Chrysothemis Brown
Synopsis
In general, the pharmacological aspects of vitamins appear 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.
• Treatment of calcium and bone disorders.
• Vitamin E: tocopherol.
Vitamins1 are substances that are essential for normal metabolism but are supplied chiefly 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 available to provide prophylaxis and therapy.
Recently, there has been great interest in the suggestion that subclinical vitamin deficiencies may be a cause of chronic disease and liability to infection. This idea has prompted a number of clinical trials examining the potential benefit of vitamin supplementation in the prevention of cancer, cardiovascular disease and other common diseases. With the exception of vitamin D, there is little robust evidence to support this claim and, for most consumers, over-the-counter vitamin preparations are probably of little more than placebo value. Fortunately, most vitamins are comparatively non-toxic; however, prolonged administration of vitamin A and vitamin D can have serious ill-effects.
In addition to maintaining adequate nutritional levels, a number of vitamins can be used at pharmacological doses for therapy.
Vitamins fall into two groups:
• Water-soluble vitamins: the B group and vitamin 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 (called retinoids). The principal functions of retinol are to:
• sustain normal epithelia
• promote corneal and conjunctival development
• form retinal photochemicals
• enhance immune functions
• protect against infections and probably some cancers.
Deficiency of retinol leads to xerophthalmia, squamous metaplasia, hyperkeratosis and impairment of the immune system.
Therapeutic uses
Retinol and derivatives provide therapeutic benefit in a number of clinical areas.
Psoriasis
Tazorotene, a topical retinoid, is effective in the treatment of chronic stable plaque psoriasis. Skin irritation is common, making it unsuitable for the treatment of inflammatory forms of psoriasis. The 0.05% cream is better tolerated than 0.1% although less effective. Acitretin is a retinoic acid derivative (t½ 48 h) that is used orally for severe psoriasis. Dose range 25 mg alternate days – 50 mg daily (see p. 262, as well as other disorders of keratinisation).
Acne
Tretinoin is retinoic acid and is used in acne by topical application (see p. 273). Isotretinoin is a retinoic acid isomer (t½ 20 h) given orally for acne (see p. 273). It is also effective for preventing second tumours in patients following treatment for primary squamous cell carcinoma of the head and neck.
Acute promyelocytic leukaemia
Tretinoin can be used to induce remission in conjunction with chemotherapy in acute promyelocytic leukaemia, a subgroup of acute myeloid leukaemia (AML) involving chromosomal translocation of the retinoic acid receptor-alpha gene. Initially, it proved remarkably successful, but the high doses given caused the fatal ‘differentiation syndrome’ (previously called ‘retinoic acid syndrome’; respiratory distress, fever and hypotension) and the duration of treatment is now shorter.
Vitamin A deficiency
Primary deficiency is common in developing countries. Retinol is used to prevent and treat deficiency; 1 microgram = 3.3 IU (t½ 7—14 days). For prevention of deficiency in susceptible individuals, supplements are given at 4–6-monthly intervals. Dosing is according to age. More frequent doses are required for treatment of xerophthalmia. Secondary deficiency resulting from fat malabsorption is seen with pancreatic insufficiency and disorders of the gastrointestinal tract. Vitamin A supplementation at pharmacological doses is standard for patients with cystic fibrosis. This can result in chronic toxicity and serum retinol levels should be monitored.
Adverse effects
Acute toxicity occurs in adults with a single dose of more than 600 000 IU/day. Symptoms include headache, nausea, vomiting and drowsiness. Travellers have become ill by eating the livers of Arctic carnivores.
Chronic toxicity occurs with prolonged high intake (in children 25 000–50 000 IU/day, 10 times the recommended daily allowance, RDA). A diagnostic sign is the presence of painful tender swellings on long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding and general malaise also occur. Vitamin A accumulates in liver and fat, and effects take weeks to wear off. Chronic overdose also makes the biological membranes and the outer layer of the skin more liable to peel.
Teratogenicity
Vitamin A and its derivatives are teratogenic at pharmacological doses (for precautions, see use in acne and psoriasis, p. 273). Supplements should not exceed 8000 IU (2400 micrograms) per day.
Vitamin B complex
A number of widely differing substances are now, for convenience, classed as the ‘vitamin B complex’. Those used for pharmacotherapy include the following:
Thiamine (B1)
Deficiency is associated with three distinct conditions: Wernicke–Korsakoff syndrome, beriberi, and Leigh's syndrome. The UK RDA of thiamine is 1 mg for men and 0.8 mg for women. It is given orally for nutritional purposes, but intravenously in serious emergencies, e.g. Wernicke–Korsakoff syndrome. Give the injection over 10 min (or intramuscularly); note that it can cause anaphylactic shock.
Cobalamins (B12)
See Chapter 20.
Folic acid
See Chapter 20.
Pyridoxine (B6)
is a coenzyme in the metabolic transformation of many amino acids, including decarboxylation and transamination. The UK RDA of vitamin B6 is 1.4 mg for men and 1.2 mg for women. As pharmacotherapy, pyridoxine is given to treat certain pyridoxine-dependent inborn errors of metabolism, e.g. 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, in doses sometimes exceeding 100 mg/day, has found use for a variety of conditions including premenstrual syndrome and nausea in pregnancy.
Niacin (nicotinic acid, B3)
is converted to nicotinamide, and subsequently to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADPH), the cofactors that are essential for the oxidation–reduction reactions that comprise tissue respiration. Nicotinamide is used for nutritional purposes. Pellagra resulting from dietary deficiency of niacin is rarely seen in developed countries. Causes other than dietary include alcoholism, carcinoid syndrome and Hartnup disease. Nicotinic acid at pharmacological doses is used for the treatment of some hyperlipidaemias (see p. 444). Adverse effects include peripheral vasodilatation, unpleasant flushing, itching and fainting.
Vitamin C: ascorbic acid
Vitamin C is a powerful reducing agent (antioxidant) and is an essential cofactor and substrate in a number of enzymatic reactions, including collagen synthesis and noradrenaline synthesis. It also functions as an antioxidant, mopping up free radicals produced endogenously or in the environment, e.g. cigarette smoke (see vitamin E). There has been considerable interest in using vitamin C as an antioxidative agent to reduce oxidation of low-density lipoproteins (LDL) in atherosclerosis and prevent formation of carcinogens to reduce risk of cancer. However, randomised trials have not shown any beneficial effect thus far of vitamin C on either cancer incidence or primary or secondary prevention of coronary heart disease.
Indications
• The prevention and cure of scurvy.
• Methaemoglobinaemia.
Scurvy
Deficiency of ascorbic acid leads to scurvy, which is characterised by petechial haemorrhages, haematomas, bleeding gums (if teeth are present) and anaemia.
Methaemoglobinaemia
A reducing substance is needed to convert the methaemoglobin (ferric iron) back to oxyhaemoglobin (ferrous iron) whenever enough has formed seriously to impair the oxygen-carrying capacity of the blood. Ascorbic acid is non-toxic (it acts by direct reduction) but is less effective than methylene blue (methylthioninium chloride). Both can be given orally, intravenously or intramuscularly. 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. Where symptoms are severe enough to warrant urgent treatment, methylene blue given intravenously at 1–2 mg/kg gives response within 30 min. Patients should be monitored for rebound methaemoglobinaemia. Methylene blue turns the urine blue and high concentrations can irritate the urinary tract, so that fluid intake should be high when large doses are used. Methlyene blue should not be administered to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency since its action is dependent on NADPH produced by G6PD. In addition to being ineffective in this circumstance it may induce haemolysis. Ascorbic acid is inadequate for the treatment of acute methaemoglobinaemia requiring treatment.
Congenital methaemogobinaemia can be treated long term with either oral methylene blue or ascorbic acid with partial effect.
Adverse effects
High doses may cause sleep disturbances, headaches and gut upsets. Ascorbic acid is eliminated partly in the urine unchanged and partly metabolised to oxalate. Doses above 4 g/day increase urinary oxalate concentration and there is a potential risk of renal oxalate stones with chronic ascorbic acid administration. Intravenous ascorbic acid may precipitate a haemolytic attack in subjects with G6PD deficiency.
Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone
Vitmain D is closely interrelated with calcium homeostasis and bone metabolism and these topics are therefore discussed together.
Vitamin D
Vitamin D comprises a number of structurally related sterol compounds having similar biological properties (but different potencies) in that they prevent or cure the vitamin D-deficiency diseases, rickets and osteomalacia. The most relevant form of vitamin D is vitamin D3 (colecaciferol). This is made by ultraviolet irradiation of 7-dehydrocholesterol in the skin. It is also absorbed in the intestinal tract; however, few foods contain significant levels of vitamin D (Fig. 39.1). Vitamin D2 (ergocalciferol) is made by ultraviolet irradiation of ergosterol in plants. This is not the naturally occurring form.
Fig. 39.1 Metabolism of vitamin D. D3, Vitamin D3 (cholecalciferol); pre-D3, pre-vitamin D3; DBP, vitamin D-binding protein; 25-OHase, liver 25-hydroxylase; 25(OH)D3, 25-hydroxycholecalciferol (25(OH)D3; 1-OHase, 25-hydroxyvitamin D3-1-hydroxylase; 1,25(OH)2D3, calcitriol; PTH, parathyroid hormone.
(From Deeb K K, Trump D L, Johnson C S 2007 Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Reviews Cancer 7(9): 684.)
Vitamin D3 (and D2) undergo two successive hydroxylations: first in the liver to form 25-hydroxyvitamin D and second in the proximal tubules of the kidney (under the control of parathyroid hormone, PTH) to form 1α,25-dihydroxyvitamin D3 (calcitriol), the most physiologically active form of vitamin D.
There exist also a variety of synthetic vitamin D analogues, developed to treat vitamin D deficiency and hypoparathyroidism. The vitamin D derivative 1α-hydroxycolecalciferol (alfacalcidol) requires only hepatic hydroxylation to become calcitriol. The usual adult maintenance dose, 0.25–1 micrograms/day, indicates its potency.
Other 1α-hydroxylated vitamin D analogues include paricalcitol. In addition, a structural variant of vitamins D2 and D3, dihydrotachysterol (ATIO, Tachyrol), is also biologically activated by hepatic 25-hydroxylation. All are effective in renal failure as they bypass the defective renal hydroxylation stage.
Pharmacokinetics
Alfacalcidol and dihydrotachysterol have a fast onset and short duration of clinical effect (days) which renders them suitable for rapid adjustment of plasma calcium, e.g. in hypoparathyroidism. 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 of calcium and phosphate in the gut (increased absorption) and renal tubule (reduced excretion), and thus controls, with PTH, the plasma calcium concentration and the mineralisation of bone (see Fig. 39.1). After a dose of D2 or D3 there is a lag of about 21 h before the intestinal effect begins; this is probably due to the time needed for its metabolic conversion to the more active forms. With the biologically more 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 (see toxicity).
Indications
• The prevention and cure of rickets of all kinds and osteomalacia (vitamin D deficiency).
• Osteoporosis.
• Hypoparathyroidism.
• Psoriasis.
• CKD-MBD (renal osteodystrophy).
Vitamin D deficiency
This can be treated with a variety of vitamin D analogues. Selecting the appropriate preparation requires a knowledge of the underlying aetiology. There are no absolute criteria for vitamin D deficiency; however, serum 25(OH)VitD3 levels are used as a guide to vitamin D levels and there is a general consensus that a 25(OH)D concentration of 50–75–nmol/L reflects insufficiency, and concentrations of less than 50–nmol/L indicate deficiency.
Although rickets due to primary vitamin D deficiency is rare in developed countries, subclinical vitamin D deficiency and vitamin D insufficiency are now recognised to be extremely common in the UK and in other populations with limited exposure to sunlight, particularly in individuals with increased skin pigmentation, in whom greater amounts of sun exposure are required for adequate synthesis, or in those with excessive body cover. There is accumulating evidence that subclinical vitamin D deficiency has adverse effects on health. Vitamin D deficiency in pregnancy is a significant public health issue: babies born to mothers with low vitamin D levels are at increased risk of neonatal hypocalcaemia and other vitamin D deficiency-related symptoms. Vitamin D deficiency can be prevented in susceptible individuals by taking an oral supplement of ergocalciferol 20 micrograms (800 units) daily. All pregnant and lactating women should receive vitamin D supplementation. Breast milk contains negligible amounts of vitamin D thus breast-fed infants receiving less than 500 mL of formula should be supplemented with vitamin D: Abidec and Dalivit are two paediatric multivitamin preparations, both containing colecalciferol 400 IU.
For the treatment of simple nutritional vitamin D deficiency oral doses of either colecalciferol or ergocalciferol, 10 000 units daily or 60 000 units weekly, should be given for 12 weeks. Infants and children should receive between 1000 and 5000 units of vitamin D3 daily, depending on age (usually ergocalciferol), for 12 weeks. Where there are concerns with regards to compliance, ‘Stoss’ therapy – a single dose of intramuscular ergocalciferol 500–000 units – can be given. Nutritional vitamin D insufficiency can be treated with 800–1000 units daily for 12 weeks. 25(OH)-vitamin D3 levels should be measured after 12 weeks of treatment. Alfacalcidol should not be given for the treatment of vitamin D deficiency as it does not replete vitamin D stores.
Vitamin D deficiency resulting from intestinal malabsorption or chronic liver disease usually requires vitamin D in pharmacological doses, e.g. ergocalciferol tablets up to 50 000 units daily. The maximum antirachitic effect of vitamin D occurs after 1–2 months, and the plasma calcium concentration reflects the dosage given days or weeks before. Frequent changes of dose are therefore not required. Vitamin D deficiency resulting from chronic renal failureis discussed below (see renal osteodystrophy).
Epileptic patients taking enzyme-inducing drugs long term can develop osteomalacia (adults) or rickets (children). This may arise from the accelerated metabolism, increasing vitamin D breakdown and causing deficiency, or from inhibition of one of the hydroxylations that increase biological activity.
Osteoporosis
Calcitriol is licensed for the management of post-menopausal osteoporosis (see below).
Hypoparathyroidism
The hypocalcaemia of hypoparathyroidism requires 1000–1500 mg of elemental calcium daily in divided doses as well as vitamin D. Ergocalciferol may be required in doses up to 100 000 units daily to achieve normocalcaemia, but the dose is difficult to titrate and hypercalcaemia from overdose may take weeks to resolve. Alfacalcidol (0.5–2.0 micrograms daily) or calcitriol (0.5–1.0 micrograms daily) are therefore preferred, as their rapid onset and offset of action makes for easier control of plasma calcium levels.
Psoriasis
Calcipotriol and tacalcitol are vitamin D analogues available as creams or ointments for the treatment of psoriasis (see p. 269).
Renal osteodystrophy
(See below.)
Adverse effects
Vitamin D toxicity has been reported in children accidentally overdosed on vitamin D supplements. Symptoms of overdosage are due mainly to an excessive increase in plasma calcium concentration and include anorexia, nausea and vomiting, diarrhoea, constipation, weight loss, polyuria and thirst. 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 form. Recent research has suggested that the safe upper limit of vitamin D therapy be revised. It was previously considered dangerous to exceed 10 000 units daily of vitamin D in an adult for more than about 12 weeks; however, it has now become apparent that such doses are required to render a vitamin D-deficient individual replete. In general, use of vitamin D at pharmacological doses requires monitoring of plasma calcium.
Treatment of calcium and bone disorders
Hypocalcaemia
In acute hypocalcaemia requiring systemic therapy, give a slow intavenous infusion of 10 mL of 10% calcium gluconate injection over 10 min. This should not be given at a faster rate because of the risk of cardiac arrhythmias and arrest. Correction of hypocalcaemia is temporary and this should be followed by a continuous intravenous infusion containing ten 10 mL ampoules of 10% calcium gluconate in 1 L of 0.9% saline given at an initial infusion rate of 50 mL/h. Plasma calcium should be monitored and the rate adjusted accordingly. Oral calcium therapy should be initiated meanwhile and the intravenous infusion stopped once the oral agents take effect. Avoid infusing with solutions containing bicarbonate or phosphate, which cause calcium to precipitate. Intramuscular injection is contraindicated as it is painful and causes tissue necrosis. Calcium glubionate (Calcium Sandoz) can be given by deep intramuscular injection in adults. Concurrent hypomagnesaemia should be corrected as hypocalcaemia is resistant to treatment without normal serum magnesium levels.
Treatment of chronic hypocalcaemia is with 1500–2000 mg of oral elemental calcium daily in divided doses, as either calcium carbonate or calcium citrate. Additional treatment depends on the cause. Hypocalcaemia secondary to vitamin D deficiency should be treated with vitamin D as described above and there are preparations which combine calcium tablets with colecalciferol. Hypocalcaemia secondary to hypoparathyroidism requires alfacalcidol or calcitriol as PTH is required for hydroxylation of 25-hydroxy-vitamin D3, thus ergocalciferol or colecalciferol have reduced efficacy.
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, and it is advisable to avoid intravenous calcium administration in any patient taking 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 hyperkalaemia in acute renal failure may be to an extent counteracted by 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/L (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, 500 mL 0.9% saline should be given intravenously over 4 h and then adjusted to maintain urine output at 100-150 mls/hour until the plasma Ca2 + level falls below 3.0 mmol/L and the oral intake is adequate. The regimen requires careful attention to fluid and electrolyte balance, particularly in patients with renal insufficiency secondary to hypercalcaemia or heart failure who are unable to excrete excess sodium. The use of furosemide to enhance renal Ca2 + excretion has been largely abandoned owing to the exacerbation of electrolyte disturbances and the increased availability of newer agents.
• Bisphosphonates are the agents of choice in moderate to severe hypercalcaemia, There are a number of bisphosphonates licensed for this indication but pamidronate and zoledronic acid are the most widely used agents. Pamidronate2 is infused according to the schedule in Table 39.1; it is active in a wide variety of hypercalcaemic disorders. A fall in the serum calcium concentration begins within the first day, reaches a nadir in 5–6 days and lasts for 20–30 days. Zoledronic acid has the advantage of being more potent and it can be administered over a shorter time (4 mg over 15 min versus 2 h). It is a convenient regimen for patients with hypercalcaemia of malignancy where repeat courses may be required every 3–4 weeks.
• Calcitonin. When the hypercalcaemia is at least partly due to mobilisation from bone, calcitonin (4 units/kg) can be used to inhibit bone resorption, and may enhance urinary excretion of calcium. The effect develops in a few hours but responsiveness is lost over a few days owing to tachyphylaxis. Calcitonin is not as effective as the bisphosphonates; however, its shorter onset of action makes it a valuable agent for initial management of hypercalcaemia until the peak onset of action of the bisphosphonate at 2–4 days.
• An adrenocortical steroid, e.g. prednisolone 20–40 mg/day orally, is effective in particular situations; it reduces the hypercalcaemia of hypervitaminosis D (which is due to excessive intestinal absorption of calcium either secondary to intoxication or granulomatous disease, e.g. sarcoidosis). Corticosteroid may be effective in the hypercalcaemia of malignancy where the disease itself is responsive, e.g. myeloma of lymphoma. Patients with hyperparathyroidism do not respond.
• Dialysis is quick and effective and is likely to be needed in severe cases or in those with renal failure.
Table 39.1 Treatment of hypercalcaemia with disodium pamidronate
|
Calcium (mmol/L) |
Pamidronate (mg) |
|
< 3.0 |
15–30 |
|
3.0–3.5 |
30–60 |
|
3.5–4.0 |
60–90 |
|
> 4.0 |
90 |
Infuse slowly, e.g. 30 mg in 250 mL 0.9% saline over 1 h. Expect a response in 2–4 days.
The above measures are only temporary, giving time to tackle the cause.
Longer-term treatment
Sodium cellulose phosphate
(Calcisorb) is an oral ion exchange substance with a particular affinity for calcium which is bound in the gut, and the complex eliminated in the faeces. It is effective for patients who over-absorb dietary calcium and develop hypercalciuria and renal stones.
Inorganic phosphate
e.g. sodium acid phosphate (Phosphate Sandoz), taken orally, also binds calcium in the gut. It is of particular use for hypercalcaemia resulting from increased intestinal absorption of calcium, e.g. vitamin D intoxication, or increased calcitriol production (as seen with chronic granulomatous disease).
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. 463.
Parathyroid hormone
Parathyroid hormone (PTH) acts chiefly on the kidney, increasing renal tubular reabsorption of calcium and excretion of phosphate; it increases calcium absorption from the gut, indirectly, by stimulating the renal synthesis of 1α,25-vitamin D (see above and Fig. 39.1). PTH 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 concentration (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 osteoclasts) to reduce the rate of bone turnover, and on the kidney to reduce reabsorption of calcium and phosphate. It is obtained from natural sources (pork, salmon, eel) or synthesised. The t½ varies according to source; the human t½ 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 (subcutaneously, intramuscularly or intranasally) for Paget's disease of bone (relief of pain, and compression of nerves, e.g. auditory cranial), metastatic bone cancer pain, post-menopausal osteoporosis, and for initial control of hypercalcaemia (see above).
Adverse effects
include allergy, nausea, flushing and tingling of the face and hands.
Bisphosphonates
Bisphosphonates are synthetic, non-hydrolysable analogues of pyrophosphate (an inhibitor of bone mineralisation) 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. There are two classes of bisphosphonates: nitrogen containing (alendronate, risedronate, ibandronate, pamidronate and zoledronate) and non-nitrogen containing (clodronate, etidronate and tiludronate).
Actions
These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces, are imbibed by bone-resorbing osteoclasts, inhibit their function and cause osteoclast apoptosis. An additional action may be to stimulate bone formation by osteoblasts, but the therapeutic utility of bisphosphonates rests on their capacity to inhibit bone resorption.
Bisphosphonate binding to hydroxyapatite crystals can, in high doses, inhibit bone mineralisation (potentially causing osteomalacia), an effect that is unrelated to their anti-resorptive efficacy. This disadvantageous effect, prominent with non-nitrogen containing bisphosphonates, is less with newer nitrogen containing members.
Pharmacokinetics
Bisphosphonates are poorly absorbed after 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 intravenously. One trial has shown that bioavailability of oral bisphosphonates are greatest if the drug is administered in the early morning, before the first meal of the day.
Indications
• Osteoporosis (see below).
• Paget's disease of bone (see below).
• Hypercalcaemia due to malignancy (see above) and metastatic bone disease Bisphosphonates reduce skeletal fractures and loss of skeletal integrity associated with metastatic bone disease. The best evidence for such a benefit comes from use of intravenous zoledronic acid in patients with metastatic lung cancer, prostate cancer or breast cancer. There is no evidence that bisphosphonates can prevent bone metastases in these cancers.
Adverse effects
of orally administered bisphosphonates include gastrointestinal disturbances, and oesophageal irritation – a particular problem with alendronate. This drug should be taken at least 30 min before food, with the patient remaining erect during this period. Oral bisphosphonates should not be used in patients with Barrett's oesophagus. Disturbances of calcium and mineral metabolism (e.g. vitamin D deficiency, PTH dysfunction) should be corrected before starting a bisphosphonate. Increased bone pain (as well as relief) and fractures (high dose, prolonged use only) can occur due to bone demineralisation. Potential nephrotoxicity is a concern with bisphosphonate therapy although zoledronic acid has been used in patients with severe renal impairment. Intravenous administration can cause acute 'flu-like symptoms (fever, myalgia, malaise). Repeated courses of intravenous bisphosphonates for treatment of hypercalcaemia of malignancy is associated with increased risk of osteonecrosis of the jaw in patients with metastatic bone disease or multiple myeloma. The risk may be slightly greater with zoledronic acid compared with pamidronate.
Osteoporosis
Osteoporosis is a disease characterised by increased skeletal fragility, low bone mineral density (less than 2.5 standard deviations below the mean for young people; Fig. 39.2) and deterioration of bone microarchitecture. It occurs most commonly in post-menopausal women and patients taking long-term corticosteroid. Exclude underlying causes such as hyperthyroidism, hyperparathyroidism and hypogonadism (in both sexes) before treatment is initiated.
Fig. 39.2 Bone mineral density of the lumbar spine in women. The shaded area represents two standard deviations above and below the mean for bone mineral density.
Post-menopausal osteoporosis is due to gonadal deficiency; it can be prevented. In the UK, one in four women in their sixties and one in two in their seventies experience an osteoporotic fracture. Prevention with combined oestrogen–progestogen therapy was widespread until data from the UK Women's Health Initiative showed an increased risk of breast cancer, stroke and venous thromboembolic disease.
Now, patients at risk of osteoporosis are advised to increase daily exercise, stop smoking and optimise diet to ensure sufficient calories and an adequate intake of calcium and vitamin D. The recommended daily calcium intake of 1500 mg can be achieved with calcium supplementation (500–1000 mg in divided doses daily). Vitamin D supplementation with ergocalciferol can be given to ensure a daily intake of 800 IU.
Pharmacotherapy
Bisphosphonates
are the first-line treatment for post-menopausal osteoporosis. Four bisphosphonates (alendronate, etidronate, risedronate, ibandronate) are currently licensed in the UK for the treatment of osteoporosis (zoledronate is also effective). Alendronate (10 mg once daily or 70 mg once weekly) and risedronate (5 mg daily or 35 mg once weekly) are effective both at preventing post-menopausal osteoporosis and at reducing hip and vertebral fracture incidence. Ibandronate is effective as a once-monthly preparation, or intravenously every 3 months for those unable to tolerate oral bisphosphonates. Ibandronate has been shown to have efficacy in reducing the risk of new vertebral fractures; however, randomised controlled trials conducted with ibandronate did not have sufficient power to demonstrate efficacy in hip fractures All post-menopausal women with a history of hip or verterbral fracture, or with osteoporosis based on bone mineral density measurement should receive bisphosphonate therapy.
Selective oestrogen receptor modulator
Raloxifene is effective for both the prevention and treatment of osteoporosis; it reduces the incidence of vertebral but not of non-vertebral fractures. It is probably less effective than bisphosphonates but no direct comparisons have been made. Raloxifene reduces the risk of breast cancer (see p. 517) but there is a three-fold increase in the risk of venous thromboembolic disease.
Parathyroid hormone
PTH increases bone resorption but the synthetic PTH, teriparatide, administered daily (20 micrograms, subcutaneously), stimulates bone formation and reduces the risk of vertebral and non-vertebral fractures. However, in a large randomised controlled trial, teriparatide alone did not reduce the risk of hip fracture. It is indicated for severe post-menopausal osteoporosis or where bisphosphonates have proved to be ineffective.3
Oestrogen–progestogen
Though now out of favour (see above), oestrogen–progestogen therapy may yet be indicated in a small proportion of post-menopausal women with documented osteoporosis or osteopenia, or those at increased risk of osteoporosis, who do not have a personal or family history of breast cancer or cardiovascular disease and are unable to tolerate alternative anti-resorptive agents.
Selective oestrogen-receptor modulator (SERM)
Raloxifene is an oral SERM that decreased the risk of vertebral fractures by 40–49%, (?impact on non-vertebral fractures).
Calcitonin
The mode of administration (subcutaneous, intramuscular or nasal) and possible tachyphylaxis make calcitonin a less suitable choice for treatment of osteoporosis. Additionally, the increase in bone mineral density and reduction in fracture risk is small compared with alternative agents.
Fracture (usually assessed by vertebral and hip fractures) is the only important outcome of osteoporosis.
Corticosteroid-induced osteoporosis
Most bone loss occurs during the first 6–12 months of use. Patients taking the equivalent of prednisolone 7.5 mg or more each day for more than 3 months should be considered for prophylactic treatment, and it is mandatory in those aged over 65 years. All patients should receive vitamin D and calcium supplements. Bisphosphonates are first line for both prophylaxis and treatment; calcitonin may be considered where bisphosphonates are contraindicated or not tolerated.
Chronic kidney disease – mineral bone disorder (CKD-MBD)4
The pathogenesis of CKD-MBD is complex reflecting the combined contribution of hyperphosphataemia, vitamin D deficiency and secondary hyperparathyroidism. Vitamin D deficiency in chronic renal failure results from reduced synthesis of calcitriol. High serum phosphate and high levels of the phosphaturic hormone fibroblast growth factor-23 (FGF-23) both suppress 1α-hydroxylase activity and this, combined with reduced levels of renal 1α-hydroxylase, results in reduced 1α,25-dihydroxyvitamin D3 synthesis. Failure of 1α,25-dihydroxyvitamin D3 to occupy receptors on the parathyroid glands leads to increased release of PTH. In addition, reduced calcitriol results in decreased intestinal absorption of calcium and the subsequent hypocalcaemia further stimulates PTH release. The aim of treatment is to maintain normal serum phosphate and calcium levels and suppress secondary hyperparathyroidism in order to prevent disordered bone metabolism. An elevated PTH is the earliest sign of disordered bone and mineral metabolism and is usually apparent once the glomerular filtration rate (GFR) falls below 60 mL/min/1.73 m2 (CKD Stage 3).
Phosphate binders are the first step in the management of hyperphosphataemia and prevention of renal osteodystrophy. The aim of treatment has been to prevent secondary hyperparathyroidism; however, recent observational studies have suggested a link between hyperphosphataemia and adverse clinical outcomes, possible secondary to accelerated vascular calcification, providing aditional rationale for normalising serum phosphate levels. Calcium-based phosphate binders, such as calcium carbonate and calcium acetate, are the most commonly used agents with similar efficacy. Newer non calcium-based phosphate binders include the anion exchange resins sevelamer hydrocholorideand sevelamer carbonate. These have a similar phosphate lowering effect compared to calcium based agents but are associated with reduced risk of hypercalcaemia. Sevelamer hydrochloride may worsen metabolic acidosis thus sevelamer carbonate is the preferred agent. Lanthanum carbonate is a non-aluminium, non-calcium-based phosphate binder with similar efficacy to calcium-based phosphate binders. There are fewer data from good quality, large clinical trials evaluating lanthanum; short-term trials suggest increased adverse effects compared with other binders.
Phosphate binders alone may not be sufficient to control phosphate levels and prevent secondary hyperparathyroidism. Vitamin D analogues or the calcimimetic cinacalcet are instituted once PTH levels rise. There is a lack of evidence and thus consensus with regards to the ‘optimum’ PTH levels in CKD. US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend instituting therapy when PTH levels rise above 75, 110 and 300 picograms/mL for CKD 3, 4, and 5 respectively, despite optimal phosphate binder therapy, i.e. to achieve the aim of preventing hyperparathyroidism, rather than treating established osteodystrophy.However, the target PTH remains uncertain as there is currently no good evidence that normalisation of PTH levels in adults results in reduced morbidity and mortality. Recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines reflect this uncertainty and do not set target PTH levels for pre-dialysis patients.
Calcitriol and vitamin D analogues (e.g. alfacalcidol, above) inhibit PTH gene transcription by the vitamin D receptor and will also increase the serum concentration of Ca2+, which acts on the parathyroid Ca2 + receptor further to inhibit PTH secretion. Note that vitamin D analogues, by increasing intestinal phosphate absorption, can worsen hyperphosphataemia. Because of the increase in serum calcium and phosphate that can occur with vitamin D therapy, cinacalcet is preferred in patients with serum phosphate or calcium levels at the upper limit of normal. Cinacalcet is a calcium analogue that binds to the calcium sensing receptor (CaSR) in the parathyroids and increases the sensitivity of the receptor to Ca (it is the only example of an allosteric agonist in clinical use). Calcium signalling through the CaSR is the main determinant of PTH secretion. It is indicated for patients with end-stage renal disease with secondary hyperparathyroidism refractory to standard treatment.
Osteomalacia
Osteomalacia is due to primary or secondary vitamin D deficiency (see above).
Paget's disease of bone
This disease is characterised by increased bone turnover (resorption and formation) – as much as 50 times normal. The result is large, vascular, deformed and painful bones that fracture.
Bisphosphonates
The newer nitrogen-containing bisphosphonates (pamidronate, zoledronic acid, risedronate, alendronate) are the agents of choice. These bisphosphonates suppress bone turnover without impairing bone mineralisation. Alendronateand risedronate are administered orally whereas pamidronate and zoledronic acid are given intravenously. Their response is dose related and biochemical remission (normalisation of alkaline phosphatase) after a course may last for up to 2 years. Supplementation with calcium and vitamin D is required to prevent hypocalcaemia.
Calcitonin (which also inhibits bone resorption) has been largely superseded by the bisphosphonates but retains usefulness because it reduces bone blood flow before surgery.
Vitamin E: tocopherol
The functions of vitamin E may be to take up (scavenge) the free radicals generated by normal metabolic processes and by substances in the environment, e.g. hydrocarbons. This prevents free radicals from attacking polyunsaturated fats in cell membranes with resultant cellular injury.
A deficiency syndrome is recognised, including peripheral neuropathy with spinocerebellar degeneration, and a haemolytic anaemia in premature infants.
α-Tocopheryl acetate (Ephynal) pharmacotherapy may benefit the neuromuscular complications of congential cholestasis and abetalipoproteinaemia.
Vitamin K
(See p. 483)
Guide to further reading
Armitage J.M., Bowman L., Clarke R.J., et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. J. Am. Med. Assoc.. 2010;303:2486–2494.
Bone H.G., Hosking D., Devogelaer J.P., et al. Ten years' experience with alendronate for osteoporosis in post-menopausal women. N. Engl. J. Med.. 2004;350:1189–1199.
El-Kadiki A., Sutton A.J. Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. Br. Med. J.. 2005;330:871–876.
Farford B., Prescutti R.J., Moraghan T.J. Nonsurgical management of primary hyperparathyroidism. Mayo Clin. Proc.. 2007;82:351–355.
Holick M.F. Vitamin D deficiency. N. Engl. J. Med.. 2007;357:266–281.
Kalantar-Zadeh K., Shah A., Duong U., et al. Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals. Kidney Int.. 2010;78(Suppl. 117):S10–S21.
Lambrinoudaki I., Christodoulakos G., Botsis D. Bisphosphonates. Ann. N. Y. Acad. Sci.. 2006;1092:403–407.
Osterhues A., Holzgreve W., Michels K.B. Shall we put the world on folate? Lancet. 2009;374:959–961.
Rachner T.D., Khosla S., Hofbauer L.C. Osteoporosis: now and the future. Lancet. 2011;377:1276–1287.
Ralston S.H., Langston A.L., Reid I.R. Pathogenesis and management of Paget's disease of bone. Lancet. 2008;372:155–163.
Rosen C.J. Vitamin D insufficiency. N. Engl. J. Med.. 2011;364:248–254.
Sambrook P., Cooper C. Osteoporosis. Lancet. 2006;367:2010–2018.
Steddon S.J., Cunningham J. Calcimimetics and calcilytics – fooling the calcium receptor. Lancet. 2005;365:2237–2239.
Whyte M.P. Paget's disease of bone. N. Engl. J. Med.. 2006;355:593–600.
1 The term was coined by Casimir Funk in 1912 from the Latin vita meaning life and the (mistaken) belief that the organic compounds involved were amines. See: Hardy A 2004 Historical keywords. Vitamin. Lancet 364:323.
2 Formerly called aminohydroxypropylidenediphosphonate disodium, APD.
3 In a pivitol 19-month trial, teriparatide increased bone mineral density in the spine and femoral neck, and rates of new vertebral fractures and non-vertebral fractures were 5% and 6.3% compared with 14.3% and 9.7% respectively for placebo (Neer R M, Arnaud C D, Zanchetta J R et al 2001 Effect of parathyroid hormone (1–34) on fractures and bone mineral density in post-menopausal women with osteoporosis. New England Journal of Medicine 344(19):1431–1441).
4 This term refers to the various disorders of bone and mineral metabolism that occur as a result of chronic kidney disease, i.e. hyperparathyroid bone disease, osteomalacia, osteoporosis and osteosclerosis. Also referred to as renal osteodystrophy.