Page 796 - Basic _ Clinical Pharmacology ( PDFDrive )

782 SECTION VII Endocrine Drugs

STRONTIUM RANELATE ABNORMAL SERUM CALCIUM &
PHOSPHATE LEVELS
Strontium ranelate is composed of two atoms of strontium bound
to an organic ion, ranelic acid. Although not yet approved for use HYPERCALCEMIA
in the United States, this drug is used in Europe for the treatment
of osteoporosis. Strontium ranelate appears to block differentia- Hypercalcemia causes central nervous system depression, including
tion of osteoclasts while promoting their apoptosis, thus inhibit- coma, and is potentially lethal. Its major causes (other than thia-
ing bone resorption. At the same time, strontium ranelate appears zide therapy) are hyperparathyroidism and cancer, with or without
to promote bone formation. Unlike bisphosphonates, denosumab, bone metastases. Less common causes are hypervitaminosis D,
or teriparatide, this drug increases bone formation markers while sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insuf-
inhibiting bone resorption markers. Large clinical trials have ficiency, and immobilization. With the possible exception of
demonstrated its efficacy in increasing bone mineral density and hypervitaminosis D, the latter disorders seldom require emergency
decreasing fractures in the spine and hip. Toxicities reported thus lowering of serum calcium. A number of approaches are used to
far are similar to placebo. manage the hypercalcemic crisis.

■ CLINICAL PHARMACOLOGY Saline Diuresis
In hypercalcemia of sufficient severity to produce symptoms, rapid
Individuals with disorders of bone mineral homeostasis usually reduction of serum calcium is required. The first steps include
present with abnormalities in serum or urine calcium levels (or rehydration with saline and diuresis with furosemide, although the
both), often accompanied by abnormal serum phosphate levels. efficacy of furosemide in this setting has not been proved. Most
These abnormal mineral concentrations may themselves cause patients presenting with severe hypercalcemia have a substantial
symptoms requiring immediate treatment (eg, coma in malignant component of prerenal azotemia owing to dehydration, which pre-
hypercalcemia, tetany in hypocalcemia). More commonly, they vents the kidney from compensating for the rise in serum calcium
serve as clues to an underlying disorder in hormonal regula- by excreting more calcium in the urine. Therefore, the initial infu-
tors (eg, primary hyperparathyroidism), target tissue response sion of 500–1000 mL/h of saline to reverse the dehydration and
(eg, chronic kidney disease), or drug misuse (eg, vitamin D restore urine flow can by itself substantially lower serum calcium.
intoxication). In such cases, treatment of the underlying disorder The addition of a loop diuretic such as furosemide following rehy-
is of prime importance. dration enhances urine flow and also inhibits calcium reabsorp-
Since bone and kidney play central roles in bone mineral tion in the ascending limb of the loop of Henle (see Chapter 15).
homeostasis, conditions that alter bone mineral homeostasis Monitoring of central venous pressure is important to forestall the
usually affect one or both of these tissues secondarily. Effects development of heart failure and pulmonary edema in predisposed
on bone can result in osteoporosis (abnormal loss of bone; subjects. In many subjects, saline diuresis suffices to reduce serum
remaining bone histologically normal), osteomalacia (abnor- calcium to a point at which more definitive diagnosis and treatment
mal bone formation due to inadequate mineralization), or of the underlying condition can be achieved. If this is not the case or
osteitis fibrosa (excessive bone resorption with fibrotic replace- if more prolonged medical treatment of hypercalcemia is required,
ment of resorption cavities and marrow). Biochemical markers the following agents are available (discussed in order of preference).
of skeletal involvement include changes in serum levels of the
skeletal isoenzyme of alkaline phosphatase, osteocalcin, and Bisphosphonates
N- and C-terminal propeptides of type I collagen (reflecting Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledro-
osteoblastic activity), and serum and urine levels of tartrate- nate, 4 mg, infused over at least 15 minutes, have been approved
resistant acid phosphatase and collagen breakdown products for the treatment of hypercalcemia of malignancy and have largely
(reflecting osteoclastic activity). The kidney becomes involved replaced the less effective etidronate for this indication. The
when the calcium × phosphate product in serum rises above bisphosphonate effects generally persist for weeks, but treatment
the point at which ectopic calcification occurs (nephrocalci- can be repeated after a 7-day interval if necessary and if renal
nosis) or when the calcium × oxalate (or phosphate) product function is not impaired. Some patients experience a self-limited
in urine exceeds saturation, leading to nephrolithiasis. Subtle flu-like syndrome after the initial infusion, but subsequent infu-
early indicators of such renal involvement include polyuria, sions generally do not have this side effect. Repeated doses of these
nocturia, and hyposthenuria. Radiologic evidence of neph- drugs have been linked to renal deterioration and osteonecrosis of
rocalcinosis and stones is not generally observed until later. the jaw, but this adverse effect is rare.
The degree of the ensuing renal failure is best followed by
monitoring the decline in creatinine clearance. On the other
hand, chronic kidney disease can be a primary cause of bone Calcitonin
disease because of altered handling of calcium and phosphate, Calcitonin has proved useful as ancillary treatment in some
decreased 1,25(OH) D production, increased FGF23 levels, patients. Calcitonin by itself seldom restores serum calcium to
2
and secondary hyperparathyroidism. normal, and refractoriness frequently develops. However, its lack