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General Considerations

Defective mineralization of the growing skeleton in childhood causes permanent bone deformities (rickets). Defective skeletal mineralization in adults is known as osteomalacia. It is caused by inadequate calcium or phosphate mineralization of bone osteoid.

Etiology

Causes of osteomalacia are listed in Table 28-11. Causes of Osteomalacia.

A. Vitamin D Deficiency

Vitamin D is predominantly synthesized in the skin during exposure to UV B light (Table 28-11. Causes of Osteomalacia). Vitamin D is also consumed in the diet from plants (ergocalciferol, D2) or animals/fish (cholecalciferol, D3). Both forms of vitamin D are converted in the liver to 25-hydroxyvitamin D (25-OHD); 25-OHD is subsequently converted in various tissues (mainly kidney) to 1,25-dihydroxyvitamin D (1,25[OH]2D), the active hormone whose production is regulated by serum calcium, phosphorus, and PTH. 1,25(OH)2D binds to cytoplasmic vitamin D receptors, increasing the absorption of dietary calcium from the intestine and increasing the reabsorption of calcium in the renal tubule, thereby reducing calcium loss in the urine. 1,25(OH)2D also stimulates bone osteoblasts to release RANKL that stimulates osteoclasts, which release calcium from bone.

Vitamin D deficiency is the most common cause of osteomalacia; its incidence is increasing throughout the world as a result of diminished exposure to sunlight caused by urbanization with use of automobile and public transportation, living at high latitudes, winter season, institutionalization, sunscreen use, or very modest dressing. About 36% of adults in the United States are deficient in vitamin D.

Other risk factors for vitamin D deficiency include the following: pregnancy, age over 65 years, obesity, dark skin, malnutrition, and intestinal malabsorption (due to pancreatic insufficiency, cholestatic liver disease, celiac disease, IBD, jejunoileal bypass, Billroth type II gastrectomy). Orlistat causes fat and vitamin D malabsorption. Cholestyramine binds bile acids necessary for vitamin D absorption. Patients with severe nephrotic syndrome lose large amounts of vitamin D-binding protein in the urine.

Anticonvulsants (eg, phenytoin, carbamazepine, valproate, phenobarbital) inhibit the hepatic production of 25-OHD and sometimes cause osteomalacia. Phenytoin can also directly inhibit bone mineralization. Serum levels of 1,25(OH)2D are usually normal.

Vitamin D-dependent rickets type I is caused by a rare autosomal recessive disorder with a defect in the renal enzyme 1-alpha-hydroxylase leading to defective synthesis of 1,25(OH)2D. It presents in childhood with rickets and alopecia; osteomalacia develops in adults with this condition unless treated with oral calcitriol in doses of 0.5-1 mcg daily.

Vitamin D-dependent rickets type II (hereditary 1,25[OH]2D-resistant rickets) is caused by a germline mutation in the 1,25(OH)2D receptor. Patients have hypocalcemia with childhood rickets and adult osteomalacia. Alopecia is common. These patients respond variably to oral calcitriol in very large doses (2-6 mcg daily).

B. Calcium Deficiency

The total daily consumption of calcium should be at least 1000 mg daily. Patients who have deficient calcium intake develop rickets (childhood) or osteomalacia (adulthood) despite sufficient vitamin D. A nutritional deficiency of calcium can occur in any severely malnourished patient. Some degree of calcium deficiency is common in older adults, since intestinal calcium absorption declines with age. Ingestion of excessive wheat bran also causes calcium malabsorption.

C. Phosphate Deficiency

Osteomalacia develops in patients with hypophosphatemia due to lack of sufficient phosphate to mineralize bone osteoid. Such patients typically have musculoskeletal pain and muscle weakness and are prone to fractures.

1. Genetic Disorders

Fibroblast growth factor-23 (FGF23) is a phosphaturic factor (phosphatonin) that is secreted by bone osteoblasts in response to elevated serum phosphate levels. Various germline mutations can result in high serum FGF23 levels, causing hypophosphatemia and bone mineral depletion. About 80% of genetic cases are due to X-linked hypophosphatemic rickets that is caused by a mutation in the gene encoding PHEX endopeptidase that fails to cleave FGF23. Families with autosomal dominant hypophosphatemic rickets have a gain-of-function mutation in the gene encoding FGF23, which makes it resistant to proteolytic cleavage. An autosomal recessive form of hypophosphatemic rickets is caused by mutations in DMP1, a transcription factor that regulates FGF23 production in bone.

Sodium-phosphate cotransporters (NPT2a or NPT2c) reabsorb phosphate from the proximal renal tubule. Mutations in the genes encoding them or in NHERF1 or SKC34A1 also cause hypophosphatemia, bone mineral depletion, and calcium-phosphate renal calculi.

2. Tumor-Induced Osteomalacia

This is a rare paraneoplastic syndrome that can be caused by a variety of mesenchymal tumors (87% benign) that secrete FGF23 and cause marked hypophosphatemia and hyperphosphaturia due to renal phosphate wasting. Such tumors are usually phosphaturic mesenchymal tumors (70%); other tumors include hemangiopericytomas, osteosarcomas, and giant cell tumors. Other tumor types that secrete FGF23 have included osteoblastoma, angiolipoma, spindle cell lipoma, enchondroma, and desmoplastic fibroma. About 70% of such tumors stain positive for FGF23. The condition is characterized by hypophosphatemia, excessive phosphaturia, reduced or normal serum 1,25(OH)2D concentrations, and osteomalacia. Serum levels of FGF23 are elevated. Such tumors are often small and difficult to find, frequently lying in the sinuses or extremities.

3. Other Causes of Hypophosphatemia

Hypophosphatemia can be caused by alcohol use disorder (alcoholism), poor nutrition, and prolonged parenteral nutrition. Tenofovir therapy (tenofovir disoproxil fumarate more so than tenofovir alafamide) can cause renal phosphate wasting and hypophosphatemia. Severe hypophosphatemia can occur with refeeding after starvation. Hypophosphatemia can also be caused by chelation of phosphate in the gut by aluminum hydroxide antacids, calcium acetate (Phos-Lo), or sevelamer hydrochloride (Renagel). Excessive renal phosphate losses are also seen in proximal renal tubular acidosis, Fanconi syndrome, intravenous iron, and in some women using oral contraceptives.

D. Aluminum Toxicity

Bone mineralization is inhibited by aluminum. Osteomalacia may occur in patients receiving long-term renal hemodialysis with tap water dialysate or from aluminum-containing antacids used to reduce phosphate levels. Osteomalacia may develop in patients being maintained on long-term total parenteral nutrition if the casein hydrolysate used for amino acids contains high levels of aluminum.

E. Hypophosphatasia

Hypophosphatasia refers to a severe deficiency of bone alkaline phosphatase. It is a rare genetic cause of osteomalacia that is commonly misdiagnosed as osteoporosis.

It can present in adulthood with premature loss of teeth, metatarsal stress fractures, thigh pain due to femoral pseudofractures, or arthritis due to chondrocalcinosis. Bone density is low. Serum alkaline phosphatase is low (below 40 U/L in adults and often less than 20 U/L in severe cases). The differential diagnosis is asymptomatic hypophosphatasia and other causes of low serum alkaline phosphatase, such as early pregnancy, hypothyroidism, myeloma, severe anemia, or vitamin D intoxication.

F. Fibrogenesis Imperfecta Ossium

This rare condition sporadically affects middle-aged patients, who present with progressive bone pain and pathologic fractures. Bones have a dense "fishnet" appearance on radiographs. Serum alkaline phosphatase levels are elevated. Some patients have a monoclonal gammopathy, indicating a possible plasma cell dyscrasia causing an impairment in osteoblast function and collagen disarray.

Clinical Findings

Neonates and young children with hypocalcemia may have spasms and convulsions. Older children and adolescents can have bone pain and muscle weakness and may develop the skeletal deformities of classic rickets, such as delayed longitudinal growth, deformities at epiphyses leading to thickened wrists and ankles, and bowed legs or knock-knees (adolescents). Kyphoscoliosis or lumbar lordosis is common. Thickening at the costochondral joints can cause widening of the chest and deformities known as a "rachitic rosary."

In adults, osteomalacia is initially asymptomatic. Nonspecific complaints include fatigue, reduced endurance and muscle strength, and pain in the bones involving their shoulders ribs, low back, and thighs develop. Pathologic fractures can occur with little or no trauma.

Hypocalcemia causes a reduced quality of life, with fatigue, irritability, depression, anxiety, cognitive impairment, lethargy, and paresthesias in the circumoral area, hands, and feet. More severe manifestations include muscle weakness or cramps, carpopedal spasm, convulsions, tetany, laryngospasm, and stridor. Hypophosphatemia can cause severe major muscle weakness, reduced endurance, dysphagia, diplopia, cardiomyopathy, and respiratory muscle weakness. Patients may also have impaired cognition.

Diagnostic Tests

DXA BMD is used to determine the presence of low bone density that can be due to osteoporosis, osteomalacia, or both. Serum is obtained for calcium, albumin, phosphate, alkaline phosphatase, PTH, and 25-OHD determinations. Vitamin D deficiency is defined as a serum 25-OHD less than 20 ng/mL (50 nmol/L). Vitamin D insufficiency is defined as a serum 25-OHD between 20 ng/mL and 30 ng/mL (50-75 nmol/L). Patients with severe osteomalacia typically have chronic severe vitamin D deficiency (serum 25-OHD under 12 ng/mL [25 nmol/L]).

1,25(OH)2D3 may be low even when 25(OH)D2 levels are normal. In one series of biopsy-proved osteomalacia, alkaline phosphatase was elevated in 94% of patients; the calcium or phosphorus was low in 47% of patients; 25(OH)D3 was low in 29% of patients; and urinary calcium was low in 18% of patients. Pseudofractures were seen in 18% of patients. Radiographs may show diagnostic features. Bone densitometry helps document the degree of osteopenia.

Oral contraceptives can cause renal hypophosphatemia in some women, so a drug holiday from oral contraceptives is warranted. Patients with otherwise unexplained hypophosphatemia should have a measurement of serum or plasma fibroblast growth factor 23 (FGF23). Patients with high FGF23 levels can have genetic testing for X-linked hypophosphatemic rickets (PHEX), autosomal dominant hypophosphatemic rickets (FGF23), and autosomal recessive hypophosphatemic rickets (DMP1). In patients with hypophosphatemia without such mutations, searching for a tumor causing tumor-induced osteomalacia is reasonable, particularly in patients with bone pain or fractures. Such tumors are typically small and may be located anywhere, so they are best localized using a whole-body DOTATATE-PET/CT scan.

Patients with hypophosphatasia have low serum levels of alkaline phosphatase (below 40 U/L in adults and below 20 U/L in severe cases). However, immediately following a fracture, serum alkaline phosphatase rises and may obscure the diagnosis. The diagnosis of hypophosphatasia is further suggested by a 24-hour urine assay for phosphoethanolamine or serum pyridoxal 5-phosphate (B6) level; these substrates for tissue-nonspecific alkaline phosphatase are always elevated in patients with hypophosphatasia. The diagnosis is confirmed with genetic testing for mutations in the ALPL gene. Prenatal genetic testing is available for the infantile form of hypophosphatasia.

Differential Diagnosis

Osteomalacia often coexists with osteoporosis. The relative contribution of the two entities to diminished bone density may not be apparent until treatment since a dramatic rise in bone density is often seen with therapy for osteomalacia. Phosphate deficiency must be distinguished from hypophosphatemia seen in hyperparathyroidism.

Prevention & Treatment

Humans naturally receive about 90% of their vitamin D from sunlight. To obtain adequate vitamin D, the face, arms, hands, or back must have sun exposure without sunscreen for 15 minutes at least twice weekly. In sunlight-deprived individuals (eg, veiled women, confined patients, or residents of higher latitudes during winter), vitamin D3, 1000 IU daily, should be given prophylactically. Patients receiving long-term phenytoin therapy should also receive vitamin D3 supplementation. The main natural food source of vitamin D is fish, particularly salmon, mackerel, cod liver oil, and sardines or tuna canned in oil. Most commercial cow's milk is fortified with vitamin D at about 400 IU (10 mcg) per quart; however, skim milk, yogurt and cottage cheese may contain little to no vitamin D3.

Many vitamin supplements contain plant-derived vitamin D2, which has variable biologic availability. Therefore, it is prudent to recommend that patients take a dedicated vitamin D3 supplement from a reliable manufacturer. Over-the-counter multivitamin/mineral supplements contain variable amounts of vitamin D, and vitamin D toxicity has occurred from two different multivitamins sold in the United States.

Severe vitamin D deficiency can be treated with ergocalciferol (D2), 50,000 IU orally once weekly for 8 weeks. Some patients require long-term supplementation with D2 of up to 50,000 IU weekly. The danger of high-dose D2 therapy is that some patients may mistakenly take it daily. The alternative is to treat vitamin D-deficient patients with daily cholecalciferol D3 at doses of at least 2000 IU daily. High daily doses of vitamin D3 (10,000 IU/day for adults) are sometimes required for patients with obesity, intestinal malabsorption, or following gastric bypass surgery; rarely, severe malabsorption may require 25,000-100,000 IU daily. Patients with steatorrhea may respond better to oral 25(OH)D3 (calcifediol), 50-100 mcg/day. Serum levels of 25-OHD should be monitored, and the dosage of vitamin D adjusted to maintain serum 25-OHD levels above 30 ng/mL. The Endocrine Society recommends a target range of serum 25-OHD of 40-60 ng/mL. Serum 25-OHD levels above this range provide no additional benefit and may actually cause reduce bone strength.

The addition of calcium supplements to vitamin D is unnecessary for the prevention of osteomalacia in most otherwise well-nourished patients. Patients with malabsorption or poor nutrition should receive supplementation with calcium citrate (eg, Citracal), 0.4-0.6 g elemental calcium per day, or calcium carbonate (eg, OsCal, Tums), 1-1.5 g elemental calcium per day with meals.

In hypophosphatemic rickets or osteomalacia, nutritional deficiencies are corrected, aluminum-containing antacids are discontinued, and patients with renal tubular acidosis are given bicarbonate therapy.

For patients with tumoral hypophosphatemia, resection of the tumor normalizes serum phosphate levels but about 20% experience recurrence, usually in the same location. Tumors in difficult locations may be treated with radiofrequency ablation. With both tumoral and genetic FGF23-related hypophosphatemia, therapy with burosumab improves osteomalacia. For patients who cannot receive burosumab or who continue to have hypophosphatemia, oral phosphate supplements must be given long-term; oral phosphate causes diarrhea at higher doses, however, so many patients do not achieve normal serum phosphate levels. Calcitriol, 0.25-0.5 mcg daily, is given to improve the impaired calcium absorption caused by the oral phosphate.

Patients with hypophosphatasia may be treated with asfotase alfa (Strensiq). Teriparatide can improve bone pain and fracture healing. Bisphosphonates are contraindicated.

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