especially in dependent, institutionalized patients, but experience with this mode of vitamin D administration is relatively limited.

The response to vitamin D supplementation will depend on the degree and severity of deficiency and the secondary changes in mineral and bone metabolism. In severe cases with rickets or osteomalacia, dramatic responses in the signs, symptoms, and laboratory parameters will occur. Bone pain and muscle weakness will improve quickly, pseudofractures can heal, and serum Ca²⁺, PTH, and biochemical markers of bone turnover will return towards normal. In moderate or mild vitamin D deficiency or insufficiency, the response is more subtle. Muscle weakness and bone pain may improve as serum 25-hydroxyvitamin D and PTH return to normal (this will reflect the severity of the initial vitamin D deficiency). Bone mineral density can increase somewhat, and the incidence of fractures may decrease in adults with osteomalacia.

For infants and young children with vitamin D-deficiency rickets, liquid preparations of vitamin D₂ are available (Table 4.10.3). They can be given 4000 IU of vitamin D₂ (100 μg) orally each day for several months to heal their rickets and replenish vitamin D stores (13, 14). If capsules can be swallowed, one 50 000 IU (1.25 mg) dose of vitamin D₂ orally each week for three or four doses is also an inexpensive and straight-forward treatment. It is prudent for the physician to see that at least the first capsule is swallowed. Biochemical and radiographic improvement then typically occurs within just a few weeks (13, 14).

After healing, children who persist without adequate sunlight exposure should receive 400 IU vitamin D₂ or D₃ per day, either by consuming fortified foods or using over-the-counter multivitamin or vitamin D supplements (2, 3).

For patients with severe vitamin D deficiency causing symptomatic hypocalcaemia, it is helpful to administer a ‘loading dose’ of vitamin D₂ to replete body stores rapidly. Ca²⁺ intake must also be supplemented. Insufficient Ca²⁺ for the suddenly mineralizing skeleton could exacerbate the hypocalcaemia. A single oral dose of 5000 IU of vitamin D per kg body weight can be given. For a 70 kg adult, this is 350 000 IU of vitamin D. Although this quantity of vitamin D seems great, it illustrates the storage capacity for vitamin D (2, 3). With symptomatic hypocalcaemia, Ca²⁺ can be given intravenously over 24 hours (as much as 20 mg of elemental Ca²⁺ per kg of body weight per day). Ca²⁺ infusions should be given continuously, or slowly in portions, and always regulated by serum Ca²⁺ levels determined several times daily. Oral Ca²⁺ supplementation (1–2 g of elemental Ca²⁺ each day) can be initiated at this time. For patients who are not lactose intolerant and no longer hypocalcaemic, three to four glasses of milk each day will provide both Ca²⁺ and Pi to help remineralize the skeleton.

Failure to show biochemical and radiographic improvement with persistently low serum 25-hydroxyvitamin D levels could reflect failed compliance or malabsorption. Use of inexpensive vitamin D capsules may help to assure that the medication is taken. Alternatively, and if available, intramuscular injection of vitamin D in sesame oil will assure long-term access to antirachitic activity if patient compliance for oral treatment is poor, or if there is malabsorption (Table 4.10.3). Visits to a ‘tanning salon’ have also proved effective. If skeletal disease persists despite sustained correction of circulating 25-hydroxyvitamin D levels, calciopenia or one of the vitamin D-dependent or resistant syndromes (Box 4.10.1) must be considered (see below) (7, 9, 13, 22).

Prophylaxis against vitamin D-deficiency rickets could involve outdoor activity, occasional exposure to UV light using protective goggles, consumption of vitamin D-fortified foods, or vitamin D supplements (2, 3). ‘Stoss therapy’, used in Europe, consists of one depot intramuscular injection of 600 000 IU of vitamin D₂ during the autumn. However, this dose given orally has caused hypercalcaemia and renal damage (28).

Vitamin D deficiency due to enhanced clearance is relatively uncommon and usually accompanies systemic disorders (e.g. protein losing nephropathy, intestinal malabsorption) or increased liver catabolism sometimes caused by certain drugs (e.g. barbiturates, other antiepileptics, etc.). Gastrointestinal malabsorption interferes with vitamin D input from the gut, but sometimes also with the enterohepatic recirculation of vitamin D metabolites. Thus, intestinal malabsorption may contribute to vitamin D deficiency by both decreasing input and increasing excretion. Vitamin D deficiency caused by decreased input is discussed below.

Vitamin D deficiency can be caused by malabsorption, perhaps despite normal amounts of sunlight exposure (5). Gastrointestinal, pancreatic, or hepatobiliary disease may be the explanation (Box 4.10.1) (2, 3). The mechanism for the vitamin D deficiency and associated derangements in mineral metabolism is often complex. Gut malabsorption may also interfere with influx of minerals.

Vitamin D is a fat-soluble secosterol, and bile salts are necessary for its absorption (2, 3). Additionally, there is enterohepatic circulation of vitamin D and its derivatives (2, 3). Hence, hepatobiliary or pancreatic disease or short bowel syndrome can cause deficiency of bile salts, steatorrhoea, and malabsorption leading to depletion of vitamin D. Furthermore, the small bowel mediates dietary Ca²⁺ uptake, and malabsorption of Ca²⁺ can exacerbate vitamin D deficiency. With secondary hyperparathyroidism, conversion of 25-hydroxyvitamin D to both 1,25- and 24,25-dihydroxyvitamin D is enhanced, and 25-hydroxyvitamin D is depleted also by this mechanism. Nevertheless, in some conditions where osteomalacia might be anticipated (for example, primary biliary cirrhosis) the associated osteopathy is often osteoporosis. Iliac crest biopsy is especially useful in such patients. Vitamin D deficiency and its clinical and biochemical consequences may be the first sign of occult malabsorption due, for example, to coeliac disease (nontropical sprue).

Although the pathogenesis of secondary vitamin D-deficiency rickets or osteomalacia is complicated, pharmacological therapy should produce gratifying results. These patients reflect heterogeneous disturbances, and there must be individualized therapy and follow-up. Assay of serum 25-hydroxyvitamin D documents vitamin D deficiency and is essential for monitoring progress (23). Sufficient doses of vitamin D₂ or D₃ given orally should prove effective, and are relatively inexpensive. Vitamin D repletes exhausted stores, and is readily converted to 25-hydroxyvitamin D by hepatocytes despite parenchymal liver disease (2, 3).

Here too, a single oral ‘loading’ dose of about 125 μg (5000 IU) of vitamin D per kg of body weight can expedite treatment prior to maintenance dosing. Intravenous Ca²⁺ (as much as 20 mg of elemental Ca²⁺ per kg of body weight daily) over 24 hours by continuous infusion, or slowly in divided doses, is regulated by frequent measurements of serum Ca²⁺ and is helpful for symptomatic hypocalcaemia and ‘hungry bones’. Serum Mg²⁺ should be assayed for newly diagnosed hypocalcaemia, and treated if levels are low (17).

After the loading dose of vitamin D, patients with secondary vitamin D deficiency will require supplemental vitamin D unless the primary disorder is also corrected. It is impossible to predict the maintenance dose. Hence, clinical and biochemical follow-up is mandatory. Initially, patients should be seen every few weeks. Adjustments in dosing will be needed when the rickets or osteomalacia heals, or the gastrointestinal, hepatobiliary, or pancreatic disturbance evolves or responds to treatment.

For milder disease, a reasonable starting dose of vitamin D₂ or D₃ is 50 000 IU (1.25 mg) orally twice weekly. Assay of the circulating 25-hydroxyvitamin D level about 1 month later, and about every 4 months thereafter, will determine what dose of vitamin D is effective. Serum 25-hydroxyvitamin D levels should be maintained above the threshold value of 30 ng/ml (75 nmol/l). Ca²⁺ supplements can be added. Then, assay of the Ca²⁺ and creatinine content 24-h urine collections periodically can be used to monitor therapy. This should show correction of any hypocalciuria unless circulating levels of PTH (which reclaims urinary Ca²⁺) are persistently elevated and do not suppress with treatment. In this situation, assay of serum Ca²⁺ levels becomes especially important. Attention to urinary Ca²⁺ levels will help to guard against vitamin D toxicity manifesting as hypercalciuria.

Although oral vitamin D therapy is nearly always successful (unless there has been almost complete resection of the small intestine requiring total parenteral nutrition), intramuscular injection (if available) of depot vitamin D₂ in oil can be an alternative. Here, 12.5 mg of vitamin D₂ (500 000 IU) is dissolved in 1 ml of sesame oil (Table 4.10.3), providing prolonged bioavailability of vitamin D₂ (29). An increment in the circulating 25-hydroxyvitamin D level may not appear for several weeks, but vitamin D₂ release will persist for months. Injections of 500 000 IU of vitamin D₂ every few months should provide effective and continuous supplementation for an adult, but biochemical monitoring is important.

Hypophosphataemia due to secondary hyperparathyroidism or primary renal Pi wasting contributes importantly to the pathogenesis of defective mineralization of skeletal matrix in most patients. However, some individuals with hypocalcaemia alone from hypoparathyroidism or pseudohypoparathyroidism develop rickets or osteomalacia despite elevated serum Pi levels.

Severe deficiency of dietary Ca²⁺ despite intact stores of vitamin D can also lead to defective skeletal mineralization (13, 22). So-called calciopenic rickets has been described in children fed a cereal-based diet (13), and in premature infants (14). Poor dietary Ca²⁺ intake can also exacerbate vitamin D-deficiency rickets (22). Several religious, ethnic, and other groups have vegetarian members who are at risk because they do not consume dairy products. Altering the diet, or using Ca²⁺ supplements, should readily reverse this disorder.

Rickets and osteomalacia have been reported in institutionalized people receiving anticonvulsants, especially multiple pharmaceuticals (2, 3, 14). Phenobarbital can alter hepatic vitamin D metabolism predisposing to vitamin D depletion (2, 3). However, primary deficiency of vitamin D also afflicts many such individuals.

If serum 25-hydroxyvitamin D levels are low, epileptics who take phenobarbital and other anticonvulsants can receive a 50 000 IU dose of vitamin D orally once weekly, thereafter adjusted by following serum 25-hydroxyvitamin D concentrations.

Osteomalacia can result from excessive use of Pi-binders (e.g. magnesium and aluminium hydroxide antacids) (17). Rickets complicated by craniosynostosis has occurred when such preparations were added to infant formula to treat colic (30). Significant hypophosphataemia can occur. Assay of urinary phosphorous will reveal low levels. Conversely, patients may hyperabsorb dietary Ca²⁺ and become hypercalciuric because hypophosphataemia stimulates renal 25-hydroxyvitamin D, 1α-hydroxylase activity and augments the biosynthesis of 1,25-dihydroxyvitamin D. Rarely, kidney stones develop. Despite the increased Ca²⁺ levels, hypophosphataemia impairs skeletal mineralization, but elimination of the Pi-binder will rapidly correct the hypophosphataemia and skeletal defect. Pi supplementation or vitamin D therapy will not be necessary. However, it may take several months for serum ALP activity to correct.

This chemotherapeutic drug can cause transient or permanent kidney tubule damage leading to urinary Pi wasting and hypophosphataemic skeletal disease (31).

This first-generation bisphosphonate used for Paget’s bone disease and hypercalcaemia of malignancy can, with excessive or prolonged exposure, cause rickets or osteomalacia. Etidronate retains sufficient similarity to inorganic pyrophosphate to act as an inhibitor of mineralization (4).

Rickets or osteomalacia follow long-term exposure to several other inhibitors of skeletal mineralization.

Patients with uraemia who were exposed to aluminium-containing antacids or contaminated dialysis fluid or parenteral feedings have developed osteomalacia (17). Treatment with desferoxamine has been helpful (17). Unusual case reports suggest that bone mineralization can be impaired in healthy individuals if sufficient aluminium is leached from cookware. With use of newer agents for Pi-binding, this disorder is now rare.

Excessive fluoride from well water, industrial exposure, inordinate tea drinking, or sodium fluoride given for osteoporosis can cause osteomalacia (17). Defective bone mineralization will respond gradually to cessation of fluoride poisoning and Ca²⁺ supplementation.

Oncogenic rickets or osteomalacia is a rare, sporadic disorder that is often caused by a benign ‘mixed mesenchymal’ tumour in soft tissues (Fig. 4.10.5) (11, 17). However, a considerable variety of other indolent neoplasms, nonossifying fibroma, and (rarely) malignant bone tumours or other cancers can cause this condition (17). Patients are often profoundly weak. These tumours secrete FGF-23 and sometimes other phosphatonins that cause phosphaturia and profoundly inhibit renal 25-hydroxyvitamin D, 1α-hydroxylase activity (10). Low circulating 1,25-dihydroxyvitamin D levels can cause malabsorption of dietary Ca²⁺ and mild hypocalcaemia, secondary hyperparathyroidism, and hypocalciuria. Hypophosphataemia is, however, the major biochemical abnormality, and sufficiently lowers the blood Ca²⁺ × Pi product to impair skeletal mineralization.

Definitive diagnosis and treatment of oncogenic rickets or osteomalacia is achieved by resection of the neoplasm. Therefore, thorough diagnostic evaluation is especially important in sporadic, acquired hypophosphataemic skeletal disease. If a soft tissue tumour is not apparent, bone scintigraphy and/or octreotide scanning is performed. If these studies are not revealing, the nasopharynx should be examined, sometimes by computed tomography. Whole body magnetic resonance imaging and positron emission tomography scanning have proven useful (17).

When removal of the causal neoplasm is not possible, Pi supplementation with 1,25-dihydroxyvitamin D₃ or 1α-hydroxyvitamin D₃ treatment will reverse patient weakness and heal the osteomalacia.

Metabolic acidosis can cause rickets or osteomalacia (Box 4.10.1). The pathogenesis is not well understood, and seems complex. Nevertheless, the skeletal disease responds well to vitamin D and alkali therapy. Ca²⁺ and potassium supplementation may be necessary at the onset of alkali therapy to prevent hypocalcaemia and hypokalaemia. Vitamin D (50 000 IU orally thrice weekly) can be used for adults, with careful follow-up until healing occurs. Alkali therapy should be continued after the mineralization defect is corrected. Urinary Ca²⁺ and creatinine levels must be monitored frequently because metabolic acidosis per se causes hypercalciuria.

In uraemia, skeletal disease usually reflects secondary or tertiary hyperparathyroidism leading to rapid bone remodelling (osteitis fibrosa cystica) (4). However, some patients manifest defective mineralization of skeletal matrix that is caused mainly by calcitriol deficiency. Additional causes have been proposed as well.

Aluminium is toxic to osteoblasts and inhibits skeletal mineralization (4). Contamination of dialysate caused ‘Newcastle bone disease’. Uraemic patients who used aluminium-containing antacids to bind dietary Pi also deposited this metal in skeletal tissue. Serum assays and bone histochemistry for aluminium support the diagnosis (4). Therapy includes substituting new Pi-binders. Desferoxamine has been a useful chelating agent (17).

Excessive use of Pi-binders in uraemic patients can cause hypophosphataemia leading to rickets or osteomalacia.

Severe osteomalacia has occurred in renal failure after excessive parathyroidectomy for secondary or tertiary hyperparathyroidism (4). PTH is necessary for bone turnover in uraemia. Pharmacological doses of calcitriol and Ca²⁺ supplementation have had some therapeutic success.

Infants and children with epidermal nevus syndrome can develop rickets due to renal Pi wasting (32). 1,25-dihydroxyvitamin D₃ and Pi supplementation therapy is effective.

A few rare, sporadic conditions manifest with osteomalacia despite normal circulating concentrations of Ca²⁺ and Pi (17). There is no established therapy. A correct diagnosis is important in part because massive doses vitamin D, either as the calciferol or active metabolite form, and Ca²⁺ supplementation could lead to hypercalcaemia and hypercalciuria.

Fibrogenesis imperfecta ossium, reported in about a dozen patients, is an acquired abnormality within skeletal matrix. Axial osteomalacia is characterized radiographically by coarsening of trabecular bone in the axial skeleton, seemingly from a primary defect in osteoblasts, and perhaps is a heritable disorder (33).

Heritable disorders that cause rickets or osteomalacia are included in Box 4.10.1. Some feature renal Pi wasting; some reflect disturbances in the bioactivation or action of vitamin D. Several have proven to be inborn errors of metabolism due to enzyme deficiencies (throughout this section, heritable disorders are referred to by their McKusick symbol and number provided in Online Mendelian Inheritance In Man) (33).

Most forms of rickets or osteomalacia reflect aberrations in vitamin D homoeostasis leading to reduced levels of Ca²⁺ in extracellular fluid (14). However, these disorders also diminish extracellular Pi concentrations partly from phosphaturia due to secondary hyperparathyroidism. Hypocalcaemia and hypophosphataemia then act in concert to impair mineralization of newly synthesized osteoid, and are reflected by a decreased blood Ca²⁺ × Pi product (1).

The importance of Pi for skeletal mineralization is especially well illustrated by types of rickets or osteomalacia due to renal phosphate leak causing osteopathy without significantly diminishing circulating Ca²⁺ levels (11). ‘Hypophosphataemic bone disease’ is a generic term which emphasizes the critical nature of this biochemical disturbance. Although pharmacological treatment for these disorders has certain themes, each entity is unique and optimal regimens can differ.

X-linked hypophosphataemia (XLH) is the most common heritable form of rickets or osteomalacia (OMIM #307800) (11). The prevalence in North America is approximately 1:20 000 live births. All races seem to have affected individuals.

XLH was first described in 1937 after vitamin D-deficiency rickets, a plague of Northern industrialized cities at the turn of the last century, had waned (34). Discovery of vitamin D in 1919, and then successful treatment and preventive measures for ‘nutritional’ rickets, represented a major triumph of medical science (2, 3). Nevertheless, some cases of rickets were puzzling because they were not cured even by massive doses of vitamin D₂ (34). XLH became the prototypic ‘vitamin D-resistant rickets’. In 1958, the disorder was recognized to manifest X-linked dominant inheritance (35). Girls and boys (2:1) are affected. Hypophosphataemia from renal Pi wasting was appreciated as a key pathogenetic factor in 1969 (36). Inappropriately normal circulating levels of 1,25-dihydroxyvitamin D despite hypophosphataemia were documented in 1982. In 1995, an international consortium identified the gene they called PHEX (phosphate-regulating gene with homology to endopeptidases on the X-chromosome) that was altered in most patients with XLH (37).

XLH causes short stature and bowing of the lower limbs after toddlers begin to bear weight (Fig. 4.10.6). They are clumsy, but otherwise strong and well. The skull is often dolichocephalic and Chiari 1 malformation can occur. The chest and upper extremities are not deformed. There is no muscle weakness in contrast to nearly all other forms of rickets. Fractures are uncommon. Skeletal disease occasionally presents with knock-knees. Without treatment, height Z scores will be minus 2–3 standard deviations (38, 39).

Adults with XLH can suffer five principal complications (38). Arthralgias, primarily involving the lower limbs and especially the knees, are due to osteoarthritis. The degree of lower extremity rachitic deformity predicts the likelihood of knee joint deterioration (38). Bone pain in the thighs is often explained by femoral pseudofractures (Fig. 4.10.3). Dental abscesses develop because brittle ‘shell’ teeth form early in life due to defective mineralization of dentin. Enthesopathy (calcification of tendons, ligaments, joint capsules, etc.) is common, but it is unclear the degree to which symptoms develop. Sensorineural hearing loss and spinal stenosis may also occur. Obstetrical histories seem benign (38). The impact of XLH during old age has not been studied, but life expectancy is probably not compromised.

Radiographs of children with XLH and bowing deformity of the lower limbs show physeal widening in the knees, which becomes especially pronounced medially (Fig. 4.10.1c). Osteopenia and evidence of secondary hyperparathyroidism is generally absent unless dietary Ca²⁺ intake is poor. In fact, the skeleton in XLH often appears dense, contrasting with other forms of rickets which characteristically increase circulating PTH levels. In adults, axial skeletal mass is typically normal, although sometimes bones appear sclerotic (40).

The biochemical hallmark of XLH is hypophosphataemia (11). Serum Ca²⁺ levels are low-normal, but usually not distinctly reduced (38, 39). Hypophosphataemia is documented if age-related changes in the normal range for serum Pi are appreciated. Healthy children have considerably higher serum Pi concentrations (and ALP activity) compared with adults. Because serum Pi levels may increase or decrease depending upon what is eaten, fasting blood specimens are necessary for diagnosis (39). In XLH, quantitation of renal Pi reclamation by calculating the transport maximum for phosphorous per glomerular filtration rate (TmP/GFR) shows that hypophosphataemia is due to decreased renal tubular reabsorption of phosphate (phosphate diabetes) (38, 39). Occasionally, trace glucosuria is detected, however, other parameters of renal proximal tubular function (e.g. serum potassium, bicarbonate, or uric acid levels) are normal; that is, Fanconi’s syndrome (see later) is absent. Serum 1,25-dihydroxyvitamin D levels in XLH are generally normal or low-normal despite hypophosphataemia, which typically increases renal 25-hydroxyvitamin D, lα-hydroxylase activity (11). Unless patients receive Pi supplements that are insufficiently matched by doses of 1,25-dihydroxyvitamin D₃ (see below), circulating PTH levels are usually normal (38, 39). Without treatment, serum ALP is always increased in children, but not always in adults. Serum FGF-23 levels are elevated in most XLH patients (10).

Histopathological examination of the skeleton shows rickets or osteomalacia in untreated patients with XLH (Fig. 4.10.4a) (38). Elevated circulating PTH levels predict features of hyperparathyroidism, including abundant osteoclasts and peritrabecular fibrosis. Additionally, in appropriately stained, nondecalcified sections (1), there are halos of hypomineralized bone surrounding osteocytes (Fig. 4.10.4a) (38). This peculiarity is considered diagnostic of XLH, reflecting an osteoblast defect persisting when these cells become osteocytes and despite successful 1,25-dihydroxyvitamin D₃ and Pi therapy.

The pathogenesis of XLH is incompletely understood (10, 11). Transport of Pi is defective across renal proximal tubule cells, where PTH and somehow dietary phosphorous control urinary Pi reclamation (11). Here, Pi movement across brush border membranes is the rate-limiting step. The murine (Hyp) model for XLH implicates a decrease in a high-affinity, low-capacity, Na⁺-dependent Pi transport system (11). However, there is also a blunted response to activators of 1,25-dihydroxyvitamin D biosynthesis in kidney mitochondria (11). Pi deprivation and supplementation accelerate and suppress, respectively, 1,25-dihydroxyvitamin D catabolism. Nevertheless, the precise intracellular disturbances that diminish Pi transport and alter vitamin D bioactivation are not known (10, 11). Parabiosis and renal transplantation studies using the Hyp mouse implicated a phosphaturic factor(s) (41), now appreciated to be principally FGF-23 (10). Tissue culture studies of Hyp mouse and XLH patient bone indicate that osteoblast function is also directly impaired (11). Malabsorption of dietary Ca²⁺ is poorly understood, but considered a manifestation of the vitamin D resistance.

In XLH, no gene dosage effect emerges from a study of prepubertal heterozygous girls and hemizygous boys (Fig. 4.10.6) (42). Nevertheless, complications such as pseudofractures and enthesopathy seem more severe in men compared to women (38). Accordingly, gender (sex steroids and/or physical labour, etc.) does appear to affect the long-term outcome (38).

XLH maps to chromosome Xp22.31–21.3 (33). More than 150 different mutations involving the splice sites or coding sequence of the PHEX gene have been discovered worldwide (33). They are expected to diminish PHEX protein function. However, such defects are detected in only approximately 50% of patients (43). Mutations involving the noncoding regions could be involved. A preliminary study indicates that defects compromising the structure of the PHEX protein per se cause severe XLH (44). Nevertheless, the putative substrate for PHEX remains uncertain (10, 11). PHEX could act at cell surfaces to inactivate a phosphaturic factor, or activate a suppressor of phosphatonins such as FGF-23 (10, 11, 45).

Renal Pi wasting is a major pathogenetic abnormality in XLH. TmP/GFR correlates positively with height Z score in paediatric patients (42), and decreases reflect the degree of bowing deformity in affected adults (38). Accordingly, this disturbance is targeted by medical therapy. Decreases in 1,25-dihydroxyvitamin D biosynthesis are also compensated.

The bioactivated forms of vitamin D are used to treat XLH. High doses of vitamin D₂ (e.g. 100 000 IU daily) can improve, but will not heal, the rickets (46). Large doses of vitamin D₂ are readily converted to 25-hydroxyvitamin D, however, the affinity of the VDR for 25-hydroxyvitamin D is two to three orders of magnitude lower than for 1,25-dihydroxyvitamin D (2, 3). Conversely, excessive vitamin D₂ therapy sometimes causes prolonged hypercalcaemia, hypercalciuria, nephrocalcinosis, and renal failure (47)reflecting the long biological half-life of vitamin D (Table 4.10.3). Hypercalcaemia can persist for months, requiring dietary Ca²⁺ restriction and glucocorticoid treatment. Additionally, high-dose vitamin D₂ therapy requires cessation months in advance of osteotomy to avoid hypercalciuria or hypercalcaemia if postoperative immobilization is prolonged.

When the pathogenetic renal Pi wasting of XLH was addressed, improved clinical, biochemical, and radiographic responses were noted (36, 39). Transient augmentation of circulating Pi levels is achieved using frequent oral Pi dosing to supply, depending on body size, about 1–2 g of phosphorous (as Pi) each day. Now, combined use of 1,25-dihydroxyvitamin D₃ and Pi supplementation currently seems to be the best regimen for XLH (39). 1,25-dihydroxyvitamin D₃ augments both Ca²⁺ and Pi uptake from the gut. Improved dietary Ca²⁺ absorption prevents secondary or tertiary hyperparathyroidism provoked by Pi lowering blood Ca²⁺ levels directly or binding Ca²⁺ in the gut. Recently, a monoclonal antibody to neutralize circulating FGF-23 has begun clinical trials.

Treatment of XLH requires a medical/ orthopaedic approach best provided by experienced centres. 1,25-dihydroxyvitamin D₃ and Pi supplementation can reverse defects in skeletal growth, modelling, and remodelling in compliant patients (39). There are two principal goals of therapy. Correction of limb deformity by the time growth plates fuse is paramount. Additionally, boys and girls both can achieve normal heights. Two potential complications of treatment are: (1) secondary or tertiary hyperparathyroidism compromising the clinical outcome and perhaps necessitating parathyroidectomy and osteotomies, and (2) renal damage.

Treatment should begin with toddlers to help promote growth and to avoid lower extremity distortions. However, dosing and monitoring will understandably be difficult at first. Control, but not complete correction, of the rickets is a reasonable objective early on. Both 0.25 and 0.50 μg capsules of 1,25-dihydroxyvitamin D₃ are commercially available. The contents can be put into applesauce, etc., but a liquid preparation is also now marketed (Table 4.10.3). Approximately 40 ng (i.e. 0.040 μg) per kg of body weight of 1,25-dihydroxyvitamin D₃ daily (divided doses is ideal) may be achieved safely over 2 to 3 months by gradually increasing the dose and monitoring its biochemical effects. In the UK and Europe, a solution of 1α-hydroxyvitamin D is available. Pi supplementation, given three to four times daily, is introduced simultaneously and also gradually increased. Tablets of neutral sodium/ potassium phosphate (e.g. K-Phos Neutral^®; Beach Pharmaceuticals, Tampa, Florida) are most convenient and generally well tolerated. Occasionally, Pi causes diarrhoea. In some ways, 1,25-dihydroxyvitamin D₃ and Pi produce opposite effects on Ca²⁺ homoeostasis (39). Accordingly, if either Pi or 1,25-dihydroxyvitamin D₃ is stopped, both should stop. Sudden decreases or especially cessation in Pi supplementation alone should be avoided, because 1,25-dihydroxyvitamin D effects can persist and urinary and then blood Ca²⁺ levels may rapidly rise. Accordingly, patients should be cautioned not to run out of medications.

Careful biochemical surveillance is essential because 1,25-dihydroxyvitamin D₃ is especially potent in increasing gastrointestinal Ca²⁺ absorption. Ca²⁺ and creatinine should be assayed in 24-h urine collections (not random specimens) (39). Initially, monitoring should occur monthly, but then every 3 months. Urinary Ca²⁺ to creatinine ratios of about 150–180 mg/g reflect adequate gut effects of 1,25-dihydroxyvitamin D₃ helping to suppress circulating PTH levels. If hypocalciuria is a persisting problem, increased milk consumption or Ca²⁺ supplementation may be helpful. Unless PTH levels are elevated and nonsuppressable (predicting hypercalcaemia before hypercalciuria), hypercalciuria will herald excessive 1,25-dihydroxyvitamin D₃ dosing. Fortunately, 1,25-dihydroxyvitamin D₃ has a short biological half-life, permitting rapid corrections (Table 4.10.3). Urine levels of 3–3.5 g phosphorous per g creatinine are efficacious, and seem less likely than greater values to cause nephrocalcinosis. Renal ultrasonography, creatinine clearance, and serum PTH levels should be monitored at least yearly. Dosage increases will be necessary as the child grows. Nephrocalcinosis in XLH seems to represent Ca²⁺–Pi deposits. Perhaps, subradiographic abnormalities will not compromise renal function (46). Partial parathyroidectomy may become necessary when elevated serum PTH levels are associated with hypercalcaemia and/or difficulty controlling the skeletal disease. Hypercalciuria (>4 mg Ca²⁺ per kg of body weight, or >220 mg Ca²⁺ per g creatinine) can occur when skeletal mineralization is fully restored or when growth plates fuse. Halving doses may provide maintenance therapy until skeletal ‘consolidation’ is complete and cessation of medical treatment can be considered.

Orthopaedic evaluation should occur at least yearly during childhood and twice yearly during the adolescent growth spurt, because limb bracing or epiphysiodesis may be necessary. Osteotomies are sometimes postponed until growth ceases to minimize the possibility of postoperative deformity. Unless patients are weight-bearing within 2 days of surgery (or fracture, etc.), 1,25-dihydroxyvitamin D₃ and then Pi therapy should be held to avoid immobilization hypercalciuria and hypercalcaemia.

Closure of physes after puberty does not mean that XLH is cured (38). The metabolic derangements persist life-long. Accordingly, affected adults should be followed perhaps yearly. Some may benefit from 1,25-dihydroxyvitamin D₃ and Pi therapy to prevent fractures or worsening deformity (38). The efficacy and benefits of medical therapy for adults with XLH are poorly understood.

X-linked recessive hypophosphataemia (Dent’s disease) maps to chromosome Xp11.22 and is due to deactivation of the CLCN5 gene involved in chloride transport (48). Hypercalciuria nephrocalcinosis, β₂-microglobinuria, and progressive glomerular disease affect males. Renal Pi wasting sometimes causes mild rickets. Treatment consists of Pi supplementation with caution not to cause hyperparathyroidism, or to exacerbate nephrocalcinosis.

This rare form of renal Pi wasting (OMIM #193100) causes relatively mild rickets appearing during adolescence. The disorder has been mapped to chromosome 12p13 and involves activating mutations in the gene encoding FGF-23 (45). Treatment is similar to XLH, but lower doses of 1,25-dihydroxyvitamin D₃ and Pi are required.

Deactivating mutation in the gene that encodes dentin matrix protein 1 (DMP1) causes a very rare, autosomal recessive form of hypophosphataemic rickets (OMIM #241520).

Fanconi’s syndrome features renal Pi wasting together with other manifestations of proximal renal tubule dysfunction causing low serum levels of Pi, potassium, bicarbonate, and uric acid as well as aminoaciduria. There are many aetiologies including cystinosis, tyrosinaemia, and Lowe’s syndrome (Table 4.10.1). Therapy with 1,25-dihydroxyvitamin D₃ and Pi supplementation (see XLH) seems helpful, but urinary Ca²⁺ levels must be monitored carefully because hypercalciuria can be present.

McCune–Albright syndrome (OMIM #174800) often causes acquired hypophosphataemic rickets (17). Treatment with 1,25-dihydroxyvitamin D₃ and Pi helps control the added skeletal disease, but therapy may be especially difficult to assess because of premature closure of growth plates and the underlying fibrodysplastic disease. In fact, even bone biopsy looking for osteomalacia may not be helpful because of the widespread fibrous dysplasia.

Vitamin D-dependent rickets (VDDR) types I and II (VDDR I and VDDR II) are rare, autosomal recessive disorders that mimic vitamin D-deficiency rickets (5–8, 49). However, there is no defect in cutaneous synthesis or accelerated loss of vitamin D. Patients are typically replete with vitamin D as shown by normal serum levels of 25-hydroxyvitamin D. In fact, heritable defects in hepatic vitamin D 25-hydroxylation have not been established (50).

VDDR I and II feature diminished biosynthesis of, and target tissue resistance to, 1,25-dihydroxyvitamin D, respectively. Because there is either disturbed conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (VDDR I) or peripheral resistance to 1,25-dihydroxyvitamin D (VDDR II), serum levels of 1,25-dihydroxyvitamin D are low and high, respectively (Table 4.10.4) (5–8, 49). Nevertheless, both types of VDDR alter mineral homoeostasis in a similar way. Dietary Ca²⁺ is malabsorbed, leading to hypocalcaemia, secondary hyperparathyroidism, and hypophosphataemia. Decreased extracellular fluid levels of Ca²⁺ and Pi together impair mineralization of skeletal matrix. Because the pathogenesis of VDDR I involves defective production of 1,25-dihydroxyvitamin D by the kidney, physiological doses of 1,25-dihydroxyvitamin D₃ control the disorder (49). However, in VDDR II even enormous doses of 1,25-dihydroxyvitamin D₃ may prove ineffective (5–8). Both VDDR I and II are now understood at the gene level and therefore have more informative names (17, 33).

1,25-dihydroxyvitamin D deficiency can be defined as low circulating levels of this hormone with normal or elevated (depending on preceding vitamin D therapy) concentrations of 25-hydroxyvitamin D. In theory, this situation could result from decreased production or increased clearance of 1,25-dihydroxyvitamin D. Decreased production can be hereditary or acquired. Acquired deficiency is usually explained by systemic disease, such as chronic renal failure or acquired Fanconi’s syndrome, etc., which affect bone and mineral metabolism in multiple and complex ways (beyond the scope of this chapter). Increased clearance is uncommon, and typically accompanies loss of other vitamin D metabolites, such as 25-hydroxyvitamin D, and would therefore fit within the definition of vitamin D deficiency. The genetic entity discussed here (OMIM #264700) is now also called hereditary 1,25-dihydroxyvitamin D deficiency, and is an inborn error of metabolism featuring defective biosynthesis of 1,25-dihydroxyvitamin D.

Prader and colleagues were the first to characterize this disorder when they described two young children who showed all of the usual clinical features of vitamin D deficiency despite adequate input of the vitamin. Complete remission depended upon continuous therapy with high doses of vitamin D—thus, the term ‘vitamin D-dependent rickets’. They coined the term ‘pseudovitamin D deficiency’. Remission could, however, be achieved by physiological (microgram) doses of 1α-hydroxylated vitamin D metabolites (51, 52). VDDR I is now understood at the molecular level and is, therefore, best described as 25-hydroxyvitamin D, 1α-hydroxylase deficiency (49).

Patients with 1α-hydroxylase deficiency appear healthy at birth. Features consistent with nutritional rickets are usually noticed before 2 years of age, and often during the first 6 months of life. There is growth retardation and poor gross motor development. Muscle weakness, irritability, pneumonia, seizures, and failure to thrive are prominent findings.

Serum 1,25-dihydroxyvitamin D levels are low or undetectable despite normal levels of 25-hydroxyvitamin D. Malabsorption of dietary Ca²⁺ leads to hypocalcaemia, secondary hyperparathyroidism, and hypophosphataemia. Serum ALP activity is elevated.

Radiographic changes are in keeping with nutritional rickets. In addition to growth plate abnormalities and rachitic deformities, osteopenia and other features of secondary hyperparathyroidism are present. Undecalcified bone documents defective matrix mineralization and secondary hyperparathyroidism including osteoclastosis and peritrabecular fibrosis (49).

Early reports of affected siblings in inbred kindreds indicated that VDDR I is an autosomal recessive condition especially prevalent in French-Canadians (33). A founder effect seems to have occurred in this population and, in 1990, linkage studies mapped the disorder to chromosome l2q14 (49). The molecular defect involves the kidney mitochondrial cytochrome P450clα enzyme responsible for rate-limiting, hormonally regulated, 25-hydroxyvitamin D bioactivation to 1,25-dihydroxyvitamin D (i.e. 25-hydroxyvitamin D, lα-hydroxylase). Actually, this enzyme has several components, cytochrome P-450D10t, ferredoxin, and ferredoxin reductase (49). Several mutations have been found in the P450clα gene (CYP27B1: OMIM 609506) (51). French-Canadian patients are commonly homozygous for a 958ΔG defect in this single copy gene. None of these mutations engenders an enzyme with decreased (rather than absent) activity (51).

Serum concentrations of 25-hydroxyvitamin D are normal in VDDR I (elevated if pharmacological doses of vitamin D or 25-hydroxyvitamin D are given), yet 1,25-dihydroxyvitamin D levels are subnormal, or remain only partially corrected by vitamin D or 25-hydroxyvitamin D therapy (49). Because pharmacological doses of vitamin D₂ or D₃ or 25-hydroxyvitamin D₃ produce therapeutic responses in VDDR I similar to physiological (replacement) doses of 1,25-dihydroxyvitamin D₃, it is apparent that 25-hydroxyvitamin D (or some metabolite) at sufficient levels can activate the VDR. Alternatively, perhaps enhanced local 1,25-dihydroxyvitamin D biosynthesis occurs with pharmacological doses of the prohormones.

The 1α-hydroxylase gene from more than 25 families has been studied by site-directed mutagenesis and cDNA expression in transfected cells. All patients had homozygous mutations. Most French-Canadian patients had the same mutation causing a frame shift and a premature stop codon in the putative haem-binding domain. The same mutation was observed in additional families of diverse origin. All other patients had either a base-pair deletion causing premature termination codon upstream from the putative ferredoxin and haem-binding domains, or missense mutations. No 1α-hydroxylase activity was detected when the mutant enzyme was expressed in various cells. The sequence of the human 1α-hydroxylase gene from keratinocytes and peripheral blood mononuclear cells has been shown to be identical with the renal gene.

The differential diagnosis includes especially defects in the VDR-effector system, where serum concentrations of 1,25-dihydroxyvitamin D and the response to treatment with 1-α hydroxylated vitamin D metabolites are greatly different (Table 4.10.2).

Clinical remission has followed daily, high-dose therapy with 1–3 mg of vitamin D₂, or with 0.2–0.9 mg of 25-hydroxyvitamin D. Because there is no defect in hepatic conversion of vitamin D to 25-hydroxyvitamin D, vitamin D rather than 25-hydroxyvitamin D is cheap yet effective. However, a physiological (‘replacement’) dose of 1,25-dihydroxyvitamin D, 0.25–1.0 μg daily, bypasses the lα-hydroxylase defect and provides effective treatment (49). Although 25-hydroxyvitamin D₃ or 1,25-dihydroxyvitamin D₃ therapy is expensive, it has advantages. The physiological half-lives of these metabolites are much shorter than vitamin D, and excessive dosing will respond more rapidly to temporary cessation of therapy. Most patients, however, can be managed with vitamin D, but follow-up is essential for any regimen.

This disorder was characterized in 1978 when a patient with features of ‘pseudovitamin D deficiency’ (see above) was found to have high serum levels of 1,25-dihydroxyvitamin D (51). Thus, ‘hereditary resistance to 1,25-dihydroxyvitamin D’ or VDDR II refers to this condition (OMIM #277440) (5, 6). Autosomal recessive inheritance is well established, and parental consanguinity has been reported in approximately 50% of cases (33).

Most patients have been from the Mediterranean region. Obligate heterozygotes do not have clinical manifestations. Patients appear normal at birth, but then develop features of vitamin D deficiency during the first year in a few patients (5–8), similar to vitamin D deficiency or VDDR I within the first 2 years of life. Although several sporadic cases developed skeletal disease as late as their teenage years or middle age, these patients represent the mildest form of the disease and had complete remission when treated with vitamin D or its active metabolites. It is unclear if the adult-onset patients belong to this entity. In general, the earlier the presentation, the more severe the clinical and biochemical features (5–8).

Hypocalcaemia causes secondary hyperparathyroidism, hypophosphataemia, and elevated serum ALP activity. However, 1,25-dihydroxyvitamin D levels are elevated, sometimes as much as 10-fold (5–8). This abnormality reflects peripheral resistance to 1,25-dihydroxyvitamin D causing malabsorption of dietary Ca²⁺ and the combined effects of four subsequent activators of renal 25-hydroxyvitamin D, lα-hydroxylase activity: hypocalcaemia, increased serum PTH, hypophosphataemia and also diminished feedback inhibition by 1,25-dihydroxyvitamin D on the kidney 1α-hydroxylase.

The radiographic and histological findings of VDDR II resemble those of nutritional rickets, as described before, including growth plate disturbances, rachitic deformities, osteopenia, and evidence of secondary hyperparathyroidism. In a patient with total alopecia, hair follicles were present.

A peculiar feature, appearing in more than half of the subjects, is total alopecia or sparse hair. Alopecia usually appears during the first year of life and in one patient, at least, has been associated with additional ectodermal anomalies as oligodentia, epidermal cysts, and cutaneous milia (5–8).

Alopecia seems to be a marker for a more severe form of the disease, as judged by earlier onset, severity of the clinical features, proportion of patients who do not respond to treatment with high doses of vitamin D or its active metabolites, and the extremely elevated serum levels of 1,25-dihydroxyvitamin D during therapy. Although some patients with alopecia achieve clinical and biochemical remission of their bone disease, none have shown hair growth. The notion that total alopecia reflects a defective VDR-effector system is supported by the fact that alopecia has only been associated with hereditary defects in the VDR system, i.e. with end-organ resistance to the action of the hormone. Hair follicles normally contain the VDR.

Patients with VDDR II with normal hair can respond fully to high doses of bioactive vitamin D metabolites. However, only some with total alopecia do so. Remarkably, however, some patients with VDDR II may no longer need 1,25-dihydroxyvitamin D₃ therapy, or require lower doses, later in life (5–8).

The nature of the resistance to 1,25-dihydroxyvitamin D and aberrations in the VDR/effector system have been elucidated (5–8, 9). A variety of VDR, or post-VDR, defects block the peripheral action of 1,25-dihydroxyvitamin D. There can be an absence of the VDR, diminished or absent 1,25-dihydroxyvitamin D-binding capacity or decreased binding affinity, and failure of the 1,25-dihydroxyvitamin D–VDR complex to localize to the nucleus or bind to DNA (8). A mouse model has been developed by targeted ablation of the VDR gene. Patients without VDR hormone or DNA binding are the most difficult to treat (5, 6).A VDR-positive, mild variant has been reported in Columbia, South America (OMIM %600785) (33, 53).

If untreated, most patients with VDDR II die in early childhood (5–8). However, good control of the disorder is possible with therapy, especially in individuals without alopecia. Depending upon severity, VDDR II may require treatment with calciferols, which enhance endogenous production of 1,25-dihydroxyvitamin D, administration of high doses of both calciferols and Ca²⁺ to compensate for the target tissue resistance to 1,25-dihydroxyvitamin D, or the use of high doses of Ca²⁺ alone (given orally or intravenously) to circumvent the target cell 1,25-dihydroxyvitamin D resistance (8, 46). Whereas most patients may respond to very high oral doses of 1,25-dihydroxyvitamin D₃ (10–40 μg daily), some can have clinical, radiographic, and biochemical corrections with high doses of vitamin D₂ or 25-hydroxyvitamin D₃ (5–8). Some patients have unexplained disease fluctuation.

Before therapy, serum 1,25-dihydroxyvitamin D concentrations range from the upper normal limit to markedly elevated. With vitamin D treatment, they may reach the highest levels found in any living system (≥100 times the upper normal limit). Such values may reflect four different mechanisms acting synergistically to drive renal 25-hydroxyvitamin D, 1α-hydroxylase: hypocalcaemia, secondary hyperparathyroidism, hypophosphataemia, and perhaps failure of the negative feedback loop by which 1,25-dihydroxyvitamin D inhibits the renal enzyme activity (8).

In approximately half of the reported kindreds, parental consanguinity and multiple siblings with the same defect indicate autosomal recessive inheritance. Parents or siblings of patients who are obligate heterozygotes have been reported to be normal, i.e. no bone disease or alopecia, and have normal blood biochemistry findings. There is a striking clustering of patients around the Mediterranean, including patients reported form Europe and America who originated from the same area (7, 8). A notable exception is a cluster of kindreds from Japan (33).

The near ubiquity of a similar if not identical VDR-effector system among various cell types helped clarify the nature of the intracellular and molecular defects in these patients (7, 8).

Defects in the 1,25-dihydroxyvitamin D-binding region range from no hormone binding (the most common abnormality), to defective hormone binding capacity and defective hormone binding affinity. A defect that compromises RXR heterodimerization with the VDR (which is essential for nuclear localization and probably for recognition of the vitamin D responsive element in the DNA as well) was characterized in several kindreds with and without alopecia (7, 8). In one patient, the receptor exhibited a marked impairment in binding coactivators essential for transactivation of the hormone–VDR complex and initiation of the physiological response. In kindreds with defects in the VDR binding to DNA, different single nucleotide mutations in the DNA binding region were found (7, 8). All point mutations affected the region of the two zinc fingers of the VDR essential for functional interaction of the hormone–receptor complex with DNA. Interestingly, all altered amino acids are highly conserved in the steroid receptor superfamily. In all of those patients, no response followed very high doses of vitamin D or its active 1α-hydroxylated metabolites.

Normal hair is usually associated with milder and usually complete clinical and biochemical remission on high doses of vitamin D or its metabolites (7, 8). Only about half of the patients with alopecia have shown satisfactory clinical and biochemical remission to high doses of vitamin D or its active 1α-hydroxylated metabolites, but the dose requirement is about 10-fold higher than in patients with normal hair.

It seems that defects characterized as deficient hormone binding affinity and deficient heterodimerization with RXR achieve remission on high doses of vitamin D or its active 1α-hydroxylated metabolites. Most with other defects could not be cured. However, not all patients received prolonged treatment and with sufficiently high doses (see below).

Typical clinical and biochemical features (Table 4.10.4) support the diagnosis. The issue becomes more complicated when the clinical features are atypical, i.e. late onset, sporadic cases, and normal hair. Failure of a therapeutic trial with Ca²⁺ and/or physiological replacement doses of vitamin D or its active metabolites may support the diagnosis but direct proof requires demonstration of a cellular, molecular, and functional defect in the VDR–effector system.

Based on the clinical and biochemical features, the following additional disease states should be considered: (1) extreme Ca²⁺ deficiency: e.g. some children from South Africa who consume a very low calcium diet of about 125 mg/day with severe bone disease and histologically proven osteomalacia, biochemical features of hypocalcaemic rickets with elevated levels of serum 1,25-dihydroxyvitamin D, and sufficient vitamin D. Ca²⁺ repletion caused complete clinical and biochemical remission. Nutritional history and the response to Ca²⁺ supplementation support this diagnosis; and (2) severe vitamin D deficiency: during the initial stages of vitamin D therapy in children with severe vitamin D-deficient rickets, the biochemical picture may resemble 1,25-dihydroxyvitamin D resistance, i.e. hypocalcaemic rickets with elevated 1,25-dihydroxyvitamin D levels. This may represent a ‘hungry bone syndrome’, i.e. high Ca²⁺ demands of the abundant osteoid tissue becoming mineralized. However, this is a transient condition that may be differentiated from hereditary resistance to 1,25-dihydroxyvitamin D by a history of vitamin D deficiency and the final therapeutic response to vitamin D.

In about half of the kindreds, the bioeffects of 1,25-dihydroxyvitamin D₃ were measured in vitro. Nearly always, correlation was documented between the in vitro effect and the therapeutic response in vivo, i.e. patients with no calcaemic response to high levels of 1,25-dihydroxyvitamin D₃ showed no effects of 1,25-dihydroxyvitamin D₃ on their cells in vitro (either induction of 25-hydroxyvitamin D-24-hydroxylase or inhibition of lymphocyte proliferation) and vice versa (7, 8). If the predictive therapeutic value of the in vitro cellular response to 1,25-dihydroxyvitamin D₃ could be substantiated convincingly, it may eliminate the need for time consuming and expensive therapeutic trials with massive doses of vitamin D or its active metabolites. In the meantime, it is mandatory to treat every patient with this disease irrespective of the type of receptor defect.

An adequate therapeutic trial must include vitamin D at sufficient doses to maintain high serum concentrations of 1,25-dihydroxyvitamin D because patients can produce high serum 1,25-dihydroxyvitamin D levels if supplied with substrate. If high serum levels are not achieved, 1α-hydroxylated vitamin D metabolites should be given in daily doses up to 6 μg/kg weight or a total of 30–60 μg and up to 3 g of elemental Ca²⁺ orally daily; therapy must continue for a period sufficient to mineralize the abundant osteoid (usually 3–5 months). Therapy may be considered a failure if no change in the clinical, radiological, or biochemical parameters occurs while serum 1,25-dihydroxyvitamin D concentrations are maintained at approximately 100 times average normal values.

In some patients unresponsive to vitamin D or its metabolites, clinical and biochemical remission, including catch-up growth, accompanied large amounts of Ca²⁺ achieved by long-term (months) intracaval infusions of up to 1000 mg of Ca²⁺ daily. Alternatively, increasing oral Ca²⁺ intake was used successfully in only very few patients and this approach is limited by dose and patient tolerability.

Several patients have shown unexplained fluctuations in response to therapy or in presentation of the disease (7, 8). One patient, after a prolonged remission, became completely unresponsive to much higher doses of active 1α-hydroxylated vitamin D metabolites, and another patient seemed to show amelioration of resistance to serum 1,25-dihydroxyvitamin D₃ after a brief therapeutic trial with 24,25-dihydroxyvitamin D. In several patients, spontaneous healing occurred in their teens or rickets did not recur for 14 years after cessation of therapy.

VDRs are abundant and widely distributed among most tissues studied and multiple effects of 1,25-dihydroxyvitamin D are observed on various cell functions in vitro. Yet, the clinical and biochemical features in patients with hereditary 1,25-dihydroxyvitamin D deficiency and resistance seems to demonstrate that the only disturbances of clinical relevance are perturbations in mineral and bone metabolism. This emphasizes the pivotal role of 1,25-dihydroxyvitamin D in transepithelial net Ca²⁺ fluxes. Moreover, the fact that in patients with extreme end-organ resistance to 1,25-dihydroxyvitamin D, Ca²⁺ infusions correct the disturbances in mineral homoeostasis and cure the bone disease may support the notion that defective bone matrix mineralization is secondary to disturbances in mineral homoeostasis.

In 1948, hypophosphatasia (OMIM #241500, #146300, #241510) was coined to distinguish a rare form of heritable rickets characterized biochemically by hypophosphatasaemia and deficient activity of the tissue-nonspecific (liver/ bone/ kidney) isoenzyme of ALP (TNSALP) (15). At least 200 different mutations in the TNSALP gene (OMIM *171760) have been discovered in patients worldwide (55). Hence, hypophosphatasia is an instructive inborn error of metabolism which verifies the theory promulgated by Robert Robison, beginning in 1923, that ALP conditions mineralization of cartilage and bone matrix.

Approximately 300 cases of hypophosphatasia have been described. However, the severity of this disorder is remarkably variable and spans intrauterine death from profound skeletal hypomineralization to merely premature loss of teeth in adults (15). Traditionally, six clinical forms are reported depending on patient age when skeletal disease is documented. Although TNSALP is ubiquitous in tissues, and especially rich in liver and kidney as well as in cartilage and bone, hypophosphatasia seems to affect directly only hard tissues (55). Perinatal, infantile, childhood, and adult hypophosphatasia feature rickets and osteomalacia, respectively, and dental disease (15). Children and adults who manifest premature tooth loss without skeletal disease (radiographically or on bone biopsy) have odontohypophosphatasia. Although artificial and somewhat conflicting, this clinical classification has provided a sense of recurrence risk and prognosis.

Perinatal hypophosphatasia is diagnosed at birth and is almost invariably lethal (15, 55). Stillbirth is common. Profound skeletal hypomineralization with caput membranaceum and short and deformed limbs is obvious. Severe osteogenesis imperfecta or cleidocranial dysplasia may be suspected, but can be distinguished radiographically and by gene testing (16). Occasionally, bony spurs protrude from the shafts of major long bones. Failure to gain weight, irritability with a high-pitched cry, unexplained fever, anaemia, periodic apnoea with bradycardia, and intracranial haemorrhage can occur. Respiratory compromise from pulmonary hypoplasia and chest deformity proves fatal.

Infantile hypophosphatasia becomes clinically apparent before 6 months of age with failure to thrive, widened fontanelles, hypotonia, and sometimes vitamin B₆-responsive seizures (15). Poor feeding and rickets are noted. Hypercalcaemia and hypercalciuria may explain bouts of vomiting and nephrocalcinosis, sometimes with significant renal impairment. Rachitic deformity of the chest and rib fractures predispose to recurrent pneumonia. Seizures and spells of apnoea may occur. Despite the impression from palpation or radiographs that skull hypomineralization reflects widely open fontanelles, functional craniosynostosis is common. Infantile hypophosphatasia often features progressive clinical and radiographic deterioration, and about 50% of patients die within the first year of life. However, the prognosis seems better if there is survival past infancy, although persisting skeletal disease seems likely (15).

Childhood hypophosphatasia is especially variable (14). Premature loss of deciduous teeth (age <5 years) from hypoplasia of cementum may be the most remarkable manifestation. Cementum anchors dentition to the periodontal ligament, therefore, teeth are shed without root resorption. Incisors are usually lost first, but the entire dentition can be exfoliated. Enlarged pulp chambers and root canals result in ‘shell’ teeth. Skeletal deformity can include scaphalocephaly with frontal bossing, a rachitic rosary, bowed legs or knock-knees, short stature, and wrist, knee, or ankle enlargement. When radiographs disclose rickets, delayed walking and a characteristic waddling gait are common. Childhood hypophosphatasia may improve when growth plates fuse after puberty, but recurrence of symptoms seems likely during the adult years (15, 55).

Adult hypophosphatasia presents during middle age (15, 55). Approximately 50% of patients mention rickets and/or premature loss of teeth during childhood. Often, there are recurrent, poorly healing, metatarsal stress fractures. Subtrochanteric femoral pseudofractures may be found proximally in the lateral cortices (18). Chondrocalcinosis is common, but Ca²⁺ pyrophosphate dihydrate crystal deposition rarely causes arthritis or pseudogout.

Radiographic findings in hypophosphatasia are helpful for diagnosis, especially in paediatric patients. Perinatal hypophosphatasia features pathognomonic changes. The skeleton can be so hypomineralized that only the skull base is apparent. Individual vertebrae appear to be ‘missing’, and bony spurs may protrude from major long bones. Alternatively, severe rachitic changes are seen. Calvarial bones can be mineralized only centrally, giving the illusion that sutures are widely patent. Fractures are not uncommon. In infants, abrupt transition from well mineralized diaphyses to hypomineralized metaphyses suggests sudden metabolic deterioration. Relentless skeletal demineralization, worsening rachitic disease, and progressive deformity or vitamin B₆-responsive seizures predict a lethal outcome. Bone scintigraphy showing little tracer uptake in widely separated cranial ‘sutures’ suggests functional suture closure. Patients who survive infancy can have true premature cranial sutures fusion causing a ‘beaten-copper’ radiographic appearance and raised intracranial pressure (Fig. 4.10.7). In children, characteristic tongues of radiolucency extend from physes into metaphyses of major long bones (Fig. 4.10.2). Adult hypophosphatasia causes recurrent, poorly healing, metatarsal stress fractures and femoral pseudofractures occur laterally (rather than medially as in other forms of osteomalacia). There can also be osteopenia and chondrocalcinosis with changes of pyrophosphate arthropathy.

Subnormal serum ALP activity for age and sex (hypophosphatasaemia) is the biochemical hallmark of hypophosphatasia. The levels reflect disease severity (15, 55). Patients with odontohypophosphatasia have mild but discernible decreases. In fact, this finding is especially impressive because rickets or osteomalacia typically cause hyperphosphatasaemia (14). Several other conditions, some with skeletal manifestations, lower blood ALP levels (15), but are readily distinguished from hypophosphatasia, partly because patients do not accumulate TNSALP substrates (see below). Serum levels of Ca²⁺ and Pi are not diminished. Hypercalciuria and hypercalcaemia often complicate the infantile form. The pathogenesis seems to involve a ‘dyssynergy’ between gut absorption of dietary Ca²⁺ and defective skeletal mineralization; however, skeletal demineralization may also be a factor. Serum levels of PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D are usually unremarkable unless there is hypercalcaemia or renal compromise. Serum Pi concentrations are above control mean levels, and mild hyperphosphataemia occurs in about one-half of children and adults. The pathogenesis involves enhanced renal reclamation of Pi only sometimes explained by suppressed serum PTH levels (55).

Three phosphocompounds, natural substrates for TNSALP, accumulate endogenously in hypophosphatasia: phosphoethanolamine, inorganic pyrophosphate (PPi), and pyridoxal 5′-phosphate (PLP) (15, 55). Assays are commercially available for urinary phosphoethanolamine and plasma PLP. Mild phosphoethanolaminuria occurs in several metabolic bone diseases (15), and fortunately increased plasma PLP concentration is a particularly sensitive and specific marker for hypophosphatasia. However, patients must not be taking vitamin B₆ when tested. Endogenous accumulation of PPi seems to be a key pathogenetic factor (see below), yet quantitation of PPi remains a research technique.

Defective skeletal mineralization occurs in all clinical forms of hypophosphatasia except odontohypophosphatasia (2). Unless evaluation of the ALP activity in bone is undertaken, the histopathological findings are those of other types of rickets or osteomalacia lacking secondary hyperparathyroidism.

Hypophosphatasia occurs in all races, but seems to be especially common among Mennonites and Hutterites in Canada, where the incidence of severe disease is approximately 1/100 000 live births (15). Perinatal and nearly all cases of infantile hypophosphatasia are transmitted as autosomal recessive traits. Obligate carriers can have diminished or low-normal levels of serum ALP activity, and sometimes demonstrate modest elevations in plasma PLP levels, especially after a vitamin B₆ challenge (15, 55). The inheritance pattern(s) for childhood, adult, and odonto forms of hypophosphatasia is autosomal recessive for some cases. In others, there is generation to generation transmission with mild clinical expression.

The gene for TNSALP has 12 exons and appears to exist as a single copy in the haploid genome on the tip of the short arm of chromosome 1 (lp36.1–lp34). In 1988, a missense mutation in the TNSALP gene was identified in a severely affected infant from an inbred Canadian kindred (55). Studies of patients with severe hypophosphatasia have disclosed approximately 200 different mutations in the TNSALP gene (55). Most are missense mutations. Perinatal and infantile hypophosphatasia reflect homozygosity or compound heterozygosity for these defects. The childhood and adult forms of hypophosphatasia can indeed be the ‘same’ disease (15). Mouse models that recapitulate the infantile form of hypophosphatasia have been developed by TNSALP gene knock-out (56).

ALP (orthophosphoric monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1), found in nearly all organisms, is a glycosylated, plasma membrane-bound, ectoenzyme (55). Discovery of the accumulation of three phosphocompounds, phosphoethanolamine, PPi, and PLP, in hypophosphatasia revealed how TNSALP may function (15, 55). Accumulation of PLP, the principal cofactor form of vitamin B₆, indicates that TNSALP acts primarily as an ectoenzyme. Patients with hypophosphatasia do not have symptoms or signs of vitamin B₆, deficiency or toxicity despite their markedly increased plasma PLP levels.

In 1965, discovery of elevated urinary levels of PPi in hypophosphatasia disclosed the pathogenesis of the rickets and osteomalacia. Excess PPi was found to be a potent inhibitor of biomineralization. PPi levels are increased in plasma and urine in hypophosphatasia. Matrix vesicles are devoid of ALP activity but do contain hydroxyapatite crystals (4). However, only a few isolated crystals are observed outside these extracellular structures. Excess PPi blocks hydroxyapatite crystal formation in the extracellular matrix of bone.

Conventional treatments for rickets or osteomalacia are generally best avoided in hypophosphatasia because patients are usually vitamin D replete and serum levels of Ca²⁺ and Pi are not reduced (15). Indeed, such treatment could exacerbate or provoke hypercalcaemia and hypercalciuria. Hypercalcaemia in infantile hypophosphatasia generally responds to reduction in dietary Ca²⁺ intake, but may require glucocorticoid or calcitonin therapy. Enzyme replacement by intravenous infusion of various soluble forms of ALP has generally been disappointing (55), but administration of an investigational, bone-targeted, TNSALP fusion protein is showing considerable success (56). Additionally, two infants who seemed destined to die from infantile hypophosphatasia showed clinical and radiographic improvement following transplantation of marrow or bone-derived cells (57). Supportive therapy is important for hypophosphatasia. Fractures do mend, but delayed healing after casting or osteotomy has been observed. In affected adults, placement of intramedullary rods, rather than load-sparing devices (e.g. plates), seems to be preferable for the acute or prophylactic treatment of fractures and pseudofractures (18). Expert dental care is especially important for children, because their nutrition can be impaired by premature tooth loss. Craniotomy may be crucial in cases with craniosynostosis. Fetuses that are severely affected (perinatal form) can be detected reliably in utero by ultrasonography, but a relatively mild ‘benign prenatal’ form of hypophosphatasia must be considered. TNSALP gene mutation studies have improved prenatal diagnosis (15).

Supported in part by Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, and The Barnes-Jewish Hospital Foundation.