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Drugs affecting calcium
balance
Preparations of calcium
S.No Preparation Characteristic
1 Calcium
chloride
27 % calcium , highly irritant , not
for IM use...
Uses of calcium
• Tetany
• As dietary supplement
• Osteoporosis
• Empirical:
– dermatoses, parasthesias, weakness, vague
c...
Treatment of hypercalcemia
• Hydration & dietary calcium restriction < 400 mg/day
• Sodium chloride:
• Saline administrati...
Preparations of calcitonin
• Porcine (Natural) calcitonin:
• Antigenic
• Synthetic salmon calcitonin:
• More potent due to...
Uses of calcitonin
• Hypercalcemia states (e.g associated with
neoplasia)
• Pagets disease of bone:
• Postmenopausal osteo...
Preparations of vit D
• Ergocalciferol: Vit D2 oral capsules
• Cholecalciferol: Vit D3
• Oral/IM injection 3-6 lac IU ever...
Uses of Vit D
1. Prophylaxis: 400 IU/day and treatment 3000 -4000 IU/day
of rickets & osteomalacia alternatively Oral/IM i...
Vitamin D deficiency
•Deficiency of vitamin D leads to:
 Rickets in small children.
 Osteoporosis
Clinical manifestation
1. Osseous changes:
1) Head: craniotabes, frontal bossing, box like skull,
delayed closure of anter...
Treatment
1. Food and nursing care
2. Prevention of complications
3. Special therapy
1) Vitamin D therapy
A. General metho...
Prevention
1. pregnant and lactating women should take
adequate amount of vitamin D.
2. Advocate sunbathing
3.Advocate bre...
Vitamin D - Sources
• Sunlight is the most important
source
• Not found naturally in many foods
• Synthesized in body
• Pl...
TOXICITY
•Hypervitaminosis D
causes hypercalcemia, which manifest as:
• Nausea & vomiting
• Excessive thirst , polyuria & ...
Biphosphonates
• Analogs of pyrophosphate
• First generation:
• Etidronate
• Second generation:
• Pamidronate
• Alendronat...
• Mechanism of action
Protect dissolution
of hydroxyapatite
from bone
Accelerates apoptosis
of osteoclasts
Inhibits releas...
• Highly polar so less poorly absorbed through GIT
• Part of absorbed drug is incorporated into bone &
remains for long pe...
Biphosphonates uses and adverse effects
• Uses
• Pagets disease of bone: treatment of choice
• For prevention and treatmen...
Osteoporosis
Osteoporosis
• A systemic skeletal disease characterized by
low bone mass and microarchitectural
deterioration of bone tis...
Primary osteoporosis
• Postmenopausal
– ↓ estrogen results in ↑ osteoclastic activity
without ↑ osteoblastic activity
– Bo...
Secondary Osteoporosis
Disease states
 Acromegaly
 Addison’s disease
 Amyloidosis
 Anorexia
 COPD
 Hemochromatosis
...
Drugs causing osteoporosis
Aluminum
Anticonvulsants
Excessive thyroxine
Glucocorticoids
GnRH agonists
Heparin
Lithi...
Normal Bone Remodeling:
A Balance of Bone Resorption and Formation
2–4 weeks 3–4 months
Resting
Stage
Formation Remodeling...
Osteoporosis: Resorption Exceeds
Formation
2–4 weeks 3–4 months
Lining cells
Osteoclast
precursors
Bone remodeling unit
1....
Treatment Objectives
29
Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation
Osteoporosis drugs used
Anabolic Agent Antiresorptive Agents
Function Forms new bone Suppresses bone resorption
Mechanism ...
Antiresorptive Agents
Bisphosphonates
• Etidronate
• Pamidronate
• Alendronate
• Risedronate
• Ibandronate
• Tiludronate
• Zoledronate
Bisphosphonates
 Advantages
Increases BMD by 1-4%,
decreases fracture risk
by 41-44%
No increased risk of
breast, uteri...
Estrogen Replacement Therapy (ERT)
Indication: Used to prevent and treat
osteoporosis (FDA indication is for prevention)
...
ERT
 Advantages
Increases bone density
(1-5%) and decreases
risk of fracture (25%)
Relief of hot flashes,
vaginal dryne...
Selective Estrogen Receptor Modulators
(SERMs)
1.Raloxifene: partial agonist in bone and
CVS but an antagonist in endomet...
SERMS
 Advantages
Increases bone density
(2%) and decreases
fracture risk (30%)
No stimulation of breast
or endometrial...
Vitamin D
• It may improve intestinal calcium
absorption ,suppress bone remodeling
and improve BMD in individuals with
mar...
Thiazide diuretics
• Reduce urinary calcium excretion and
constrain bone loss in patients with
hypercalciuria.
• Dosage :
...
Bone forming agents
rParathyroid hormone [rPTH(1-34), teriparatide]
Mechanism of action:
Stimulates new bone formation on trabecular and
corti...
Strontium ranelate
• Oral strontium ranelate is an alternative oral
treatment, belonging to a class of drugs called
"dual ...
Glucocorticoid-Induced Osteoporosis: Treatment
• Only bisphosphonates have been demonstrated in large clinical
trials to r...
Investigational Agents
• Ospemifene, Lasofoxifene
• Bazedoxifene
• Arzoxifene
• Strontium ranelate
–Increases collagen & n...
• Ahuman monoclonal antibody to the receptor activator of NFkB
ligand (RANKL), which is given subcutaneously once every si...
Thank You.
Treatment of osteoporosis and  drugs affecting calcium balance
Treatment of osteoporosis and  drugs affecting calcium balance
Treatment of osteoporosis and  drugs affecting calcium balance
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Treatment of osteoporosis and drugs affecting calcium balance

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

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Treatment of osteoporosis and drugs affecting calcium balance

  1. 1. Drugs affecting calcium balance
  2. 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. 3. Uses of calcium • Tetany • As dietary supplement • Osteoporosis • Empirical: – dermatoses, parasthesias, weakness, vague complaints • As antacid • Lead colic, hypermagnesemia, hyperkalemia • Cardiac arrest
  4. 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. 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. 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. 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. 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. 9. Vitamin D deficiency •Deficiency of vitamin D leads to:  Rickets in small children.  Osteoporosis
  10. 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
  11. 11. 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.
  12. 12. 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:
  13. 13. 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
  14. 14. 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
  15. 15. Biphosphonates • Analogs of pyrophosphate • First generation: • Etidronate • Second generation: • Pamidronate • Alendronate • Third generation : • Risedronate • Zoledronate
  16. 16. • Mechanism of action Protect dissolution of hydroxyapatite from bone Accelerates apoptosis of osteoclasts Inhibits release of IL-6
  17. 17. • 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
  18. 18. 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
  19. 19. Osteoporosis
  20. 20. 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.
  21. 21. 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
  22. 22. 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
  23. 23. Drugs causing osteoporosis Aluminum Anticonvulsants Excessive thyroxine Glucocorticoids GnRH agonists Heparin Lithium
  24. 24. 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
  25. 25. 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
  26. 26. Treatment Objectives 29 Osteoclast Inhibition of resorption Osteoblast Stimulation of formation
  27. 27. 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
  28. 28. Antiresorptive Agents
  29. 29. Bisphosphonates • Etidronate • Pamidronate • Alendronate • Risedronate • Ibandronate • Tiludronate • Zoledronate
  30. 30. 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
  31. 31. 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)
  32. 32. 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)
  33. 33. 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
  34. 34. 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
  35. 35. 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.
  36. 36. Thiazide diuretics • Reduce urinary calcium excretion and constrain bone loss in patients with hypercalciuria. • Dosage : Hydrochlorothiazide – 25 mg once or twice daily.
  37. 37. Bone forming agents
  38. 38. 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
  39. 39. 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
  40. 40. 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.
  41. 41. 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
  42. 42. • 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
  43. 43. Thank You.

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