Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 38) pptx

Vitamins, calcium, bone SYNOPSIS The principally pharmacological aspects of vitamins are described here.The nutritional aspects, physiological function, sources, daily requirements and d

Vitamins, calcium, bone

SYNOPSIS

The principally pharmacological aspects of

vitamins are described here.The nutritional

aspects, physiological function, sources, daily

requirements and deficiency syndromes

(primary and secondary) are to be found in any

textbook of medicine

• Vitamin A: retinol

• Vitamin B: complex

• Vitamin C: ascorbic acid

• Vitamin D, calcium, parathyroid hormone,

calcitonin, bisphosphonates, bone

• Treatment of calcium and bone disorders

• Vitamin E:tocopherol

Vitamins are substances that are essential for normal

metabolism and must be chiefly supplied in the diet.

Humans cannot synthesise vitamins in the body

except some vitamin D in the skin and nicotinamide

from tryptophan Lack of a particular vitamin may

lead to a specific deficiency syndrome This may be

primary (inadequate diet), or secondary, due to failure

of absorption (intestinal abnormality or chronic

diarrhoea), or to increased metabolic need (growth,

pregnancy, lactation, hyperthyroidism).

Vitamin deficiencies are commonly multiple,

and complex clinical pictures occur There are

numerous single and multivitamin preparations to

provide prophylaxis and therapy.

It has often been suggested, but never proved,

that subclinical vitamin deficiencies are a cause of much chronic ill-health and liability to infections This idea has led to enormous consumption of vitamin preparations, which, for most consumers, probably have no more than placebo value Fortunately most of the vitamins are comparatively

nontoxic, but prolonged administration of vitamins

A and D can have serious ill-effects.

Vitamins fall into two groups:

• water-soluble vitamins: the B group and C

• fat-soluble vitamins: A, D, E and K

Vitamin A: retinol

Vitamin A is a generic term embracing substances having the biological actions of retinol and related

substances (which are called retinoids) The principal

functions of retinol are to:

• sustain normal epithelia

• form retinal photochemicals

• enhance immune functions

• protect against infections and probably some cancers.

Deficiency of retinol leads to metaplasia and hyperkeratosis throughout the body This metaplasia

is reminiscent of the early stage of transformation of normal tissue to cancer.

Retinol and derivatives are used in doses above those needed for nutrition, i.e pharmacotherapy, in

dyskeratotic skin diseases (psoriasis, acne) and in

leukaemia.

Tretinoin is retinoic acid It is used in acne by

topical application, see page 313, and orally to

induce remission in promyelocytic leukaemia.

Isotretinoin is a retinoic acid isomer (t1^ 20 h) It is

used orally in acne (see p 313) It is effective in

preventing second primary tumours in patients who

have been treated for squamous cell carcinoma of

the head and neck.

Acitretin is a retinoic acid derivative (tl/2 48 h) It is

used orally for psoriasis, see p 313.

Retinol itself is used in prevention and treatment

of deficiency (ta/2 7-14 d).

Adverse effects

Toxic effects occur with prolonged high intake (in

children 25 000-500 000 IU daily) A diagnostic sign

of chronic poisoning is the presence of painful tender

swellings on the long bones Anorexia, skin lesions,

hair loss, hepatosplenomegaly, papilloedema,

bleeding and general malaise also occur Vitamin A

is very cumulative (it is stored in liver and fat) and

effects take weeks to wear off Most cases of vitamin

A poisoning have been due to mothers administering

large amounts of fish-liver oils to their children in

the belief that it was good for them.

Chronic overdose also causes an increased liability

of biological membranes and of the outer layer of

the skin to peel An extreme example of this is the

case of the hungry Antarctic explorer who in 1913

ate the liver of his husky sledge dogs His feet felt

sore and

the sight of my feet gave me quite a shock, for the

thickened skin of the soles had separated in each

case as a complete layer I did what appeared to

be the best thing under the circumstances: smeared

the new skin with lanoline and with bandages

bound the skin soles back in place.1

Vitamin A and its derivatives are teratogenic at

1 Shearman J C 1978 Vitamin A and Sir Douglas Mawson

British Medical Journal 1: 283

above physiological doses, i.e with pharmacotherapy (for precautions, see use in acne and psoriasis,

p 313) Misguided pregnant health enthusiasts may take enough self-prescribed supplements to hazard

a fetus The Teratology Society advises that ments should not exceed 8000 IU (2400 micrograms) per day.

supple-Acute overdose: Travellers have been made ill by eating the livers of Arctic carnivores:

Eskimos never eat polar-bear liver, knowing it to

be toxic, and husky dogs, with instinctive wisdom, also avoid it Those who pooh-pooh the Eskimos' fears of the husky dogs' instincts and are tempted

to enjoy a man's portion of polar-bear liver — appetites get sharp near the North Pole — will consume anything up to 10 000 000 IU of vitamin A (normal daily requirement is 5000 IU) This is too much of a good thing, and the diner will probably soon find himself drowsy then overcome by headache and vomiting, and finally losing the outer layer of his skin.2

Vitamin B complex

A number of widely differing substances are now, for convenience, classed the Vitamin B complex'.

Those used for pharmacotherapy include the following:

Thiamine (B:) is used orally for nutritional poses, but is given i.v in serious emergencies, e.g Wernicke-Korsakoff syndrome, when it can cause anaphylactic shock; the injection should be given over 10 min (or i.m.).

pur-Cobalamins (B12): see Chapter 29.

Folic acid: see Chapter 29.

Pyridoxine (B6) is a coenzyme (including boxylases) for transamination and is concerned with many metabolic processes Normal adult requirements are about 2 mg/d As pharmacotherapy,

decar-; Editorial 1962 British Medical Journal 1: 855

pyridoxine is given to treat certain

pyridoxine-dependent inborn errors of metabolism, namely

homocystinuria, hereditary sideroblastic anaemia

and primary hyperoxaluria Deficiency may be

induced by drugs such as isoniazid, hydralazine

and penicillamine; pyridoxine 10 mg/day prevents

the development of peripheral neuritis without

interfering with therapeutic action.

Pyridoxine has also been used for a variety of

conditions including premenstrual tension, vomiting

in pregnancy and radiation sickness in doses

some-times exceeding 100 mg/day Concerns that

pro-longed exposure to high doses may be harmful, e.g.

causing sensory neuropathy, have not been

resolved.

Niacin (nicotinic acid, nicotinamide) (B7) is an

essential part of codehydrogenases I and II, and so

it is present in every living cell It is used in some

hyperlipidaemias, see page 527.

Adverse effects do not occur with standard doses

of nicotinamide Nicotinic acid, which is converted

into nicotinamide, causes peripheral vasodilatation

accompanied by an unpleasant flushing and itching,

and the patient may faint.

Vitamin C: ascorbic acid

Deficiency of ascorbic acid leads to scurvy,3 which

is characterised by petechial haemorrhages,

haematomas, bleeding gums (if teeth are present)

and anaemia It has a memorable place in the

history of therapeutic measurement.

Scurvy had been a scourge for thousands of

years, particularly amongst sailors on long voyages.

In 1753, Dr James Lind performed a simple controlled

therapeutic trial on 12 sailors with advanced scurvy.

They were all on the same basic diet and were

living in the same quarters on board ship at sea He

divided them into pairs and dosed each pair

separately on cider, sulphuric acid, sea-water, vinegar,

a concoction of garlic, mustard, balsam and myrrh,

and two oranges and a lemon The pair receiving

3 Only man (and other primates), guinea-pigs, the Indian

fruit bat and the red-vented bulbul (a bird) get scurvy; other

animals are able to synthesise ascorbic acid for themselves

the oranges and lemon recovered and were back on duty within a week; of the others, only the pair taking cider was slightly improved The efficacy of oranges and lemons in the prevention and cure of scurvy was repeatedly confirmed Eventually the British Navy provided a regular daily allowance of lemon juice, unfortunately later replaced by the cheaper lime4 juice which contained insufficient ascorbic acid to prevent scurvy completely.

Function

Ascorbic acid is required for the synthesis of collagen.

It is also a powerful reducing agent (antioxidant) and plays a part in intracellular oxidation-reduction systems, and in mopping up oxidants (free radicals) produced endogenously or in the environment, e.g cigarette smoke (see Vitamin E).

Indications for ascorbic acid

• The prevention and cure of scurvy

• Urinary acidification (rarely appropriate)

• Methaemoglobinaemia, for its properties as reducing agent (see below)

• Coryza: it is possible that large daily doses (1 g or more/d) of ascorbic acid (daily nutritional requirement 60 mg) may reduce the incidence and severity of coryza (common cold) Reliable trials in this disease are difficult and the results are inconclusive To justify use of such doses in populations, benefit must be shown to

be clinically, as well as statistically, significant; and harm insignificant This has not been achieved.

Adverse effects

High doses may cause sleep disturbances, headaches and gut upsets Ascorbic acid is partly eliminated in the urine unchanged and partly metabolised to oxalate Doses above 4 g/d, which have been taken over long periods in the hope of preventing coryza, increase urinary oxalate concentration sufficiently

to from oxalate stones Intravenous ascorbic acid

4 Hence the term 'limey' for British sailors; generally usedpejoratively, but obsolete except in Australia

may precipitate a haemolytic attack in subjects with

glucose-6-phosphate dehydrogenase deficiency.

METHAEMOGLOBINAEMIA

A reducing substance is needed to convert the

methaemoglobin (ferric iron) back to

oxyhaemo-globin (ferrous iron) whenever enough has formed

seriously to impair the oxygen-carrying capacity of

the blood Ascorbic acid is nontoxic (it acts by direct

reduction) but is less effective than methylene blue

(methylthioninium chloride) Both can be given

orally, i.v or i.m Excessive doses of methylene blue

can cause methaemoglobinaemia (by stimulating

NADPH-dependent enzymes).

Methaemoglobinaemia may be induced by

oxidising drugs: sulphonamides, nitrites, nitrates

(may also occur in drinking water), primaquine,

-caine local anaesthetics, dapsone, nitrofurantoin,

nitroprusside, vitamin K analogues, chlorates, aniline

and nitrobenzene In the rare instance of there being

urgency, methylene blue 1 mg/kg slowly i.v benefits

within 30 min (Ascorbic acid competes directly

with the chemical cause but is inadequate in severe

cases, which are the only ones that need treatment.)

In the congenital form, oral methylene blue with

or without ascorbic acid gives benefit in days to

weeks.

Methylene blue turns the urine blue and high

concentrations can irritate the urinary tract, so that

fluid intake should be high when big doses are used.

Sulphaemoglobinaemia cannot be treated by drugs.

It can be caused by sulphonamides, nitrites or nitrates.

Vitamin D comprises a number of structurally

related sterol compounds having similar biological properties in that they prevent or cure the vitamin

D deficiency diseases, rickets and osteomalacia The important forms are:

• D2 or ergocalcif erol (calciferol) made by

ultraviolet irradiation of ergosterol

• D3 or colecalcif erol made by ultraviolet

irradiation of 7-dehydrocholesterol; it is the form that occurs in natural foods and is formed in the skin.

Vitamins D2 and D3 are made more active by two hydroxylation reactions: (a) 25-hydroxylation in the

liver, and (b) la-hydroxylation in the kidney (under

the control of parathormone) to form, dihydroxycholecalciferol; this, the most active

la-25-natural form of vitamin D, is available as calcitriol.

In renal disease this final rate-limited renal hydroxylation is inadequate, and administration of the less biologically active precursors is therefore liable to lack efficacy.

a-Subsequently there was introduced a hydroxylated form (loc-hydroxycholecalciferol)

loc-alf acalcidol (One-Alpha), that requires only hepatic

hydroxylation to become the highly active dihydroxycholecalciferol (calcitriol) Alf acalcidol (and of course calcitriol) is therefore effective in renal failure since the defective renal hydroxylation stage is bypassed Its extraordinary potency and efficacy is indicated by the usual adult maintenance dose, often only 0.25-1 micrograms/d.

lcx-25-In addition there is a structural variant of vitamins

D2 and D3 dihydrotachysterol (ATIO, Tachyrol),

which is also biologically activated by hepatic hydroxylation.

25-Advantages of alfacalcidol and dihydrotachysterol

include a fast onset and short duration of clinical effect (days) which renders them suitable for rapid adjustment of plasma calcium, e.g in hypopara- thyroidism Such factors are not relevant to the slower adjustment of plasma calcium (weeks) with vitamins D2 and D3 in the ordinary management of vitamin D deficiency.

Actions are complex Vitamin D promotes the active transport (absorption) of calcium and therefore

of phosphate from the gut, to control, with parathormone, the mineralisation of bone and to

promote the renal tubular reabsorption of calcium

and phosphate The plasma calcium concentration

rises After a dose of D2 or D3 there is a lag of about

21 h before the intestinal effect begins and this is

probably due to the time needed for its metabolic

conversion to the more active forms But with the

biologically active calcitriol the lag is only 2 h.

A large single dose of vitamin D has biological

effects for as long as 6 months (because of metabolism

and storage) Thus the agent is cumulative and

overdose by a mother anxious that her child shall

have strong bones can cause serious toxicity.

Indications for vitamin D are the prevention and

cure of rickets of all kinds and osteomalacia, and

the symptomatic treatment of some cases of

hypo-parathyroidism; also psoriasis.

Calcitriol is licensed for the management of

postmenopausal osteoporosis.

In osteomalacia secondary to steatorrhoea or renal

disease there is defective absorption of calcium

from the gut and large amounts of vitamin D are

often needed to enhance absorption.

Use of vitamin D as pharmacotherapy should in

general be accompanied by monitoring of plasma

calcium.

Dose and preparations (1.0 microgram = 40 units).

Simple vitamin D deficiency can be prevented by

taking an oral supplement of only 10 micrograms

(400 units) of ergocalciferol daily Vitamin D deficiency

is not uncommon in Asians consuming unleavened

bread and in the elderly living alone; it can be

pre-vented by taking an oral supplement of ergocalciferol

20 micrograms (800 units) daily Vitamin D in

deficiency caused by intestinal malabsorption or

chronic liver disease usually requires vitamin D in

pharmacological doses, such as ergocalciferol tablets

up to 1 mg (40 000 units) daily The maximum

antirachitic effect of vitamin D is delayed for 1-2

months and the plasma calcium concentration reflects

the dosage given days or weeks before Frequent

changes of dose are therefore not required.

The hypocalcaemia of hypoparathyroidism may

require ergocalciferol in doses up to 2.5 mg

(100 000 units) daily to achieve normocalcaemia but

the dose is difficult to titrate and hypercalcaemia

from overdose may take weeks to resolve The

synthetic vitamin D derivatives, alfacalcidol and

calcitriol, are therefore preferred as their rapid onset

and offset of action makes for easier control of plasma calcium Supplementary calcium by mouth may also be needed.

Alfacalcidol or calcitriol, but not ergocalciferol,

should be prescribed if patients with severe renal impairment require vitamin D therapy (see above).

Calcipotriol and tacalcitol are vitamin D analogues

available as creams or ointments for the treatment

of psoriasis (p 313).

Symptoms of overdose are due mainly to excessive

rise in plasma calcium General effects include: malaise, drowsiness, nausea, abdominal pain, thirst, constipation and loss of appetite Other long-term effects include ectopic calcification almost anywhere

in the body, renal damage and an increased calcium output in the urine; renal calculi may be formed It

is dangerous to exceed 10 000 units daily of vitamin

D in an adult for more than about 12 weeks Vitamin D toxicity may arise from well-meaning, but needless, administration by parents The US Food and Drug Administration warns that intake of fortified diet supplements should not exceed 400 units a day.

Patients with sarcoidosis are intolerant of vitamin

D possibly even to the tiny amount present in a normal diet, and to that synthesised in their skin by sunlight The intolerance may be due to over- production of calcitriol (see above) by macrophages activated by interferon; the overproduction is reversed by corticosteroid, which is also used in the treatment of severe hypervitaminosis D (see below).

Epileptic patients taking drugs that are enzyme

inducers can develop osteomalacia (adults) or rickets (children) This may be due to enzyme induction increasing vitamin D metabolism and causing deficiency, or there may be inhibition of one of the hydroxylations that increase biological activity.

Treatment of calcium and bone disorders

HYPOCALCAEMIA

In acute hypocalcaemia requiring systemic therapy

calcium gluconate inj is given as a 10% solution,

10-20 ml at the rate of about 2 ml per min and

followed by a continuous i.v infusion containing

40 ml (9 mmol) per day with monitoring of plasma

calcium It must not be given i.m as it is painful and

causes necrosis Calcium glubionate (Calcium Sandoz)

can be given by deep i.m injection in adults.

For chronic use, e.g hypoparathyroidism,

alfa-calcidol or calcitriol are needed Dietary calcium is

increased by giving calcium gluconate (an

effer-vescent tablet is available) or lactate Aluminium

hydroxide binds phosphate in the gut causing

hypo-phosphataemia, which stimulates renal formation

of the most active vitamin D metabolite and usefully

enhances calcium absorption.

Adverse effects of intravenous calcium may be

very dangerous An early sign is a tingling feeling

in the mouth and of warmth spreading over the

body Serious effects are those on the heart, which

mimic and synergise with digitalis (fatal cardiac

arrest may occur in digitalised animals) and it would

seem advisable to avoid i.v calcium in any patient

on a digitalis glycoside (except in severe symptomatic

hypocalcaemia) The effect of calcium on the heart

is antagonised by potassium and similarly the toxic

effects of a high serum potassium in acute renal failure

may be to some extent counteracted with calcium.

HYPERCALCAEMIA

Treatment of severe acute hypercalcaemia causing

symptoms is needed whether or not the cause can

be removed; generally a plasma concentration of

3.0 mmol/1 (12 mg/100 ml) needs urgent treatment

if there is also clinical evidence of toxicity

(individual tolerance varies greatly).

Temporary measures

After taking account of the patient's cardiac and

renal function, the following measures may be

employed selectively:

• Physiological saline solution is important, firstly to

correct sodium and water deficit and secondly to

promote sodium-linked calcium diuresis in the

proximal renal tubule Initially, 0.9% saline

500 ml should be given i.v every 4-6 h for

2-3 days and continued at a rate of 21/day until plasma calcium falls below 3.0 mmol/1 and the oral intake is adequate The regimen requires careful attention to fluid and electrolyte balance, including potassium Furosemide may be added

to the regimen once salt depletion has been corrected.

• Bisphosphonates (see later) Pamidronate5 is infused according to the schedule in Table 38.1; it

is active in a wide variety of hypercalcaemic disorders Fall in serum calcium begins in 1-2 d, reaches a nadir in 5-6 d and lasts 20-30 d Etidronate may be given i.v in hypercalcaemia of malignant disease It acts in 1-2 d and a dose lasts 3-4 weeks; it may also provide benefit for neoplastic metastatic disease in bone Clodronate (oral or i.v.) or zoledonic acid (i.v.) are alternatives.

• Calcitonin (see below) When the hypercalcaemia

is at least partly due to mobilisation from bone, calcitonin can be used to inhibit bone resorption, and it may enhance urinary excretion of calcium The effect develops in a few hours, and

responsiveness may be lost over a few days (but may sometimes be restored by an adrenal steroid).

• An adrenocortical steroid, e.g prednisolone

20-40 mg/d orally, is effective in particular situations; it reduces the hypercalcaemia of vitamin D intoxication (which is due to excessive intestinal absorption of calcium) and of

sarcoidosis (principally by its disease-modifying effect) Steroid may be effective in the

hypercalcaemia of malignancy where the disease itself is responsive, e.g myeloma of lymphoma Most patients with hyperparathyroidism do not respond.

TABLE 38.1 Treatment of hypercalcaemia with disodium pamidronate

<3.03.0-3.53.5-4.0

>4.0

15-3030-6060-9090

Infuse slowly, e.g 30 mg in 250 ml 0.9% saline over I hour Expect response in 3-5 days.

5 formerly called arninohydroxypropylidenediphosphonatedisodium, APD

• Phosphate i.v is quickly effective but lowers

calcium by precipitating calcium phosphate in

bone and soft tissues and inhibiting osteoclastic

activity; it should be used only when other

methods have failed.

• Trisodium edetate (therapeutically equivalent to

disodium edetate) i.v chelates calcium and the

inert complex is excreted by glomerular

filtration Although it is rapidly effective, it

causes pain in the limb receiving the infusion

and may cause renal damage.

• Dialysis is quick and effective and is likely to be

needed in severe cases or with renal failure.

The above measures are temporary only, giving

time to tackle the cause.

Long-term use

To bind dietary calcium in the gut sodium cellulose

phosphate (Calcisorb) is an oral ion exchange substance

with a particular affinity for calcium Bound calcium

is eliminated in the faeces It is used particularly for

patients who overabsorb dietary calcium and who

develop hypercalciuria and renal stones.

Inorganic phosphate, e.g sodium acid phosphate

(Phosphate Sandoz) taken orally also binds calcium

in the gut.

HYPERCALCIURIA

In renal stone formers, in addition to general

measures (low calcium diet, high fluid intake),

urinary calcium may be diminished by a thiazide

diuretic (with or without citrate to bind calcium)

and oral phosphate (see above) See also

Nephrolithiasis (p 543).

PARATHYROID HORMONE

Parathyroid hormone acts chiefly on kidney increasing

renal tubular resorption and bone resorption of

calcium; it increases calcium absorption from the

gut, indirectly, by stimulating the renal synthesis of

la-25-dihydroxycholecalciferol (see Vitamin D) It

increases the rate of bone remodelling (mineral and

collagen) and osteocyte activity with, at high doses,

an overall balance in favour of resorption (osteoclast

activity) with a rise in plasma calcium

con-centration (and fall in phosphate); but, at low doses, the balance favours bone formation (osteoblast activity).

CALCITONIN

Calcitonin is a peptide hormone produced by the C cells of the thyroid gland (in mammals) It acts on bone (inhibiting osteoclasis) to reduce the rate of bone turnover, and on the kidney to reduce reabsorption of calcium and phosphorus It is obtained from natural sources (pork, salmon, eel),

or synthesised The t1/2 varies according to source; tl/2

human is 10 min Antibodies develop particularly to pork calcitonin and neutralise its effect; synthetic

salmon calcitonin (salcatonin) is therefore preferred

for prolonged use; loss of effect may also be due to down-regulation of receptors Calcitonin is used (s.c., i.m or intranasally) to control hypercalcaemia (rapid effect), Paget's disease of bone (relief of pain, and to relieve compression of nerves, e.g auditory cranial), metastatic bone cancer pain, and post- menopausal osteoporosis.

Adverse effects include allergy, nausea, flushing

and tingling of the face and hands.

BISPHOSPHONATES

Bisphosphonates are synthetic, nonhydrolysable analogues of pyrophosphate in which the central oxygen atom of the -P-O-P- structure is replaced with a carbon atom to give the -P-C-P- group.

Actions These compounds are effective calcium

chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone- resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis The

bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate)

inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts They also bind strongly to hydrox- yapatite crystals and, in high doses, can inhibit the mineralisation of bone The doses at which effects on mineralisation occur are not related to antiresorptive efficacy There is wide variation between these compounds in terms of their capacity to inhibit

resorption relative to that of inhibiting mineralisation.

Etidronate, for instance, must be administered

cyclically to prevent demineralisation whereas

alendronate, more recently available, does not appear

to interfere with mineralisation at antiresorptive

doses and can be used continously.

Pharmacokinetics Bisphosphonates are poorly

absorbed after oral ingestion Absorption is further

impaired by food, drinks and drugs containing

calcium, magnesium, iron or aluminium salts A

proportion of bisphosphonate that is absorbed is

rapidly incorporated into bone; the remaining

fraction is excreted unchanged by the kidneys.

Once incorporated into the skeleton, bisphosphonates

are released only when the bone is resorbed during

turnover They may be given orally or i.v.

Uses Three bisphosphonates (alendronate, etidronate,

risedronate) are currently licensed in the UK for the

treatment of osteoporosis (zoledronate is also

effective), and the others are used in Paget's disease

of bone, and hypercalcaemia due to cancer

(pamidronate, clodronate, zoledronate)

Bisphos-phonates may also provide benefit for neoplastic

disease that has spread to bone; evidence indicates

that clodronate by mouth and pamidronate i.v are

effective in the secondary prevention of bone

metastases due to multiple myeloma and breast

cancer.

Adverse effects include gastrointestinal

disturb-ances, with oesophageal irritation being a particular

problem with alendronate This should be given at

least 30 minutes before food, with the patient

remaining erect during this period Alendronate

can be taken weekly (70 mg) instead of daily

(10 mg) Disturbances of calcium and mineral

metabolism (e.g vitamin D deficiency, parathyroid

hormone dysfunction) should be corrected before

starting a bisphosphonate Increased bone pain (as

well as relief), fractures (high dose, prolonged use

only) can occur due to demineralisation of bone.

OSTEOPOROSIS

Osteoporosis is an abnormal decrease in amount of

bone, but what is there is of normal quality Low

bone mass is reflected in reduced bone mineral

density measurements It occurs most commonly in postmenopausal women and patients taking cor- ticosteroid long-term Underlying causes such as hyperthyroidism, hyperparathyroidism and hypo- gonadism (in both sexes) should be excluded before treatment is initiated.

People at risk of osteoporosis, e.g elderly housebound persons, must maintain an adequate intake of calcium and vitamin D Calcium dietary supplementation (Ca gluconate, carbonate, hyd- roxyapatite, citrate, maleate) reduces nett bone loss where intake may be inadequate, i.e below 800 mg/d, and ergocalciferol 10 micrograms (400 units)

by mouth corrects dietary vitamin D deficiency.

Postmenopausal osteoporosis is due to gonadal deficiency; it can be prevented One in 4 women in

her 60s and one in 2 in her 70s in the UK experiences

an osteoporotic fracture.

• Oestrogen arrests the process by reducing bone

resorption.

• Progestogen arrests the process by increasing

bone formation, but therapeutic benefit is less than with oestrogen.

Oestrogen inhibits the age-related loss of bone that occurs in most women after menopause Observational studies have indicated that the use of oestrogen reduces the risk of vertebral fracture by approximately 50% and the risk of hip fracture by 25-30% Unopposed oestrogen increases by 10-fold the risk of endometrial cancer, which is diminished

by added progestogen Therefore combinations of oestrogen and progestogen are the mainstay of treatment for postmenopausal osteoporosis; they inhibit the rapid bone loss that occurs immediately after the menopause and should be continued for 5 years.

Longer-term use is more problematic, given the probable increase (though < 2-fold) in the risk of breast cancer associated with extended use Reasonable candidates are the small proportion of postmenopausal women with documented osteo- porosis or osteopenia (decreased bone density) or those at increased risk for osteoporosis (personal or family history of nontraumatic fracture, current smokers, or those with a body-mass index < 22) who do not have a personal or family history of breast cancer or other contraindications and who are willing to try this therapy With more long-term

evidence, raloxifene 60 mg daily where affordable

will become an attractive option This selective

oestrogen receptor agonist can be used unopposed

without apparent increase in risk of breast or

endometrial cancer.

Bisphosphonates increase bone mineral density in

osteoporosis.

A schema for the prevention of osteoporosis with

HRT beyond 5 years, or other options, appears in

Figure 38.1

Treatment of osteoporosis It is usual to start with

HRT or a bisphosphonate and, if these are unsuitable,

calcitriol, calcitonin or raloxifene may be used.

Calcitonin, additionally, is effective for relief of pain

for up to 3 months after vertebral fracture where

other analgesics fail.

Fracture is the only important outcome of

osteoporosis and the evidence to support the efficacy

of various interventions appears in Table 38.2.

Corticosteroid-induced osteoporosis The greatest

TABLE 38.2 Anti-fracture efficacy of interventions inpost menopausal osteoporotic women: grades ofrecommendation

AlendronateCalcitoninCalcitriolCalciumCalcium plus vitamin DCyclical etidronateHip protectorsHRTPhysical exerciseRaloxifeneRisedronateTiboloneVitamin D

SpineA A A ANDAANDAA ND ND

NonvertebralA

B A BABABNDA ND B

Hip A A ND BABABBNDA ND BGrade A, meta-analysis of randomised, controlled trials or from atleast one randomised, controlled trial, or from at least one welldesigned, controlled study without randomisation; grade B, from atleast one other type of well designed, quasi-experimental study, orfrom well designed, nonexperimental studies (e.g comparativestudies, correlation studies, case-control studies); grade C, fromexpert committee reports/opinions and/or clinical experience ofauthorities ND, not demonstrated Data from the Royal College ofPhysicians and the Bone and Tooth Society

Fig 38.1 The prevention of osteoporosis.With permission from

J Manson, Harvard Medical School and the New England Journal of

Medicine

rate of bone loss occurs during the first 6-12 months

of corticosteroid use Patients taking the equivalent

of prednisolone 7.5 mg or more each day for

3 months or longer should be considered for prophylactic treatment, and this is mandatory in those over 65 years Treatment for osteoporosis should be given when a patient taking a cor- ticosteroid sustains a low-trauma fracture Long- term use of inhaled corticosteroids may reduce bone mineral density and place patients at risk The treatment options for both the prophylaxis and treatment are: hormone replacement (HRT in women, testosterone in men), a bisphosphonate and calcitriol.

OSTEOMALACIA

Osteomalacia is due to primary or secondary vitamin

D deficiency In secondary cases, e.g malabsorption

or renal disease, high doses of vitamin D are sometimes needed Long-term therapy with some

antiepilepsy drugs may cause osteomalacia see

Vitamin D).

PAGET'S DISEASE OF BONE

This disease is characterised by bone resorption and

formation (bone turnover) being increased as much

as 50 times normal, the results of which are large,

vascular, deformed, painful bones which fracture.

Bisphosphonates (etidronate, pamidronate,

til-udronate) are effective because of their inhibition of

crystal formation, growth and dissolution, such as

must occur in bone mineralisation and

demineralisation The response is dose-related and

remission after a course may last up to two years.

Calcition (which inhibits bone resorption) has been

largely superseded by the bisphosphonates but is

useful to reduce bone blood flow before operation.

Vitamin E: tocopherol

The functions of vitamin E may be to take up

(scavenge) the free radicals generated by normal

metabolic process and by substances in the

environ-ment, e.g hydrocarbons, and so to prevent them

attacking polyunsaturated fats in cell membranes

with resultant cellular injury A deficiency syndrome

is now recognised, including peripheral neuropathy

with spinocerebellar degeneration; and a haemolytic

anaemia in premature infants.

Alpha tocopheryl acetate (Ephynal)

pharmaco-therapy may benefit the neuromuscular complications

of congential cholestasis and abetalipoproteinaemia.

Vitamin K

see page 568.

GUIDETO FURTHER READING

Bates C J 1995 Vitamin A Lancet 345: 31-35 Bushinsky D A, Monk R D 1998 Calcium Lancet 352:306-311

Cooper C, Eastell R 1993 Bone gain and loss in premenopausal women British Medical Journal 306:1357-1358

Delmas P D, Meunier P J 1997 The management of Paget's disease of bone New England Journal of Medicine 336: 558-566.

Editorial 1962 Arctic offal British Medical Journal 1:855

Eastell R 1998 Treatment of postmenopausal osteoporosis New England Journal of Medicine 338: 736-746.

Eraser D R 1995 Vitamin D Lancet 345:104-107 Greenberg E R, Sporn M B 1996 Antioxidant vitamins, cancer and cardiovascular disease New England Journal of Medicine 334:1198-1190

Humphrey J H, Rice A L 2000 Vitamin A supplementation in young infants Lancet 356:422-424

Manolagas S C et al 1995 Bone marrow, cytokines, and bone remodeling New England Journal of

Medicine 332: 305-311 Manson J E, Martin K A 2001 Postmenopausal Hormone-Replacement Therapy New England Journal of Medicine 345: 3 4 - 0

Meydani M 1995 Vitamin E Lancet 345: 170-175 Relston S H 1992 Medical management of hypercalcaemia British Journal of Clinical Pharmacology 34:11-20

Seeman E 2002 Pathogenesis of bone fragility in women and men Lancet 359:1841-1850 Spector T D, Sambrook P N 1993 Steroid osteoporosis British Medical Journal 307: 519-520

Willett W C, Stampfer M J 2001 What vitamins should

I be taking, doctor? New England Journal of Medicine 345:1819-1824