Metabolic and Endocrine Disorders of Bone

Vitamin D Disorders

Vitamin D ₃ (Cholecalciferol) is endogenously produced in keratinocytes of the skin within the epidermal layer, predominantly in the stratum basale and spinosum, upon exposure to ultraviolet light B; wavelength 290 to 315 nm. Vitamin D is then twice hydroxylated to its active metabolite, calcitriol (see Fig. 38.1 ). In that sense vitamin D is not actually a vitamin but rather a hormone producing endocrine, autocrine, and paracrine signaling effects. Endocrine signaling occurs when a hormone synthesized by a glandular cell is released into the circulation to be delivered to a receptor on a different target cell to express its biologic function. Autocrine signaling occurs when a cell secrets a hormone that binds to receptors on the same cell, and paracrine signaling occurs when the hormone released by a cell induces a response in an adjacent but different cell.

Vitamin D formation and activation is a complex process that involves the gut, skin, liver, and kidney. Ergosterol (provitamin D) is a sterol precursor found in plant tissue (see Fig. 38.1 ). Ergosterol is lipid soluble, ingested and absorbed from the small intestine, and is irradiated in the skin to vitamin D ₂ (ergocalciferol). On the other hand, 7-dehydrocholesterol is a zoosterol that is converted also in the skin to cholecalciferol, as a result of exposure to ultraviolet light. Mal-absorption syndromes can result in vitamin D dependent rickets. Conditions resulting in decreased skin conversion to cholecalciferol, such as scarce sunshine, skin shielding, and dark-toned skin, can also result in vitamin D deficiency rickets.

Both cholecalciferol and ergocalciferol are biologically inert and must undergo a series of hydroxylation reactions in their transformation to the active form, calcitriol (1,25(OH) ₂ vitamin D). The first hydroxylation takes place in the liver to produce 25(OH) vitamin D mediated by CYP2R1 enzyme. The liver also produces 7-dehydrocholesterol (provitamin). Deficiency in CYP2R1 result in VDDR type 1B ( Table 38.2 ). Liver disease or medications that increase the degradation of calcidiol can result in VDRR. Ninety percent of calcidiol is bound to vitamin D binding protein (DBP). Calcidiol is the major form of vitamin D in circulation with a half-life of 15 days whereas the half-life of the active form, calcitriol, is only 15 hours (see Fig. 38.1 ). Thus, serum calcidiol level better reflects vitamin D stores in the body and is a better indicator of vitamin D level than serum calcitriol level. Calcidiol is transported to the cite of the second hydroxylation via DBP. Megalin is involved in internalizing calcidiol-DBP complex from the luminal side into the proximal tubule of the kidney. Cubilin is a megalin-calcidiol co-receptor. It is proposed that cubilin binds the excreted DBP-calcidiol complex on the cell surface of the tubular cell thus facilitating endocytosis. The second hydroxylation occurs in the kidney via 1α-hydroxylase enzyme (CYP27B1) , which produces the active form, calcitriol. A mutation in CYP27B1 causes VDDR type 1A ( Table 38.3 ). Calcitriol binds to specific nuclear, vitamin D receptors (VDR) that regulate the transcription of target genes which control mineral homeostasis and cell differentiation. The VDR gene is located on the long (q) arm of chromosome 12 at position 13.1 (12q13.1). A mutation in the VDR gene causes VDDR type 2A. Post VDR defects result in VDDR type 2B.

Calcitriol plays a critical role in the intestinal absorption of calcium and phosphorus. Several intestinal transport proteins found in the brush border of intestinal cells are involved in calcium absorption: Ca/Mg ATPase, alkaline phosphatase, intestinal membrane calcium binding proteins, and calcium channels TPRV5 and TRPV6. Calcitriol has additional roles independent of its action on the gut. This includes anti-proliferative effect on parathyroid cells, stimulation of osteoclast differentiation, and regulation of formation of several matrix proteins. Calcitriol in turn increases FGF23 production, which down-regulates 1α-hydroxylase activity as a negative feedback mechanism. Calcitriol and calcidiol are further catabolized into an inactive form 1,24,25 (OH) ₃ vitamin D by CYP24A1 enzyme (see Fig. 38.1 ). Deficiency in CYP24A1 causes hypercalcemia.

Pathology

In rickets, the primary disturbance is failure of mineralization of growth plate cartilage and osteoid tissue, which decreases longitudinal bone growth and weakens the mechanical properties of tubular bone. ^{, , , ,} Thus the pathologic manifestations of the disease are most noticeable around growth plates and along long bones. Normal longitudinal growth of bone is the result of endochondral ossification. The key elements of the process are proliferation of chondrocytes in columns (zone of proliferation), cellular maturation to become hypertrophic chondrocytes, calcification of the cartilage matrix (zone of provisional calcification), vascular invasion of the terminal hypertrophic chondrocytes, and deposition of new bone. In rickets, failure of deposition of calcium along the matrix of the maturing chondrocyte columns is observed, along with a disorderly invasion of cartilage by blood vessels, lack of resorption at the zone of provisional calcification, and consequently increased thickness of the growth plate ( Fig. 38.2 ). The chondrocytes proliferate normally, but the normal process of endochondral ossification fails to take place.

Osteoblastic activity on the endosteal and periosteal surfaces of bone is normal, and abundant osteoid (nonmineralized bone matrix) is formed. With defective mineralization of osteoid, osteoclastic resorption of the osteoid does not take place. However, increased resorption of the mineralized bone occurs from secondary hyperparathyroidism due to hypocalcemia. Hence, the overly abundant osteoid produced by normal osteoblasts generates widened osteoid seams. Because of a lack of resorption of osteoids, the osteoid islets may even persist down into the diaphysis.

In rickets, an abnormality in the arrangement of bundles of collagen fibers in compact bone also exists. Instead of running parallel to the haversian canals, they course perpendicularly and are biomechanically inferior. Grossly, the rachitic bone is soft and becomes misshapen under the force of weight bearing. If the disease remains untreated, angular deformities of the lower extremities and deformities of the thoracic cage and pelvis may develop.

After treatment of rickets with vitamin D, calcium absorption increases and calcification of the cartilage columns and osteoid occurs. Osteoclasts resorb the calcified cartilage, and normal remodeling and improvement of bone follows.

Laboratory Findings

Vitamin D deficiency rickets mainly results in an inability to absorb calcium and phosphorus from the gut. Vitamin D status is best evaluated by measuring the level of serum 25(OH) vitamin D (calcidiol), which reflects the degree of deficiency as discussed above. In contrast, the serum level of 1,25(OH) ₂ vitamin D (calcitriol) is not helpful because it may be normal in most patients with vitamin D deficiency rickets. The PTH level is elevated in response to hypocalcemia (secondary hyperparathyroidism), which attempts to ameliorate the serum calcium level. Serum calcium levels are normal to mildly decreased, but phosphate levels are low (hypophosphatemia). Bone turnover markers such as alkaline phosphatase, osteocalcin, pro-collagen I N-propeptide, and COL1 N-terminal and C-terminal telopeptide levels are elevated ( Table 38.4 ). ^{, , , ,} Urinary excretion of calcium is low because of enhanced renal tubular reabsorption.

Clinical Features

Children with nutritional rickets are usually first seen between the ages of 6 months and 3 years, a period of rapid growth. The clinical features of nutritional rickets depend on the severity of the disease and may be subtle. Initial findings are listlessness, periarticular swelling, or angular deformities. Hypocalcemic seizure is also a common presentation during the first 2 years of life. Infants demonstrate generalized muscular weakness, lethargy, and irritability. Sitting, standing, and walking are delayed. The abdomen may appear protuberant.

Early bone manifestations include a slight thickening of the ankles, knees, and wrists. Beading of the ribs, referred to as the rachitic rosary, is caused by enlargement of the costochondral junctions. As the disease continues, the pull of the diaphragm on the ribs produces a horizontal depression known as Harrison’s groove. Short stature results from insufficient longitudinal growth. Pectus carinatum is caused by forward projection of the sternum. Closure of the fontanelles is delayed and the sutures are thickened, which leads to a skull appearance described as resembling hot cross buns. The dentition is affected, with delays in appearance of the teeth and defects in the enamel.

As the child begins standing and walking, the softened long bones bow, and it is at this time that the child is usually brought to the orthopaedic surgeon for a diagnosis. In toddlers, bowleg, or genu varum, is one of the most common initial signs. In older children, genu valgum and coxa vara may be initial features. Stress fractures of the long bones may be present. Children may be seen acutely with unexplained fractures suggesting child abuse, tetany, and hypocalcemic seizures. Later, kyphoscoliosis may develop.

Radiographic Findings

Failure of the physeal cartilage to calcify and undergo normal endochondral ossification leads to an increased thickness of the physis and a hazy appearance of the provisional zone of calcification. ^{, ,} The widened growth plate is particularly suspect for rickets, which differentiates this rare condition from the more common physiologic angular deformities of the lower extremities ( Fig. 38.3 ). The metaphysis abutting the physis is brush-like in appearance, with islands or columns of cartilage persisting well into the metaphysis ( Fig. 38.4 ). The metaphysis also appears cupped or flared. The bones have an osteopenic appearance overall, with thinning of the cortices. The bony trabeculae are indistinct. Looser lines, or radiolucent transverse bands (pseudofracture lines) that extend across the axes of the long bones, are evident on radiographs in 20% of patients with rickets.

As the rickets continues, deformities of the long bones, ribs, pelvis, and spine develop. Thoracolumbar kyphosis—rachitic cat back—may be apparent on radiographs.

Treatment of Vitamin D Deficiency

After diagnosis of vitamin D deficiency rickets is confirmed, therapy should be initiated. Medical treatment of rickets is multidisciplinary and involves primary care provider and a dietitian. Dietary counseling evaluating daily intake of calcium, phosphorus, and vitamin D is an essential part of managing vitamin D supplementation in the form of either cholecalciferol or ergocalciferol, which is the backbone of therapy. Vitamin D replacement could be daily or high doses involving biweekly or monthly regimen. 25(OH) vitamin D serum concentration should be checked 6 to 8 weeks after initiation of therapy. The usual duration of initial treatment is 6 to 10 weeks. After 2 to 4 weeks, radiographs show improvement in mineralization. The physis thins, and bone density increases ( Fig. 38.5 ). ^, Vitamin D stores are usually replenished after 8 weeks of therapy and vitamin D intake should be maintained afterward. Because residual deformity is rare after medical treatment of nutritional rickets, there is no specific orthopaedic treatment of nutritional rickets.

Other forms of vitamin D deficiency rickets need to be treated based on understanding of the pathogenesis. Malabsorptive causes of vitamin D deficiency rickets, such as biliary atresia, and urinary losses of DBP are treated with high doses of vitamin D. Vitamin D deficiency rickets secondary to liver disease should be treated with calcitriol or calcidiol when available. Vitamin D deficiency rickets secondary to kidney disease is treated with calcitriol.

Laboratory Findings

Laboratory studies in VDRR depend on the primary etiology (see Table 38.3 ). In XLH, normal or almost normal levels of calcium are found. The serum phosphate concentration is significantly decreased, whereas the 1,25(OH) ₂ vitamin D level may be inappropriately low in response to the hypophosphatemia. The PTH level is normal. Urine assays for phosphate demonstrate an increased concentration of phosphate in the urine. The serum alkaline phosphatase concentration is elevated (see Table 38.5 ). The diagnosis is often confirmed by genetic testing/sequencing for PHEX, DMP1, FGF23, and SLC34A1 gene mutations or by FGF23 peptide assay.

Clinical Features

When suspected, XLH is often diagnosed within first 6 months of life. First signs include hypophosphatemia, increased alkaline phosphatase, and rachitic bone changes in the metaphysis of the ulna. With positive family history, the diagnosis is confirmed by clinical and biochemical changes on a genetic test for PHEX gene mutations. Most patients become symptomatic between 1 and 2 years of age. Because XLH is inherited as an X-linked dominant trait, the disease is more severe in males than females. Severe hypophosphatemic rickets can be recognized in early infancy. When the disease is suspected because of clinical presentation and the family history, laboratory determination of phosphorus concentrations can lead to the diagnosis in infants as young as 3 months. The usual initial complaints are delayed walking and angular deformities of the lower extremities. In contrast to what is seen in nutritional rickets, systemic manifestations such as irritability and apathy are minimal. TIO often presents in early childhood. AD VDRR has milder presentation than male patients with XLH.

Physical findings in hypophosphatemic rickets include skeletal deformities, which resemble those seen in other forms of rickets. Once affected children begin to walk, genu varum develops, although genu valgum may occur in some children ( Fig. 38.6 ). Periarticular enlargement is present as a result of widening of the physes and metaphyses. The rachitic rosary may also occur.

Short stature is a feature of hypophosphatemic rickets. Height is usually two standard deviations or less below the mean for age in these patients.

Radiographic Findings

The radiographic changes are the same as those seen in nutritional rickets and include physeal widening and indistinct osteopenic metaphyses. In the lower extremities, genu varum is obvious, and the distal femoral and proximal tibial physes are particularly widened medially ( Fig. 38.7 ). Coxa vara is present, and there may be general anterior and lateral bowing of the entire femur. The varus of the tibia is also generalized, not only present proximally but also producing varus angulation of the ankle. Treatment can result in craniosynostosis and dolichocephaly.

The upper extremities are involved as well, but to a lesser degree because of absence of the influence of weight bearing ( Fig. 38.8 ).

Treatment

Orthopaedic Treatment

The deformity most commonly seen in patients with hypophosphatemic rickets is a gradual anterolateral bowing of the femur, combined with tibia vara. Genu valgum can also occur. The orthotic management of VDRR is not efficacious. Surgical intervention should be considered in patients having pain or difficulty walking due to persistent or progressive worsening of the deformity despite optimal medical therapy. In patients with growth remaining and on medical therapy, guided growth has been shown to successfully correct varus or valgus limb deformity ( Fig. 38.9 ). In a retrospective study of patients with X-linked dominant rickets, 15 out of 23 limbs (65%) treated with guided growth achieved neutral alignment while 7 limbs attained some improvement but not neutral alignment. The mean correction time was 16 months (range 9 to 27 months). Patients with ≥3years of growth remaining or valgus deformity responded better to guided growth than older patients or those with varus deformity, respectively. The rate of recurrence of deformity was low, and the authors did not recommend overcorrection as one patient had a persistent overcorrected deformity. Interestingly, improvements in knee alignment also improved femoral and tibial diaphyseal bowing and the alignment and radiographic appearance of proximal femoral and distal tibial physes in younger patients. These results are explained by the Hueter-Volkmann principle of normalization of mechanical load across the physis correcting the metaphyseal-diaphyseal deformity over time. Because of the potential benefit of restoring neutral mechanical axis to lower limb physeal function, early intervention using guided growth is advocated by some surgeons.

For symptomatic patients with significant deformity or near skeletal maturity, multilevel osteotomy is generally required to satisfactorily correct the mechanical axis of the limb ( Fig. 38.10 ). In those patients with growth remaining, mechanical axis should be mildly overcorrected at surgery as recurrence of deformity is a common sequela of osteotomies in patients with hypophosphatemic rickets. ^, Younger patients have a higher risk of recurrence. One study reported a recurrence rate of 90% after the first corrective procedure. For this reason, milder deformities should be corrected by guided growth in early childhood. Some children have severe varus at a very young age that leads to thrust during gait. When gait is compromised or patient is symptomatic, guided growth should be considered.

The suggested fixation for osteotomies varies among reports. External fixation allows fine tuning of the alignment postoperatively, when the patient is able to stand ( Fig. 38.11 ). Others advocate the use of intramedullary fixation or plating ( Fig. 38.12 ). ^, Regardless of the type of fixation used, careful preoperative planning of the surgical treatment of these multiplanar deformities is crucial to restoring alignment. It is important to work closely with the nephrologist or endocrinologist who is managing the medical therapy because calcium levels can suddenly increase in a patient who is immobilized after surgery. Discontinuation of vitamin D before surgery should be discussed.

Spinal deformity may be seen in patients with hypophosphatemic rickets. Kyphoscoliosis, Arnold-Chiari malformations, and spinal stenosis have all been described in patients with VDRR. ^,

Adults with hypophosphatemic rickets are prone to the development of arthritis. Degradation of articular cartilage resembling osteochondritis dissecans has been described. Joint stiffness and bone pain are common complaints.

Medical Treatment

Calcitriol and calcium supplement are used to treat all forms of VDDR. Very high doses of calcitriol are needed to treat type 2A and 2B VDDR.

Orthopaedic Treatment

Because residual deformity is rare after medical treatment, there is no specific orthopaedic treatment for VDDR.

Pathology

Histologically, wide osteoid seams are found around the trabeculae, similar to what is seen in rickets. The physis, however, is well calcified and normal in width and length. Metastatic calcification may be found in the kidneys, arteries, thyroid, pancreas, lungs, stomach, and brain. Deposition of calcium salts in the kidneys and degenerative changes in the arteries may produce significant morbidity.

Laboratory Findings

The hypercalcemia can be severe. The serum phosphate concentration is normal, with a diminished alkaline phosphatase concentration. ^,

Clinical Features

Symptoms and signs of hypercalcemia are seen. Early manifestations include hypertension, acute kidney injury, anorexia, constipation, nausea and vomiting, polyuria, thirst, and symptoms of dehydration. The child feels very tired. With progression of the intoxication, mental depression and stupor develop. Renal failure and hypertension are common.

Radiographic Findings

Dense metaphyseal bands are seen in the long bones and result from an increase in the proximal zone of calcification. The diaphyses show osteopenia as a result of demineralization. Osteosclerosis is visible at the base of the skull, and there may be premature closure of the sutures. The vertebral endplates are dense. Metastatic calcifications are seen in soft tissues and joints ( Fig. 38.13 ). ^,

Treatment

Treatment is medical and consists of the immediate cessation of vitamin D supplements. Due to the availability of different forms of medicinal vitamin D the duration of vitamin D toxicity varies with their half-life. Saline diuresis along with loop diuretics are used to treat hypercalcemia. Steroids inhibit calcium intestinal absorption in the kidney and gut and are helpful in correcting the calcium level. BPs inhibit bone release of calcium from bone and have been useful in treating vitamin D intoxication. Sodium phosphate intravenous infusion should be used sparingly because its administration leads to extra-skeletal calcification.

Clinical Features

Clinically, the soft tissues overlying the hyperostotic bones are swollen and tender. Proliferation of basal cells and hyperkeratinization cause dry, itchy skin. Anorexia, vomiting, and lethargy are caused by increased intracranial pressure and rachitic skeletal changes. The child fails to thrive. Hepatomegaly with cirrhosis-like liver damage or splenomegaly may be present.

Radiographic Findings

Radiographs may appear normal initially as the development of bone changes in patients with hypervitaminosis A is slow. Once changes do occur, there is periosteal hyperostosis and thickening of the cortex of the long bones. The ulna, radius, metacarpals, and metatarsals are particularly affected. The mandible is spared, a fact that distinguishes hypervitaminosis A from Caffey disease. Subperiosteal new bone formation is seen (previous Fig. 38.14 ). Bone scintigraphy shows increased uptake. Premature partial or complete physeal closure may be present. ^{, ,}

Diagnosis

The diagnosis is made by determining the plasma concentration of vitamin A, which will be elevated 5 to 15 times the normal value. Hypercalcemia can be present. ^, Hypervitaminosis A must be differentiated from infantile cortical hyperostosis (Caffey disease), scurvy, and congenital syphilis.