Page 800 - Basic _ Clinical Pharmacology ( PDFDrive )

786 SECTION VII Endocrine Drugs

maxacalcitol [22-oxa-calcitriol] and falecalcitriol [26,27 F - calcifediol should be the drug of choice under these conditions,
6
1,25(OH) D ] are approved for this purpose.) Their principal because no impairment of the renal metabolism of 25(OH)D to
2
3
advantage is that they are less likely than calcitriol to induce 1,25(OH) D and 24,25(OH) D exists in these patients. However,
2
2
hypercalcemia for any given reduction in PTH (less true for fale- calcifediol is only approved in the United States for use in chronic
calcitriol). Their greatest impact is in patients in whom the use kidney disease and secondary hyperparathyroidism. Both calcitriol
of calcitriol may lead to unacceptably high serum calcium levels. and 24,25(OH) D may be of importance in reversing the bone
2
Regardless of the drug used, careful attention to serum calcium disease. Intramuscular injections of vitamin D would be an alter-
and phosphate levels is required. A calcium × phosphate product native form of therapy, but there are currently no FDA-approved
(in mg/dL units) less than 55 is desired with both calcium and intramuscular preparations available in the United States. The skin
phosphate in the normal range. Calcium adjustments in the diet remains a good source of vitamin D production, although care is
and dialysis bath and phosphate restriction (dietary and with oral needed to prevent UVB overexposure (ie, by avoiding sunburn) to
ingestion of phosphate binders) should be used along with vitamin reduce the risk of photoaging and skin cancer.
D metabolites. Monitoring of serum PTH and alkaline phospha- As in the other diseases discussed, treatment of intestinal
tase levels is useful in determining whether therapy is correcting osteodystrophy with vitamin D and its metabolites should be
or preventing secondary hyperparathyroidism. In patients on accompanied by appropriate dietary calcium supplementation and
dialysis, a PTH value of approximately twice the upper limits of monitoring of serum calcium and phosphate levels.
normal is considered desirable to prevent adynamic bone disease.
Although not generally available, percutaneous bone biopsies for
quantitative histomorphometry may help in choosing appropriate OSTEOPOROSIS
therapy and following the effectiveness of such therapy, especially
in cases suspected of adynamic bone disease. Unlike the rapid Osteoporosis is defined as abnormal loss of bone predisposing
changes in serum values, changes in bone morphology require to fractures. It is most common in postmenopausal women but
months to years. Monitoring of serum vitamin D metabolite levels also occurs in men. The annual direct medical cost of fractures in
is useful for determining adherence, absorption, and metabolism. older women and men in the United States is estimated to be at
least $20 billion per year and is increasing as the population ages.
Osteoporosis is most commonly associated with loss of gonadal
INTESTINAL OSTEODYSTROPHY function as in menopause but may also occur as an adverse effect
of long-term administration of glucocorticoids or other drugs,
A number of gastrointestinal and hepatic diseases cause disordered including those that inhibit sex steroid production; as a manifesta-
calcium and phosphate homeostasis, which ultimately leads to tion of endocrine disease such as thyrotoxicosis or hyperparathy-
bone disease. As bariatric surgery becomes more common, this roidism; as a feature of malabsorption syndrome; as a consequence
problem is likely to increase. The bones in such patients show a of alcohol abuse and cigarette smoking; or without obvious cause
combination of osteoporosis and osteomalacia. Osteitis fibrosa (idiopathic). The ability of some agents to reverse the bone loss of
does not occur, in contrast to renal osteodystrophy. The important osteoporosis is shown in Figure 42–5. The postmenopausal form
common feature in this group of diseases appears to be malabsorp- of osteoporosis may be accompanied by lower 1,25(OH) D levels
2
tion of calcium and vitamin D. Liver disease may, in addition, and reduced intestinal calcium transport. This form of osteoporo-
reduce the production of 25(OH)D from vitamin D, although its sis is due to reduced estrogen production and can be treated with
importance in patients other than those with terminal liver failure estrogen (combined with a progestin in women with a uterus to
remains in dispute. The major explanation for the low 25(OH)D prevent endometrial carcinoma). However, concern that estrogen
levels in patients with liver disease is the reduction in D-binding increases the risk of breast cancer and fails to reduce or may actu-
protein production, the major carrier of vitamin D metabolites ally increase the development of heart disease has reduced enthu-
in the blood. Free 25(OH)D is generally normal in patients with siasm for this form of therapy, at least in older individuals.
liver disease. The malabsorption of vitamin D is probably not Bisphosphonates are potent inhibitors of bone resorption.
limited to exogenous vitamin D as the liver secretes into bile a They increase bone density and reduce the risk of fractures in
substantial number of vitamin D metabolites and conjugates that the hip, spine, and other locations. Alendronate, risedronate,
are normally reabsorbed in (presumably) the distal jejunum and ibandronate, and zoledronate are approved for the treatment of
ileum. Interference with this process could deplete the body of osteoporosis, using daily dosing schedules of alendronate, 10 mg/d,
endogenous vitamin D metabolites in addition to limiting absorp- risedronate, 5 mg/d, or ibandronate, 2.5 mg/d; or weekly sched-
tion of dietary vitamin D. ules of alendronate, 70 mg/week, or risedronate, 35 mg/week; or
In mild forms of malabsorption, high doses of vitamin D monthly schedules of ibandronate, 150 mg/month; or quarterly
(25,000–50,000 IU one to three times per week) should suffice (every 3 months) injections of ibandronate, 3 mg; or annual infu-
to raise serum levels of 25(OH)D into the normal range. Many sions of zoledronate, 5 mg. These drugs are effective in men as well
patients with severe disease do not respond to vitamin D. Clinical as women and for various causes of osteoporosis.
experience with the other metabolites is limited, but both calcitriol As previously noted, estrogen-like SERMs (selective estrogen
and calcifediol have been used successfully in doses similar to those receptor modulators, Chapter 40) have been developed that prevent
recommended for treatment of renal osteodystrophy. Theoretically, the increased risk of breast and uterine cancer associated with estrogen