Osteoporosis - Therapeutics


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Osteoporosis - Therapeutics

  1. 1. OSTEOPOROSIS Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 1
  3. 3. INTRODUCTION  OSTEOPOROSIS is a condition characterized by a decrease in the density of bone, its strength, structural deterioration of bone tissue and resulting in fragile bones having increased risk to fractures.  Osteoporosis leads to abnormal porous bone that is compressible, like a sponge resulting in frequent fractures in the bones.  Osteoporosis can cause fracture that can be either in the form of a. Cracking (as in a hip fracture) or b. Collapsing (as in a compression fracture of the vertebrae of the spine). Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 3
  4. 4. The Common areas of bone fractures from osteoporosis  Spine, Hips, Ribs, and Wrists  Although osteoporosis-related fractures can occur in almost any skeletal bone. HALLMARK OF OSTEOPOROSIS is the loss of bone mineral and bone matrix. Bone mineral density (T-score): Normal <1 SD Osteopenia 1-2.5 SD Osteoporosis ≥ 2.5 SD Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 4
  5. 5. EPIDEMIOLOGY  Over 200 million people worldwide suffer from this disease.  Aging of populations worldwide is responsible for a major increase of the incidence of osteoporosis in postmenopausal women.  After 50 years of age there is an exponential rise of fractures, such that 40% of women and 13% of men develop one or more osteoporotic fractures.  Women loss appro 50% of trabecular and 30% of cortical bone on over life. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 5
  6. 6. CLASSIFICATION Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 6
  7. 7. Primary Type I or Postmenopausal osteoporosis (first 3 to 6 years after menopause) associated with increased cortical and cancellous bone loss resulting from increased bone resorption. Manifested by vertebral fractures, distal radius fractures, hip fractures, and even an increased tooth loss secondary to osteoporosis of the mandible. Primary Type II or senile osteoporosis, occurs in both women and men 75 years of age and older with a female:male ratio of 2:1. These persons are at greatest risk for hip, pelvic, and vertebral fractures. Secondary osteoporosis results from the use of various medications or the presence of particular disease states . This type of osteoporosis can occur at any age and is equally common in men and women. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 7
  8. 8. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 8
  9. 9. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 9
  10. 10. The skeleton undergoes constant remodeling throughout life. Peak bone mass is achieved by age 20 to 30 years. Involves teams of osteoclasts and osteoblasts, termed basic multicellular units (BMUs), Phases in remodeling are: 1. Resorption (3 to 4 weeks) 2. Reversal 3. Formation(3 to 4 months) 4. Quiescence BONE REMODELLING Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 10
  11. 11. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 11
  12. 12. Calcium AND Vitamin D - required for bone growth. PTH, Glucocorticoid Hormones, Calcitonin, Estrogen, And Testosterone - involved in bone remodeling. PTH & Glucocorticoid - Bone resorption Calcitonin, Estrogen & Testosterone - Bone formation. Calcium is primarily regulated by the actions of PTH, vitamin D, and calcitonin. The parathyroid gland releases PTH in response to low serum calcium levels, which in turn facilitates the mobilization of calcium and phosphate from bone and stimulates reabsorption of calcium through the tubular system in the kidneys. Increase in Vitamin D levels decreases PTH levels increasing bone resorption to prevent symptomatic hypocalcemia. Calcitonin is released in response to high serum calcium levels and decreases intestinal absorption of calcium and phosphorous, inhibits calcium excretion in the kidneys, and prevents bone resorption. CALCIUM HOMEOSTASIS Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 12
  13. 13. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 13
  14. 14. • PRIMARY OSTEOPOROSIS: Multifactorial, resulting from a combination of factors including nutrition, peak bone mass, genetics, level of physical activity, age of menopause (spontaneous vs. Surgical), and estrogen status. • SECONDARY OSTEOPOROSIS: Associated decrease in bone mass resulting from an identified cause, including endocrinopathies, hypogonadism, hyperthyroidism, hyperparathyroidism, cushing’s syndrome,hyperprolactinemia, acromegaly, diabetes mellitus, gastrointestinal disease, malabsorption, primary biliary cirrhosis, gastrectomy, malnutrition (including anorexia),and medications (corticosteroids, PPIs, rosiglitazone, pioglitazone) ETIOLOGY Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 14
  15. 15. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 15
  16. 16. LOW BONE DENSITY:  Bone mineral density (BMD) is a major predictor of fracture risk.  Bone loss occurs when bone resorption exceeds bone formation, usually from high bone turnover; when the number and/or depth of bone resorption sites greatly exceed the rate and ability of osteoblasts to form new bone.  Women and men begin to lose a small amount of bone mass starting in the third to fourth decade of life as a consequence of a slight reduction in bone formation. ETIOLOGY Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 16
  17. 17. IMPAIRED BONE QUALITY:  In addition to BMD, the strength of bone is highly impacted by the quality of the bone’s material properties and its structure.  For example, accelerated bone turnover can result in bone loss, but also can impair bone quality and the structural integrity of bone by increasing the quantity of immature bone that is not yet adequately mineralized.  Bone quality assessment is important because changes in bone quality effect bone strength much more than bone mass changes. ETIOLOGY Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 17
  18. 18. PATHOPHYSIOLOGY POSTMENOPAUSAL OSTEOPOROSIS: The accelerated bone loss during pre-menopause and postmenopause results from enhanced resorption mainly as a result of the loss in ovarian hormone production, Estrogen. Estrogen deficiency increases proliferation, differentiation, and activation of new osteoclasts and prolongs survival of mature osteoclasts.  The number of remodeling sites increases and resorption pits are deeper and inadequately filled by normal osteoblastic function.  Trabecular bone is most susceptible leading to vertebral and wrist fractures. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 18
  19. 19. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 19
  20. 20. PATHOPHYSIOLOGY MALE OSTEOPOROSIS:  Men are at a lower risk for developing osteoporosis and osteoporotic fractures because of larger bone size, greater peak bone mass, and fewer falls.  Men also do not undergo a period of accelerated bone resorption similar to menopause. However, men have a higher mortality rate after fractures.  The etiology of male osteoporosis tends to be multifactorial with secondary causes and aging being the most common contributing factors. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 20
  21. 21.  In young and middle-age men, a secondary cause for bone loss is usually identified, with hypogonadism being the most common. Idiopathic osteoporosis (no known cause) can occur and is probably a result of genetic factors that have yet to be determined Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 21
  22. 22. AGE-RELATED OSTEOPOROSIS:  Age-related osteoporosis occurs in seniors mainly as a result of hormone, calcium, and vitamin D deficiencies leading to an accelerated bone turnover rate in combination with reduced osteoblast bone formation.  Hip fracture risk rises dramatically in gedriatics as a consequence of the cumulative loss of cortical and trabecular bone and an increased risk for falls. PATHOPHYSIOLOGY Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 22
  23. 23.  Current cigarette smoking  Low body weight or body mass index  Advanced age  Alcohol in amounts >2 drinks/day  Systemic glucocorticoid therapy  Female sex  Osteoporotic fracture in a first-degree relative (especially hip fracture)  Secondary osteoporosis (especially rheumatoid arthritis )  Low calcium intake & physical activity  Poor health/frailty  Minimal sun exposure  Recent falls  Estrogen deficiency before 45 years old  Impaired vision Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 23
  24. 24. CONDITION ASSOCIATED WITH OSTEOPOROSIS OR LOW BONE MASS: - Chronic renal disease - Cushing’s syndrome - Cystic fibrosis - Diabetes mellitus - Eating disorders - Gastrointestinal disorders (e.g., gastrectomy, - Malabsorption syndromes) (e.g., hemophilia) - Hyperparathyroidism - Hyperthyroidism - Hypogonadal states - Organ transplantation - Skeletal cancer (e.g., myeloma) Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 24
  25. 25. DRUGS ASSOCIATED WITH OSTEOPOROSIS OR LOW BONE MASS: -Anticonvulsants (phenytoin, phenobarbital) -Aromatase inhibitors (anastrazole, exemestane, letrozole) -Cytotoxic drugs (e.g., methotrexate, cisplatin) -Glucocorticoids, Thyroid supplements -Gonadotropin-releasing hormone analogs (e.g., leuprolide acetate, nafarelin, gosarelin) -Heparin, Immunosuppressants (e.g., tacrolimus) -Lithium, Medroxyprogesterone acetate Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 25
  26. 26. Clinical Manifestations Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 26
  27. 27. CONSEQUENCE Elderly patients can develop pneumonia and blood clots in the leg veins that can travel to the lungs (pulmonary embolism) due to prolonged bed rest after the hip fracture. Osteoporosis has even been linked with an increased risk of Hip fracture (more common) Fractures Vertebrae fracture Wrist fracture Death Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 27
  28. 28. DIAGNOSIS WORKUP • History and physical examination (20% of women with type I osteoporosis have associated secondary cause), with appropriate evaluation for identified risk factors and secondary causes • Diagnosis of osteoporosis made by bone mineral density (BMD) determination (BMD should ideally evaluate the hip, spine, and wrist): 1. DUAL-ENERGY X-RAY ABSORPTIOMETRY 2. Single-energy x-ray 3. Peripheral dual-energy x-ray 4. Single-photon absorptiometry 5. Dual-photon absorptiometry 6. Quantitative CT scan 7. Radiographic absorptiometry Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 28
  29. 29. DUAL-ENERGY X-RAY ABSORPTIOMETRY SCAN (DXA)  Reveals bones status, whether appears much thinner and lighter than normal bones.  The National Osteoporosis Foundation, the American Medical Association, and other major medical organizations recommend a dual-energy X-ray absorptiometry scan (DXA, formerly known as DEXA) for diagnosing osteoporosis.  DXA measures bone density in the hip and the spine. The test takes only five to 15 minutes to perform, exposes patients to very little radiation and is quite precise.  The bone density of the patient is compared to the average peak bone density of young adults of the same sex and race.  This score is called the "T score," and it expresses the bone density in terms of the number of standard deviations (SD) below peak young adult bone mass. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 29
  30. 30.  Osteoporosis is defined as a bone density T score of -2.5 or below.  It is important to note that while osteopenia is considered a lesser degree of bone loss than osteoporosis, it nevertheless can be of concern when it is associated with other risk factors (such as smoking, cortisone steroid usage, rheumatoid arthritis, family history of osteoporosis, etc.) that can increase the chances for developing vertebral, hip, and other fractures. Bone Mineral Density (T-score): Normal <1 SD Osteopenia 1-2.5 SD Osteoporosis ≥ 2.5 SD Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 30
  31. 31. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 31
  32. 32. PREVENTION AND TREATMENT: DESIRED OUTCOMES: Pharmacologic and Non-pharmacologic therapies are aimed at the following goals: (1) Preventing Fractures And Their Complications, (2) Maintaining Or Increasing Bone Mineral Density, (3) Preventing Secondary Causes Of Bone Loss, And (4)Reducing Morbidity And Mortality Associated With Osteoporosis. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 32
  33. 33. TO PREVENT FALL AND CONSEQUENT FRACTURES Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 33
  34. 34. MODIFICATION OF RISK FACTORS: Non-modifiable - Family history, age, ethnicity, sex, and concomitant disease states. Modifiable - bone loss may be minimized or prevented by early intervention, including smoking, low calcium intake, poor nutrition, inactivity, heavy alcohol use, and vitamin D deficiency. In order to prevent certain risk factors and maximize peak bone mass, efforts must be directed toward osteoporosis prevention at an early age. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 34
  35. 35. NUTRITION: Good nutrition is essential for intake of sufficient nutrients and maintenance of appropriate weight. Dietary calcium intake is important for achieving peak bone mass and maintaining bone density. Adequate dietary intake of vitamin D is essential for calcium absorption. Good dietary sources of calcium include dairy products. The most common source of vitamin D comes from exposure to sunlight. Ultraviolet rays from the sun promote the synthesis of vitamin D3 (cholecalciferol) in the skin. This generally occurs within 15 minutes of sunlight exposure. Vitamin D also may be found in some dietary sources, including fortified milk, egg yolks, saltwater fish, and liver. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 35
  36. 36. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 36
  37. 37. EXERCISE: Exercise can be beneficial in preventing fragility fractures. Weight-bearing exercise such as walking, jogging, and climbing stairs can help to build and maintain bone strength. Muscle-strengthening or resistance exercises can help to improve and maintain strength, agility, and balance, which can reduce falls. A Word Of Caution About Exercise: It is important to avoid over exercises that can injure already weakened bones. In patients over 40 and those with heart disease, obesity, diabetes mellitus, and high blood pressure, exercise should be prescribed and monitored by physicians. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 37
  38. 38. PREVENTION OF HIP FRACTURES IN ELDERLY PEOPLE WITH OSTEOPOROSIS: The FDA has approved hip protector garments for the prevention of hip fractures in elderly people with known osteoporosis. Brand names available include Hipsaver and Safe-hip. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 38
  39. 39. Prevention Of Osteoporosis Due To Long-term Corticosteroids: • The long-term use of corticosteroids (such as prednisone, cortisone, and prednisolone) can lead to osteoporosis. • Corticosteroids cause decreased calcium absorption from the intestines, increased loss of calcium through the kidneys in urine, and increased calcium loss from the bones. • To prevent bone loss while on long-term corticosteroids, patients should have an adequate calcium (1,000 mg daily if premenopausal, 1,500 mg daily if postmenopausal) and vitamin D intake; however, calcium alone or combined with vitamin D cannot be relied upon to prevent bone loss from corticosteroids unless other prescription medications are added. • Having a DXA bone density scan prior to beginning therapy and careful monitoring for osteoporosis during therapy.Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 39
  40. 40. PHARMACOLOGICAL THERAPY Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 40
  41. 41. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 41
  42. 42. ANTI-RESORPTIVE THERAPY: CALCIUM AND VITAMIN D: Calcium and vitamin D supplements to meet requirements should be added to all drug therapy regimens for osteoporosis. M.O.A: Physiology--Hypocalcemia can result from inadequate dietary intake, decreased fractional calcium absorption (as seen with increasing age), or enhanced calcium excretion. To restore calcium homeostasis after hypocalcemia, PTH concentrations rise, and vitamin D metabolism increases to enhance intestinal calcium absorption, renal calcium reabsorption, and bone resorption. SIDE EFFECTS: Loss of appetite, nausea , headache , fever , vomit , stomach ache , constipation, irregular or rapid heart beat . DOSE: SHELCAL-500 - Calcium with Vitamin D Tablet (500 mg). Daily calcium and vitamin D requirements are highest in postmenopausal women and elderly men: 1500 mg elemental calcium and 400 to 800 IU vitamin D. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 42
  43. 43. TOXICITY: Calcium intake greater than 2500 mg/day should be avoided due to increased risk of toxicity, including hypercalciuria and hypercalcemia. SALT FORMS: Calcium carbonate should be taken with food to maximize absorption. Better absorption may occur in form of calcium citrate because an acid environment is not needed for absorption; it may be taken with or without food. Common adverse effects of calcium salts include constipation, bloating, cramps, and flatulence. Changing to a different salt form may alleviate symptoms for some patients. PARENTERAL – Calcium gluconate inj – hyperkalaemia VITAMIN D is often combined in varying amounts with calcium salts. Vitamin D is also available as a single entity. Doses above 2000 IU/day should be avoided owing to the risk of hypercalciuria and hypercalcemia. Ergocalciferol (vitamin D2) and Cholecalciferol (vitamin D3) are available in higher doses and generally are reserved for patients with vitamin D deficiency. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 43
  44. 44. INTERACTION: Alendronate -interfere with the absorption of alendronate, should be taken atleast 2 hours before or after alendronate. Antacids that contain aluminum-particular problem for people with kidney disease, for whom the aluminum levels may become toxic. Cholesterol-lowering medications -cholestyramine, colestipol, may interfere with normal calcium absorption and increase the loss of calcium in the urine. Digoxin - may increase the risk of a toxic reaction to digoxin. Diuretics - Thiazide diuretics can raise calcium levels in the blood. Loop diuretics (such as furosemide and bumetanide) can decrease calcium levels. Estrogens - increase in calcium blood levels. Gentamicin - increase the potential for toxic effects on the kidneys. Antibiotics - Different types of antibiotics interact with calcium. Quinolones: interfere with the body's ability to absorb quinolone antibiotics. Tetracyclines: interfere with the body's ability to absorb tetracycline antibiotics. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 44
  45. 45. HORMONE THERAPY MENOPAUSAL HORMONE THERAPY: Estrogen hormone therapy after menopause (previously referred to as hormone replacement therapy or HRT) to prevent bone loss, increase bone density, and prevent bone fractures. Estrogen also is available in combination with progesterone as pills and patches. Progesterone is routinely given along with estrogen to prevent uterine cancer that might result from estrogen use alone. Women who have had a hysterectomy (surgical removal of the uterus) may take estrogen alone since they no longer have a uterus to become cancerous. HRT does not provide contraception and a woman is considered potentially fertile for 2 years after her last menstrual period if she is under 50 years, and for 1 year if she is over 50 years. A woman who is under 50 years and free of all risk factors for venous and arterial disease can use a low-oestrogen combined oral contraceptive pill to provide both relief of menopausal symptoms and contraception. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 45
  46. 46. ESTROGEN SYNTHETIC ESTROGEN STERIODAL Ethinylestradiol, Tibolone NON-STEROIDAL Diethylstilbestrol—oral Dienestrol—topical NATURAL ESTROGEN ESTRODIOL Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 46
  47. 47. KINETICS: Well absorbed orally and transdermally. Conjugates with glucuronic acid and sulfate to get excreted via urine. Ethinylestradiol metabolises very slowly (t1/2-12-24hr) that more active and potent. SIDE-EFFECTS: Abdominal cramps and bloating, weight changes, Breast enlargement and tenderness, Premenstrual-like syndrome, Sodium and fluid retention, cholestatic jaundice, Pancreatitis, changes in libido, depression, Mood changes, headache, migraine, dizziness &, vaginal candidiasis Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 47
  48. 48. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 48
  49. 49. Counselling on patches Patch should be removed after 3–4 days (or once a week in case of 7-day patch) and replaced with fresh patch on slightly different site; recommended sites: clean, dry, unbroken areas of skin on trunk below waistline. CAUTION: Increase risk of developing endometrial cancer ; Migraine (or migraine-like headaches); Diabetes (increased risk of heart disease); History of breast nodules or fibrocystic disease. Tumours (e.g. Breast cancer in first-degree relative); Symptoms of Endometriosis may be exacerbated; Thromboembolism DOSE: Progynon: im 10 mg/ml(Estradiol) Dienestrol: 0.01% cream Estraderm-MX: 25-50 µg per 24 hrs (Estradiol patch) Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 49
  50. 50. CALCITONIN: Calcitonin is a naturally occurring mammalian hormone that plays a major role in regulation of calcium levels. KINETICS: Calcitonin is available in injectable and intranasal formulations. It cannot be administered orally owing to inactivation by gastric fluids. M.O.A: It inhibits bone resorption by binding to osteoclast receptors. Direct action on osteoclast –decreasing their ruffled surface. Inhibits proximal tubular calcium and resorption by direct action kidney. R.O.A: The parenteral formulation must be administered either subcutaneously or intramuscularly every other day. ADVERSE EFFECTS: including flushing, urinary frequency, nausea, vomiting, abdominal cramping, and irritation at the injection site. DOSE: Postmenopausal osteoporosis Adult: 100 units daily or every other day by SC/IM Inj together with calcium and vitamin D supplements. Renal impairment: Dosage reduction may be required. Nasal Postmenopausal osteoporosis 200 u/day, alternating nostrils everyday. INTERACTION: Calcitonin reduces effect of lithium.Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 50
  51. 51. BISPHOSPHONATES: - Analogue of pyrophosphate. -Both alendronate and risedronate are approved for the prevention and treatment of postmenopausal osteoporosis and treatment of steroid-induced osteoporosis. -Alendronate is approved for treatment of osteoporosis in men. -Risedronate is also approved for the prevention of steroid-induced osteoporosis. CLASSIFICATION: 1) First-generation drugs (e.g., medronate, clodronate, and etidronate) 2) Second-generation (e.g., pamidronate, alendronate, and ibandronate): 10– 100 times more potent than the first-generation drugs. 3) Third-generation drugs (e.g., risedronate and zoledronate): are up to 10,000 times more potent than first-generation drugs. Dose: DRONATE: 200 mg (ETIDRONATE) AREDRONATE: 30 mg (PAMIDRONATE) ALENDRONATE: 5, 10 mg Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 51
  52. 52. M.O.A: Bisphosphonates concentrate at sites of active remodeling Incorporates into the bone matrix When the bone is remodeled, they are released in the acid environment of the resorption Lacunae INDUCES APOPTOSIS TO OSTEOCLAST Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 52
  53. 53. ABSORPTION, FATE, AND EXCRETION: All oral bisphosphonates have very limited bioavailability. They should be administered with a full glass of water following an overnight fast and at least 30 minutes before breakfast. Patient should be advised not to lie down for 30 min after administering orally. They are excreted primarily by the kidneys and are not recommended for patients with a creatinine clearance of less than 30 mL/min. INTERACTIONS: Antacids: absorption of bisphosphonates reduced by antacids Antibacterials: increased risk of hypocalcaemia when bisphosphonates given with aminoglycosides Calcium Salts: absorption of bisphosphonates reduced by calcium salts Iron: absorption of bisphosphonates reduced by oral iron. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 53
  54. 54. TESTOSTERONE: Decreased testosterone concentrations are seen with certain gonadal diseases, eating disorders, glucocorticoid therapy, oophorectomy, and menopause, and in aging men with hypogonadism. DOSE: Women receiving methyltestosterone 1.25 or 2.5 mg oral daily or testosterone implants 50 mg every 3 months had increased BMD. Transdermal gel, oral, intramuscular, and pellet testosterone products are available. Patients using these products should be evaluated within 1 to 2 months of onset and then every 3 to 6 months thereafter. M.O.A: Acts on bone leading to increased BMD in hypogonadal men and senior men with normal or mild hormonal deficiency. Testosterone replacement should not be used solely for the prevention or treatment of osteoporosis, but might be beneficial to reduce bone loss in patients needing therapy for hypogonadal symptoms. As antiresorptive agents to reduce bone turnover but may also stimulate osteoblastic activity.Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 54
  55. 55. TESTOSTERONE: acts on both osteoblasts and osteoclasts via both androgen receptorsand, following aromatization, via estrogen receptors. Thus,the conversion of testosterone to estrogens is of crucial importancefor maintaining normal bone metabolism. Androgen receptor- mediated effects Estrogen receptor- mediated effects Increased osteoblast lifespan (by increasing proliferation and decreasing apoptosis) Decreased osteoclast lifespan (by decreasing proliferation and increasing apoptosis) Decreased early bone turnover Decreased bone turnover Increased bone formation Decreased bone resorption and possible increased bone formation Increased periosteal apposition of bone Decreased periosteal apposition of bone Increased long bone growth Promotion of epiphyseal closure Increased bone size Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 55
  56. 56. KINETICS: Inactive orally due to 1st pass metabolism in liver. In circulation 98% bound to a specific golbulin and to albumin. T ½ is 10-20 mins. SIDE EFFECTS: Virilization Acne Oligozoospermia Cholestatic jaundice Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 56
  57. 57. PARATHYROID HORMONE: Teriparatide, recombinant human parathyroid hormone, is the first anabolic agent approved by the FDA for treatment of osteoporosis. This agent differs from antiresorptive therapies in that it stimulates osteoblastic activity to form new bone with once-daily administration. Its action similar to endogenous parathyroid hormone, and continuous infusions actually stimulate osteoclastic activity and increase bone resorption. M.O.A: Teriparatide increases bone formation by increasing the number of bone- building cells (osteoblasts). It also increases serum levels of calcium and calcitriol (a metabolite of vitamin D that promotes absorption and use of calcium in bone- building). It is recommended for use in patients with severe osteoporosis or those who have not responded adequately to other treatments. DOSE AND ROA: The dose of teriparatide is 20 mcg given by subcutaneous injection once daily. It is available in a prefilled multiple-dose pen delivery system. ADVERSE: Nausea, headache, leg cramps, dizziness, injection-site discomfort, and hypercalcemia. It should not be used in patients with preexisting hypercalcemia CONTRA-INDICATION: Pregnancy Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 57
  58. 58. SELECTIVE ESTROGEN RECEPTOR MODULATOR: The actions of SERMs on various tissues: Bone turnover and postmenopausal osteoporosis respond favorably to most SERMs, Breast - all SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer. Deep venous thrombosis - the risk may be elevated in at least some SERMs. Hot flashes are increased by some SERMs. Name Uses Effects/location clomifene used in anovulation antagonist at hypothalamus Femarelle managing menopause symptoms, osteoporosis agonist at brain and bone Ormeloxifene Contraception agonist at bone; antagonist at uterus and breast Raloxifene osteoporosis, breast cancer agonist at bone; antagonist at uterus and breast Tamoxifen breast cancer agonist at bone and uterus, antagonist at breast Toremifene breast cancerDr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 58
  59. 59. RALOXIFENE: is used to prevent and treat bone loss (osteoporosis) in women after menopause. It’s an estrogen agonist in bone and reduces the number of vertebral fractures by up to 50% in a dose-dependent manner. M.O.A: It works by acting like estrogen (as a selective estrogen receptor modulator or SERM) in body. Raloxifene helps to preserve bone mass, but it does not affect the breast and uterus like estrogen or relieve symptoms of menopause such as hot flashes. ADV: The drug also acts as an estrogen agonist in reducing total cholesterol and LDL but does not increase HDL or normalize plasminogen-activator inhibitor in postmenopausal women. Raloxifene does not cause proliferation of the endometrium. Raloxifene has an antiproliferative effect on ER-positive breast tumors and on proliferation of ER positive breast cancer cell lines and significantly reduces the risk of ER- positive but not ER-negative breast cancer. Raloxifene does not alleviate the vasomotor symptoms associated with menopause. ADR: Leg cramps and a threefold increase in deep vein thrombosis and pulmonary embolism. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 59
  60. 60. CONTRA: This medication is not recommended for use in women before menopause. It should not be used in children. R.O.A: orally once a day, with or without food. SIDE EFFECTS: Hot flashes, sweating, or leg cramps may occur. If these effects persist or worsen, unlikely but serious side effects occur: leg swelling/pain, trouble breathing, chest pain, vision changes. PRECAUTIONS: active or past history of blood clots (e.g., deep venous thrombosis, pulmonary embolism, retinal vein thrombosis). Lack of movement may increase the risk for blood clots. DOSE: Evista - (raloxifene hydrochloride, 60 mg) for the prevention of osteoporosis in postmenopausal women. Evista, the first in a class of new drugs called selective estrogen receptor modulators (SERMs) to be approved by the FDA for marketing for the prevention of osteoporosis. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 60
  61. 61. Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 61
  63. 63. DRUGS DOSE KINETICS SIDE EFFECTS Dr.Prabhakar B.Pharm, PharmD - SRMC, Chennai 63