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1
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
3
Drugs affecting calcium balance
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
5
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)
6
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
7
Calcium - Uses
1. 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
8
Drugs affecting calcium balance
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
10
VITAMIN D SYNTHESIS
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
VITAMIN D3
25(OH)VITAMIN D
h
25-HYDROXYLASE
25(OH)VITAMIN D
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
1a-HYDROXYLASE
TISSUE-SPECIFIC VITAMIN D RESPONSES 11
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.
12
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
13
 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
14
VITAMIN D MECHANISM OF
ACTION
5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
RNA POLVIT D / VDR
IN THE NUCLEUS
15
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
16
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
17
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
18
Vitamin D deficiency
•Deficiency of vitamin D leads to:
 Rickets in small children.
 Osteoporosis
19
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
20
21
22
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.
23
Prevention
1. 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 vegetarians
25
TOXICITY
•Hypervitaminosis D
causes 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
kidneys
26
Parathyroid Hormone
 Location : Posterior to thyroid gland , 4 in nos
 Secreted by principal cells
 Preproparathyroid hormone  proparathyroid
hormone  PTH(84 AA polypeptide)
 Hypocalcemia is a principal factor regulating PTH
synthesis & release, mediated through activation
of adenylate cyclase & subsequent increase in
cAMP level
27
 Rapidly metabolised in liver & kidney
 T1/2 is 2-5 min
 Actions
 Bone
 Kidney
 Intestine
28
PTH receptor  G protein coupled receptor on activation increases
cAMP formation & intracellular Ca++ in target cells, in bone target cells
are osteoblast
29
PTH,
Calcium &
Phosphate
30
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 PRODUCTION
31
Calcitonin
32
 Calcitonin, peptide hormone secreted by the
thyroid gland, tends to decrease plasma Ca
concentration and, in general, has effects
opposite to those of PTH
 Parafollicular cells, or C cells, lying in the
interstitial fluid between the follicles of the
thyroid gland
 32-amino acid peptide with a molecular weight of
about 3400
33
 The primary stimulus for calcitonin
secretion is increased plasma Ca ion
concentration
 calcitonin decreases blood Ca ion
concentration rapidly, within minutes
after injection of the calcitonin
34
 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
35
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
36
• 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
37
Bisphophonates (BPNs)
38
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
39
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.
40
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 etidronate
and 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.
41
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 osteoclasts
42
Therapeutic Uses
1. 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
43
Individual Drugs
1. 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
44
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
45
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
46
47
Osteoporosis
48
 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.
49
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
50
Secondary Osteoporosis
Disease 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
51
Drugs causing osteoporosis
Aluminum
Anticonvulsants
Excessive thyroxine
Glucocorticoids
GnRH agonists
Heparin
Lithium
52
Normal Bone Remodeling:
A Balance of Bone Resorption and Formation
2–4 weeks 3–4 months
Resting
Stage
Formation Remodeling
Completed
Activation Resorption
Lining cells
Osteoclast
precursors
Osteoclasts Osteoblasts
Bone remodeling unit
Lining cells
Formation
Resorption
Secondary
mineralization
53
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
Osteoclasts
Osteoblasts
Formation
Resorption
Pits develop that weaken
bone
Resting
Stage Formation Remodeling
Completed
Activation Resorption Secondary
Mineralization
54
Treatment Objectives
Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation
55
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
Bisphosphonates
Calcitonin , ERT,SERMs,
Calcium,VitD ,Thiazides
Dual action bone agent :Strontium ranelate
56
Drugs affecting calcium balance
Bisphosphonates
 Etidronate
 Pamidronate
 Alendronate
 Risedronate
 Ibandronate
 Tiludronate
 Zoledronate
58
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
59
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)
60
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 thromboembolic
events
 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)
61
Selective Estrogen Receptor
Modulators (SERMs)
1.Raloxifene: partial agonist in bone and
CVS but an antagonist in endometrium
and breast.
2.Tamoxifen: antagonist in breast
carcinoma cells, blood vessels but agonist
in uterus, bone, liver and pitutary
Dose: Raloxifene 60mg od
62
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
63
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.
67
Thiazide diuretics
 Reduce urinary calcium excretion and constrain bone
loss in patients with hypercalciuria.
 Dosage :
Hydrochlorothiazide – 25 mg once or twice daily.
68
Bone forming agents
69
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
70
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
71
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.
77
Investigational Agents
 Ospemifene, Lasofoxifene
 Bazedoxifene
 Arzoxifene
 Strontium ranelate
 Increases collagen & noncollagen protein
synthesis, enhances preosteoblast
differentiation, reduces osteoclast function
 Denosumab
 Human mAb, inhibits RANKL which inhibits
osteoclast activation and survival
78
 A human monoclonal antibody to the receptor activator of NFkB
ligand (RANKL), which is given subcutaneously once every six
months
Oral calciomimetic drugsthat stimulate intermittent production
of parathyroid hormone
Selective oestrogen receptor modulatorswith mixed oestrogenic
and anti-oestrogenic effects
Inhibitors of sclerostin, a proteinproduced by bone that is a
negative regulator of bone formation,and its signalling pathway
 Investigationof the causes and management of poor compliance
and persistence
 Assessment of the long term effectsof anti-resorptive treatments
on bone strength
Ongoing research
79
Thank you
80

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Drugs affecting calcium balance

  • 1. 1
  • 2. 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
  • 3. 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 3
  • 5. 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 5
  • 6. 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) 6
  • 7. 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 7
  • 8. Calcium - Uses 1. 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 8
  • 10. 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 10
  • 11. VITAMIN D SYNTHESIS SKIN LIVER KIDNEY 7-DEHYDROCHOLESTEROL VITAMIN D3 VITAMIN D3 25(OH)VITAMIN D h 25-HYDROXYLASE 25(OH)VITAMIN D 1,25(OH)2 VITAMIN D (ACTIVE METABOLITE) 1a-HYDROXYLASE TISSUE-SPECIFIC VITAMIN D RESPONSES 11
  • 12. 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. 12
  • 13. 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 13
  • 14.  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 14
  • 15. VITAMIN D MECHANISM OF ACTION 5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE TRANSCRIPTION START SITE RNA POLVIT D / VDR IN THE NUCLEUS 15
  • 16. 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 16
  • 17. 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 17
  • 18. 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 18
  • 19. Vitamin D deficiency •Deficiency of vitamin D leads to:  Rickets in small children.  Osteoporosis 19
  • 20. 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 20
  • 21. 21
  • 22. 22
  • 23. 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. 23
  • 24. Prevention 1. 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
  • 25. 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 vegetarians 25
  • 26. TOXICITY •Hypervitaminosis D causes 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 kidneys 26
  • 27. Parathyroid Hormone  Location : Posterior to thyroid gland , 4 in nos  Secreted by principal cells  Preproparathyroid hormone  proparathyroid hormone  PTH(84 AA polypeptide)  Hypocalcemia is a principal factor regulating PTH synthesis & release, mediated through activation of adenylate cyclase & subsequent increase in cAMP level 27
  • 28.  Rapidly metabolised in liver & kidney  T1/2 is 2-5 min  Actions  Bone  Kidney  Intestine 28
  • 29. PTH receptor  G protein coupled receptor on activation increases cAMP formation & intracellular Ca++ in target cells, in bone target cells are osteoblast 29
  • 31. 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 PRODUCTION 31
  • 33.  Calcitonin, peptide hormone secreted by the thyroid gland, tends to decrease plasma Ca concentration and, in general, has effects opposite to those of PTH  Parafollicular cells, or C cells, lying in the interstitial fluid between the follicles of the thyroid gland  32-amino acid peptide with a molecular weight of about 3400 33
  • 34.  The primary stimulus for calcitonin secretion is increased plasma Ca ion concentration  calcitonin decreases blood Ca ion concentration rapidly, within minutes after injection of the calcitonin 34
  • 35.  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 35
  • 36. 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 36
  • 37. • 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 37
  • 39. 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 39
  • 40. 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. 40
  • 41. 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 etidronate and 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. 41
  • 42. 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 osteoclasts 42
  • 43. Therapeutic Uses 1. 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 43
  • 44. Individual Drugs 1. 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 44
  • 45. 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 45
  • 46. 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 46
  • 47. 47
  • 49.  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. 49
  • 50. 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 50
  • 51. Secondary Osteoporosis Disease 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 51
  • 52. Drugs causing osteoporosis Aluminum Anticonvulsants Excessive thyroxine Glucocorticoids GnRH agonists Heparin Lithium 52
  • 53. Normal Bone Remodeling: A Balance of Bone Resorption and Formation 2–4 weeks 3–4 months Resting Stage Formation Remodeling Completed Activation Resorption Lining cells Osteoclast precursors Osteoclasts Osteoblasts Bone remodeling unit Lining cells Formation Resorption Secondary mineralization 53
  • 54. 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 Osteoclasts Osteoblasts Formation Resorption Pits develop that weaken bone Resting Stage Formation Remodeling Completed Activation Resorption Secondary Mineralization 54
  • 55. Treatment Objectives Osteoclast Inhibition of resorption Osteoblast Stimulation of formation 55
  • 56. 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 Bisphosphonates Calcitonin , ERT,SERMs, Calcium,VitD ,Thiazides Dual action bone agent :Strontium ranelate 56
  • 58. Bisphosphonates  Etidronate  Pamidronate  Alendronate  Risedronate  Ibandronate  Tiludronate  Zoledronate 58
  • 59. 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 59
  • 60. 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) 60
  • 61. 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 thromboembolic events  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) 61
  • 62. Selective Estrogen Receptor Modulators (SERMs) 1.Raloxifene: partial agonist in bone and CVS but an antagonist in endometrium and breast. 2.Tamoxifen: antagonist in breast carcinoma cells, blood vessels but agonist in uterus, bone, liver and pitutary Dose: Raloxifene 60mg od 62
  • 63. 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 63
  • 64. 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. 67
  • 65. Thiazide diuretics  Reduce urinary calcium excretion and constrain bone loss in patients with hypercalciuria.  Dosage : Hydrochlorothiazide – 25 mg once or twice daily. 68
  • 67. 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 70
  • 68. 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 71
  • 69. 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. 77
  • 70. Investigational Agents  Ospemifene, Lasofoxifene  Bazedoxifene  Arzoxifene  Strontium ranelate  Increases collagen & noncollagen protein synthesis, enhances preosteoblast differentiation, reduces osteoclast function  Denosumab  Human mAb, inhibits RANKL which inhibits osteoclast activation and survival 78
  • 71.  A human monoclonal antibody to the receptor activator of NFkB ligand (RANKL), which is given subcutaneously once every six months Oral calciomimetic drugsthat stimulate intermittent production of parathyroid hormone Selective oestrogen receptor modulatorswith mixed oestrogenic and anti-oestrogenic effects Inhibitors of sclerostin, a proteinproduced by bone that is a negative regulator of bone formation,and its signalling pathway  Investigationof the causes and management of poor compliance and persistence  Assessment of the long term effectsof anti-resorptive treatments on bone strength Ongoing research 79