Nonhormonal Agents Affecting Bone Mineral Homeostasis

NONHORMONAL AGENTS AFFECTING BONE MINERAL HOMEOSTASIS

BISPHOSPHONATES

The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42–4). Currently available bisphosphonates include etidronate, pamidronate, alendronate, risedronate, tiludronate, ibandronate, and zoledronate. With the development of themore potent bisphosphonates, etidronate is seldom used.

Results from animal and clinical studies indicate that less than 10% of an oral dose of these drugs is absorbed. Food reduces absorption even further, necessitating their administration on an empty stomach. A major adverse effect of oral forms of the bis-phosphonates (risedronate, alendronate, ibandronate) is esopha-geal and gastric irritation, which limits the use of this route by patients with upper gastrointestinal disorders. This complication can be circumvented with infusions of pamidronate, zoledronate, and ibandronate. Intravenous dosing also allows a larger amount of drug to enter the body and markedly reduces the frequency of administration (eg, zoledronate is infused once per year). Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine. Decreased renal function dic-tates a reduction in dosage. The portion of drug retained in bone depends on the rate of bone turnover; drug in bone often is retained for months if not years.

The bisphosphonates exert multiple effects on bone mineral homeostasis, which make them useful for the treatment of hyper-calcemia associated with malignancy, for Paget’s disease, and for osteoporosis (see Box: Newer Therapies for Osteoporosis). They owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Some of the newer bisphosphonates appear to increase bone mineral density well beyond the 2-year period predicted for a drug whose effects are limited to slowing bone resorption. This may be due to their other cellular effects, which include inhibition of 1,25(OH)₂D produc-tion, inhibition of intestinal calcium transport, metabolic changes in bone cells such as inhibition of glycolysis, inhibition of cell growth, and changes in acid and alkaline phosphatase activity.Amino bisphosphonates such as alendronate and risedronate inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast sur-vival. The cholesterol-lowering statin drugs (eg, lovastatin), which block mevalonate synthesis , stimulate bone for-mation, at least in animal studies. Thus, the mevalonate pathway appears to be important in bone cell function and provides new targets for drug development. The mevalonate pathway effects vary depending on the bisphosphonate (ie, only amino bisphos-phonates have this property), and may account for some of the clinical differences observed in the effects of the various bisphos-phonates on bone mineral homeostasis.

With the exception of the induction of a mineralization defect by higher than approved doses of etidronate and gastric and esophageal irritation by the oral bisphosphonates, these drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis. Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes or by using the intra-venous forms of these compounds. Of the other complications, osteonecrosis of the jaw has received considerable attention but is rare in patients receiving usual doses of bisphosphonates (perhaps 1/100,000 patient-years). This complication is more frequent when high intravenous doses of zoledronate are used to control bone metastases and cancer-induced hypercalcemia. More recently, concern has been raised about over-suppressing bone turnover, and case reports have appeared describing unusual subtrochanteric (femur) fractures in patients on long-term bisphosphonate treat-ment. This complication appears to be rare, comparable to that of osteonecrosis of the jaw, but has led some authorities to recom-mend a “drug holiday” after 5 years of treatment if the clinical condition warrants it (ie, if the fracture risk of discontinuing the bisphosphonate is not deemed high).

DENOSUMAB

Denosumab is a fully human monoclonal antibody that binds to and prevents the action of RANKL. As described earlier, RANKL is produced by osteoblasts. It stimulates osteoclastogenesis via RANK, the receptor for RANKL that is present on osteoclasts and osteoclast precursors. By interfering with RANKL function, denosumab inhibits osteoclast formation and activity. It is at least as effective as the potent bisphosphonates in inhibiting bone resorption and has recently been approved for treatment of post-menopausal osteoporosis and some cancers (prostate and breast). The latter application is to limit the development of bone metas-tases or bone loss resulting from the use of drugs suppressing gonadal function. Denosumab is administered subcutaneously every 6 months, which avoids gastrointestinal side effects. The drug appears to be well tolerated but two concerns remain. First, a number of cells in the immune system also express RANKL, suggesting that there could be an increased risk of infection associ-ated with the use of denosumab. Second, because the suppression of bone turnover with denosumab is similar to that of the potent bisphosphonates, the risk of osteonecrosis of the jaw and subtro-chanteric fractures may be increased, although this has not been reported in the clinical trials leading to its approval by the Food and Drug Administration (FDA).

CALCIMIMETICS

Cinacalcet is the first representative of a new class of drugs thatactivates the calcium-sensing receptor (CaSR). CaSR is widely distributed but has its greatest concentration in the parathyroid gland. By activating the parathyroid gland CaSR, cinacalcet inhib-its 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 hypoparathy-roidism or as a means to stimulate intermittent PTH secretion in the treatment of osteoporosis.

PLICAMYCIN (MITHRAMYCIN)

Plicamycin is a cytotoxic antibiotic  that has been used clinically for two disorders of bone mineral metabolism: Paget’s disease and hypercalcemia. The cytotoxic properties of the drug appear to involve binding to DNA and interruption of DNA-directed RNA synthesis. The reasons for its usefulness in the treatment of Paget’s disease and hypercalcemia are unclear but may relate to the need for protein synthesis to sustain bone resorp-tion. The doses required to treat Paget’s disease and hypercalcemia are about one tenth the amount required to achieve cytotoxic effects. With the development of other less toxic drugs for these purposes, the clinical use of plicamycin is seldom indicated.

THIAZIDE DIURETICS

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 mem-brane 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 forma-tion 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

Fluoride is well established as effective for the prophylaxis of den-tal caries and has previously been investigated for the treatment of osteoporosis. Both therapeutic applications originated from epide-miologic observations that subjects living in areas with naturally fluoridated water (1–2 ppm) had less dental caries and fewer ver-tebral 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 fluo-ride 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.

Because of the paucity of agents that stimulate new bone growth in patients with osteoporosis, fluoride for this disorder has been examined (see Osteoporosis, below). Results of earlier studies indicated that fluoride alone, without adequate calcium supple-mentation, produced osteomalacia. More recent studies, in which calcium supplementation has been adequate, have demonstrated an improvement in calcium balance, an increase in bone mineral, and an increase in trabecular bone volume. Despite these promis-ing 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 FDA for treatment or prevention of osteoporosis, and it is unlikely to be.

Adverse effects observed—at the doses used for testing fluo-ride’s effect on bone—include nausea and vomiting, gastrointesti-nal 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).

STRONTIUM RANELATE

Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic acid. Although not yet approved for use in the USA, 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 resorp-tion 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.