A Textbook of Clinical Pharmacology and Therapeutics

BISPHOSPHONATES 299

effective in life-threatening hyperkalaemia-induced cardiac
dysrhythmias (Chapter 32). Calcium and vitamin D supple-
ments 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 metas-
tases or ectopic PTH synthesis, sarcoidosis and vitamin D intoxi-
cation. 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,
     furosemidefurther 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.
   
   
   
   

BISPHOSPHONATES

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 com-

pounds very stable – no enzyme is known that degrades them.

Uses

Alendronic acidorrisedronate(by mouth) are first-choice

bisphosphonates for the prevention and treatment of osteo-

porosis; etidronateis 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.

clodronatep.o. or i.v.). They are effective for glucocorticoid-

associated and post-menopausal osteoporosis. In Paget’s dis-

ease,risedronateis given for two months and this can be

repeated after at least two months off treatment. Etidronateis

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 pro-

long 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 hydroxypro-

line 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 bis-

phosphonates. Oesophagitis and ulceration can be severe.

This is minimized by taking alendronic acidorrisedronate

when sitting upright or standing, on an empty stomach before

breakfast, and remaining standing for half an hour before eat-

ing. Other adverse effects include the gamut of gastrointest-

inal symptoms. Etidronateincreases the risk of fracture in

patients with Paget’s disease.

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.

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 t1/2in plasma and long
  t1/2in 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).