Osteomalacia

Definition, Etiology, PathogenesisTop

Osteomalacia is a metabolic bone disease resulting from loss of bone calcium or inadequate calcium salt deposition in bones, which leads to impaired mechanical properties of bones, bending under mechanical stress, and finally to permanent deformation.

Causes:

1) Deficiency of active metabolites of vitamin D: The most common cause, usually due to the combination of inadequate dietary intake of vitamin D and low sunlight exposure. Malabsorption of vitamin D may contribute, including after bariatric surgery. Patients with morbid obesity have a very high prevalence of vitamin D deficiency, for reasons that are not fully understood. Patients with anorexia nervosa may experience nutritional deficiencies of vitamin D, calcium, and phosphate, severe enough to cause osteomalacia. Finally, the synthesis of active metabolites requires 1-hydroxylation in the kidney and 25-hydroxylation in the liver to calcitriol (1,25-dihydroxycholecalciferol [1,25(OH)2D3]). That is why a low glomerular filtration rate (GFR) or liver failure may lead to deficiency of the active 1,25(OH)2D3.

2) Phosphate deficiency: This most commonly results from renal loss of phosphates or inadequate dietary intake (in the case of alcohol use disorder).

3) Calcium deficiency: This is most frequently due to inadequate dietary intake.

Chronic vitamin D deficiency leads to impaired calcium absorption and to secondary hyperparathyroidism, which in turn causes hypophosphatemia and impaired bone mineralization. Rickets is the equivalent of osteomalacia in children (before the fusion of epiphyses).

Clinical Features and Natural HistoryTop

Signs and symptoms of early osteomalacia include generalized bone pain, bone hypersensitivity to pressure, and muscle fatigue (weakness of the proximal muscles of the lower limbs, which causes a waddling gait and difficulties in standing up from a chair or climbing stairs; muscle weakness is the initial and at the same time the most common manifestation of vitamin D deficiency). In very advanced disease bones become deformed, which is best seen in lower limbs exhibiting the “O” pattern (varus knee alignment). Bones become increasingly prone to fractures. Tetany may occur in severe vitamin D deficiency (see Hypocalcemia).

DiagnosisTop

Diagnosis is based on signs, symptoms, and results of laboratory tests. Radiologic signs are present only in advanced disease.

Diagnostic Tests

1. Laboratory tests: Low or normal serum calcium levels, low serum phosphate and 25-hydroxyvitamin D (25[OH]D) levels, high serum levels of alkaline phosphatase (ALP) and parathyroid hormone (PTH), and low urinary calcium excretion. The assessment of calcium and phosphate metabolism: see Calcium Disturbances; see Phosphate Disturbances.

2. Radiography: Lesions are only seen in patients with advanced osteomalacia and may include reduced bone mineral density (BMD), which is distinguished from osteoporosis by the presence of the Looser–Milkman remodeling zones (pseudofractures).

3. Densitometry may reveal a low BMD that fulfills the criteria for osteopenia or osteoporosis.

TreatmentTop

1. Vitamin D deficiency:

1) In patients with deficiency caused by low dietary vitamin D intake or inadequate sunlight exposure, the most common replacement is in the form of oral vitamin D (D3 [cholecalciferol] or D2, [ergocalciferol]) ≥4000 IU/d (0.1 mg/d) for 3 to 12 months, depending on the needs, or 20,000 IU twice a week for several weeks, until serum 25(OH)D levels >30 ng/mL (75 nmol/L) and <80 ng/mL (200 nmol/L) are achieved. It is usually followed by a maintenance dose of 1000 to 2000 IU/d (0.02-0.05 mg/d). In patients with dietary calcium intake <1000 mg/d, administer calcium supplements. In patients nonadherent to oral medications, one may administer 50,000 IU of vitamin D weekly for 8 weeks, followed by the standard supplementation (1000-2000 IU/d). Depending on the perceived severity and urgency, one may monitor serum levels of calcium, phosphate, PTH, and magnesium, as well as urinary calcium excretion after 1, 3, and 6 months of treatment. The confirmation of serum 25(OH)D levels after 3 and 6 months of treatment may be of value. Radiologic features of osteomalacia improve after several weeks and completely resolve after 6 months of treatment. Varus deformities do not resolve.

2) In patients with deficiency caused by impaired intestinal absorption of vitamin D, the dose of vitamin D may be higher, and the level of 25(OH)D should be checked while on treatment. Note that vitamin D can be synthesized in the skin upon sunlight exposure. Intravenous calcitriol (1,25[OH]2D3) may be required.

Patients with morbid obesity being considered for bariatric surgery have a high prevalence of preoperative vitamin D deficiency (>90% with levels <30 ng/mL or 75 nmol/L) and further depletion may occur postoperatively from rapid weight loss, bile salt deficiency, and bacterial overgrowth leading to malabsorption. Monitoring of vitamin D, calcium, and PTH levels and repletion, often with larger-than-usual doses, under expert supervision, are recommended.

3) In patients in whom treatment with vitamin D is ineffective and in those with liver or renal impairment, use active metabolites of vitamin D. The availability of such metabolites differs among countries. In patients with deficiency of an active metabolite due to severe liver failure, where available, one can use oral calcifediol/calcidiol (25[OH]D3) 20 to 50 microg/d. In patients with deficiency due to kidney disease, where available, one can use oral alfacalcidol (1[OH]D3) 0.25 to 1 microg/d (some authors recommend the use of alfacalcidol instead of vitamin D in all patients to avoid treatment failure in the case of undiagnosed problems with the alpha-hydroxylation that occurs in the kidney). In Canada the usual active metabolite replacement in patients with chronic kidney disease is alfacalcidol or calcitriol (1,25[OH]2D3); the latter may be used in patients with liver dysfunction. The level of this active form may be used for monitoring, with frequency depending on the severity of the condition (from weekly to monthly, until stable). In patients receiving active metabolites of vitamin D, an alternative or complement to 1,25(OH)2D3 measurement is monitoring of calcium, phosphate, PTH, and ALP.

Adequate activated vitamin D should lead to normalization of calcium levels in patients with liver disease; calcium supplementation may be considered if the patient is initially hypocalcemic. Patients with kidney disease are often treated with both active vitamin D (1[OH]D3 or 1,25[OH]2D3) and oral calcium if hypocalcemic. Because of the low GFR, the phosphate level tends to be high. Once normocalcemia is attained, calcium can be given before meals as a phosphate binder. It is very unusual for hypophosphatemia to be severe in patients with vitamin D deficiency and it would be expected to correct with vitamin D; consider supplementation only for a short term and if the disease is severe.

2. Phosphate deficiency: Chronic hypophosphatemia not associated with vitamin D deficiency should be corrected by treating the underlying condition. Increased intake of milk and dairy products is recommended in such patients.

3. Calcium deficiency: Provision of a normal diet is the cornerstone of care. Calcium supplementation may also be required; particularly if a normal diet cannot be resumed or absorbed because of structural or functional intestinal abnormalities or an eating disorder.