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
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
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
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
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
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