Page 803 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 789

may be involved. The disease is fairly common, although symp- 6 months if necessary. The principal toxicity of etidronate is the
tomatic bone disease is less common. Recent studies indicate that development of osteomalacia and an increased incidence of frac-
this infection may produce a factor that increases the stimulation tures when the dosage is raised substantially above 5 mg/kg per
of bone resorption by 1,25(OH) D. The biochemical parameters day. The newer bisphosphonates such as risedronate and alendro-
2
of elevated serum alkaline phosphatase and urinary hydroxypro- nate do not share this adverse effect. Some patients treated with
line are useful for diagnosis. Along with the characteristic radio- etidronate develop bone pain similar in nature to the bone pain of
logic and bone scan findings, these biochemical determinations osteomalacia. This subsides after stopping the drug. The principal
provide good markers by which to follow therapy. adverse effect of alendronate and the newer bisphosphonates is
The goal of treatment is to reduce bone pain and stabilize or gastric irritation when used at these high doses. This is reversible
prevent other problems such as progressive deformity, fractures, on cessation of the drug.
hearing loss, high-output cardiac failure, and immobilization
hypercalcemia. Calcitonin and bisphosphonates are the first-line
agents for this disease. Calcitonin is administered subcutaneously ENTERIC OXALURIA
or intramuscularly in doses of 50–100 MRC (Medical Research
Council) units every day or every other day. Nasal inhalation at Patients with short bowel syndromes and associated fat malab-
200–400 units/d is also effective. Higher or more frequent doses sorption can present with renal stones composed of calcium and
have been advocated when this initial regimen is ineffective. oxalate. Such patients characteristically have normal or low urine
Improvement in bone pain and reduction in serum alkaline phos- calcium levels but elevated urine oxalate levels. The reasons for
phatase and urine hydroxyproline levels require weeks to months. the development of oxaluria in such patients are thought to be
Often a patient who responds well initially loses the response to twofold: first, in the intestinal lumen, calcium (which is now
calcitonin. This refractoriness is not correlated with the develop- bound to fat) fails to bind oxalate and no longer prevents its
ment of antibodies. absorption; second, enteric flora, acting on the increased sup-
Sodium etidronate, alendronate, risedronate, and tiludronate ply of nutrients reaching the colon, produce larger amounts of
are the bisphosphonates currently approved for clinical use in Pag- oxalate. Although one would ordinarily avoid treating a patient
et’s disease of bone in the United States. Other bisphosphonates, with calcium oxalate stones with calcium supplementation, this
including pamidronate, are being used in other countries. The is precisely what is done in patients with enteric oxaluria. The
recommended doses of bisphosphonates are etidronate, 5 mg/kg increased intestinal calcium binds the excess oxalate and prevents
per day; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludro- its absorption. Calcium carbonate (1–2 g) can be given daily in
nate, 400 mg/d. Long-term remission (months to years) may be divided doses, with careful monitoring of urinary calcium and
expected in patients who respond to a bisphosphonate. Treatment oxalate to be certain that urinary oxalate falls without a danger-
should not exceed 6 months per course but can be repeated after ous increase in urinary calcium.

SUMMARY Major Drugs Used in Diseases of Bone Mineral Homeostasis

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities

VITAMIN D, METABOLITES, ANALOGS
• Cholecalciferol (D 3 ) Regulate gene transcription Stimulate intestinal calcium Osteoporosis, Hypercalcemia, hypercalciuria
• Ergocalciferol (D 2 ) via the vitamin D receptor absorption, bone resorption, renal osteomalacia, renal • the vitamin D preparations
• Calcitriol calcium and phosphate reabsorption failure, malabsorption, have much longer half-lives
• Calcifediol • decrease parathyroid hormone psoriasis than the metabolites and
• Doxercalciferol (PTH) • promote innate immunity analogs
• Paricalcitol • inhibit adaptive immunity
• Calcipotriene

BISPHOSPHONATES
• Alendronate Suppress the activity of Inhibit bone resorption and Osteoporosis, bone Adynamic bone, possible renal
• Risedronate osteoclasts in part via secondarily bone formation metastases, failure, rare osteonecrosis of the
• Ibandronate inhibition of farnesyl hypercalcemia jaw, rare subtrochanteric (femur)
• Pamidronate pyrophosphate synthesis fractures
• Zoledronate
(continued)