Chapter 24 Drugs Affecting Calcium Balance

CALCIUM Influences affecting bone turnover

After C, O, H and N, calcium is the most abun- ↑ Resorption ↓ Resorption

dant body constituent, making up about 2% of
Corticosteroids Androgens/Estrogens
body weight, or 1–1.5 kg in an adult. Over 99% Parathormone Calcitonin
of this is stored in bones, the rest being distributed Thyroxine (excess) Growth hormone
in plasma and all tissues and cells. Calcium serves Hypervitaminosis D Bisphosphonates
Prostaglandin E2 Fluoride
important physiological roles.
Interleukin 1 & 6 Gallium nitrate
Alcoholism Mithramycin
Physiological roles Loop diuretics Thiazide diuretics
1. Calcium controls excitability of nerves and
muscles and regulates permeability of cell mem- to albumin; 10% is complexed with citrate, phos-
branes. It also maintains integrity of cell phate and carbonate in an undissociable form;
membranes and regulates cell adhesion. the remaining (about 50%) is ionized and physio-
2. Ca2+ ions are essential for excitation-contrac- logically important. For example, in hypoalbu-
tion coupling in all types of muscle and excitation- minemia, total plasma calcium may be low but
secretion coupling in exocrine and endocrine the concentration of Ca2+ ion is usually normal.
glands, release of transmitters from nerve ending Acidosis favours and alkalosis disfavours ioniza-
and other release reactions. tion of calcium. As such, hyperventilation (by
3. Ca 2+ is an intracellular messenger for raising plasma pH) precipitates tetany and
hormones, autacoids and transmitters. laryngospasm in calcium deficiency by reducing
4. Ca2+ controles impulse generation in heart; ionization.
determines level of automaticity and A-V Calcium turnover Major fraction of calcium in the bone
conduction. is stored as crystalline hydroxyapatite deposited on the organic
bone matrix osteoid, while a small labile pool is in dynamic
5. Ca2+ is essential for coagulation of blood.
equilibrium with plasma. Even the fully laid down parts
6. Calcium serves structural function in bone of the bone undergo constant remodeling by way of two
and teeth. closely coupled but directionally opposite processes of
resorption and new bone formation (Fig. 24.2). Millions of
Plasma calcium level It is precisely regulated tiny remodeling units are working on the surface of bone
by 3 hormones almost exclusively devoted to this trabeculae and Haversian canals to dig micropits by
function, viz. parathormone (PTH), calcitonin and osteoclastic activity and then repair by osteoblastic activity
in which first collagen and other proteins (osteoid) are
calcitriol (active form of vit D). These regulators deposited followed by mineralization; the full cycle taking
control its intestinal absorption, exchange with 4–6 months. Diet, exercise, several hormones and drugs
bone and renal excretion as summarized in Fig. regulate the number and efficiency of bone remodeling units
24.1. In addition, several other hormones, meta- at any given time. Remodeling deficits accumulate over life-
time to account for age related bone loss, the pace of which
bolites and drugs influence calcium homeostasis can be retarded or accelerated by modulating the above listed
(see box). influences. Estrogen lack after menopause mainly causes loss
of trabecular bone, particularly affecting vertebrae, wrist bones
Normal plasma calcium is 9–11 mg/dl. Of this and femoral neck. Minimal trauma/compression fractures are
about 40% is bound to plasma proteins—chiefly most common at these sites.
336 HORMONES AND RELATED DRUGS

Fig. 24.1: Regulation of plasma level of calcium.

————→ stimulation, - - - - - - → Inhibition; Bold arrow indicates—major action.
PTH—Parathormone; 25-OHD3—Calcifediol; 1,25 (OH)2D3—Calcitriol.

Absorption and excretion Calcium is absor- Preparations

bed by facilitated diffusion from the entire small 1. Calcium carbonate (40% Ca): It is an insoluble, tasteless
and nonirritating salt. Reacts with gastric HCl to form chloride,
intestine as well as from duodenum by a carrier- and can be used as antacid. It is the most common salt
mediated active transport under the influence present in calcium supplements, but gastric acid is required
of vit D. Phytates, phosphates, oxalates and for converting it into the absorbable form. Calcium availability
from it is poor in patients taking proton pump inhibitors
tetracyclines complex with Ca2+ in an insoluble (PPIs), H2 blockers, and in elderly.
form in the intestines and interfere with its 2. Calcium citrate (as tetrahydrate, 21% Ca2+): Slightly
SECTION 5

absorption. Glucocorticoids and phenytoin also soluble in water, but dissolves well in presence of HCl. It
is nonirritating and is used in supplements; absorption in
reduce calcium absorption. patients taking PPIs/H2 blockers and elderly is satisfactory.
Ionized calcium is totally filtered at the glome- 3. Calcium gluconate (9% Ca): is available as 0.5 g and
rulus and most of it is reabsorbed in the tubules. 1 g tablets and 10% injection (5 ml amp.). It is nonirritating
to g.i.t. and the vascular endothelium. A sense of warmth
Vit D and PTH increase, while calcitonin decreases
is produced on i.v. injection: extravasation should be guarded.
tubular reabsorption of Ca2+. About 300 mg of It is the preferred injectable salt.
endogenous calcium is excreted daily: half in urine 4. Calcium lactate: (13% Ca) is given orally, nonirritating
and half in faeces. To maintain calcium balance, and well tolerated.
5. Calcium dibasic phosphate (23% Ca): is insoluble,
the same amount has to be absorbed in the small reacts with HCl to form soluble chloride in the stomach.
intestine from the diet. Because normally only 1/3rd It is bland; used orally as antacid and to supplement calcium.
of ingested calcium is absorbed, the dietary Availability of calcium from it is reduced by PPIs and H2
blockers.
allowance for calcium is 0.8–1.5 g per day. However, 6. Calcium chloride (27% Ca): It is freely soluble in water,
fractional calcium absorption is greater in presence but highly irritating to gastric mucosa and tissues; therefore
of calcium deficiency and low dietary calcium. not used.
Thiazide diuretics impede calcium excretion Side effects Calcium supplements are
by facilitating tubular reabsorption. usually well tolerated; only g.i. side effects like
 DRUGS AFFECTING CALCIUM BALANCE 337

constipation, bloating and excess gas (especially given to fracture patients, but if diet is adequate
with cal. carbonate) have been reported. this does not accelerate healing.
Some combined formulations 3. Osteoporosis In the prevention and treat-
CALCINOL-RB: Cal. carb 0.375 g, Cal. Phos 75 mg + vit ment of osteoporosis with alendronate/HRT/
D3 250 IU tab. raloxifene, it is important to ensure that calcium
MILICAL: Cal. citrate 1 g + vit D3 200 IU tab. deficiency does not occur. Calcium + vit D3 have
CALCIBONE: Cal. citrate 1 g + vit D3 200 IU tab and susp.
CALSHINE: Cal. citrate 0.5 g + vit D3 500 IU tab. adjuvant role to these drugs in prevention and
CALCIUM-SANDOZ: Cal. gluco-bionate 137.5 mg/ml inj. treatment of osteoporosis.
10 ml amp., also tabs containing cal. carbonate 650 mg. However, the efficacy of calcium ± vit D
KALZANA: Cal. dibasic phos 430 mg + Vit C and D3 200 supplements alone in increasing bone mass or
IU tab, also syrup: Cal. gluconate 300 mg, Cal. lactobionate
1.1 g, Cal. phos. 75 mg per 5 ml, containing Vit A, C, preventing fractures among menopausal women/
niacinamide and D3 200 IU. elderly men is controversial. It does not appear to
OSTOCALCIUM: Cal. phos 380 mg + Vit D3 400 IU tab, reduce fracture risk in otherwise healthy subjects
also syrup: Cal. phos 240 mg per 5 ml containing Vit D3 taking adequate diet. In the recently concluded
200 IU and B12.
SHELCAL: Cal. carb. 625 mg (eq 250 mg elemental cal), 7 year prospective WHI study involving >36000
Vit D3 125 IU tab and per 5 ml syr. postmenopausal women (51–79 years), the overall
MACALVIT: Cal. carb. 1.25 g, cholecalciferol 250 IU tab; risk of fractures was the same in the calcium
Cal. gluconate 1.18 g, Cal. lactobionate 260 mg + Vit D3 (1 g/day) + vit D (400 IU/day) group as in the
100 IU per 5 ml syr.
CALCIMAX: Cal. carb. (150 mg cal), dibasic cal. phos. placebo group, though the bone mineral density
(23.3 mg cal) with magnesium, zinc and vit D3 200 IU at the hip was 1% higher in the treated group.
tab.; also syrup cal. carb. (150 mg cal) with magnesium, Certain subgroups of osteoporotic subjects may
zinc and vit D3 200 IU per 5 ml syrup. benefit from calcium supplements, but the benefit
Use appears to be marginal and limited to cortical
bone loss only. On the other hand, a metaanalysis
1. Tetany For immediate treatment of severe has shown that subjects receiving calcium
cases 10–20 ml of Cal. gluconate (elemental supplements had a 27% higher incidence of MI.
calcium 90–180 mg) is injected i.v. over 10 min, Thus, calcium supplements should be given only
followed by slow i.v. infusion. A total of 0.45- to subjects taking diet low in calcium.
0.9 g calcium (50 to 100 ml of cal. gluconate 4. Empirically, Cal. gluconate i.v. has been used

CHAPTER 24
solution) over 6 hours is needed for completely in dermatoses, paresthesias, weakness and other
reversing the muscle spasms. Supportive treatment vague complaints. Any benefit is probably psy-
with i.v. fluids and oxygen inhalation may be chological due to warmth and other subjective
required. Long-term oral treatment to provide 1– effects produced by the injection.
1.5 g of calcium daily is instituted along with 5. As antacid (see Ch. 46).
vit. D. Milder cases need oral therapy only.
2. As dietary supplement especially in growing PARATHYROID HORMONE
children, pregnant, lactating and menopausal (Parathormone)
women. The dietary allowance recommended by
Vassale and Generali (1900) were the first to perform selective
National Institute of Health (1994) is— parathyroidectomy (without removing thyroids) and found
• Children 1–10 yr : 0.8–1.2 g that it produced tetany and death. MacCallum and Voegtlin
• Young adult 11–24 yr, pregnant in 1909 established this to be due to decrease in plasma
and lactating women : 1.2–1.5 g calcium levels; parathormone (PTH) was isolated in 1925.
• Men 25–65 yr, women 25–50 yr
PTH is a single chain 84 amino acid poly-
and 51–65 yr if taking HRT : 1.0 g
• Women 51–65 yr not taking HRT, peptide, MW 9500. It is synthesized as prepro-
every one > 65 yr : 1.5 g PTH, the excess amino acids are split off in two
Calcium supplement can reduce bone loss in steps and it is then stored in intracellular vesicles.
predisposed women as well as men. It is often Secretion of PTH is regulated by plasma Ca2+
338 HORMONES AND RELATED DRUGS

concentration through a calcium-sensing receptor of vit D) in the kidney by activating 1α-

(CaSR), that is a G-protein coupled receptor on hydroxylase. Calcitriol then promotes intestinal
the surface of parathyroid cells. There is no trophic absorption of calcium.
hormone for it. Fall in plasma Ca2+ induces PTH
4. PTH decreases calcium levels in milk, saliva
release and rise inhibits secretion by decreasing
and ocular lens. This may be responsible for
cAMP in the parathyroid cells. Agents that increase
development of cataract in hypoparathyroidism.
cAMP cause PTH release, but direct activation
of protein kinase C by fall in Ca2+ concentration Mechanism of action The PTH receptor is
is more important physiologically. Prolonged a G protein coupled receptor which on activation
hypocalcaemia causes hypertrophy and increases cAMP formation and intracellular Ca2+
hyperplasia of parathyroids, while sustained in target cells. In bone, the target cell is the osteo-
hypercalcaemia has the opposite effect. Changes blast because PTH receptors are not expressed
in phosphate concentration in plasma affect PTH on the surface of osteoclasts. Acting on the
secretion indirectly by altering Ca2+ concentration. osteoblast, PTH induces a factor ‘Receptor for
The active form of vit. D calcitriol inhibits activation of nuclear factor-κB-ligand’ (RANKL)
expression of PTH gene in parathyroid cells which diffuses and combines with RANK on
reducing PTH production. PTH is rapidly osteoclast precursors and transforms them into
degraded in liver and kidney; its plasma t½ is osteoclasts as well as activates osteoclasts (Fig.
2–5 min. 24.2). In addition, birth rate of bone remodeling
units into which osteoclasts are recruited is
Actions enhanced. Formation of the remodeling pit is
followed by osteoblastic deposition of new bone
PTH increases plasma calcium levels by:
into it. PTH enhances proliferation and
1. Bone PTH promptly increases resorption of differentiation of preosteoblasts and deposition
calcium from bone. This is the most prominent of osteoid as well. Bone resorption predominates
action of PTH—exerted by increasing the number when high concentrations of PTH are present
of bone remodeling units and activating osteo- continuously, but intermittent exposure to low
clasts when high concentrations are present concentrations has the opposite effect.
continuously. Since bone resorption is followed Hypoparathyroidism Manifestations are:
SECTION 5

by new bone deposition, this is also promoted Low plasma calcium levels, tetany, convulsions, laryngospasm,
by PTH: increased bone formation occurs when paresthesias, cataract and psychiatric changes. Pseudohypo-
PTH is given intermittently and in low doses. parathyroidism occurs due to reduced sensitivity of target
cells to PTH caused by a mutant G protein that couples
2. Kidney PTH increases calcium reabsorption PTH receptor activation to cAMP generation in target cells.
in the distal tubule and provides moment to Hyperparathyroidism It is mostly due to parathyroid
tumour. It produces—
moment regulation of calcium excretion. It also Hypercalcaemia, decalcification of bone—deformities and
promotes phosphate excretion which tends to fractures (osteitis fibrosa generalisata), metastatic calcification,
supplement the hypercalcaemic effect. However, renal stones, muscle weakness, constipation and anorexia.
grossly increased plasma calcium level occurring Treatment is surgical removal of the parathyroid tumour.
in hyperparathyroidism overrides the direct action When this is not possible—low calcium, high phosphate diet
on tubules and calcium excretion in urine is with plenty of fluids is advised.
actually increased. The converse occurs in Cinacalcet It activates the Ca2+ sensing receptor (CaSR) in
hypoparathyroidism. the parathyroids and blocks PTH secretion. It is indicated in
secondary hyperparathyroidism due to renal disease and in
3. Intestines PTH has no direct effect on parathyroid tumour.
calcium absorption but increases it indirectly by Use PTH is not used in hypoparathyroidism because plasma
enhancing the formation of calcitriol (active form calcium can be elevated and kept in the normal range more
 DRUGS AFFECTING CALCIUM BALANCE 339

Fig. 24.2: Hormonal regulation of bone remodeling unit

The monocyte osteoclast precursor cells in the marrow near the bony surface are activated to proliferate and fuse to
form multinucleated osteoclasts. The osteoclast-precursors express a ‘receptor for activation of nuclear factor-κ B’
(RANK) on their surface. The osteoblasts on activation release a protein RANK-ligand (RANKL). When RANKL is
bound to RANK on the surface of osteoclast-precursors they are transformed into mature osteoclasts and develop
bone lysing ruffled surface. A bone resorption pit is dug out by secretion of acid and proteolytic acid hydrolases.
Osteoblasts produce another protein osteoprotegerin (OPG) as well, which can bind RANKL and prevent it from
combining with RANK to activate osteoclasts. Thus, osteoblasts by producing RANKL and OPG regulate bone
resorption.
After formation of the remodeling pit, preosteoblasts from bone marrow stem cells proliferate, migrate to the base
of the pit, transform into mature osteoblasts and laydown new osteoid, which is later mineralized.
Parathormone (PTH) acts on PTH-receptor located on the osteoblast membrane and induces RANKL production—
indirectly activating osteoclast differentiation and function. Subsequently PTH promotes new bone formation as well.
Calcitriol also induces RANKL in osteoblasts to indirectly activate osteoclasts. Similarly, it promotes laying of
osteoid as well as bone mineralization.
Calcitonin directly inhibits osteoclast function and probably enhances osteoblastic new bone formation.

CHAPTER 24
conveniently by vit D therapy. PTH has to be given intermittent action is produced and the bone forming action
parenterally, while vit D can be given orally. Vit D is cheap. predominates over bone resorbing action. High cost and need
However, recombinant human PTH (1–84 amino acid) has for daily s.c. injections are the limitations. Its use may be
been produced and is being clinically evaluated for use in justified in severely osteoporotic women, those who have
hypoparathyroidism. already suffered osteoporotic fractures or have multiple risk
factors for fracture. Treatment beyond 2 years is not
Teriparatide This recombinant preparation of 1–34 residues
recommended. Side effects include dizziness and leg
of amino terminal of human PTH has been recently introduced
cramps. Pagets disease and hypercalcaemia are the contraindi-
for the treatment of severe osteoporosis. It duplicates all
cations.
the actions of long (1–84) PTH. Injected s.c. 20 μg once
daily, it acts only for 2–3 hours, and has been found to Diagnostic use To differentiate pseudo from true hypopara-
increase bone mineral density in osteoporotic women. The thyroidism: teriparatide is given i.v.: if plasma calcium level
effect was faster and more marked than that produced by fails to rise, then it is pseudohypoparathyroidism.
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 CALCITONIN
was found to be equally or more effective than estrogens
and BPNs in reducing risk of vertebral as well as non-vertebral Calcitonin is the hypocalcaemic hormone dis-
fractures in osteoporotic women as well as men. After s.c. covered by Copp in 1962. It is a 32 amino acid
injection its plasma t½ is 1 hr; given once daily only single chain polypeptide (MW 3600) produced
340 HORMONES AND RELATED DRUGS

by parafollicular ‘C’ cells of thyroid gland. Therefore, used only to supplement BPNs initially, because
Parathyroids, thymus and cells of medullary BPNs take 24–48 hours to act.
2. Postmenopausal osteoporosis Though i.m. or s.c.
carcinoma of thyroid also contain calcitonin. calcitonin can be used, a nasal spray formulation delivering
Synthesis and secretion of calcitonin is regu- 200 IU per actuation is employed. MIACALCIN NASAL
lated by plasma Ca2+ concentration itself: rise in SPRAY, OSTOSPRAY 2200 IU metered dose vial,
plasma Ca2+ increases, while fall in plasma Ca2+ CALCINASE 200 IU per actuation nasal spray. One spray
in alternate nostril daily has been shown to increase bone
decreases calcitonin release. However, circulating mineral density in menopausal women and to reduce vertebral,
level of calcitonin is low and its physiological but not nonvertebral, fractures. It is less effective than BPNs/
role in regulating plasma Ca2+ appears to be minor. HRT. Calcitonin is indicated only when other drugs cannot
The plasma t½ of calcitonin is 10 min, but its be given and in women who are menopausal for at least
5 years with definite evidence of osteoporosis. Though nausea
action lasts for several hours.
and flushing are less with nasal spray, rhinitis, epistaxis,
nasal ulceration and headache are produced frequently.
Actions
3. Paget’s disease 100 IU i.m./s.c. daily or on alternate
The actions of calcitonin are generally opposite days produces improvement for few months. Later, resistance
to that of PTH. It inhibits bone resorption by usually develops due to production of antibodies.
Bisphosphonates are preferred; calcitonin may be used as
direct action on osteoclasts—decreasing their adjuvant or 2nd line drug.
ruffled surface which forms contact with the
4. Diagnosis of medullary carcinoma of thyroid Detection
resorptive pit. Whether it also promotes calcium
of high blood level of calcitonin is diagnostic of this tumour,
deposition by osteoblasts is not certain. The which arises from the calcitonin producing parafollicular cells
hypocalcaemic action of calcitonin lasts ~8 hours. of thyroid.
Calcitonin inhibits proximal tubular
reabsorption of calcium and phosphate by direct VITAMIN D
action on the kidney. However, hypocalcaemia
Vitamin D is the collective name given to
overrides the direct action by decreasing the total
antirachitic substances synthesized in the body
calcium filtered at the glomerulus—urinary Ca2+
is actually reduced. and found in foods activated by UV radiation.
The actions of calcitonin are mediated through D3 : cholecalciferol — synthesized in the skin
a G-protein coupled calcitonin receptor (CTR) under the influence of UV rays.
and increase in cAMP formation, but its target D2 : calciferol—present in irradiated food—
yeasts, fungi, bread, milk.
SECTION 5

cells are different from that of PTH.

D1 : mixture of antirachitic substances found in
Preparation and unitage Synthetic salmon calcitonin
is used clinically, because it is more potent and longer acting food—only of historic interest.
due to slower metabolism. Human calcitonin has also been In 1919 it was established that rickets was due to deficiency
produced. of a dietary factor as well as lack of exposure to sunlight.
1 IU = 4 µg of the standard preparation. McCollum (1922) showed that this fat soluble dietary factor
CALSYNAR, ZYCALCIT: Synthetic salmon calcitonin 100 was different from vit A and its structure was determined
IU/ml amp. for i.m. or s.c. injection. in 1935. The interrelation between calciferol and
Nausea, flushing and tingling of fingers is frequent after cholecalciferol and their activation in the body has been
calcitonin injection. Bad taste, flu-like symptoms, allergic fully understood only in the 1970s.
reactions and joint pain are the other adverse effects.
Activation of vit D It takes place in the
Uses
1. Hypercalcaemic states Hyperparathyroidism, hyper-
following manner—
vitaminosis D, osteolytic bony metastasis and hypercalcaemia Ergosterol differs from 7-dehydrocholesterol in
of malignancy; 4–8 IU/kg i.m. 6–12 hourly only for 2 days. having an extra double bond between C22–23
It acts rapidly within 4 hours, the response peaks at 48 hours and a methyl group at C24. In man vit D2 and
and then refractoriness develops. It also relieves bone pain.
For emergency treatment of hypercalcaemia 5–10
D3 are equally active and calcitriol (active form
IU/kg may be diluted in 500 ml saline and infused i.v. over of D3) is more important physiologically; 25-OH
6 hours. Calcitonin is a relatively weak hypocalcaemic drug. D3 is released in blood from the liver and binds
 DRUGS AFFECTING CALCIUM BALANCE 341

7-DEHYDROCHOLESTEROL ERGOSTEROL
(Synthesized in skin) (yeast, bread, milk)
UV Light
CHOLECALCIFEROL (Vit D 3) CALCIFEROL (Vit D2)
Liver microsomes
CALCIFEDIOL (25-OH-D3) 25-OH-D2
Kidney mitochondria
CALCITRIOL (1,25 (OH)2D3) 1,25 (OH) 2D2
ACTIVE FORMS

loosely to a specific vit D binding globulin. The by mechanisms not involving gene regulation.
final 1α-hydroxylation in kidney is rate limiting 2. Calcitriol enhances resorption of calcium and
and is controlled by many factors. This step is phosphate from bone by promoting recruitment
activated or induced by calcium/vit D deficiency and differentiation of osteoclast precursors in the
as well as by PTH, estrogens and prolactin, while bone remodeling units, but mature osteoclasts lack
calcitriol inhibits it in a feedback manner. VDR. Like PTH, calcitriol induces RANKL in
Thus, vit D should be considered a hormone osteoblasts which may then activate the
because: osteoclasts. Osteoblastic cells express VDR and
(a) It is synthesized in the body (skin); under respond to calcitriol by laying down osteoid, but
ideal conditions it is not required in the diet. it mainly appears to help bone mineralization
(b) It is transported by blood, activated and then indirectly by maintaining normal plasma calcium
acts on specific receptors in the target tissues. and phosphate concentration. Its action is indepen-
(c) Feedback regulation of vit D activation dent of but facilitated by PTH.
occurs by plasma Ca2+ level and by the active 3. Calcitriol enhances tubular reabsorption of
form of vit D itself. calcium and phosphate in the kidney, but the
action is less marked than that of PTH. However,
Actions in hypervitaminosis D, influence of hypercal-

CHAPTER 24
caemia overrides the direct action and more
1. Calcitriol enhances absorption of calcium and
calcium is excreted in urine.
phosphate from intestine. This is brought about
4. Other actions Actions of calcitriol on immu-
by increasing the synthesis of calcium channels
nological cells, lymphokine production, prolifera-
and a carrier protein for Ca2+ called ‘calcium
tion and differentiation of epidermal and certain
binding protein’ (Ca BP) or Calbindin. The action
malignant cells, neuronal and skeletal muscle
of calcitriol is analogous to that of steroid
function have also been demonstrated.
hormones. It binds to a cytoplasmic vitamin D
receptor (VDR) → translocate to the nucleus → Vit D deficiency Plasma calcium and phos-
increase synthesis of specific mRNA → regulation phate tend to fall due to inadequate intestinal
of protein synthesis. Another line of evidence absorption. As a consequence, PTH is secreted
suggests that activation of VDR promotes → calcium is mobilized from bone in order to
endocytotic capture of calcium, its transport restore plasma Ca2+. The bone fails to mineralize
across the duodenal mucosal cell and finally its normally in the newly laid area, becomes soft
active extrusion through the serosal membrane. → rickets in children and osteomalacia in adults.
At least part of vit D action is quick (within However, in contrast to osteoporosis, the organic
minutes) and, therefore, appears to be exerted matrix (osteoid) is normal in these conditions.
342 HORMONES AND RELATED DRUGS

Hypervitaminosis D It may occur due to chronic ingestion 4. Alfacalcidol It is 1 α-OHD3—a prodrug that is rapidly
of large doses (~50,000 IU/day) or due to increased sensi- hydroxylated in the liver to 1,25 (OH)2 D 3 or calcitriol.
tivity of tissues to vit D. Manifestations are due to elevated Therefore, it does not require hydroxylation at position 1 which
plasma calcium and its ectopic deposition. These are: is the limiting step in the generation of active form of vit D,
hypercalcaemia, weakness, fatigue, vomiting, diarrhoea, and which takes place in the kidney. As such, it is effective
sluggishness, polyuria, albuminuria, ectopic Ca2+ deposition in renal bone disease, vit D dependent rickets, vit D resistant
(in soft tissues, blood vessels, parenchymal organs), renal rickets, hypoparathyroidism, etc. i.e. indications for which
stones or nephrocalcinosis, hypertension, growth retardation calcitriol is needed. It is also being used in osteoporosis.
in children. Even coma has been reported. Alfacalcidol is orally active and clinically equally effective
Treatment: consists of withholding the vitamin, low calcium on long term basis to calcitriol. Its metabolic activation in liver
diet, plenty of fluids and corticosteroids. Recovery may be does not pose a problem even in severe liver disease.
incomplete in many cases. Dose: 1–2 µg/day, children < 20 kg 0.5 µg/day. Repeated
serum calcium measurements are essential for regulation of
maintenance dose. Hypercalcaemia should be watched for
Pharmacokinetics and therapy promptly interrupted for few days when it
develops.
Vit D is well absorbed from the intestines in the ONE ALPHA, ALPHA D3, ALPHADOL 0.25 and 1 µg caps,
presence of bile salts, mainly through lymphatics. ALFACAL 0.25, 0.5 µg caps.
Absorption of the D3 form is somewhat better 5. Dihydrotachysterol A synthetic analogue of vit D2 that
than that of D2. Malabsorption and steatorrhoea is much less active in antirachitic tests, but directly mobilizes
calcium from bone after 25-hydroxylation in liver, and does
interfere with its absorption. not require PTH dependent activation in the kidney. It is
In the circulation, it is bound to a specific particularly useful in hypoparathyroidism and renal bone
α globulin and is stored in the body, mostly in disease.
adipose tissues, for many months. It is hydroxy- Dose: 0.25–0.5 mg/day.
Combination preparations of vit D are listed on p. 337 and in
lated in the liver to active and inactive metabolites. Table 67.2.
The t½ of different forms varies from 1–18 days:
25-OHD3, having the longest t½ , constitutes the Use
primary circulating form. Calcitriol is cleared
rapidly. 1. Prophylaxis (400 IU/day) and treatment
Metabolites of vit D are excreted mainly in bile. (3000–4000 IU/day) of nutritional vit D
deficiency This is given to prevent and treat
rickets in children and osteomalacia in adults.
Unitage and preparations
1 µg of cholecalciferol = 40 IU of vit D. Alternatively 300,000–600,000 IU can be given
SECTION 5

The daily requirement varies, depending on exposure to orally or i.m. once in 2–6 months. Prophylactic
sunlight. It is estimated that if no vit D3 is synthesized treatment may be given in obstructive jaundice,
in the body, a dietary allowance of 400 IU/day will prevent steatorrhoea and other conditions which
deficiency symptoms. However, higher amounts (upto 1000
IU/day) are also recommended. The forms in which vit D
predispose to vit D deficiency.
is supplied are— 2. Metabolic rickets These are a group of
1. Calciferol (Ergocalciferol, vit D2) As solution in oil,
filled in gelatin capsules 25,000 and 50,000 IU caps.
conditions in which tissues do not respond to
2. Cholecalciferol (vit D3) As granules for oral ingestion normal doses of vit D.
and oily solution for i.m. injection. (a) Vit D resistant rickets: X-linked hereditary
ARACHITOL 300,000 IU (7.5 mg) and 600,000 IU (15 mg) disease in which vit D metabolism is normal but
per ml inj.
calcium and phosphate metabolism is deranged.
CALCIROL, CALCIBEST SACHET 60,000 IU in 1 g
granules—suspended in milk/water and taken at 3–4 weeks Administration of phosphate with high dose of
intervals, and then every 2–6 months. calcitriol or alfacalcidol is beneficial.
3. Calcitriol 0.25–1 µg orally daily or on alternate days; (b) Vit D dependent rickets: Another genetic
CALTROL, ROLSICAL, ROCALTROL 0.25 µg cap. CALCI- disorder due to deficiency of renal hydroxylating
BEST 1 μg in 1 ml aqueous inj; 0.5–1 μg i.v. on alternate
days.
mechanism which converts 25-OHD3 into calci-
Hypercalcaemia is the main adverse effect; must be watched triol. Administration of calcitriol or alfacalcidol
for and therapy promptly stopped if plasma Ca2+ rises. is effective in normal doses.
 DRUGS AFFECTING CALCIUM BALANCE 343

(c) Renal rickets: Conversion of 25-OHD3 into drugs enhance degradation of vit D. However,
calcitriol does not occur due to chronic renal now it has been shown that plasma level of
disease. Calcitriol/alfacalcidol or dihydrotachys- calcitriol is normal, but its effect on intestine and
terol are needed in usual doses. bone is diminished.
3. Senile or postmenopausal osteoporosis
BISPHOSPHONATES
Age-related decrease in calcium absorption from
gut has been noted. Vit D3 + calcium have been Bisphosphonates (BPNs) are analogues of pyro-
shown to improve calcium balance in osteoporotic phosphate: carbon atom replacing oxygen in
females and elderly males. However, benefit in the P-O-P skeleton. They inhibit bone resorption
terms of improved bone mass or reduced fracture and have recently attracted considerable attention
risk is controversial or marginal (see p. 337). But because of their ability to prevent osteoporosis
this does not apply to active therapy with calcitriol/ in addition to their usefulness in metabolic bone
alfacalcidol for patients with established osteo- diseases and hypercalcaemia. They are the most
porosis, treated with BPNs, etc. because calcitriol effective antiresorptive drugs. Chronologically and
suppresses parathyroids and reduces bone according to potency, the BPNs can be grouped
remodeling. Vit D deficiency results in secondary into 3 generations (see box). The first generation
hyperparathyroidism which contributes to compounds have simpler side chains, are the least
osteoporosis. Calcitriol therapy carries the risk potent and seldom used now. The second and
of hypercalcaemia, calcium stones and metastatic third generation compounds have an amino or
calcification which should be watched for. nitrogenous ring substitution in the side chain,
are more potent, have higher efficacy and additional
4. Hypoparathyroidism Dihydrotachysterol or
mode of action.
calcitriol/alfacalcidol are more effective than vit,
D2 or D3, because they act quickly and directly Bisphosphonate Relative potency
without requiring hydroxylation in kidney which First generation BPNs
needs PTH. Alternatively, conventional
Etidronate 1
preparations of vit D3 may be given in high doses *Tiludronate 10
(25000-100,000 IU/day). Second generation BPNs
Pamidronate 100
5. Fanconi syndrome Vit D can raise the

CHAPTER 24
Alendronate 100–500
lowered phosphate levels that occur in this *Ibandronate 500–1000
condition. Third generation BPNs
Risedronate 1000
6. A nonhypercalcaemic analogue of vit D Zoledronate 5000
Calcipotriol (DAIVONEX 0.005% oint) is used * Not marketed in India
locally in plaque type psoriasis, and has yielded
good results (see Ch. 64). Systemically it has O R1 O
been tried in skin cancer and immunological HO || | || OH
disorders. P—C—P
NaO | ONa
R2
Interactions
Bisphosphonate
1. Cholestyramine and chronic use of liquid
O OH O
paraffine can reduce vit D absorption. HO || | || OH
2. Phenytoin and phenobarbitone reduce the P—C—P
responsiveness of target tissues to calcitriol; their NaO | ONa
prolonged use (for epilepsy) can cause rickets/ CH2 — CH 2 — NH2
osteomalacia. It was believed earlier that these Pamidronate
344 HORMONES AND RELATED DRUGS

The mechanism of action of BPNs is not fully are effective in preventing and treating post-
understood, but two facets of action have been menopausal osteoporosis in women as well as
delineated: age related, idiopathic and steroid-induced
(a) BPNs have strong affinity for calcium osteoporosis in both men and women. Alendronate
phosphate and have selective action in calcified is equally or more effective than HRT or raloxifene
tissue. The two main components of bone are in conserving bone mineral density and has
protein matrix and the solid mineral phase reduced the risk of vertebral as well as hip fracture
(hydroxyapatite). On the surface of resorptive pits by 47–56%.
the mineral phase is solubilized in the clear acidic Estrogens prevent vertebral but not other
zone created at the ruffled border of osteoclasts, fractures. BPNs are more effective than calcitonin
followed by resorption of protein matrix in this and continue to afford protection for at least 5
area by acid hydrolases secreted from osteoclasts. years of continuous use. Thus, they are the first
BPNs localise in the acidic zone under the choice drugs now for osteoporosis. Since the t½
osteoclasts due to their high affinity for Ca2+ ions. of alendronate in bone is ~ 10 years, treatment
When Ca2+ ions are released from the bone surface beyond 5 years is considered unnecessary.
due to high acidity, the BPNs are also released
and are internalized into osteoclasts by 2. Paget’s disease This disease due to abnor-
endocytosis. This results in: mal osteoclast function producing disordered bone
• Accelerated apoptosis of osteoclasts reducing remodeling and honeycomb-like bone architecture
their number. is benefited by BPNs. They arrest osteolytic
• Disruption of cytoskeleton and ruffled border lesions, reduce bone pain and improve secondary
of osteoclasts. symptoms. Long-lasting remissions may be
In addition, BPNs appear to affect osteoclast induced. Alendronate, risedronate, pamidronate
precursors and inhibit their differentiation by and zoledronate are used now. They are more
suppressing IL-6. convenient, more effective and cheaper than
(b) It has been shown now that BPNs, especially calcitonin. Combined use of BPNs and calcitonin
the second and third generation potent amino- further increases efficacy. Treatment with BPNs
derivatives like alendronate, zoledronate, have should not exceed 6 months; but courses may
important metabolic effects in the mevalonate be repeated after a gap.
SECTION 5

pathway for isoprenoid lipid synthesis. They 3. Hypercalcaemia of malignancy Severe

inhibit prenylation of certain GTP-binding proteins hypercalcaemia, a common complication of
involved in cytoskeletal organization, membrane malignancy, is a medical emergency with altered
ruffling and vesicle movement. The net result is consciousness. Pamidronate (60–90 mg i.v. over
inactivation of osteoclasts, impaired vesicle fusion 2–4 hours) or zoledronate (4 mg i.v. over 15 min)
and enhanced apoptosis. Interference with are the most effective drugs, but take 24–48 hours
mevalonate pathway may also impart antitumor to act. They may be supplemented by i.m.
action on bony metastasis. calcitonin 6–12 hourly for 2 days to achieve rapid
All oral BPNs are poorly absorbed, and produce action. Vigorous i.v. hydration is instituted first.
gastric irritation, esophagitis as the major side
After volume repletion, furosemide is added to
effect. They are contraindicated in gastroesophageal
enhance Ca2+ excretion and to prevent volume
reflux, peptic ulcer and renal impairment.
overload. This is followed by BPN infusion. This
The BPNs are useful in conditions characteri-
therapy reduces serum calcium within few hours
zed by enhanced bone turnover.
and corrects the attending dehydration. Oral BPNs
1. Osteoporosis The second and third are not useful. Corticosteroids also lower plasma
generation BPNs (e.g. alendronate, risedronate) Ca2+, but are slow to act, take 1–2 weeks.
 DRUGS AFFECTING CALCIUM BALANCE 345

4. Osteolytic bone metastasis Parenteral unchanged mainly by the kidney. The terminal
pamidronate/zoledronate arrests osteolytic lesions elimination t½ of alendronate has been measured
and reduces bone pain. as 10.5 years.
Etidronate This is the first BPN to be used clinically, Risedronate It is an oral 3rd generation BPN,
employed in hypercalcaemia and Paget’s disease. However, more potent than alendronate, but equally
it also interferes with bone mineralization: continuous therapy
produces osteomalacia. Therefore, it has been largely replaced
efficacious. Oral bioavailability of 1% and other
by zoledronate for hypercalcaemia and alendronate/risedronate features are similar to alendronate. It is indicated
for Paget’s disease. Etidronate is administered both orally in the treatment of osteoporosis and Paget’s
and i.v., but is not preferred now. disease.
Dose: 5–7.5 mg/kg/day. Dose: 35 mg/week oral in the morning with a full glass
DRONATE-OS 200 mg tab, 300 mg inj. of water.
RISOFO 5, 35, 70 mg tabs. GEMFOS, ACTONEL 35 mg
Pamidronate A second generation potent BPN tab.
which is administered only by i.v. infusion in a
dose of 60–90 mg over 2–4 hours weekly or Zoledronate This parenteral highly potent 3rd
monthly depending on the condition. It is used generation BPN is indicated for hypercalcaemia,
in Paget’s disease, hypercalcaemia of malignancy bony metastasis, osteolytic lesions, and Paget’s
and in bony metastasis. Adverse effects are disease. Osteoclastic activity is markedly
thrombophlebitis of injected vein, bone pain, fever suppressed and an additional antitumor effect may
be exerted by interference with mevalonate
and leukopenia. A flu-like reaction may occur
pathway. Proliferation of bony metastasis of
initially due to cytokine release.
AREDIA 15, 30, 60 mg inj; AREDRONET 30, 90 mg inj.
prostate/breast cancer and multiple myeloma cells
BONAPAM 30, 60, 90 mg inj. may be arrested. For hypercalcaemia, it is more
effective, faster acting than pamidronate and
Alendronate This potent orally effective
therefore the drug of choice now. Another
second generation amino-BPN is used primarily advantage is that it can be infused over 15 min
for prevention and treatment of osteoporosis both (because of less venous irritation), whereas
in women and men, as well as for Paget’s disease. pamidronate needs 2–4 hours. Flu-like symptoms
It is to be taken on empty stomach in the morning due to cytokine release attend the i.v. infusion.
with a full glass of water and patient is instructed Nausea, vomiting, bodyache, dizziness are also

CHAPTER 24
not to lie down or take food for at least 30 min. common. Renal toxicity has been encountered.
These measures are needed to prevent contact Osteonecrosis of the jaw is a rare complication
of the drug with esophageal mucosa which results of i.v. high dose BPN therapy.
in esophagitis. Calcium, iron, antacids, mineral Zoledronate 4 mg infused i.v. once every 12
water, tea, coffee, fruit juice interfere with months has been used for osteoporosis in
alendronate absorption. NSAIDs accentuate postmenopausal women who do not tolerate oral
gastric irritation caused by alendronate. Other alendronate/risedronate.
adverse effects are gastric erosion, retrosternal Dose: 4 mg diluted in 100 ml saline/glucose solution and
pain, flatulence, headache, bodyache and initial infused i.v. over 15 min; may be repeated after 7 days and
then at 3–4 week intervals.
fall in serum Ca2+ level. ZOBONE, ZOLDRIA, ZOLTERO 4 mg/vial inj.
Dose: 5–10 mg OD; or 35–70 mg weekly; weekly treatment is
as effective, more convenient and better tolerated.
OSTEOPHOS, DENFOS 5, 10, 35, 70 mg tab. RESTOFOS, Other drugs for hypercalcaemia
DRONAL 10, 70 mg tab. 1. Gallium nitrate: It is a potent inhibitor of bone resorption;
acts by depressing ATP-dependent proton pump at the ruffled
Oral bioavailability of alendronate is ~1%. membrane of osteoclasts. Indicated in resistant cases of hyper-
Up to 50% of the drug entering the body is calcaemia, it is given by continuous i.v. infusion daily for 5
sequestrated in bone while the rest is excreted days. It is nephrotoxic and only a reserve drug.
346 HORMONES AND RELATED DRUGS

2. Glucocorticoids: High doses of prednisolone (and others) a reserve drug for elderly women >75 years age who have
enhance calcium excretion, decrease calcium absorption and already suffered osteoporotic fracture and are unable to tolerate
have adjuvant role in hypercalcaemia due to lymphoma, BPNs.
myeloma, leukaemia, carcinoma breast, etc. 2. Denosumab: It is a human monoclonal antibody which
inhibits osteoclast differentiation and function as well as
Other drugs for osteoporosis promotes their apoptosis. It is a treatment option for
1. Strontium ranelate: It suppresses bone resorption as well postmenopausal osteoporosis when no other drug is
as stimulates bone formation, and has been introduced as appropriate.
SECTION 5