Cinacalcet is the first representative of a new class of drugs that activates the calcium-sensing receptor (CaSR) described above. CaSR is widely distributed but has its greatest concentration in the parathyroid gland. By activating the parathyroid gland CaSR, cinacalcet inhibits PTH secretion. Cinacalcet is approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of parathyroid carcinoma. CaSR antagonists are also being developed, and may be useful in conditions of hypoparathyroidism or as a means to stimulate intermittent PTH secretion in the treatment of osteoporosis.
The chemistry and pharmacology of the thiazide family of drugs are discussed in Chapter 15. The principal application of thiazides in the treatment of bone mineral disorders is in reducing renal calcium excretion. Thiazides may increase the effectiveness of PTH in stimulating reabsorption of calcium by the renal tubules or may act on calcium reabsorption secondarily by increasing sodium reabsorption in the proximal tubule. In the distal tubule, thiazides block sodium reabsorption at the luminal surface, increasing the calcium-sodium exchange at the basolateral membrane and thus enhancing calcium reabsorption into the blood at this site (see Figure 15–4). Thiazides have proved to be useful in reducing the hypercalciuria and incidence of urinary stone formation in subjects with idiopathic hypercalciuria. Part of their efficacy in reducing stone formation may lie in their ability to decrease urine oxalate excretion and increase urine magnesium and zinc levels, both of which inhibit calcium oxalate stone formation.
Fluoride is well established as effective for the prophylaxis of dental caries and has previously been investigated for the treatment of osteoporosis. Both therapeutic applications originated from epidemiologic observations that subjects living in areas with naturally fluoridated water (1–2 ppm) had fewer dental caries and fewer vertebral compression fractures than subjects living in nonfluoridated water areas. Fluoride accumulates in bones and teeth, where it may stabilize the hydroxyapatite crystal. Such a mechanism may explain the effectiveness of fluoride in increasing the resistance of teeth to dental caries, but it does not explain its ability to promote new bone growth.
Fluoride in drinking water appears to be most effective in preventing dental caries if consumed before the eruption of the permanent teeth. The optimum concentration in drinking water supplies is 0.5–1 ppm. Topical application is most effective if done just as the teeth erupt. There is little further benefit to giving fluoride after the permanent teeth are fully formed. Excess fluoride in drinking water leads to mottling of the enamel proportionate to the concentration above 1 ppm.
Fluoride has also been evaluated for the treatment of osteoporosis. Results of earlier studies indicated that fluoride alone, without adequate calcium supplementation, produced osteomalacia. Subsequent studies in which calcium supplementation has been adequate demonstrated an improvement in calcium balance, an increase in bone mineral, and an increase in trabecular bone volume. Despite these promising effects of fluoride on bone mass, clinical studies have failed to demonstrate a reliable reduction in fractures, and some studies showed an increase in fracture rate. At present, fluoride is not approved by the U.S. Food and Drug Administration (FDA) for treatment or prevention of osteoporosis, and it is unlikely to be.
Adverse effects observed—at the higher doses used for testing fluoride’s effect on bone—include nausea and vomiting, gastrointestinal blood loss, arthralgias, and arthritis in a substantial proportion of patients. Such effects are usually responsive to reduction of the dose or giving fluoride with meals (or both).