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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  • Calcium chloride: freely soluble in water but highly irritating can cause tissue necrosis if injected IM or extravasation takes place during IV injection. Orally also the solution irritates. It is valuable in treatment of hypocalcemictetany given slow IV. After administration there is peripheral vasodilation and cutaneous burning sensation. It is used in conc of 10% solution iv not over 1ml/min. it is not used in hypocalcemia due to renal insufficiency. Calcium gluceptate: 5 to 20 ml of 20 % solution may be given iv for hypocalcemictetany . May produce transient tingling sensation. It may also be given by im route upto 5 ml which may produce local reaction. Calcium gluconate: it is available in tablet form as well iv as 10 % soulution 0.45 meq ca /ml . Not given im as painful necrosis may occur Calcium lactate : 4 gm + 8 gm lactose bd
  • Mild hypercalcemiaControl of underlying causative factorHydration Oral glucocorticoidsEdetate sodium rarely used because of toxicity Gallium nitrate: used in hypercalcemia of malignancy only it is nephrotoxic , single or multiple iv I jections 200 mg/m2 over 24 hours Prednisolone: 40-80 mg/day is given orally which reduces intestinal absorption of calcium efficacious in vit d intoxication and sarcoidosis. It may take 1-2 weeks before calcium levels fall. Intravenous bisphosphonates: etidronate, pamidronate which are potent inhibitors of osteoclatic bone resorption. For treating hypercalcemia, etidronate 7.5 mg/kg/d is infused iv over several hours for 3 days . Pamidronate is also given iv 60-90 mg over 4-6 hours . With these drugs the resolution of hypercalcemia occurs over several days and the effect lasts for several weeks.
  • Adverse events experienced are nausea, flushing, tingling of fingers, bad taste allergic reactions By lowering plasma calcium calcitonin may interfere with action of digoxin.
  • Hypercalcemia: hyperparathyroidism , hypervitaminosos, osteolytic bony metatsis : 4-8IU/Kg im 6 -12 hrly for 2 days acts rapidly within 4 hrs the response peaks at 48 hrs Weak hypocalcemic so only used to supplement BPN generally. Pagets disease 100 units daily or on alternate days
  • Alfacalcidiol:1 alpha hydroxyD3 DOSE 1-2 MICROGRAM /DAY & dihydrotachysterol: SYNTHETIC ANALOG OF VIT D2 LESS EFFECTIVE IN ANTIRACHITIC TESTS BUT DIRECTLY MOBILIZES CALCIUM FROM BONE : DOES NOT REQUIRE PTH dependent activation in kidney dose = 0.25 -0.5 mg/day
  • Hypervitaminosos D: m ay occur because of chronic ingestion of large doses of vit D > 50000 IU/DAYMANIFESTATIONS ARE DUE TO INCREASED CALCIUM LEVELS & ECTOPIC DEPOSITION HYPERCALCEMIA , weakness, fatigue, vomiting , diarrhoea, sluggishness, poluria, albuminuria, ectopic calcium deposition, renal stones, hypertension, growth retardation in children, . Coma T/t = no vitamin D , low calcium diet, plenty of fluids & glucocorticoids recovery may be incomplete in many cases.
  • Early stageUsually begin at 3 months oldSymptoms: mental psychiatric symptoms Irritability, sleepless, hidrosisSigns: occipital baldAdvanced stageOn the base of early rickets, osseous changes become marked and motor development becomes delayed. 1. Osseous changes: 1) Head: craniotables, frontal bossing, boxlike appearance of skull, delayed closure of anterior fontanelle 2) Teeth: delayed eruption, with abnormal order, defects 3) Chest: rachitic rosary, Harrison’s groove, pigeon chest, funnel-shaped chest, flaring of ribs) Spinal column: scoliosis,kyphosis, and lordosis5) Extremities: bowlegs,or knock knee, greenstick fracture6) Rachitic dwarfism2. Muscular system: potbelly, late in standing and walking3. Motor development: delayed4. Other nervous and mental symptoms
  • Calcium supplementation:only used for special cases, such as baby fed mainly with cereal, or infants under 3 months of age, and those who have already developed tetany. Dosage:1-3 g/day.3) Plastic therapy:In children with bone deformities after 4 years old plastic surgery may be useful.
  • Plants do not contain vitamin D3
  • PrimaryPostmenopausalDecreased estrogen results in increased osteoclastic activity without increased osteoblastic activityBone loss – 2-3% per year of total bone massMost common fx: vertebral, distal forearm Age related – 3rd decade of life starts slow decline in bone mass at rate of 0.5-1% per yearMost common types of fx: hip and radiusF>M
  • Recent discovery of 2 estrogen receptors and that ligand binding could change their configuration in number of ways aloowing their interaction with corepressors and co-activators in a tissue specific manner has paved the way for development of compounds with unique profile of agonistic and antagonistic actions in different tissues . These drugs have been designed selective estrogen receptor modulators.
  • Unlike fluoride this new bone appears structurally normal and is associated with a substantial reduction in the incidence of fracture.
  • Glucocorticoids increase bone loss by multiple mechanisms including
  • 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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