Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic acid. Although not yet approved for use in the United States, this drug is used in Europe for the treatment of osteoporosis. Strontium ranelate appears to block differentiation of osteoclasts while promoting their apoptosis, thus inhibiting bone resorption. At the same time, strontium ranelate appears to promote bone formation. Unlike bisphosphonates, denosumab, or teriparatide, this drug increases bone formation markers while inhibiting bone resorption markers. Large clinical trials have demonstrated its efficacy in increasing bone mineral density and decreasing fractures in the spine and hip. Toxicities reported thus far are similar to placebo.
Individuals with disorders of bone mineral homeostasis usually present with abnormalities in serum or urine calcium levels (or both), often accompanied by abnormal serum phosphate levels. These abnormal mineral concentrations may themselves cause symptoms requiring immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an underlying disorder in hormonal regulators (eg, primary hyperparathyroidism), target tissue response (eg, chronic kidney disease), or drug misuse (eg, vitamin D intoxication). In such cases, treatment of the underlying disorder is of prime importance.
Since bone and kidney play central roles in bone mineral homeostasis, conditions that alter bone mineral homeostasis usually affect one or both of these tissues secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone; remaining bone histologically normal), osteomalacia (abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption cavities and marrow). Biochemical markers of skeletal involvement include changes in serum levels of the skeletal isoenzyme of alkaline phosphatase, osteocalcin, and Nand C-terminal propeptides of type I collagen (reflecting osteoblastic activity), and serum and urine levels of tartrateresistant acid phosphatase and collagen breakdown products (reflecting osteoclastic activity). The kidney becomes involved when the calcium × phosphate product in serum rises above the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium × oxalate (or phosphate) product in urine exceeds saturation, leading to nephrolithiasis. Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria. Radiologic evidence of nephrocalcinosis and stones is not generally observed until later. The degree of the ensuing renal failure is best followed by monitoring the decline in creatinine clearance. On the other hand, chronic kidney disease can be a primary cause of bone disease because of altered handling of calcium and phosphate, decreased 1,25(OH)2D production, increased FGF23 levels, and secondary hyperparathyroidism.
Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer, with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, the latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.