A Textbook of Clinical Pharmacology and Therapeutics

effective in life-threatening hyperkalaemia-induced cardiac
dysrhythmias (Chapter 32). Calcium and vitamin D supplements
are used in patients at risk of osteoporosis if intake is
below 1 g of elemental calcium daily. Effervescent or chewable
preparations are available and easy to take.
TREATMENT OF HYPERCALCAEMIA
Hypercalcaemia may be a life-threatening emergency. Causes
include hyperparathyroidism, malignancy with bone metastases
or ectopic PTH synthesis, sarcoidosis and vitamin D intoxication.
Treating the underlying cause is crucial. Management
of hypercalcaemia per se buys time for this and can be divided
into general and specific measures.
GENERAL MEASURES
The following general measures apply:
1. rehydration;
2. avoid thiazide diuretics (cause Ca 2� retention, see
Chapter 36);
3. avoid excessive vitamin D;
4. avoid immobilization if possible.
Specific measures to:
1. increase calcium excretion:
• intravenous saline increases calcium excretion;
• once extravascular volume has been restored,
furosemide further increases urinary calcium
excretion.
2. decrease bone resorption:
• bisphosphonates (see below);
• calcitonin (see below);
3. glucocorticosteroids:
• glucocorticosteroids are useful for treating the
hypercalcaemia associated with sarcoidosis.
Key points
Management of acute hypercalcaemia
• Avoid thiazides, vitamin D (milk), any calcium
preparations and, if possible, immobilization.
• Vigorously replace fluid losses with intravenous 0.9%
sodium chloride. Once replete, furosemide
administration further increases urinary calcium
loss.
• Give parenteral bisphosphonates (e.g. disodium
etidronate or disodium pamidronate).
• Calcitonin lowers calcium levels more rapidly than
bisphosphonates, and may be used concomitantly in
severe cases.
• Glucocorticosteroids are used for the hypercalcaemia of
sarcoidosis.
BISPHOSPHONATES
BISPHOSPHONATES 299
Bisphosphonates resemble pyrophosphate structurally, except
that the two phosphorus atoms are linked by carbon rather than
by oxygen. The P-C-P backbone structure renders such compounds
very stable – no enzyme is known that degrades them.
Uses
Alendronic acid or risedronate (by mouth) are first-choice
bisphosphonates for the prevention and treatment of osteoporosis;
etidronate is an alternative if these are not tolerated.
Bisphosphonates are also used to treat Paget’s disease of bone,
in the treatment of hypercalcaemia of malignancy (e.g.
pamidronate i.v.) and to reduce skeletal complications in
breast cancer metastatic to bone and multiple myeloma (e.g.
clodronate p.o. or i.v.). They are effective for glucocorticoidassociated
and post-menopausal osteoporosis. In Paget’s disease,
risedronate is given for two months and this can be
repeated after at least two months off treatment. Etidronate is
started at low dosage up to six months when many patients
achieve remission; a further course may be given following
relapse. Use for longer than six months at a time does not prolong
remission. High doses should be used only if lower doses
fail or if rapid control of disease is needed. Serum alkaline
phosphatase, phosphate and if possible urinary hydroxyproline
are monitored during treatment of Paget’s disease.
Mechanism of action
Bisphosphonates modify the crystal growth of calcium
hydroxyapatite by chemical adsorption to the crystal surface,
reducing bone remodelling and turnover by osteoclasts.
Adverse effects
Renal impairment is a caution or contraindication for all bisphosphonates.
Oesophagitis and ulceration can be severe.
This is minimized by taking alendronic acid or risedronate
when sitting upright or standing, on an empty stomach before
breakfast, and remaining standing for half an hour before eating.
Other adverse effects include the gamut of gastrointestinal
symptoms. Etidronate increases the risk of fracture in
patients with Paget’s disease.
Key points
Bisphosphonates and bone disease
• Used to treat malignant hypercalcaemia, bone pain from
metastatic cancer (breast, prostate) and Paget’s disease,
and to prevent and reduce the progression of osteoporosis.
• Inhibit bone resorption by osteoclasts; etidronate also
inhibits mineralization with chronic use.
• Oral absorption is poor; short t 1/2 in plasma and long
t 1/2 in bone; renal clearance.
• Food and/or calcium-containing antacids further reduce
gastrointestinal absorption of bisphosphonates.
• The most common side effects are gastro-intestinal
disturbances (Note: with regard to oesophagitis and
ulceration with alendronic acid, this drug must be
taken with water and the patient must be able to stand
for 30 minutes post-ingestion).