Interpretation

Based on animal studies and large human epidemiological studies, 25-hydroxyvitamin D2 and D3 (25-OH-VitD) levels below 25 ng/mL are associated with an increased risk of secondary hyperparathyroidism, reduced bone mineral density, and fractures, particularly in the elderly. Intervention studies support this clinical cutoff, showing a reduction of fracture risk with 25-OH-VitD replacement.

Levels less than 10 ng/mL may be associated with more severe abnormalities and can lead to inadequate mineralization of newly formed osteoid, resulting in rickets in children and osteomalacia in adults. In these individuals, serum calcium levels may be marginally low, and parathyroid hormone (PTH) and serum alkaline phosphatase are usually elevated. Definitive diagnosis rests on the typical radiographic findings or bone biopsy/histomorphometry.

Baseline biochemical work-up of suspected cases of rickets and osteomalacia should include measurement of serum calcium, phosphorus, PTH, and 25-OH-VitD. In patients where testing is not completely consistent with the suspected diagnosis, particularly if serum 25-OH-VitD levels are greater than 10 ng/mL, an alternative cause for impaired mineralization should be considered. Possible differential diagnosis includes partly treated vitamin D deficiency, extremely poor calcium intake, vitamin D resistant rickets, renal failure, renal tubular mineral loss with or without renal tubular acidosis, hypophosphatemic disorders (eg, X-linked or autosomal dominant hypophosphatemic rickets), congenital hypoparathyroidism, activating calcium sensing receptor mutations, and osteopetrosis. Measurement of serum urea, creatinine, magnesium, and 1,25-dihydroxyvitamin D (DHVD) is recommended as a minimal additional workup for these patients.

25-OH-VitD replacement in the United States typically consists of vitamin D2. Lack of clinical improvement and no reduction in PTH or alkaline phosphatase may indicate patient noncompliance, malabsorption, resistance to 25-OH-VitD, or additional factors contributing to the clinical disease. Measurement of serum 25-OH-VitD levels can assist in further evaluation, particularly as the liquid chromatography tandem mass spectrometry methodology allows separate measurement of 25-OH-VitD3 and of 25-OH-VitD2, which is derived entirely from dietary sources or supplements.

Patients who present with hypercalcemia, hyperphosphatemia, and low PTH may suffer either from ectopic, unregulated conversion of 25-OH-VitD to 1,25-OH-VitD, as can occur in granulomatous diseases, particular sarcoid, or from nutritionally-induced hypervitaminosis D. Serum 1,25-OH-VitD levels will be high in both groups, but only patients with hypervitaminosis D will have serum 25-OH-VitD concentrations of greater than 80 ng/mL, typically greater than 150 ng/mL.