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Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD

Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD. BONE PHYSIOLOGY. Most common bone disease in humans Characterized by: Low bone mass Microarchitectural deterioration Compromised bone strength Increased risk for fracture. BONE PHYSIOLOGY.

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Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD

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  1. Pharmacologic Options for Osteoporosis Prevention and Treatment Alireza Khabbazi, MD

  2. BONE PHYSIOLOGY • Most common bone disease in humans • Characterized by: • Low bone mass • Microarchitectural deterioration • Compromised bone strength • Increased risk for fracture

  3. BONE PHYSIOLOGY • Bone Resorption • Osteoclast • Bone Formation • Osteoblast • Bone Multicellular Unit (BMU) • Positive < age 30 • Negative > age 30

  4. Remodeling (Resorption) Bone Multicellular Unit (BMU) Lining cells

  5. Remodeling (Resorption) Bone Multicellular Unit (BMU) Lining cells

  6. Remodeling (Resorption) Lymphocyte Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage

  7. Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage IL1, TNFα, IL6, IL11 RANKL Osteoblast

  8. Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage IL1, TNFα, IL6, IL11 RANKL Preosteoclast Osteoblast

  9. Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage IL1, TNFα, IL6, IL11 RANKL Preosteoclast RANKL RANK  IL1,TNFα,IL6 Osteoclast Osteoblast

  10. Remodeling (Resorption) Lymphocyte PTH Vit D Bone Multicellular Unit (BMU) RANKL CSF RANK  Macrophage IL1, TNFα, IL6, IL11 RANKL Preosteoclast RANKL RANK  IL1,TNFα,IL6 Osteoclast Osteoblast Cathepsin K

  11. Remodeling (Formation) Lymphocyte IL1 Estrogen OPG Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast

  12. Remodeling (Formation) Lymphocyte - IL1 Estrogen OPG Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast

  13. Remodeling (Formation) Lymphocyte - PTH Vit D IL1 Estrogen Mechanical stimuli Estrogen Androgen OPG IGF Osteoclast inhibition RANKL RANK  IL1,TNFα,IL6 Osteoblast stimulation Osteoblast

  14. Remodeling (Formation) Osteoblast proliferation

  15. Remodeling (Formation) Lining cells Osteocyte Osteoid

  16. Etiology and pathogenesis of Osteoporosis

  17. Pathogenesis Hyperparathyroidism Estrogen deficiencyInflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  18. Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activityAndrogen deficiencyDrugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  19. Pathogenesis Hyperparathyroidism Estrogen deficiency InflammationLow Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  20. Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  21. Pathogenesis Hyperparathyroidism Estrogen deficiencyInflammation Low Vitamin D, Ca Low physical activity Androgen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  22. Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, CaLow physical activityAndrogen deficiency Drugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  23. Pathogenesis Hyperparathyroidism Estrogen deficiency Inflammation Low Vitamin D, Ca Low physical activity Androgen deficiencyDrugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  24. Pathogenesis Hyperparathyroidism Estrogen deficiencyInflammation Low Vitamin D, Ca Low physical activityAndrogen deficiencyDrugs toxins PTH Vit D Estrogen PTH Vit D Lymphocyte Progestrone Estrogen IL1 TNFα IL6 IL11 OPG Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast Osteoblast Osteoblast Cathepsin K

  25. Drugs used for osteoporosis treatment

  26. Odanacatib Denosumab Treatment Strontium Teriparatide SERMs _ PTH Biphosphonates Estrogen Calcitonine PTH Vit D + Ca, Vit D + Lymphocyte Exercise Estrogen Progestrone IL1 TNFα IL6 IL11 OPG _ _ + _ Androgen IGF RANKL RANK IL1,TNFα,IL6 Osteoclast + Osteoblast _ Osteoblast Cathepsin K

  27. Drugs used for osteoporosis • Antiresorptive drugs - Bisphosphonates - Calcitonin - Estrogen - SERM’s - Denosumab • Bone formation stimulators - PTH (Teriparatide) • Dual action - Strontium

  28. Vitamin D and calcium

  29. Vitamin D and calcium • Daily 800 IU of vitamin D is associated with a reduction in hip fractures of 30% and in nonvertebral fractures of 14% • Fall reduction in the elderly • Therapeutic dose of vitamin D: 600-800 unit

  30. Vitamin D and calcium • Calcium: 1000-1300mg • Avoid taking more than 500 mg of calcium in one dose. • Take one dose before bedtime to prevent bone loss at night. If more is needed, take several doses throughout the day. • Calcium supplements should be taken with meals to boost their absorption.

  31. Vitamin D and calcium • Certain substances can hinder absorption of calcium: foods rich in fibres and fat, zinc, iron, spinach, coffee, alcohol and antacids. Therefore, calcium should not be taken together with these. • Calcium may interfere with certain drugs, including: thyroid medications, tetracycline, anticonvulsants and corticosteroids. Therefore, these should always be taken separately.

  32. Vitamin D and calcium • There is no need to worry about development of kidney stones if the correct dosage in the suitable form of calcium is taken together with sufficient fluid. • Calcium supplements can cause gas, abdominal distension and constipation in some individuals. In this situation, it is reasonable to switch to a different preparation.

  33. Bisphosphonates

  34. Bisphosphonates • The most commonly prescribed therapy for OP prevention and management • Mechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclasts - - - GTPase Farensyl pyrophosphate synthase Attachment of osteoclast

  35. Bisphosphonates-place in treatment • Prevention and treatment of postmenopausal osteoporosis • Osteoporosis in men • Prevention and treatment of GIOP

  36. Bisphosphonates • Alendronate use for 10 years cause a continuous increase in vertebral (13.7%) and hip trochanter (10.3%) bone mineral density (BMD) • Decrease incidence of vertebral, hip, and all non-vertebral fractures by 50% • 90% reduction of multiple radiographic vertebral fractures at year 3

  37. Bisphosphonates-Adverse events • Gastrointestinal problems, such as difficulty swallowing, gastric ulcers, and inflammation of the esophagus. • Hypocalcemia (18%) • Hypophosphatemia (10%) • Musculoskeletal pain, cramps

  38. Bisphosphonates-Adverse events • Atrial fibrillation (3-50/100000): zoledronic acid • Osteonecrosis of the jaw (1/100000): IV bisphosphonates • Atypical femur fracture

  39. Bisphosphonates-Contraindications • Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia • Inability to stand or sit upright for at least 30 minutes • Patients at increased risk of aspiration • Hypocalcemia • Pregnancy • Renal insufficiency (Not recommended if CrCl < 30-35 ml/min)

  40. Bisphosphonates-Dosing • Alendronate: 10 mg/day or 70 mg once weekly at least 30 minutes before eating or drinking • Risedronate: 5 mg/day, 35 mg once weekly, or 150 mg once monthly • Ibandronate: 150 mg once monthly at least 60 minutes before eating or drinking • Zoledronate: 5 mg administered intravenously (IV) once yearly

  41. Bisphosphonates-Duration of therapy • The optimal duration: 5 years Repair (up to 12 months) Rebuilding (6–36 months) Maintenance (24–60 months) • After 7 years of therapy the bone mass still increased by about 1% a year. However, a drug holiday after 5 years of alendronate therapy is advisable to avoid any possible microdamage accumulation, at least in low-risk patients.

  42. Other medications

  43. Raloxifene • Mechanism: tissue-selective activity, acts as an estrogen agonist on bone - Estrogen antagonist on breast, uterus • Approved only for the prevention and treatment of postmenopausal osteoporosis.

  44. Raloxifene • Reduce the incidence of vertebral fractures by 30-50% • Reduction of the risk of invasive breast cancer in postmenopausal women with osteoporosis • Reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer.

  45. Raloxifene: Adverse events • Frequency > 10% • Hot flashes • Arthralgia • Sinusitis • Frequency 1-10% • Chest pain • Insomnia • Migraines • Peripheral edema • Diaphoresis • An increased risk of DVT: risk is similar to reported risk of HRT

  46. Raloxifene: Containdications • History of DVT/PTE or at high risk • Cardiovascular disease • History of uterine/cervical carcinoma • Discontinue at least 72 hours prior to and during prolonged immobilization

  47. Raloxifene-Dosing • For prevention and treatment • 60 mg PO once daily • Can be taken any time of day without regard to meals

  48. Calcitonin • Approved for treatment of postmenopausal osteoporosis • Mechanism: • Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption

  49. Calcitonin-Dosing • Nasal 200 international units daily • Contraindications • Clinical allergy to calcitonin-salmon • Precautions • Nasal ulcerations • Tachyphylaxis (parenteral dosage forms) • Drug interactions (DI) • No formal studies designed to evaluate DI

  50. Teriparatide • Prevention and treatment of postmenopausal osteoporosis • Treatment of osteoporosis in men • Treatment of GIOP

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