Page 795 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 781

rare, comparable to that of osteonecrosis of the jaw, but has led reducing renal calcium excretion. Thiazides may increase the
some authorities to recommend a “drug holiday” after 5 years of effectiveness of PTH in stimulating reabsorption of calcium by
treatment if the clinical condition warrants it (ie, if the fracture the renal tubules or may act on calcium reabsorption secondarily
risk of discontinuing the bisphosphonate is not deemed high). 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
DENOSUMAB basolateral membrane and thus enhancing calcium reabsorption
into the blood at this site (see Figure 15–4). Thiazides have
Denosumab is a fully humanized monoclonal antibody that proved to be useful in reducing the hypercalciuria and incidence
binds to and prevents the action of RANKL. As described earlier, of urinary stone formation in subjects with idiopathic hypercal-
RANKL is produced by osteoblasts and other cells, including ciuria. Part of their efficacy in reducing stone formation may lie
T lymphocytes. It stimulates osteoclastogenesis via RANK, the in their ability to decrease urine oxalate excretion and increase
receptor for RANKL that is present on osteoclasts and osteoclast urine magnesium and zinc levels, both of which inhibit calcium
precursors. By interfering with RANKL function, denosumab oxalate stone formation.
inhibits osteoclast formation and activity. It is at least as effective
as the potent bisphosphonates in inhibiting bone resorption and
has been approved for treatment of postmenopausal osteoporosis FLUORIDE
and some cancers (prostate and breast). The latter application is
to limit the development of bone metastases or bone loss resulting Fluoride is well established as effective for the prophylaxis of den-
from the use of drugs that suppress gonadal function. Denosumab tal caries and has previously been investigated for the treatment of
is administered subcutaneously every 6 months. The drug appears osteoporosis. Both therapeutic applications originated from epide-
to be well tolerated, but three concerns remain. First, a number of miologic observations that subjects living in areas with naturally
cells in the immune system also express RANKL, suggesting that fluoridated water (1–2 ppm) had fewer dental caries and fewer
there could be an increased risk of infection associated with the use vertebral compression fractures than subjects living in nonfluori-
of denosumab. Second, because the suppression of bone turnover dated water areas. Fluoride accumulates in bones and teeth, where
with denosumab is similar to that of the potent bisphosphonates, it may stabilize the hydroxyapatite crystal. Such a mechanism may
the potential risk of osteonecrosis of the jaw and subtrochanteric explain the effectiveness of fluoride in increasing the resistance of
fractures is comparable. Third, denosumab can lead to transient teeth to dental caries, but it does not explain its ability to promote
hypocalcemia, especially in patients with marked bone loss (and new bone growth.
bone hunger) or compromised calcium regulatory mechanisms, Fluoride in drinking water appears to be most effective in
including chronic kidney disease and vitamin D deficiency. That preventing dental caries if consumed before the eruption of the
said, denosumab can be used in patients with advanced renal dis- permanent teeth. The optimum concentration in drinking water
ease, unlike the bisphosphonates, as it is not cleared by the kidney, supplies is 0.5–1 ppm. Topical application is most effective if done
and it has the advantage over bisphosphonates in that it is readily just as the teeth erupt. There is little further benefit to giving fluo-
reversible because it does not deposit in bone. ride after the permanent teeth are fully formed. Excess fluoride in
drinking water leads to mottling of the enamel proportionate to
CALCIMIMETICS the concentration above 1 ppm.
Fluoride has also been evaluated for the treatment of osteo-
porosis. Results of earlier studies indicated that fluoride alone,
Cinacalcet is the first representative of a new class of drugs that without adequate calcium supplementation, produced osteoma-
activates the calcium-sensing receptor (CaSR) described above. lacia. Subsequent studies in which calcium supplementation has
CaSR is widely distributed but has its greatest concentration in been adequate demonstrated an improvement in calcium balance,
the parathyroid gland. By activating the parathyroid gland CaSR, an increase in bone mineral, and an increase in trabecular bone
cinacalcet inhibits PTH secretion. Cinacalcet is approved for the volume. Despite these promising effects of fluoride on bone mass,
treatment of secondary hyperparathyroidism in chronic kidney clinical studies have failed to demonstrate a reliable reduction in
disease and for the treatment of parathyroid carcinoma. CaSR fractures, and some studies showed an increase in fracture rate.
antagonists are also being developed, and may be useful in condi- At present, fluoride is not approved by the U.S. Food and Drug
tions of hypoparathyroidism or as a means to stimulate intermit- Administration (FDA) for treatment or prevention of osteoporo-
tent PTH secretion in the treatment of osteoporosis.
sis, and it is unlikely to be.
Adverse effects observed—at the higher doses used for test-
THIAZIDE DIURETICS ing fluoride’s effect on bone—include nausea and vomiting,
gastrointestinal blood loss, arthralgias, and arthritis in a
The chemistry and pharmacology of the thiazide family of substantial proportion of patients. Such effects are usually
drugs are discussed in Chapter 15. The principal application responsive to reduction of the dose or giving fluoride with
of thiazides in the treatment of bone mineral disorders is in meals (or both).