Pharmacology Lec 4 PDF

Pharmacology Drugs affecting bone metabolism Lec 4 Pharmacology |Drugs affecting bone metabolism Contents : Osteoporosis 3 Paget disease 5 Osteomalacia 7 Bone remodeling 9 Prevention of osteoporosis 12 Treatment of osteoporosis 15 Bisphosphonates 16 Denosumab 23 Parathyroid agents 25 Selective estro...

Pharmacology Drugs affecting bone metabolism Lec 4 Pharmacology |Drugs affecting bone metabolism Contents : Osteoporosis 3 Paget disease 5 Osteomalacia 7 Bone remodeling 9 Prevention of osteoporosis 12 Treatment of osteoporosis 15 Bisphosphonates 16 Denosumab 23 Parathyroid agents 25 Selective estrogen receptor modulators 28 Calcitonin 30 Pharmacology |Drugs affecting bone metabolism Osteoporosis, Paget disease, and Osteomalacia are disorders of the bone. Osteoporosis Osteoporosis is characterized by progressive loss of bone mass and skeletal fragility. Patients with osteoporosis have an increased risk of fractures, which can cause significant morbidity. Osteoporosis occurs most frequently in postmenopausal women and older adults of both sexes. Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism Paget disease Paget disease is a disorder of bone remodeling that results in disorganized bone formation and enlarged or misshapen bones. Unlike osteoporosis, Paget disease is usually limited to one or a few bones. Patients may experience bone pain, bone deformities, or fractures. Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism Osteomalacia: Osteomalacia is softening of the bones that is most often attributed to vitamin D deficiency. Note: Osteomalacia in children is referred to as rickets Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism Bone remodeling Throughout life, bone undergoes continuous remodeling, with about 10% of the skeleton replaced each year. Bone remodeling serves to remove and replace damaged bone and to maintain calcium homeostasis. Osteoclasts are cells that break down bone, a process known as bone resorption. Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism Following bone resorption, osteoblasts or bone-building cells synthesize new bone. Crystals of calcium phosphate known as hydroxyapatite are deposited in the new bone matrix during the process of bone mineralization. Bone loss occurs when bone resorption exceeds bone formation during the remodeling process. Pharmacology |Drugs affecting bone metabolism Prevention of osteoporosis Strategies to reduce bone loss in postmenopausal women include adequate dietary intake of calcium and vitamin D, weight-bearing exercise, smoking cessation, and avoidance of excessive alcohol intake. Patients with inadequate dietary intake of calcium should receive calcium supplementation. Calcium carbonate is an inexpensive and commonly used calcium supplement. Pharmacology |Drugs affecting bone metabolism It contains 40% elemental calcium and should be taken with meals for best absorption. Calcium citrate (21% elemental calcium) is better tolerated and may be taken with or without food. Adverse effects of calcium supplementation include gas and bloating. Patients at risk for osteoporosis should avoid drugs that increase bone loss such as glucocorticoids For example use of prednisone 5 mg/d for 3 months or more is significant risk factor for osteoporosis. Pharmacology |Drugs affecting bone metabolism Calcium may interfere with absorption of iron preparations, thyroid replacement, and fluoroquinolone and tetracycline antibiotics, and administration of these drugs should be separated by several hours. Vitamin D is essential for absorption of calcium and bone health, and older patients are often at risk for vitamin D deficiency. Supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) is used for treatment. Pharmacology |Drugs affecting bone metabolism Treatment of osteoporosis Pharmacologic therapy for osteoporosis is warranted in postmenopausal women and men aged 50 years or over who have a previous osteoporotic fracture, a bone mineral density that is 2.5 standard deviations or more below that of a healthy young adult, or a low bone mass (osteopenia) with a high probability of future fractures. Pharmacology |Drugs affecting bone metabolism Bisphosphonates Bisphosphonates including alendronate, risedronate, and zoledronic acid are preferred agents for treatment of postmenopausal osteoporosis. These bisphosphonates, along with etidronate, ibandronate, pamidronate, and tiludronate, comprise an important drug group used for the treatment of bone disorders such as osteoporosis and Paget disease, as well as for treatment of bone metastases and hypercalcemia of malignancy. Pharmacology |Drugs affecting bone metabolism Mechanism of action Bisphosphonates bind to hydroxyapatite crystals in the bone and decrease osteoclastic bone resorption, resulting in a small increase in bone mass and a decreased risk of fractures in patients with osteoporosis. The beneficial effects of alendronate persist over several years of therapy, but discontinuation results in a gradual loss of effects. Pharmacology |Drugs affecting bone metabolism Pharmacokinetics The oral bisphosphonates alendronate, risedronate, and ibandronate are dosed on a daily, weekly, or monthly basis depending on the drug. Absorption after oral administration is poor, with less than 1% of the dose absorbed. Food and other medications significantly interfere with absorption of oral bisphosphonates. Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism Bisphosphonates are rapidly cleared from the plasma, primarily because they avidly bind to hydroxyapatite in the bone. Elimination is predominantly via the kidney, and bisphosphonates should be avoided in severe renal impairment. For patients unable to tolerate oral bisphosphonates, intravenous ibandronate and zoledronic acid are alternatives. Pharmacology |Drugs affecting bone metabolism Adverse effects These include diarrhea, abdominal pain, and musculoskeletal pain. Alendronate, risedronate, and ibandronate are associated with esophagitis and esophageal ulcers. To minimize esophageal irritation, patients should remain upright after taking oral bisphosphonates. Pharmacology |Drugs affecting bone metabolism Although uncommon, osteonecrosis of the jaw and atypical femur fractures may occur with use of bisphosphonates. The risk of atypical fractures seems to increase with long-term use of bisphosphonates. Therefore, current guidelines recommend a drug holiday for some patients after 5 years of oral bisphosphonates or 3 years of zoledronic acid. Pharmacology |Drugs affecting bone metabolism Denosumab: Denosumab is a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand and inhibits osteoclast formation and function. Denosumab is approved for the treatment of postmenopausal osteoporosis in women at high risk of fracture. It is administered via subcutaneous injection every 6 months. Pharmacology |Drugs affecting bone metabolism Denosumab is considered a first-line agent for osteoporosis, particularly in patients at higher risk of fractures. The drug has been associated with an increased risk of infections, dermatological reactions, hypocalcemia, and rarely, osteonecrosis of the jaw, and atypical fractures. Pharmacology |Drugs affecting bone metabolism Parathyroid agents Teriparatide is a recombinant form of human parathyroid hormone and abaloparatide is an analog of parathyroid hormone-related peptide. These drugs act as agonists at the parathyroid hormone receptor, and once-daily subcutaneous administration results in stimulation of osteoblastic activity and increased bone formation and bone strength. By contrast, other drugs for osteoporosis inhibit bone resorption. Pharmacology |Drugs affecting bone metabolism Pharmacology |Drugs affecting bone metabolism These agents should be reserved for patients at high risk of fractures and those who have failed or cannot tolerate other osteoporosis therapies. Both drugs have been associated with hypercalcemia, orthostatic hypotension, and an increased risk of osteosarcoma in rats. Cumulative lifetime use of either agent for more than 2 years is not recommended. Pharmacology |Drugs affecting bone metabolism Selective estrogen receptor modulators Lower estrogen levels after menopause promote proliferation and activation of osteoclasts, and bone mass can decline rapidly. Estrogen replacement is effective for the prevention of postmenopausal bone loss. However, since estrogen may increase the risk of endometrial cancer, breast cancer, stroke, venous thromboembolism, and coronary events, it is no longer recommended as a preventive therapy for osteoporosis. Pharmacology |Drugs affecting bone metabolism Raloxifene is a selective estrogen receptor modulator approved for the prevention and treatment of osteoporosis. It has estrogen-like effects on bone and estrogen antagonist effects on breast and endometrial tissue. Therefore, raloxifene increases bone density without increasing the risk of endometrial cancer, raloxifene should be used as an alternative to bisphosphonates or denosumab in the treatment of postmenopausal osteoporosis. Adverse effects include hot flashes, leg cramps, and increased risk of venous thromboembolism. Pharmacology |Drugs affecting bone metabolism Calcitonin Salmon calcitonin is indicated for the treatment of osteoporosis in women who are at least 5 years postmenopausal. The drug reduces bone resorption, but it is less effective than other agents, and is no longer routinely recommended for the treatment of osteoporosis. The intranasal formulation is most commonly used in osteoporosis, and adverse effects include rhinitis and other nasal symptoms.