Drugs Affecting Calcium Balance

 Chapter - 24 

Drugs Affecting Calcium Balance

CALCIUM

After C, O, H and N, calcium is the most abundant body constituent, making up about 2% of body weight: 1–1.5 kg in an adult. Over 99% of this is stored in bones, the rest being distributed in plasma and all tissues and cells. Calcium serves important physiological roles

Physiological roles

• Calcium controls excitability of nerves and muscles and regulates permeability of cell membranes. It also maintains integrity of cell membranes and regulates cell adhesion. 

• Ca2+ ions are essential for excitation-contraction coupling in all types of muscle and excitation-secretion coupling in exocrine and endocrine glands, release of transmitters from nerve ending and other release reactions. 

• Intracellular messenger for hormones, autacoids and transmitters. 

• Impulse generation in heart—determines level of automaticity and A-V conduction. 

• Coagulation of blood.

• Structural function in bone and teeth.

Plasma calcium level It is precisely regulated by 3 hormones almost exclusively devoted to this function, viz. parathormone (PTH), calcitonin and calcitriol (active form of vit D). These regulators control its intestinal absorption, exchange with bone and renal excretion as summarized in Fig. 24.1. In addition, several other hormones, metabolites and drugs influence calcium homeostasis (see box).

Normal plasma calcium is 9–11 mg/dl. Of this about 40% is bound to plasma proteins—chiefly albumin; 10% is complexed with citrate, phosphate and carbonate in an indissociable form; the remaining (about 50%) is ionized and physiologically important. For example, in hypoalbuminemia, total plasma calcium may be low but the concentration of Ca2+ ion is usually normal. Acidosis Favours and alkalosis disfavors ionization of calcium: hyperventilation precipitates tetany and laryngospasm in calcium deficiency by reducing ionization.

Calcium turnover Major fraction of calcium in the bone is stored as crystalline hydroxyapatite deposited on the organic bone matrix osteoid, while a small labile pool is in dynamic equilibrium with plasma. Even the fully laid down parts of the bone undergo constant remodeling by way of two closely coupled but directionally opposite processes of resorption and new bone formation (Fig. 24.2). Millions of tiny remodeling units are working on the surface of bone trabeculae and Haversian canals to dig micropigs by osteoclastic activity and then repair by osteoblastic activity in which first collagen and other proteins (osteoid) are deposited followed by mineralization; the full cycle taking 4–6 months. Diet, exercise, several hormones and drugs regulate the number and efficiency of bone remodeling units at any given time. Remodeling deficits accumulate over lifetime to account for age related bone loss, the pace of which can be retarded or accelerated by modulating the above listed influences. Estrogen lack after menopause mainly causes loss of trabecular bone, particularly affecting vertebrae, wrist bones and femoral neck. Minimal trauma/compression fractures are most common at these sites.

Absorption and excretion Calcium is absorbed by facilitated diffusion from the entire small intestine as well as from duodenum by a carrier mediated active transport under the influence of vit D. Phytates, phosphates, oxalates and tetracyclines complex Ca2+ in an insoluble form in the intestines and interfere with absorption. Glucocorticoids and phenytoin also reduce calcium absorption.

All ionized calcium is filtered at the glomerulus and most of it is reabsorbed in the tubules. Vit D increases and calcitonin decreases proximal tubular reabsorption, while PTH increases distal tubular reabsorption of Ca2+. About 300 mg of endogenous calcium is excreted daily: half in urine and half in faces. To maintain calcium balance, the same amount has to be absorbed in the small intestine from the diet. Because normally only 1/3rd of ingested calcium is absorbed, the dietary allowance for calcium is 0.8–1.5 g per day. However, calcium deficiency and low dietary calcium increases fractional calcium absorption.

Thiazide diuretics impede calcium excretion by facilitating tubular reabsorption.

Preparations

• Calcium chloride (27% Ca): is freely water soluble but highly irritating—tissue necrosis occurs if it is injected i.e. or extravasation takes place during i.e. injection. Orally also the solution irritates.

• Calcium gluconate (9% Ca): is available as 0.5 g and 1 g tablets and 10% injection (5 ml amp.) It is nonirritating to g.i.t. and the vascular endothelium—a sense of warm this produced on i.e. injection: extravasation should be guarded. It is the preferred injectable salt. 

• Calcium lactate (13% Ca): is given orally, nonirritating and well tolerated.

• Calcium dibasic phosphate (23% Ca): is insoluble, reacts with HCl to form soluble chloride in the stomach. It is bland; used orally as antacid and to supplement calcium. 

• Calcium carbonate (40% Ca): insoluble, tasteless and nonirritating. It has been used as an antacid—reacts with HCl to form chloride which may be absorbed from the intestines.

Side effects Calcium supplements are usually well tolerated; only gain side effects like constipation, bloating and excess gas (especially with cal. carbonate) have been reported.

Some combined formulations

• CALCINOL-RB: Cal. carb 0.375 g, Cal. Phos 75 mg + vit D3 250 IU tab.

• CALCIUM-SANDOZ: Cal. gluco-bionate 137.5 mg/ml inj. 10 ml amp., also tabs containing cal. carbonate 650 mg. KALZANA: Cal. dibasic phot 430 mg + Vit C and D3 200 IU tab, also syrup: Cal. gluconate 300 mg, Cal. latipinnate 1.1 g, Cal. phot. 75 mg per 5 ml, containing Vit A, C, niacinamide and D3 200 IU

• OSTOCALCIUM: Cal. phot 380 mg + Vit D3 400 IU tab, also syrup: Cal. phos 240 mg per 5 ml containing Vit D3 200 IU and B12.

• SHELCAL: Cal. carb. 625 mg (eq 250 mg elemental cal), Vit D3 125 IU tab and per 5 ml syr.

• MACALVIT: Cal. carb. 1.25 g, cholecalciferol 250 IU tab; Cal. gluconate 1.18 g, Cal. latipinnate 260 mg + Vit D3 100 IU per 5 ml syr.

• CALCIMAX: Cal. carb. (150 mg Cal), dibasic cal. phots. (23.3 mg Cal) with magnesium, zinc and vit D3 200 IU tab.; also syrup cal. carb. (150 mg Cal) with magnesium, zinc and vit D3 200 IU per 5 ml syrup.

Use

1. Tetany For immediate treatment of severe cases 10–20 ml of Cal. gluconate (elemental calcium 90–180 mg) is injected i.v. over 10 min, followed by slow i.v. infusion. A total of 0.45-0.9 g calcium (50 to 100 ml of cal. gluconate solution) over 6 hours is needed for completely reversing the muscle spasms. Supportive treatment with i.v. fluids and oxygen inhalation may be required. Long-term oral treatment to provide 1–1.5 g of calcium daily is instituted along with vit. D. Milder cases need oral therapy only.

• As dietary supplement especially in growing children, pregnant, lactating and menopausal women. The dietary allowance recommended by National Institute of Health (1994) is

• Children 1–10 yr : 0.8–1.2 g 

• Young adult 11–24 yr, pregnant and lactating women: 1.2–1.5 g 

• Men 25–65 yr, women 25–50 yr and 51–65 yr if taking HRT: 1.0 g 

• Women 51–65 yr not taking HRT, everyone > 65 yr : 1.5 g

Calcium supplement can reduce bone loss in predisposed women as well as men. It is often given to fracture patients, but if diet is adequate this does not accelerate healing.

• Osteoporosis In the prevention and treatment of osteoporosis with HRT/raloxifene/ alendronate, it is important to ensure that calcium deficiency does not occur. Calcium + vit D3 have adjuvant role to HRT/raloxifene/bisphosphonates in prevention and treatment of osteoporosis.

• However, the efficacy of calcium ± vit D supplements alone in increasing bone mass or preventing fractures among menopausal women/elderly men is controversial. While several studies have reported a reduction in fracture risk, others have found no benefit. In the recently concluded 7-year prospective WHI study involving >36000 postmenopausal women (51-79 years), the overall risk of fractures was the same in the calcium (1 g/day) + vit D (400 IU/ day) group as in the placebo group, though the bone mineral density at the hip was 1% higher in the treated group. Certain subgroups of osteoporotic subjects may benefit from calcium supplements, but the benefit appears to be marginal and limited to cortical bone loss only. 

• Empirically, Cal. gluconate i.v. has been used in dermatoses, paresthesia's, weakness and other vague complaints. Any benefit is probably psychological due to warmth and other subjective effects produced by the injection.

• As antacid (see Ch. 46).

PARATHYROID HORMONE

(Parathormone)

• Vassal and Generali (1900) were the first to perform selective parathyroidectomy (without removing thyroids) and found that it produced tetany and death. MacCallum

• and Voegtlin in 1909 established this to be due to decrease in plasma calcium levels; parathormone (PTH) was isolated in 1925.

• PTH is a single chain 84 amino acid polypeptide, MW 9500. It is synthesized as preprophase, the excess amino acids are split off in two steps and it is then stored in intracellular vesicles. Secretion of PTH is regulated by plasma Ca2+ concentration through a calcium-sensing receptor (Car), that is a G-protein coupled receptor on the surface of parathyroid cells. There is no trophic hormone for it. Fall in plasma Ca2+ induces PTH release and rise inhibits secretion by decreasing cAMP in the parathyroid cells. Agents that increase cAMP cause PTH release, but direct activation of protein kinase C by fall in Ca2+ concentration is more important physiologically. Prolonged hypocalcemia causes hypertrophy and hyperplasia of parathyroids, while sustained hypercalcemia has the opposite effect. Changes in phosphate concentration in plasma affect PTH secretion indirectly by altering Ca2+ concentration. The active form of vit. D calcitriol inhibits expression of PTH gene in parathyroid cells. PTH is rapidly degraded in liver and kidney; its plasma t½ is 2–5 min.

Actions

• PTH increases plasma calcium levels by:

• Bone PTH promptly increases resorption of calcium from bone. This is the most prominent action of PTH—exerted by increasing the number of bone remodeling units and activating osteoclasts when high concentrations are present continuously. Since bone resorption is followed by new bone deposition, this is also promoted by PTH: increased bone formation occurs when PTH is given intermittently and in low doses.

• Kidney PTH increases calcium reabsorption in the distal tubule and provides moment to moment regulation of calcium excretion. It also promotes phosphate excretion which tends to supplement the hypercalcemic effect. However, grossly increased plasma calcium level occurring in hyperparathyroidism overrides the direct action on tubules and calcium excretion in urine is actually increased. The converse occurs in hypoparathyroidism.

• Intestines PTH has no direct effect on calcium absorption but increases it indirectly by enhancing the formation of calcitriol (active form of vit D) in the kidney by activating 1αhydroxylase. Calcitriol then promotes intestinal absorption of calcium.

• PTH decreases calcium levels in milk, saliva and ocular lens—may be responsible for development of cataract in hypoparathyroidism.

• Mechanism of action The PTH receptor is a G protein coupled receptor which on activation increases cAMP formation and intracellular Ca2+ in target cells. In bone, the target cell is the osteoblast because PTH receptors are not expressed on the surface of osteoclasts. Acting on the osteoblast, PTH induces a factor ‘Receptor for activation of nuclear factor-κB-ligand’ (RANKL) which diffuses and combines with RANK on osteoclast precursors and transforms them into osteoclasts as well as activates osteoclasts (Fig. 24.2). Moreover, birth rate of bone remodeling units into which osteoclasts are recruited is enhanced. Formation of the remodeling pit is followed by osteoblastic deposition of new bone into it. PTH enhances proliferation and differentiation of preosteoclasts and deposition of osteoid as well. Bone resorption predominates when high concentrations of PTH are present continuously, but intermittent exposure to low concentrations has the opposite effect.

• Hypoparathyroidism Manifestations are:

• Low plasma calcium levels, tetany, convulsions, laryngospasm, paresthesia's, cataract and psychiatric changes. Pseudohypoparathyroidism occurs due to reduced sensitivity of target cells to PTH caused by a mutant G protein that couples PTH receptor activation to cAMP generation in target cells.

• Hyperparathyroidism It is mostly due to parathyroid tumor. It produces—

• Hypercalcemia, decalcification of bone—deformities and fractures (osteitis fibrosa general Isata), metastatic calcification, renal stones, muscle weakness, constipation and anorexia.

• Treatment is surgical removal of the parathyroid tumor. When this is not possible—low calcium, high phosphate diet with plenty of fluids is advised.

• Cinacalcet, It activates the Ca2+ sensing receptor (Car) in the parathyroids and blocks PTH secretion. It is indicated in secondary hyperparathyroidism due to renal disease and in parathyroid tumor.

• Use PTH is not used in hypoparathyroidism because plasma calcium can be elevated and kept in the normal range more conveniently by vit D therapy. PTH has to be given parenterally, while vit D can be given orally. Vit D is cheap. However, recombinant human PTH (1–84 amino acid) has been produced and is being clinically tested.

• Teriparatide This recombinant preparation of 1–34 residues of amino terminal of human PTH has been recently approved for the treatment of severe osteoporosis. It    duplicates all the actions of long (1–84) PTH. Injected s.c. once daily, it has been found to increase bone mineral density in osteoporotic women. The effect was faster and more marked than that produced by estrogens and bisphosphonates (BPNs). Teriparatide is the only agent which stimulates bone formation, whereas the other two only check bone resorption. In clinical trials it was found to be equally or more effective than estrogens and BPNs in reducing risk of vertebral as well as non-vertebral fractures. Its plasma t½ is 1 hr; given once daily only intermittent action is produced and bone forming action predominates over bone resorbing action. High cost and need for daily such injections are the limitations.

• Diagnostic use To differentiate pseudo from true hypoparathyroidism: teriparatide is given i.v.: if plasma calcium level fails to rise, then it is pseudohypoparathyroidism.

CALCITONIN

• Calcitonin is the hypocalcemia hormone discovered by Copp in 1962. It is a 32 amino acid single chain polypeptide (MW 3600) produced by parafollicular ‘C’ cells of thyroid. Parathyroids, thymus and cells of medullary carcinoma of thyroid also contain calcitonin.

• Synthesis and secretion of calcitonin is regulated by plasma Ca2+ concentration itself: rise in plasma Ca2+ increases, while fall in plasma Ca2+ decreases calcitonin release. However, the physiological role of calcitonin in regulating plasma Ca2+ appears to be minor. The plasma t½ of calcitonin is 10 min, but its action lasts for several hours.

Actions

• The actions of calcitonin are generally opposite to that of PTH. It inhibits bone resorption by direct action on osteoclasts—decreasing their ruffled surface which forms contact with the resorptive pit. Whether it also promotes calcium deposition by osteoblasts is not certain. The hypocalcaemic action of calcitonin lasts ~8 hours.

• Calcitonin inhibits proximal tubular calcium and phosphate reabsorption by direct action on kidney. However, hypocalcemia overrides the direct action by decreasing the total calcium filtered at the glomerulus urinary Ca2+ is actually reduced.

• The actions of calcitonin are mediated through a G-protein coupled receptor and increase in cAMP formation, but its target cells are different from that of PTH.

• Preparation and unitage Synthetic salmon calcitonin is used clinically, because it is more potent due to slower metabolism. Human calcitonin has also been produced. 1 IU = 4 μg of standard preparation.

• CALSYNAR, ZYCALCIT: Synthetic salmon calcitonin 100 IU/ml amp. for a.m. or sac injection.

• Adverse effects experienced are nausea, flushing, tingling of fingers, bad taste and allergic reaction. By lowering plasma Ca2+ calcitonin may interfere with the action of digoxin.

Uses

• Hypercalcemic states Hyperparathyroidism, hypervitaminosis D, osteolytic bony metastasis and hypercalcemia of malignancy; 4–8 IU/kg a.m. 6–12 hourly only for 2 days. It acts rapidly within 4 hours, the response peaks at 48 hours and then refractoriness develops. Calcitonin is a relatively weak hypocalcemia drug. Therefore, used only to supplement BPNs initially, because they take 24–48 hours to act.

• Postmenopausal osteoporosis: 100 IU sac or i.e. daily along with calcium and vit D supplements.

• A nasal spray formulation delivering 200 IU per actuation has become available (MIACALCIN NASAL SPRAY 2200 IU in 2 ml). One spray in one nostril daily has been shown to increase bone mineral density in menopausal women. It is less effective than HRT/BPNs. Calcitonin is indicated only when other drugs cannot be given and in women who are menopausal for at least 5 years with definite evidence of osteoporosis. Rhinitis, epistaxis, nasal ulceration and headache are the side effects.

• Paget’s disease 100 U daily or on alternate days produces improvement for few months. Later, resistance usually develops due to production of antibodies. Bisphosphonates are preferred; calcitonin may be used as adjuvant or 2nd line drug.

VITAMIN D

• Vitamin D is the collective name given to antirachitic substances synthesized in the body and found in foods activated by UV radiation.

• D3 : cholecalciferol — synthesized in the skin under the influence of UV rays.

• D2 : calciferol—present in irradiated food— yeasts, fungi, bread, milk.

• D1 : mixture of antirachitic substances found in food—only of historic interest.

• In 1919 it was established that rickets was due to deficiency of a dietary factor as well as lack of exposure to sunlight. McCollum (1922) showed that this fat-soluble dietary factor was different from vit A and its structure was determined in 1935. The interrelation between calciferol and cholecalciferol and their activation in the body has been fully understood only in the 1970s.

• Activation of vit D It takes place in the following manner

• Ergosterol differs from 7-dehydrocholesterol in having an extra double bond between C22–23 and a methyl group at C24. In man vit D2 and D3 are equally active and calcitriol (active form of D3) is

 more important physiologically; 25-OH D3 is released in blood from the liver and binds loosely to a specific vit D binding globulin. The final hydroxylation in kidney is rate limiting and is controlled by many factors. This step is activated or induced by calcium/vit D deficiency as well as by PTH, estrogens and prolactin, while calcitriol inhibits it in a feedback manner.

Thus, vit D should be considered a hormone because:

• It is synthesized in the body (skin); under ideal conditions it is not required in the diet. 

• It is transported by blood, activated and then acts on specific receptors in the target tissues. 

• Feedback regulation of vit D activation occurs by plasma Ca2+ level and by the active form itself.

Actions

• Calcitriol enhances absorption of calcium and phosphate from intestine. This is brought about by increasing the synthesis of calcium channels and a carrier protein for Ca2+ called ‘calcium binding protein’ (Ca BP) or Calbindin. The action of calcitriol is analogous to that of steroid hormones. It binds to a cytoplasmic vitamin D receptor (VDR) → translocate to the nucleus → increase synthesis of specific mRNA → regulation of protein synthesis. Another line of evidence suggests that activation of VDR promotes endocytosis capture of calcium and transports it across the duodenal mucosal cell in vesicular form. At least part of vit D action is quick (within minutes) and, therefore, appears to be exerted by mechanisms not involving gene regulation.

• Calcitriol enhances resorption of calcium and phosphate from bone by promoting recruitment and differentiation of osteoclast precursors in the bone remodeling units, but mature osteoclasts lack VDR. Like PTH, calcitriol induces RANKL in osteoblasts which may then activate the osteoclasts. Osteoblastic cells express VDR and respond to calcitriol by laying down osteoid, but it mainly appears to help bone mineralization indirectly by maintaining normal plasma calcium and phosphate concentration. Its action is independent of but facilitated by PTH.

• Calcitriol enhances tubular reabsorption of calcium and phosphate in the kidney, but the action is less marked than that of PTH. However, in hypervitaminosis D, influence of hypercalcemia overrides the direct action and more calcium is excreted in urine.

• Other actions Actions of calcitriol on immunological cells, lymphokine production, proliferation and differentiation of epidermal and certain malignant cells, neuronal and skeletal muscle function have also been demonstrated.

• Vit D deficiency Plasma calcium and phosphate tend to fall due to inadequate intestinal absorption. As a consequence, PTH is secreted → calcium is mobilized from bone in order to restore plasma Ca2+. The bone fails to mineralize normally in the newly laid area, becomes soft → rickets in children and osteoma Lacia in adults. However, in contrast to osteoporosis, the organic matrix (osteoid) is normal in these conditions.

• Hypervitaminosis D It may occur due to chronic ingestion of large doses (~50,000 IU/day) or due to increased sensitivity of tissues to vit D. Manifestations are due to elevated plasma calcium and its ectopic deposition.

• Hypercalcemia, weakness, fatigue, vomiting, diarrhea, sluggishness, polyuria, albuminuria, ectopic Ca2+ deposition (in soft tissues, blood vessels, parenchymal organs), renal stones or nephrocalcinosis, hypertension, growth retardation in children. Even coma has been reported. Treatment: consists of withholding the vitamin, low calcium diet, plenty of fluids and corticosteroids. Recovery may be incomplete in many cases.

Pharmacokinetics

• Vit D is well absorbed from the intestines in the presence of bile salts, mainly through lymphatics. Absorption of D3 form is somewhat better than that of D2. Malabsorption and steatorrhea interfere with its absorption

• In the circulation, it is bound to a specific α globulin and is stored in the body, mostly in adipose tissues, for many months. It is hydroxylated in the liver to active and inactive metabolites. The t½ of different forms varies from 1–18 days: 25-OHD3, having the longest t½ , constitutes the primary circulating form. Calcitriol is cleared rapidly.

• Metabolites of vit D are excreted mainly in bile.

Unitage and preparations

• μg of cholecalciferol = 40 IU of vit D. The daily requirement varies, depending on exposure to sunlight. It is estimated that if no vit D3 is synthesized in the body, a dietary allowance of 400 IU/day will prevent deficiency symptoms. The forms in which vit D is supplied are—

• Calciferol (Ergocalciferol, vit D2) As solution in oil, filled in gelatin capsules 25,000 and 50,000 IU caps.

• Cholecalciferol (vit D3) As granules for oral ingestion and oily solution for a.m. injection. ARACHITOL 300,000 IU (7.5 mg) and 600,000 IU (15 mg) per ml inj. CALCIROL 60,000 IU in 1 g granules—given at 3–4 weeks intervals, and then every 2–6 months

• Calcitriol 0.25–1 μg orally daily or on alternate days; CALTROL, ROLSICAL, ROCALTROL 0.25 μg cap. CALCI-BEST 1 μg in 1 ml aqueous inj; 0.5–1 μg i.e. on alternate days. Hypercalcemia is the main adverse effect; must be watched for and therapy promptly stopped if plasma Ca2+ rises.

• Alcaide It is 1 α-OHD3—a prodrug that is rapidly hydroxylated in the liver to 1, 25 (OH)2 D3 or calcitriol. Therefore, it does not require hydroxylation at position 1 which is the limiting step in the generation of the active form of vit D, and which takes place in the kidney. As such, it is effective in renal bone disease, vit D dependent rickets, vit D resistant rickets, hypoparathyroidism, etc.— indications for which calcitriol is needed. It is also being used in osteoporosis.

• Alcaide is orally active and clinically equally effective on long term basis to calcitriol. Its metabolic activation in liver does not pose a problem even in severe liver disease.

• Dose: 1–2 μg/day, children < 20 kg 0.5 μg/day. Repeated serum calcium measurements are essential for regulation of maintenance dose. Hypercalcemia should be watched for, and therapy promptly interrupted for few days when it develops.

• ONE ALPHA, ALPHA D3, ALPHADOL 0.25 and 1 μg caps, ALFACAL 0.25, 0.5 μg caps.

• Dihydrotachysterol (DHT) A synthetic analogue of vit D2—less active in antirachitic tests, but directly mobilizes calcium from bone: does not require PTH dependent activation in the kidney—particularly useful in hypoparathyroidism and renal bone disease. Dose: 0.25–0.5 mg/day.

• Combination preparations of vit D are listed in Table 67.2.    

Use

• Prophylaxis (400 IU/day) and treatment (3000–4000 IU/day) of nutritional vit D deficiency which causes rickets in children and osteoma Lacia in adults. Alternatively, 300,000–600,000 IU can be given orally or a.m. once in 2–6 months. Prophylactic treatment may be given in obstructive jaundice, steatorrhea and other conditions which predispose to vit D deficiency.

• Metabolic rickets These are a group of conditions in which tissues do not respond to normal doses of vit D.     

• Vit D resistant rickets: X-linked hereditary disease in which vit D metabolism is normal but calcium and phosphate metabolism is deranged. Administration of phosphate with high dose of calcitriol or alfacalcidol is beneficial.    

• Vit D dependent rickets: Another genetic disorder due to deficiency of renal hydroxylating mechanism which converts 25-OHD3 into calcitriol. Administration of calcitriol or alfacalcidol is effective in normal doses.

• Renal rickets: Conversion of 25-OHD3 into calcitriol does not occur due to chronic renal disease. Calcitriol/alfacalcidol or dihydrotachysterol are needed in usual doses.

• Senile or postmenopausal osteoporosis Age-related decrease in calcium absorption from gut has been noted. Vit D3 + calcium have been shown to improve calcium balance in osteoporotic females and elderly males. However, benefit in terms of improved bone mass or reduced fracture risk is controversial or marginal (see p. 327). But this does not apply to active therapy with calcitriol/alfacalcidol for patients with established osteoporosis, because it suppresses parathyroids and reduces bone remodeling. Vit D deficiency results in secondary hyperparathyroidism which contributes to osteoporosis. Though bone mineral density may be improved, calcitriol therapy carries the risk of hypercalcemia, calcium stones and metastatic calcification.

• Hypoparathyroidism Dihydrotachysterol or calcitriol/alfacalcidol are more effective than vit D2 or D3 because they act quickly and directly without the need for hydroxylation in kidney which needs PTH. Alternatively, conventional preparations of vit D3 may be given in high doses (25000-100,000 IU/day).    

• Fanconi syndrome Vit D can raise the lowered phosphate levels that occur in this condition

• A nonhypercalcaemic analogue of vit D Calcipotriol (DAIVONEX 0.005% point) is used locally in plaque type psoriasis, and has yielded good results (see Ch. 64). Systemically it has been tried in skin cancer and immunological disorders.

Interactions

• Cholestyramine and chronic use of liquid paraffine can reduce vit D absorption

• Phenytoin and phenobarbitone reduce the responsiveness of target tissues to calcitriol; their prolonged use (for epilepsy) can cause rickets/ osteoma Lacia. It was believed earlier that these drugs enhance degradation of vit D. However, now it has been shown that plasma level of calcitriol is normal, but its effect on intestine and bone is diminished.

BISPHOSPHONATES

Bisphosphonates (BPNs) are analogues of pyrophosphate: carbon atom replacing oxygen in the P-O-P skeleton. They inhibit bone resorption and have recently attracted considerable attention because of their ability to prevent osteoporosis in addition to their usefulness in metabolic bone diseases and hypercalcemia. They are the most effective antiresorptive drugs. Chronologically and according to potency, the BPNs can be grouped into 3 generations (see box). The first-generation compounds have simpler side chains, are the least potent and seldom used now. The second and third generation compounds have an amino or nitrogenous ring substitution in the side chain, are more potent, have higher efficacy and additional mode of action.

The mechanism of action of BPNs is not fully understood, but two facets of action have been delineated:

• BPNs have strong affinity for calcium phosphate: have selective action in calcified tissue. The two main components of bone are protein matrix and the solid mineral phase (hydroxyapatite). On the surface of resorptive pits the mineral phase is solubilized in the clear acidic zone created at the ruffled border of osteoclasts, followed by resorption of protein matrix in this area by acid hydrolases secreted from osteoclasts. BPNs localize in the acidic zone under the osteoclasts due to their high affinity for Ca2+ ions. When Ca2+ ions are released from the bone surface due to high acidity, the BPNs are also released and are internalized into osteoclasts by endocytosis. This results in:     

• Accelerated apoptosis of osteoclasts reducing their number. 

• Disruption of cytoskeleton and ruffled border of osteoclasts.

In addition, BPNs appear to affect osteoclast precursors and inhibit their differentiation by suppressing IL-6.

• It has been shown recently that BPNs, especially the second and third generation potent amino derivatives like alendronate, zoledronate, have important metabolic effects in the mevalonate pathway for isoprenoid lipid synthesis. They inhibit prenylation of certain GTP-binding proteins involved in cytoskeletal organization, membrane ruffling and vesicle movement. The net result is inactivation of osteoclasts, impaired vesicle fusion and enhanced apoptosis. Interference with mevalonate pathway may also impart antitumor action on bony metastasis.

• All oral BPNs are poorly absorbed, and produce gastric irritation, esophagitis as the major side effect. They are contraindicated in gastroesophageal reflux, peptic ulcer and renal impairment

• The BPNs are useful in conditions characterized by enhanced bone turnover

• Osteoporosis The second and third generation BPNs (e.g. alendronate, risedronate)     are effective in preventing and treating postmenopausal osteoporosis in women as well as age related, idiopathic and steroid-induced osteoporosis in both men and women. Alendronate has been found equally or more effective than HRT or raloxifene in conserving bone mineral density and has reduced the risk of vertebral as well as hip fracture by 47–56%.

• Estrogens prevent vertebral but no other fractures. BPNs are more effective than calcitonin and continue to afford protection for at least 5 years of continuous use.

• Paget’s disease This disease due to abnormal osteoclast function producing disordered bone remodeling and honeycomb-like bone architecture is benefited by BPNs. They arrest osteolytic lesions, reduce bone pain and improve secondary symptoms. Long-lasting remissions may be induced. Alendronate, risedronate, pamidronate and zoledronate are used now. They are more convenient, more effective and cheaper than calcitonin. Combined use of BPNs and calcitonin further increases efficacy. Treatment with BPNs should not exceed 6 months; but courses may be repeated after a gap.

• Hypercalcemia of malignancy Severe hypercalcemia, a common complication of malignancy, is a medical emergency with altered consciousness. Pamidronate (60–90 mg i.v. over 2–4 hours) or zoledronate (4 mg i.v. over 15 min) are the most effective drugs, but take 24–48 hours to act. They may be supplemented by i.m. calcitonin 6–12 hourly for 2 days for rapid action. Vigorous i.v. hydration along with furosemide to prevent volume over load is started before BPN infusion. It reduces serum calcium within few hours and corrects the attending dehydration. Oral BPNs are not useful.

• Osteolytic bone metastasis Parenteral pamidronate/zoledronate arrests osteolytic lesions and reduces bone pain.

• Etidronate This is the first BPN to be used clinically, employed in hypercalcemia and Paget’s disease. However, it also interferes with bone mineralization: continuous

• therapy produces osteoma Lacia. Therefore, it has been largely replaced by zoledronate for hypercalcemia and alendronate/risedronate for Paget’s disease. Etidronate is administered both orally and i.v., but is not preferred now. Adverse effects are gastric irritation, bone pain, headache, metallic taste, pyrexia and hypersensitivity. Dose: 5–7.5 mg/kg/day; DRONATE-OS 200 mg tab, 300 mg inj; DISONATE, ETIFEM 200 mg tab.

• Pamidronate A second generation potent BPN which is administered only by i.v. infusion in a dose of 60–90 mg over 2–4 hours weekly or monthly depending on the condition. It is used in Paget’s disease, hypercalcemia of malignancy and in bony metastasis. Adverse effects are thrombophlebitis of injected vein, bone pain, fever and leukopenia. A flue-like reaction may occur initially due to cytokine release. AREDIA 15, 30, 60 mg in; AREDRONET 30, 90 mg inj. BONAPAM 30, 60, 90 mg ing.     

• Alendronate This potent orally effective second generation amino-BPN is used primarily for prevention and treatment of osteoporosis both in women and men. It is to be taken on empty stomach in the morning with a full glass of water and patient is instructed not to lie down or take food for at least 30 min. These measures are needed to prevent contact with esophageal mucosa which results in esophagitis. Calcium, iron, antacids, mineral water, tea, coffee, fruit juice interfere with alendronate absorption. NSAIDs accentuate gastric irritation caused by alendronate. Other adverse effects are gastric erosion, retrosternal pain, flatulence, headache, body ache and initial fall in serum Ca2+ level.

• Dose: 5–10 mg OD; or 35–70 mg weekly; weekly treatment is as effective, more convenient and better tolerated. OSTEOPHOS, 5, 10, 35, 70 mg tab. DENFOS 5, 10 mg tab, RESTOFOS, DRONAL 10 mg tab.

• Oral bioavailability of alendronate is ~1%. Up to 50% of the drug entering the body is sequestrated in bone while the rest is excreted unchanged mainly by the kidney. The terminal elimination t½ of alendronate has been measured as 10.5 years.

• Risedronate It is an oral 3rd generation BPN, more potent than alendronate, but equally efficacious. Oral bioavailability of 1% and other features are also similar to alendronate. It is indicated in the treatment of osteoporosis and Paget’s disease.

• Dose: 35 mg/week oral in the morning with a full glass of water. RESTOFOS, GEMFOS, ACTONEL 35 mg tab

• Zoledronate This parenteral highly potent 3rd generation BPN is indicated for hypercalcemia, bony metastasis and Paget’s disease. Osteoclastic activity is markedly suppressed, and an additional antitumor effect may be exerted by interference with mevalonate pathway. Proliferation of bony metastasis of prostate/breast cancer and multiple myeloma cells may be arrested. For hypercalcemia, it is more effective, faster acting than pamidronate and therefore the drug of choice now. Another advantage is that it can be infused over 15 min (because of less venous irritation), whereas pamidronate needs 2–4 hours. Flu-like symptoms due to cytokine release attend the i.e. infusion. Renal toxicity has been encountered. Dose: 4 mg diluted in 100 ml saline/glucose solution and infused i.e. over 15 min; may be repeated after 7 days and then at 3–4-week intervals

• ZOBONE, ZOLDRIA 4 mg/vial inj

Other drugs for hypercalcemia

• Gallium nitrate: It is a potent inhibitor of bone resorption; acts by depressing ATP-dependent proton pump at the ruffled membrane of osteoclasts. Indicated in resistant cases of hypercalcemia, it is given by continuous i.v. infusion daily for 5 days. It is nephrotoxic and only a reserve drug.

• Mithramycin (Plicamycin) A cytotoxic drug which inhibits bone resorption in 10 times lower doses than for cancer. It is used only in non-responsive cases of hypercalcemia and Paget’s disease. Toxicity is high.

• Glucocorticoids: High doses of prednisolone (and others) enhance calcium excretion, decrease calcium absorption and have adjuvant role in hypercalcemia due to lymphoma, myeloma, leukemia, carcinoma breast, etc.