Page 793 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 779

GLUCOCORTICOIDS OH OH

Glucocorticoid hormones alter bone mineral homeostasis by O P O P O Inorganic pyrophosphoric acid
antagonizing vitamin D–stimulated intestinal calcium transport, OH OH
stimulating renal calcium excretion, blocking bone formation,
and at least initially stimulating bone resorption. Although these OH OH OH
observations underscore the negative impact of glucocorticoids O P C P O Etidronate: ethane-1-hydroxy-1,
on bone mineral homeostasis, these hormones have proved useful 1-bisphosphonate
in reversing the hypercalcemia associated with lymphomas and OH CH 3 OH
granulomatous diseases such as sarcoidosis (in which unregulated
ectopic production of 1,25[OH] D occurs) or in cases of vitamin OH OH OH
2
D intoxication. Prolonged administration of glucocorticoids is a O P C P O Pamidronate: 3-Amino-1-hydroxy-
propylidene bisphosphonate
common cause of osteoporosis in adults and can cause stunted OH CH OH
skeletal development in children (see Chapter 39). 2
CH 2 NH 2

ESTROGENS OH OH OH
O P C P O Alendronate: 4-Amino-1-hydroxy-butylidene
bisphosphonate
Estrogens can prevent accelerated bone loss during the immediate OH CH OH
postmenopausal period and at least transiently increase bone in 2
postmenopausal women. CH 2 CH 2 NH 2
The prevailing hypothesis advanced to explain these observa-
tions is that estrogens reduce the bone-resorbing action of PTH. FIGURE 42–4 The structure of pyrophosphate and of the
Estrogen administration leads to an increased 1,25(OH) D level in first three bisphosphonates—etidronate, pamidronate, and
2
blood, but estrogens have no direct effect on 1,25(OH) D produc- alendronate—that were approved for use in the United States.
2
tion in vitro. The increased 1,25(OH) D levels in vivo following
2
estrogen treatment may result from decreased serum calcium and ibandronate, and zoledronate. With the development of the more
phosphate and increased PTH. However, estrogens also increase potent bisphosphonates, etidronate is seldom used.
DBP production by the liver, which increases the total concentra- Results from animal and clinical studies indicate that less than
tions of the vitamin D metabolites in circulation without necessar- 10% of an oral dose of these drugs is absorbed. Food reduces
ily increasing the free levels. Estrogen receptors have been found absorption even further, necessitating their administration on
in bone, and estrogen has direct effects on bone remodeling. Case an empty stomach. A major adverse effect of oral forms of the
reports of men who lack the estrogen receptor or who are unable bisphosphonates (risedronate, alendronate, ibandronate) is esoph-
to produce estrogen because of aromatase deficiency noted marked ageal and gastric irritation, which limits the use of this route by
osteopenia and failure to close epiphyses. This further substantiates patients with upper gastrointestinal disorders. This complication
the role of estrogen in bone development, even in men. The princi- can be circumvented with infusions of pamidronate, zoledronate,
pal therapeutic application for estrogen administration in disorders and ibandronate. Intravenous dosing also allows a larger amount
of bone mineral homeostasis is the treatment or prevention of of drug to enter the body and markedly reduces the frequency of
postmenopausal osteoporosis. However, long-term use of estrogen administration (eg, zoledronate is infused once per year). Nearly
has fallen out of favor due to concern about adverse effects. Selec- half of the absorbed drug accumulates in bone; the remainder
tive estrogen receptor modulators (SERMs) have been developed to is excreted unchanged in the urine. Decreased renal function
retain the beneficial effects on bone while minimizing deleterious dictates a reduction in dosage. The portion of drug retained in
effects on breast, uterus, and the cardiovascular system (see Box: bone depends on the rate of bone turnover; drug in bone often is
Newer Therapies for Osteoporosis and Chapter 40). retained for months to years.
The bisphosphonates exert multiple effects on bone mineral
NONHORMONAL AGENTS homeostasis, which make them useful for the treatment of hyper-
calcemia associated with malignancy, for Paget’s disease, and for
AFFECTING BONE MINERAL osteoporosis (see Box: Newer Therapies for Osteoporosis). They
HOMEOSTASIS owe at least part of their clinical usefulness and toxicity to their
ability to retard formation and dissolution of hydroxyapatite
BISPHOSPHONATES crystals within and outside the skeletal system. Some of the newer
bisphosphonates appear to increase bone mineral density well
The bisphosphonates are analogs of pyrophosphate in which the beyond the 2-year period predicted for a drug whose effects are
P-O-P bond has been replaced with a nonhydrolyzable P-C-P limited to slowing bone resorption. This may be due to their
bond (Figure 42–4). Currently available bisphosphonates include other cellular effects, which include inhibition of 1,25(OH) D
2
etidronate, pamidronate, alendronate, risedronate, tiludronate, production, inhibition of intestinal calcium transport, metabolic