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Calcium –Physiological Roles

Excitability of nerves and muscles and regulates permeability of cell membranes. Also integrity of cell menbanes

Ca++ essential for excitation and coupling of all types of muscles

Excitation and secretion of endocrine and exocrine glands and release of neurotransmitters from erve endings

Intracellular messenger for hormones, autacoids and transmitters

Impulse generation and conduction in heart

Coagulation of Blood

Structural function of Bone and Teeth - hydroxyapatite 2

Plasma Calcium Level

Regulated by 3 hormones Parathormone, calcitonin and Calcitriol (active vit. D)

Normal plasma level = 9-11 mg/dl

40% is bound to plasma protein – albumin, 10% -citrate, carbonate and phosphate and 50% is free ionized and important form

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Circulating Calcium Ionized calcium (free calcium)

Responsible for calcium function

Can be directly measured

Hypoalbuminemia – total Ca++ may be low but conc. of Ca++ is usually normal

Acidosis – favours ionization

Alkalosis – disfavours ionization – hyperventilation precipitates tetany and laryngospasm in Calcium deficiency

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Pharmacokinetics Absorbed from entire small intestine including duodenum

– carrier mediated active transport under the influence of Vit.D

Phytates, phosphates, oxalates and tetracycline – reduces absorption

Glucocorticoides and Phenytoin reduces Ca absorption

Filtered through glomerulus but mostly reabsorbed

Vit. D increases and Calcitonin decreases reabsorption in proximal tuule

PTH increases distal tubular reabsorption

300 mg is excreted daily in urine and faeces

Daily requirement: 800 -1500 mg per day (1/3rd absorbed)

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Calcium Preparations

Calcium chloride (27% Ca): freely water soluble, but irritant - tissue necrosis on IM or IV (extravasation). Orally also irritant

Calcium gluconate (9 % Ca): 0.5 gm/1 gm tabs and 10% injections – non irritant (preferred)

Calcium lactate: orally non irritant

Calcium dibasic phosphate (23% Ca): Insoluble, but with HCl form soluble salts - antacids and replacement

Calcium chloride: Insoluble and no irritant – antacids

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Calcium - Uses1. Tetany: Severe cases Calcium gluconate 10 to 20 ml IV

over 10 minutes followed by 50 to 100 ml of Ca gluconate solution over 6 Hrs Oxygen inhalation, IV fluids then oral therapy

2. Dietary supplement: growing children, pregnant, lactating and meopausal etc. Also in men and women reduce the bone loss

3. Osteoporosis: Prevention ant treatment of osteoporosis with HRT/raloxifene/Alendronate – to ensure Ca++ deficiency does not occur Calcium and Vit. D3 used as adjuvant

4. Empirically in dermatoses, parathesia and weakness

5. Antacids

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Vitamin D Mainly D3 (cholecalciferol) and D2 (calciferol)

Both are equally active in man

Calcitriol (active form of D3) is more important physiologically

Released from liver in blood and binds to specific vit D binding globulin

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VITAMIN D SYNTHESIS

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL

VITAMIN D3

VITAMIN D3

25(OH)VITAMIN D

h25-HYDROXYLASE

25(OH)VITAMIN D

1,25(OH)2 VITAMIN D

(ACTIVE METABOLITE)

1a-HYDROXYLASE

TISSUE-SPECIFIC VITAMIN D RESPONSES11

Vitamin D

The body can supply its own Vitamin D via the synthetic pathways

Alternatively, Vitamin D may be supplied by Vitamin D - enriched foods. The classic examples are milk and multiple vitamins.

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Actions of calcitriol Enhancement of absorption of Ca and PO4 from

intestine

By increasing the synthesis of calcium channels and a carrier “calcium binding protein (CaBP)” or calbindin

Analogous to stroid hormones – binds to cytoplasmic vit D receptor (VDR)-translocation-increased synthesis of mRNA-regulation of protein synthesis

But, why quick? - Activation of VDR also promotes endocytotic capture of Calcium and transport across the duodenal mucosa

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Calcitriol also enhances recruitment and differentiation of osteoclast precursor for remodelling – resorption of Calcium and PO4 from bone

Mature osteoclasts lack VDR, induces “receptor for acivaton of nuclear factor-kB-ligand (RAANKL)” in osteoblasts and activates osteoclasts indirectly

Laying down and mineralization of osteoids

Also enhances tubular reabsorption of Calcium

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VITAMIN D MECHANISM OF ACTION

5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE

TRANSCRIPTION START SITE

RNA POLVIT D / VDR

IN THE NUCLEUS

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Pharmacokinetics Absorbed fro intestine in presence of Bile salts mainly

by lymphatics

D3 is better absorbed than D2

Binds to alpha-globulin and stored in fatty tissues for many months

Half life varies from 1 – 18 days

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Unitage and preparation

1mcg of Cholecalciferol = 40 IU of vit.D

Calciferol (D2): oily solutions in gelatin capsules –25000/50000 IU caps

Cholecalciferol (D3): oral and IM injections –given 3 to 4 weeks intervals

Calcitriol: 0.25 to 1 mcg orally on altenate days

Alfacalcidol: Prodrug – rapidly hydrolysed to calcitriol in liver. Equally active to calitriol on long term use. Dose – 1-2 mcg/day

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Vit D - Uses Prophylaxis (400 IU/day ) and treatment(3000 -4000

IU/day) of rickets & osteomalacia : alternatively Oral/IM injection 3-6 lac IU every 2-6

month interval

Metabolic Rickets Vit D resistant rickets: PO4 with high doses of calcitriol

Vit D dependent rickets

Renal rickets

Senile or postmenopausal osteoporosis

Hypoparathyroidism: calcitriol/alfacalcitriol

Fanconi like syndrome Calcipotriol : Vitamin D analog used topically in psoriasis

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Vitamin D deficiency

•Deficiency of vitamin D leads to:

Rickets in small children.

Osteoporosis

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Clinical manifestation

1. Osseous changes:

1) Head: craniotabes, frontal bossing, box like skull, delayed closure of anterior fontanelle

2) Teeth: delayed eruption, with abnormal order

3) Chest: rachitic rosary, pigeon chest, funnel-shaped chest

4) Spinal column: scoliosis,kyphosis, and lordosis

5) Extremities: bowlegs

6) Rachitic dwarfism

2. Muscular system: potbelly, late in standing and walking

3. Motor development: delayed

4. Other nervous and mental symptoms

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Treatment

1. Food and nursing care

2. Prevention of complications

3. Special therapy

1) Vitamin D therapy

A. General method

Vitamin D 2000-4000IU/day for 2-4 weeks, then

change to preventive dosage (400IU).

B. A single large dose:

For severe case, or Rickets with complication, or those who

can’t bear oral therapy. Vitamin D3 3 LAC -6 LAC IU, im,

preventive dosage can be used after 2-6 months.

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Prevention1. pregnant and lactating women should take

adequate amount of vitamin D.

2. Advocate sunbathing

3.Advocate breast feeding, give supplementary food on time

4. Vitamin D supplementation:

• In prematures, twins & weak babies: 800 IU/day

• For term babies and infants : 400 IU per day,

• For those babies who can’t maintain a daily supplementation: Vitamin D3 1L-2L IU IM.

5. Calcium supplementation: 24

Vitamin D - Sources• Sunlight is the most

important source

• Not found naturally in many foods

• Synthesized in body

• Plants (ergosterol)– Sun-cured forages

• Fluid milk products are fortified with vitamin D

• Oily fish & Fish liver oil

• Egg yolk

• Butter

• Liver

• Difficult for vegetarians25

TOXICITY

•Hypervitaminosis Dcauses hypercalcemia, which manifest as:

• Nausea & vomiting• Excessive thirst , polyuria & anorexia • Severe itching• Joint & muscle pains• Disorientation & coma.• Calcification of soft tissue

– Lungs, heart, blood vessels ,

• Hypercalcemia– Normal is ~ 10 mg/dl– Excess blood calcium leads to stone formation in

kidneys26

Parathyroid Hormone Location : Posterior to thyroid gland , 4 in nos

Secreted by principal cells

Preproparathyroid hormone proparathyroidhormone PTH(84 AA polypeptide)

Hypocalcemia is a principal factor regulating PTH synthesis & release, mediated through activation of adenylate cyclase & subsequent increase in cAMP level

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Rapidly metabolised in liver & kidney

T1/2 is 2-5 min

Actions Bone

Kidney

Intestine

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PTH receptor G protein coupled receptor on activation increases cAMP formation & intracellular Ca++ in target cells, in bone target cells are osteoblast

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PTH,

Calcium &

Phosphate

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CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPS

NORMAL BLOOD Ca

RISING BLOOD Ca

FALLING BLOOD Ca

SUPPRESS PTH

STIMULATE PTH

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION31

Calcitonin

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Calcitonin, peptide hormone secreted by thethyroid gland, tends to decrease plasma Caconcentration and, in general, has effectsopposite to those of PTH

Parafollicular cells, or C cells, lying in theinterstitial fluid between the follicles of thethyroid gland

32-amino acid peptide with a molecular weight ofabout 3400

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The primary stimulus for calcitoninsecretion is increased plasma Ca ionconcentration

calcitonin decreases blood Ca ionconcentration rapidly, within minutesafter injection of the calcitonin

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Inhibit bone resorption by direct action on Osteoclasts

Also inhibits the proximal tubular reabsorption of calcium and phosphate by direct action on kidney

Action is mediated through G- protein coupled calcitonin receptor & increased cAMP formation but target cells are different from that of PTH

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Calcitonin : Preparations Porcine (Natural) calcitonin:

Antigenic

Synthetic salmon calcitonin:

More potent due to slower metabolism

Synthetic human calcitonin:

1 IU = 4 μg of std preparation

Calcitonin is given by SC/IM routes. Salmon calcitonin is also available as nasal spray

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• Hypercalcemia states (e.g associated with neoplasia)

• Pagets disease of bone:

• Postmenopausal osteoporosis & corticosteroid induced osteoporosis:

• Salmon calcitonin is used as nasal spray along with Vit D supplements 200 IU /day

Uses

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Bisphophonates (BPNs)

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Introduction Non-hormonal agent in Ca++ homeostasis

Recently attracted considerable attention

Prevent osteoporosis and useful in metabolic bone diseases and hypercalcaemia

Most effective “antiresorptive” drug at present

BPNs are analogous of pyrophosphates – Carbon atom replacing “P-O-P skeleton”

BPNs have selective affinity for Calcium phosphate –so calcified tissues

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Bisphosphonates have two side

chains:

R1 affects binding affinity to

bone;

R2 affects antiresorptive capacity

and, possibly,Side-effect profile.

Bisphosphonates vary in potency

Based on these specific side

chains.

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Generations of Bisphosphonates With each successive generation, there has been

increased potency, with more selectivity for inhibition of resorption and less inhibition of bone formation.

First-generation bisphosphonates, such as etidronateand clodronate, inhibit bone formation and bone resorption equally.

Second-generation bisphosphonates include pamidronate and alendronate

The third generation includes the highly potent risedronate and zolendronate.

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BPNs - MOA BPNs have selective affinity for Calcium phosphate – so calcified

tissues

2 main component of Bone – Bone matrix and Solid mineral phase (hydroxyapatite)

• Normally, The non-mineralized osteoid covers the mineralized bone matrix preventing its resorption by osteoclasts

• For resorption – osteoids must get dissolved or mineralized (solubilized) such that osteoclasts can attach to the mineralized matrix

• In resorptive pits – acidic zone is created at ruffled boarders of osteoclasts followed by resorption of matrix by acid hydrolases

• BPNs localize in the acidic zone due to high affinity for Ca++ ions

• Ca++ ions released from bone surface due to high acidity BPNs also released – internalized into osteoclasts by endocytosis

• Results in

Accelerated apoptosis of osteoclasts reducing their number

Disruption of the cytoskeleton of the ruffled boarder of osteoclasts42

Therapeutic Uses1. Osteoporosis: Alendronate>HRT or raloxifene

I. Prevention and treatment of post-manaupasal osteoporosis

II. Both Men and Women – age related, steroid induced and idiopathic osteoporosis

Oestrogen prevents only vertebral fracture, BNPs 5 years protection

2. Pagets disease: Honeycomb like bone architecture – arrest osteolytic lesions, reduce bone pain and improve secondary symptoms. Alendronate, Risedronate, Pami and Zole are used. Calcitonin combination better

3. Hypercalcaemia of Malignancy: Medical emergency with altered consciousness – Pamidronate 60-90 mg IV 2-4 hours or Zoledronate 4 mg IV 15 minutes. Suplement with calcitonin IM 6-12 Hrly for 2 days

4. Osteolytic Bone Metastasis

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Individual Drugs1. Etidronate: Not used anymore

2. Pamidronate: Only IV 60-90 mg for 2-4 Hrs, weekly or monthly in Pagets disease and hypercalcaemia

3. Alendronate: Available in oral form 5, 10, 35, 70 mg tabs. Prevention of osteoporosis in man and woman.

a. In empty stomach with glass of water

b. Do not allow to lie down or eat till 30 minutes –oesophagitis; Tea, coffee, mineral water, Juice, NSAIDs

c. ADRs: Gastric errosion, retrosternal pain, flatulence

d. Bioavailability 1%, 50% goes to Bone, terminal elimination half-life 10.5 years

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Individual Drugs – contd.4. Risedronate: Similar to Alendronate, but more

potent

• Used in osteoporosis and Paget`s disease

5. Zolendronate: Prenterally effective, highly potent

• Suppression of osteoclastic activity and additional antitumor effect (mevalonate pathway)

• Proliferation of bony metastasis of Prostate and breast cancer cells are suppressed

• Can be infused in 15 minutes

• ADR: Flu-like symptoms due to cytokine release

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Adverse effects Oral bisphosphonates causes Gastrointestinal

complications such as gastritis or esophagitis, abdominal pain, nausea, vomiting, diarrhea, and constipation.

To minimize gastrointestinal inflammation

And ulcer, patients should remain upright (sitting or standing) for at least 30 minutes after taking the medication

Bisphosphonate-related osteonecrosis of the jaw Phossy jaw

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Osteoporosis

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A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

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Primary osteoporosis Postmenopausal

↓ estrogen results in ↑ osteoclastic activity without ↑osteoblastic activity

Bone loss – 2-3% per year of total bone mass

Most common fx: vertebral, distal forearm

Age related – 3rd decade of life starts slow decline in bone mass at rate

of 0.5-1% per year

Most common types of fx: hip and radius, F>M

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Secondary OsteoporosisDisease states

Acromegaly

Addison’s disease

Amyloidosis

Anorexia

COPD

Hemochromatosis

Hyperparathyroidism

Lymphoma and leukemia

Malabsorption states

Multiple myeloma

Multiple sclerosis

Rheumatoid arthritis

Sarcoidosis

Severe liver dz, esp. PBC

Thalessemia

Thyrotoxicosis

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Drugs causing osteoporosis Aluminum

Anticonvulsants

Excessive thyroxine

Glucocorticoids

GnRH agonists

Heparin

Lithium

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Normal Bone Remodeling: A Balance of Bone Resorption and Formation

2–4 weeks 3–4 months

Resting Stage

Formation RemodelingCompleted

Activation Resorption

Lining cells

Osteoclastprecursors

OsteoclastsOsteoblasts

Bone remodeling unit

Lining cells

FormationResorption

Secondary mineralization

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Osteoporosis: Resorption Exceeds Formation

2–4 weeks 3–4 months

Lining cells

Osteoclast precursors

Bone remodeling unit

1. Adapted from: Rosen CJ. Available at: http://www.endotext.org/parathyroid/index.htm. Accessed December 7,2007.

Lining cells

OsteoclastsOsteoblasts

FormationResorption

Pits develop that weaken bone

Resting Stage Formation Remodeling

CompletedActivation Resorption Secondary

Mineralization

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Treatment Objectives

Osteoclast

Inhibition of resorption

Osteoblast

Stimulation of formation55

Osteoporosis drugs used

Anabolic Agent Antiresorptive Agents

Function Forms new bone Suppresses bone resorption

Mechanism ↑s osteoblast activity ↓ osteoclast activity

Bone turnover

Accelerates turnover Slows turnover

BMD effect Forms new bone ↑ bone volume

↑ mineralization of existing bone

Drugs Teriparatide , Fluoride, Androgens

BisphosphonatesCalcitonin , ERT,SERMs, Calcium,VitD ,Thiazides

Dual action bone agent :Strontium ranelate56

Bisphosphonates

Etidronate

Pamidronate

Alendronate

Risedronate

Ibandronate

Tiludronate

Zoledronate

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Bisphosphonates

Advantages

Increases BMD by 1-4%, decreases fracture risk by 41-44%

No increased risk of breast, uterine ca or thromboembolic events

Weekly dosing

Disadvantages

Risk of gastrointestinal sx

ex dosing instructions

Contraindicated in ESRD; need to adjust dose according to creatinine clearance

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Estrogen Replacement Therapy (ERT)

Indication: Used to prevent and treat osteoporosis (FDA indication is for prevention)

Mechanism:↓es osteoclast activity,

Acts on osteoblast to ↓ production of IL- 6

↑ production of osteoprotegerin,there by interfering with recruitment of osteoclast precursors.

Dose: Estrogen: 0.625mg od, Progesterone 2.5mg qd (if uterus present)

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ERT

Advantages

Increases bone density (1-5%) and decreases risk of fracture (25%)

Relief of hot flashes, vaginal dryness

Decreases LDL, increases HDL

?Prevention of Alzheimer’s disease

Relatively inexpensive

Disadvantages ↑ bone loss after stopping

↑ risk of uterine ca

↑ risk of thromboembolicevents

Possible ↑ risk of breast cancer

Side effects: breast tenderness,

breakthrough bleeding

↑ risk of coronary events in women with known CAD in first year of use (HERS trial)

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Selective Estrogen Receptor Modulators (SERMs)

1.Raloxifene: partial agonist in bone and CVS but an antagonist in endometriumand breast. 2.Tamoxifen: antagonist in breast carcinoma cells, blood vessels but agonist in uterus, bone, liver and pitutary

Dose: Raloxifene 60mg od

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SERMS

Advantages

Increases bone density (2%) and decreases fracture risk (30%)

No stimulation of breast or endometrial tissue

No need for progestin in women with uterus

Decrease LDL

Disadvantages

Increased risk of thromboembolic events

Doesn’t treat post-menopausal sx

May increase hot flashes

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Vitamin D

It may improve intestinal calcium absorption ,suppress bone remodeling and improve BMD in individuals with marginal or deficient Vit D status.

Calcitriol – suppresses the PTH function and reduce bone turnover.

Dosage: 400-800 IU /day.

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Thiazide diuretics

Reduce urinary calcium excretion and constrain bone loss in patients with hypercalciuria.

Dosage :

Hydrochlorothiazide – 25 mg once or twice daily.

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Bone forming agents

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rParathyroid hormone [rPTH(1-34), teriparatide]

Mechanism of action:

Stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

Daily SC injections of 40mcg of rPTH for 12-18 months , increased BMD by 9-13% and decreased risk of vertebral fractures by 65 to 69 %

Side effects: Occasional headache and nausea

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Strontium ranelate Oral strontium ranelate is an alternative oral treatment,

belonging to a class of drugs called "dual action bone agents" (DABAs).

Proven efficacy, especially in the prevention of vertebral fracture.

Mechanism of action: ↑collagen & noncollagen protein systhesis, enhances preosteoblast differentiation, ↓osteoclast function

Dosage : 2 g oral suspension daily Adverse effects : thromboembolism

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Glucocorticoid-Induced Osteoporosis: Treatment

Only bisphosphonates have been demonstrated in large clinical trials to reduce the risk of fractures in patients being treated with glucocorticoids.

Risedronate prevents bone loss and reduces vertebral fracture risk by ~70%. Similar beneficial effects are observed in studies of alendronate.

Controlled trials of hormone therapy have shown bone-sparing effects, and calcitonin also has some protective effect in the spine.

Thiazides reduce urine calcium loss, but their role in prevention of fractures is unclear.

PTH has also been studied in a small group of women with glucocorticoid-induced osteoporosis, where bone mass increased substantially, and teriparatide is currently being investigated in a larger multicenter trial.

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Investigational Agents Ospemifene, Lasofoxifene

Bazedoxifene

Arzoxifene

Strontium ranelate

Increases collagen & noncollagen protein synthesis, enhances preosteoblastdifferentiation, reduces osteoclast function

Denosumab

Human mAb, inhibits RANKL which inhibits osteoclast activation and survival

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A human monoclonal antibody to the receptor activator of NFkBligand (RANKL), which is given subcutaneously once every sixmonthsOral calciomimetic drugs that stimulate intermittent production of parathyroid hormoneSelective oestrogen receptor modulators with mixed oestrogenicand anti-oestrogenic effectsInhibitors of sclerostin, a protein produced by bone that is a negative regulator of bone formation, and its signalling pathway

Investigation of the causes and management of poor compliance and persistence

Assessment of the long term effectsof anti-resorptive treatments on bone strength

Ongoing research

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Thank you

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