osteoporosis treatment, rickets treatment , calcium preparations, vit d , parathyroid hormone, bisphosphonates, calcitonin

1. Drugs affecting calcium
balance

2. Preparations of calcium
S.No Preparation Characteristic
1 Calcium
chloride
27 % calcium , highly irritant , not
for IM use. Orally also irritable
2 Calcium
gluconate
9 % calcium , non irritating
Sense of warmth produced on
injection
3 Calcium lactate 13 % calcium, orally well
tolerated , non irritating
4 Calcium dibasic
phosphate
23 % calcium , used as antacid and
calcium supplement
5 Calcium
carbonate
40 % calcium , tasteless, non
irritating , used as antacid

3. Uses of calcium
• Tetany
• As dietary supplement
• Osteoporosis
• Empirical:
– dermatoses, parasthesias, weakness, vague
complaints
• As antacid
• Lead colic, hypermagnesemia, hyperkalemia
• Cardiac arrest

4. Treatment of hypercalcemia
• Hydration & dietary calcium restriction < 400 mg/day
• Sodium chloride:
• Saline administration will cause renal elimination
of calcium
• Furosemide 20 -40 mg every 2-4 hrs
• Glucocorticoids: reduce intestinal absorption &
tubular reabsorption of calcium
• Calcitonin: 4 IU/kg SC OR IM twice or once daily can
be increased to 8 IU/kg IM 6 hrly
• Mithramycin : 25 μg/kg IV over period of 4- 6 Hrs
• Inorganic phosphate: phosphosoda 5 ml TDS

5. Preparations of calcitonin
• 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

6. Uses of calcitonin
• 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

7. Preparations of vit D
• Ergocalciferol: Vit D2 oral capsules
• Cholecalciferol: Vit D3
• Oral/IM injection 3-6 lac IU every 2-6 month interval
• Calcitriol: oral capsules & solution 0.25-1 μg daily or IV
on alternate days
• Alfacalcidiol & dihydrotachysterol:
• Prodrugs orally effective and rapidly biotransformed
into calcitriol in liver. They are effective in renal bone
disease & hypoparathyroidism
• Calcipotriol : Vitamin D analog used topically in
psoriasis

8. Uses of Vit D
1. 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
2. Metabolic rickets :
1. Vit D resistant rickets: high doses
2. Vit D dependent rickets: calcitriol or alphacalcidiol
3. Renal rickets: calcitriol or alphacalcidiol
3. Senile or post menopausal osteoporosis
4. Hypoparathyroidism : calcitriol or alphacalcidiol are better
5. Fanconis syndrome: Vit D can raise lowered phosphate
levels that occur in this condition
6. Calcipotriol : Vitamin D analog used topically in psoriasis

9. Vitamin D deficiency
•Deficiency of vitamin D leads to:
 Rickets in small children.
 Osteoporosis

10. 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

13. 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.

14. 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:

15. 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

16. 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

17. Biphosphonates
• Analogs of pyrophosphate
• First generation:
• Etidronate
• Second generation:
• Pamidronate
• Alendronate
• Third generation :
• Risedronate
• Zoledronate

18. • Mechanism of action
Protect dissolution
of hydroxyapatite
from bone
Accelerates apoptosis
of osteoclasts
Inhibits release of IL-6

19. • Highly polar so less poorly absorbed through GIT
• Part of absorbed drug is incorporated into bone &
remains for long periods years to months
• The free drug is excreted unchanged in urine
• Pharmacokinetics

20. Biphosphonates uses and adverse effects
• Uses
• Pagets disease of bone: treatment of choice
• For prevention and treatment of post-menopausal
osteoporosis
• To prevent corticosteroid induced osteoporosis along with
calcium carbonate
• Hypercalcemia of malignancy: Zolendronate
• Control hypercalcemia of hyperparathyroidism
• To relieve pain of lytic bone lesions
• Nausea, vomiting diarrhoea, esophagitis, peptic ulcer,
fever, myalgia, hypocalcemia, headache & skin rashes
• OSTEONECROSIS , renal impairment
• Adverse effects

22. Osteoporosis

23. Osteoporosis
• 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.

24. 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

25. 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

26. Drugs causing osteoporosis
Aluminum
Anticonvulsants
Excessive thyroxine
Glucocorticoids
GnRH agonists
Heparin
Lithium

27. 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

28. 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

29. Treatment Objectives
29
Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation

30. 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

31. Antiresorptive Agents

32. Bisphosphonates
• Etidronate
• Pamidronate
• Alendronate
• Risedronate
• Ibandronate
• Tiludronate
• Zoledronate

33. 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

34. 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)

35. 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)

36. 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

37. 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

38. 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.

39. Thiazide diuretics
• Reduce urinary calcium excretion and
constrain bone loss in patients with
hypercalciuria.
• Dosage :
Hydrochlorothiazide – 25 mg once or twice
daily.

40. Bone forming agents

41. 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

42. 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

43. 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.

44. 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

45. • Ahuman monoclonal antibody to the receptor activator of NFkB
ligand (RANKL), which is given subcutaneously once every six
months
Oral calciomimetic drugs that stimulate intermittent production of
parathyroid hormone
Selective oestrogen receptor modulators with 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 effects of anti-resorptive treatments
on bone strength
Ongoing research

46. Thank You.