HORMONES & DRUGS

AFFECTING CALCIUM
BALANCE

Dr.R.Prameela MD

Asst professor

Department of Pharmacology

04/06/2023
CONTENTS
 Introduction

 Hormonal control of calcium

 Nonhormonal agents – drugs

 Disorders associated with calcium

 Calcium preparations

 Conclusion

 References

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 INTRODUCTION

 Elemental calcium is essential for

various biological functions
 It plays a major role in body
homeostasis.
 Disturbances in calcium metabolism
leads to derangement of various
cellular functions.
 Milk and its products, green leafy veg,
cereals sources of calcium
 Ragi is rich source and rice has
minimal amounts of calcium.

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 Healthy adult men – 1300 g

women – 1000 g
 > 90% of Ca present in bones and teeth.

 Normal serum calcium 8.5 – 10.4 mg/dl

4.25 – 5.2 mEq/ l

2.1 – 2.6 mM

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Calcium Store
 99% stored as crystalline form Hydroxyapatite

[Ca10 (PO4)6 (OH)2 ] other ions, including Na+, K+, Mg2+, and F-,
also are present in the crystal lattice.

 The steady state content of calcium in bone reflects the net

effects of bone resorption and bone formation.

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Calcium absorption and excretion
 75% of dietary Ca+2 – milk and milk products
 Required daily Allowance (RDA) is

1300 mg/day – adolescents

1000 mg/day – adults

So 50 yrs- 1200 mg/day

 Median value - ≥ 9 yrs – Boys- 865 mg

Girls- 625 mg

women > 50yrs – 517 mg

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04/06/2023 7
 Calcium absorption occurs in small intestine (duodenum) by 2
mechanisms
 Facilitated transport
 Calcitriol dependent active transport

 The intestinal calcium absorption can increase to 600 mg/day

in presence of calcitriol
 Low Ca intake, PTH, Vit D, negative Ca balance, acid residue
in intestine- inc absorption

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  Phytates, oxalates, high phosphate content,free fatty acids-
dec absorption
 Diseases like steatorrhoea, diarrhoea, chronic malabsorption

 Glucocorticoids, phenytoin, tetracyclins- depress intestinal

Ca+2 transport

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 Urinary Ca+2 excretion is the net difference between the
quantity filtered at the glomerulus and the amount absorbed.
 9 gm – filtered each day

 Reabsorption is regulated by PTH and also filtered Na +

 Loop diuretics increases Ca+2 excretion

 Thiazides – uncouple the relationship between Na and Ca +2

excretion

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Physiological role of Calcium

 Excitability of nerves and muscles and regulates

permeability of cell membranes. Also integrity of cell
membranes
 Ca+2 essential for excitation and coupling (second
messenger) of all types of muscles
 Excitation and secretion of endocrine and exocrine
glands and release of neurotransmitters from nerve
endings
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  Intracellular messenger for hormones, autacoids and
transmitters
 Impulse generation and conduction in heart

 Coagulation of Blood

 Structural function of Bone and Teeth - Hydroxyapatite

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04/06/2023 13
Hormones regulating Ca+2
 Paratharmone

 Calcitonin
 Vitamin D

 Fibroblast Growth Factor- 23

 Others- glucocorticoids, estrogens, androgens, thyroid

hormone, insulin

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PARATHYROID HORMONE (PTH)
 Single polypeptide chain , 84 amino acids, molecular mass-
9500 Da
 Helps to regulate plasma Ca2+2 by affecting bone
resorption/formation, renal Ca+2 excretion/reabsorption, and
calcitriol synthesis.
 Inside the gland calcium sensitive protease cleaves the
hormone into fragments.

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Synthesis, secretion, immunoassay

115 AA

25 AA

6 AA

T1/2 – 4min

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Regulation of secretion
 Plasma Ca+2 is the major factor regulating PTH secretion.

 As the concentration of Ca+2 diminishes, PTH secretion

increases.
 Sustained hypocalcemia induces parathyroid hypertrophy
and hyperplasia
 Calcium- sensing receptor ( CaSR), stimulated by calcium
reduces PTH production and secretion.

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  Occupancy of CaSR with Ca+2 stimulates

Gq- PLC/ IP3 -Ca+2 pathway Activation of G1 pathway by Ca+2

Activation of PKC Decreases cAMP synthesis

Inhibition of PTH sectretion

Decreases activity of PKA

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 Effects on bone

 Catabolic and anabolic effects

 Elevated PTH – bone resorption to increase serum calcium
 Primary skeletal target cell for PTH is the osteoblast

Effects on kidney:
 Increases Ca+2 reabsorption
 Inhibits tubular reabsorption of phosphates
 Stimulates conversion of vit D to calcitriol

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  Cyclic AMP mediates renal effects of PTH in proximal tubule.

 PTH sensitive adenylyl cyclase is located in renal cortex

 Nephrogenous cAMP escapes into urine – measurement of

this used as indicator for parathyroid activity and renal
responsiveness.
 PTH reduces Mg+2 excretion

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  Increases excretion of water, AA, citrate, K+ , bicarbonate, Na+
, Cl- , SO42-

 Decreases H+ excretion

 Regulates calcitriol synthesis along with Vit D3 , Pi , Ca+2

 When hypocalcemia increases PTH, both the PTH-dependent

lowering of circulating Pi and the 1α-hydroxylase lead to
increased circulating concentrations of calcitriol.

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  Stimulates intestinal Ca+2 absorption

 When plasma Ca+2 activity rises, PTH secretion is suppressed,

and tubular Ca+2 reabsorption decreases.
 Which causes reduced bone remodelling.

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04/06/2023 23
 PTH decreases the synthesis and secretion of OPG from cells.
By increasing RANK and decreasing OPG locally in bone, serves to increase bone
resorption.

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 Preparations- Teriparatide
 rDNA synthetic PTH
 20-40 mcg SC in thigh or abdominal wall once daily

 Increases predominantly trabecular bone at the lumbar spine

and femoral neck.
 FDA- approved for treatment of osteoporosis for up to 2
years in both men and postmenopausal women at high risk
for fractures.
 injection-site pain, nausea, headaches, leg cramps, and
dizziness.
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 CALCITONIN
 Calcitonin is a hypocalcemic hormone whose actions
generally oppose those of PTH.
 Secreted from C cells – thyroid, parathyroid, thymus

 The biosynthesis and secretion of calcitonin are regulated by

the plasma Ca2+ concentration

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  Calcitonin is the most potent peptide inhibitor of osteoclast-
mediated bone resorption
 Calcitonins derived from salmon and eel differ from the
human hormone by 13 and 16 amino acid residues
 Normal levels – males < 15 pg/ml

females < 10 pg/ml

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  Circulating t1/2 – 10 min

 Stimulated by- catecholamines, glucagon, gastrin, and

cholecystokinin
 Lowers plasma clacium by blocking PTH induced bone
resorption
 Reduces Ca+2 , Na , K, P reabsorption in renal tubules.

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 Preparations
 Calcitonin (Pork) ( Calcitare)

4 units/kg daily SC/ IM – upto 80 units 3 times a week

 Salcalcitonin ( Salmon calcitonin)

400 units 6-8 hourly – upto 50 units 3 times a week

 Salcalcitonin nasal spray – 200 units once daily

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 VITAMIN D
 Fat soluble vitamin- it is more of a hormone

 Solar UV-B irradiation of 7-dehydro-choesterol present in

secretion of sebaceous glands covert it into vitamin D3
( cholecalciferol)
 Animal origin- cod liver oil, irradiated milk

 Irradiation of ergosterol in yeast – ergocaciferol ( D3)

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  Absorbed from small intestine.

 Vitamin D circulates in blood with Vit D binding proteins- α

globulin
 T ½ - 20-30 hrs

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 7-dehydrocholesterol

Skin UV-B

Vitamin D (cholecalciferol)
3
Dietary

Liver 25- hydroxylase

25-hydroxy vitamin D
(calcifediol)

PTH
1 α- hydroxylase
Kidney
1,25-dihydroxy vitamin D
(calcitriol)

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  Reduced extracellular Ca2+ levels stimulate 1α-hydroxyla-
tion causing formation of Vit D3
 1α-Hydroxylase is potently stimulated by PTH

 high calcium, phosphate, and vitamin D intakes suppress 1α-

hydroxylase activity

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  On entering the enterocyte, calcium binds to components of the
brush border complex .
 Calmodulin is redistributed to the brush border in response to
calcitriol - Calcitriol-inducible Calcium-Binding Protein, Calbindin-
D9K .
 The transport of calcium across the antiluminal surface of the
enterocyte is the calcitriol-inducible, ATP-dependent plasma
membrane Ca2+ pump (PMCA1b).
 The affinity of the pump for calcium is 2.5 times that of calbindin.
 With high calcium intake, a calcitriol-independent Na+/Ca2+
exchanger may also play a role in the transfer of calcium across
04/06/2023
the basolateral membrane. 34
 Preparations
 Modest supplementation with vitamin D (400-800 IU/day)

 Cholecalciferol – vit D3

As granules for oral and as oil for IM

1 mcg = 40 IU of vit D

Daily requirement to prevent deficiency – 200-400 IU/day

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  Doxercalciferol (D2) - for secondary hyperparathyroidism,
starting at 10 mg three times per week. IV
 Dihydrotachysterol (D2)-used to maintain plasma Ca2+ in
hypoparathyroidism. 0.2-1 mg/day oral
 1α-Hydroxycholecalciferol – Alfacalcidol (D3) -to treat renal
osteodystrophy
 Ergocalciferol pure D2 – to prevent vit D deficiency, familial
hypophosphatemia, hypoparathy- roidism, and vitamin D–
resistant rickets type II .
 50,000-200,000 units/day in conjunction with calcium
04/06/2023 supplements 36
  Calcipotriol- regulates calcium metabolism

Treatment for psoriasis ( plaque type)

 Paricalcitol - reduces serum PTH levels without producing
hypercalcemia or altering serum phosphorus

Secondary hyperparathyroidism in patients with chronic renal

failure.
 22-Oxacalcitriol - potent suppressor of PTH gene expression

limited activity on intestine and bone.

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 Fibroblast growth factor -23 ( FGF23)
 Hypophosphatemic hormone whose actions generally
parallel those of PTH.
 Klotho is a membrane protein that serves as an essential
cofactor in the transduction of FGF23 signaling.
 FGF23 - 251 amino acids produced by osteoblasts,
osteocytes, and lining cells.
 Principal regulator of proximal renal tubule phosphate
reabsorption and of 1,25-dihydroxyvitamin D synthesis.

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  It inhibits the synthesis of calcitriol , decreasing calcium and
phosphate absorption from intestines. PTH release is
stimulated
 The net result is maintaining Ca+2 levels.

 Secreted frizzled-related protein (s-FRP4) , matrix

extracellular phosphoglycoprotein (MEPG), along with FGF23
are called as phosphatonins.

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 Growth hormone
 Deficiency and excess of growth hormone have marked
effects on skeletal growth.
 Growth hormone increases circulating and local levels of
IGF1- mediates skeletal effects of growth hormone.
 Exogenous growth hormone and IGF1 increase bone
remodeling.
 Growth hormone also stimulates cartilage growth.

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 Glucocorticoids
 Glucocorticoids decrease the intestinal absorption of calcium
and have the potential to induce osteoclastogenesis and
bone resorption because they increase the expression of
RANKL and CSF1 in osteoblasts.
 Glucocorticoids inhibit the replication of osteoblast
precursors and their differentiation into mature osteoblasts.

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  Glucocorticoids induce the apoptosis of osteoblasts and
osteocytes- decrease in bone forming cells.
 Glucocorticoids inhibit the differentiated function of the
osteoblast and bone formation.
 This results from direct effects of glucocorticoids on the
osteoblast and suppression of IGF1 transcription.

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 Thyroid hormone
 In children, hyperthyroidism is associated with increased
skeletal growth, and hypothyroidism results in decreased
growth.
 Thyroid hormones increase bone resorption and turnover,
although their effects on bone formation are less clear.
 Increase the transcription of collagenase and gelatinase by
osteoblasts

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 Insulin
 Normal skeletal growth depends on an adequate amount of insulin.

 Excess insulin production by the fetuses of mothers with

uncontrolled diabetes results in excessive growth of the skeleton and
other tissues.
 Children and adolescents with type 1 diabetes are at increased risk
for decreased bone mineral acquisition.
 Insulin at physiologic concentrations selectively stimulates
osteoblastic collagen synthesis by a pretranslational mechanism.
Insulin can mimic the effects of IGF1.
 Insulin and IGF1 signaling is essential for maintenance of bone
remodeling
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 Gonadal hormones
 Estrogens and androgens are critical for skeletal develop-
ment and maintenance
 Gonadal hormones are crucial for the pubertal growth spurt,
and estrogen is necessary for epiphyseal closure.
 Androgens can increase bone formation

 Deficiency of estrogen or androgen increases bone

resorption

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 HORMONE TARGET MECHANISM NET EFFECT
ORGAN

PTH GIT Ca , P absorption Ca, P

Kidney Ca reabsorption, P reap Ca , P
Bones osteoclast activity Ca, P, bone
osteoblast activity Ca, P, bone

Vit D GIT Ca P absorption Ca, P

Bone osteoclast number & Ca, P
Parathyroid activity
PTH synthesis

FGF 23 Kidney P reabsorption, calcitrol P

GIT Ca, P absorp Ca, P
Bone mineralization of bone Ca, P

Calcitonin Bone osteoclast activity Ca

Kidney Ca reabsorption Ca

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 HORMONE TARGET MECHANISM NET EFFECT
ORGAN

Glucocorticoids GIT Ca absorption Ca, P

Kidney Ca, P reabsorption Ca, P
Bone osteoblast apoptosis, bone
activity bone
osteocyte apoptosis
Thyroid Bone resorption > formation Ca, bone

Gonadal Bone osteoclast activity Ca, P

steroids osteoclast apoptosis bone
osteoblast apoptosis

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 Drugs affecting calcium balance
 Bisphosphonates

 SERMs

 Calcimimetics

 Thiazide diuretics

 Fluorides

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 Bisphosphonates(BPNs)
 They are synthetic pyrophosphate derivatives

•FIRST GENERATION •SECOND GENERATION

Etidronate Alendronate
Clodronate Pamidronate
Tiludronate Ibandronate
• THIRD GENERATION

Risedronate
Zolendronate
Neridronate
Oxidronate
04/06/2023 49
 Pharmacokinetics
 All oral bisphosphonates are very poorly absorbed from the
intestine
 These drugs should be administered with a full glass of water
following an overnight fast and at least 30 minutes before
breakfast
 Excreted primarily by the kidneys

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 Mechanism
 Effective calcium chelators

 Inhibit the dissolution of bone crystal

 After ingestion by osteoclasts- hastens their death by

apoptosis
 Stimulates osteoblasts to release osteoclast inhibiting factor

 Block hydroxyapatite crystal growth

 Have to correct mineral imbalance before giving these drugs.

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 Adverse drug reactions
 General : headache, IV injection releases cytokines- fever,
joint pains, myalgia, occular inflammation
 GIT : nausea, abd pain, diarrhoea, heartburn, oesophagitis,
ulcers
 Renal : failure , electrolyte abnormalities, zolendronate-
nephrotoxic, ATN
 Others: excessive doses- demineralization, hypocalcemia,
osteonecrosis of jaw, chalk-stick fractures of femoral shaft.

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 Uses
 Osteoporosis : along with prolomged glucocorticoid therapy

 Paget’s disease:IV preparations – zolendronate, pamidronate

 Malignancy : oral Clodronate,

Pamidronate, Ibandronate, Zoledronate – slow IV

Hypercalcemia of malignancy and shrink metastasis in breast

cancer and multiple myeloma

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 Calcium Sensor Mimetics: CINACALCET

 Oral, 30-, 60-, and 90-mg tablets.

 t1/2 of 30-40 hours

 Metabolized by multiple hepatic cytochromes, including

CYPs 3A4, 2D6, and 1A2.
 Eliminated by renal excretion

04/06/2023 54
 Mechanism
 Calcimimetics - mimic the stimulatory effect of calcium on the
calcium-sensing receptor (CaSR) to inhibit PTH secretion by
the parathyroid glands.
 Lower the concentration of Ca2+ at which PTH secretion is
suppressed.
 Treatment of secondary hyperparathyroidism.

 Hypercalcemia associated with parathyroid carcinoma .

 ADR- hypocalcemia, seizures

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 RANKL Antagonist- Denosumab
 Humanized monoclonal antibody

 Reduces number of osteoclasts and bone resorption

 Increases spine and hip bone mineral deposits

 Approved for women with postmenopausal osteoporosis

04/06/2023 56
 SERMs - Raloxifene
 Estrogen agonist in bone

 Prevention and treatment of osteoporosis.

 Increases bone density and decreases vertebral fractures.

 Preferred therapy for osteoporosis in women with breast

cancer and family history of cancer.

04/06/2023 57
 Thiazide diuretics
 Reduce renal excretion of calcium

 To treat hypercalciuria and incidence of calcium oxalate

stone formation.
 Increase effects of PTH – Ca reabsorption.

 Enhances Na+/Ca+2 exchange in basolateral membrane of

DCT

04/06/2023 58
 Fluorides
 Mitogen for osteoblasts, increases trabecular bone mass.

 Hydroxyapetite to fluoroapetite –denser, more brittle

 Prophylaxis for dental caries.

04/06/2023 59
 Strontium Ranalate
 Ranelic acid salt of strontium.

 Blocks differentiation of osteoclasts – promotes apoptosis –

prevents bone resorption
 Increases bone formation

 2gm/day oral

 Reduces risk of spine and hip fractures in osteoporosis

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 Sevelamer Hydrocloride
 Phosphate binding gel – 800mg TDS with meals along with
calcium supplements
 Used to treat hyperphosphatemia due to
hyperparathyroidism and hyoervitaminosis-D
 ADR- constipation, epigastric distress, headache

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Drug interactions with calcium
DRUG EFFECT

Beta- blockers Decreased beta-blocker absorption

Calcium channel blockers reduction in efficacy of CCB

Corticosteroids Decreased calcium absorption

Fiber Decreased calcium absorption

Iron Decreased iron absorption
Oxalic acid (found in rhubarb and Decreased calcium absorption
spinach)

Phenytoin Decreased phenytoin absorption

Phosphorus (found in dairy products) Decreased calcium absorption

Phytic acid (found in bran and cereals) Decreased calcium absorption

04/06/2023 62

Quinidine Decreased quinidine renal excretion

 DRUG EFFECT

Salicylates Increased salicylic acid renal excretion

and decreased pharmacologic effects

Tetracycline Decreased serum tetracycline levels

Thiazide diuretcs Increased calcium absorption

Vitamin D Increased calcium absorption

04/06/2023 63
Diseases associated with calcium
 Hypocalcemia

 Hypercalcemia

 osteoporosis

04/06/2023 64
 Hypocalcemia
 Hypocalcemia usually occurs when the plasma calcium level
falls below 8 mg per dL.
 Irritability, seizures, laryngeal spasm, teeth hypoplasia,
atrophy of skin and nails
 Treated with Magnesium chloride

 Oral calcium, vitamin D

 Chlorthalidone – to lower renal clearance of calcium

04/06/2023 65
 Hypercalcemia
 Hypercalcemia generally occur with ingestion of calcium more
than 4 to 5 gm per day.
 Correct dehydration- isotonic saline
 Diuresis- increase calcium excretion- furosemide 40mg IM 6-12
hrly lowers Ca
 Inhibit bone resorption – bisphosphonates, calcitonin
 Reduce GI absorption –cellulose phosphate
intake,corticosteroids
 Promote uptake of calcium by bones and tissues- phosphates
04/06/2023 66
Osteoporosis
 Osteoporosis is a skeletal disorder characterized by a loss of
bone osteoid that reduces bone integrity and bone strength,
predisposing to an increased risk of fracture
 The most common causes include aging, sex hormone de
ciency, alcoholism, smoking, and high-dose glucocorticoid
administration
 Osteoporosis is usually asymptomatic until fractures occur. It
may present as backache ofvarying degrees of severity or as
a spontaneous fracture or collapse of a vertebra. Loss of
height is common.
04/06/2023 67
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  Serum PTH, calcium, phosphorus, and alkaline phosphatase
usually normal. Serum 25-hydroxyvitamin D levels – low
 Dual-energy x-ray absorptiometry (DXA) is used to determine
the bone density of the lumbar spine, hip, and distal radius.
 Fracture Risk Assessment Tool (FRAX) predict an individual's
10-year risk of fractures.

04/06/2023 69
 Treatment
 Calcium :key element in the therapy of osteoporosis.

• Calcium carbonate 40% and tribasic calcium phosphate 39%

have the greatest percentage of elemental calcium.

• Calcium carbonate should be taken with a meal, whereas

calcium citrate is not dependent on gastric pH for absorption
and may be taken without regard to meals.

• The use of calcium supplements is rarely associated with

hypercalciuria or renal calcium stones.

• Fiber and iron impairs absorption. Patients should take

tetracycline compounds and calcium at least 2 hours apart to
04/06/2023 avoid intestinal chelation. 70
  Vitamin D: oral vit D3 is supplemented 800-2000units/day

 Low-dose transdermal systemic estrogen prevents

osteoporosis in women with hypogonadism
 Testosterone replacement therapyprevents osteoporosis in
hogonadal men
 Bisphosphonates -inhibits osteoclast­induced bone
resorption. They increase bone density significantly and
reduce the incidence of vertebral fractures.

• oral calcium supplements (500-1000 mg/day) and with oral

vitamin D3 (starting at 1 000 units/day) .
04/06/2023 71
  Denosumab- 60 mg SC every 6 months

 Teriparatide- 20 meg/day SC for 2 years

 SERMs – Raloxifene -60 mg/day orally

 Tamoxifen is another SERM -women for up to 5 years after

resection of breast cancer that is estrogen receptor positive.
 Bazedoxifene is a SERM that is available as a FDC with
conjugated estrogens.

04/06/2023 72
  A nasal spray of calcitonin-salmon (Miacalcin) is available
that contains 2200 units/mL in 2-mL metered-dose bottles.
 Ipriflavone -synthetic derivative of naturally occurring
phytoestrogens. 600 mg daily
 Percutaneous vertebroplasty or kyphoplasty -vertebral
compression fractures who fail conservative pain
management.

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  Combination therapy:

• Bisphosphonates + Hormone Therapy in postmenopausal women

• Raloxifene + Alendronate

• Calcitonin + HT

• Estrogen replacement therapy + PTH -initial loss in cortical bone.

• PTH + Alendronate - increases BMD more than alendronate alone -

antagonistic effect of the combination on PTH efficacy.

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Therapeutic uses of Calcium
 To prevent or correct calcium deficiency

 In treatment of hypocalcemic tetany –

Calcium gluconate (10%) 10-20ml IV slowly followed by IV

infusion 40 ml in 1 litre saline over 4-8 hrs.
 To treat osteoporosis

04/06/2023 75
 As phosphate binders in CKD - Sevelamer

 Dietary supplement- growing children, pregnant, lactating

and menopausal etc. Also in men and women reduce the
bone loss
 Osteoporosis: Prevention and treatment of osteoporosis with
HRT/Raloxifene/Alendronate – to ensure Ca++ deficiency
does not occur
 Empirically in dermatoses, parathesia and weakness

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 Cardiac arrest- intracardiac injection of calcium in cardiac
arrest
 Placebo- calcium gluconate IV produces feeling of warmth
which spreads as a wave all over the body
 As an antacid

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Calcium Preparations
 Oral preparations-

CALCIUM SALTS Ca CONTENT Gm req to provide

Mg / gm of salt 1 gm of Ca
Carbonate 400 2.5
Phosphate 230 4.4
Citrate 211 4.7
Glycerophosphate 162 6.3
Lactate 130 7.7
Gluconate 89 11
Heptagluconate 82 12
04/06/2023 78
  Parenteral preperations.

Calcium gluconate inj – 1gm in 10 ml

Calcium laevulinate injection – IM / IV as 10% solution

Calcium chloride – ingredient in Ringer lactate solution

04/06/2023 79
 Conclusion
 Bone composed of organic and inorganic components.
Inorganic – calcium phosphate salt hyfroxyapetite.
 Dynamic structure depends on anabolic and catabolic
processes & physiologic regulators of calcium and phosphate
homeostasis.
 PTH, calcitriol, calcitonin FGF23 – modulators of bone
remodelling and mineral homeostasis.
 Bone disorders can be treated by correcting the underlying
mineral imbalances.

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