Bone Disorders 2024 PDF

PHARM 233 Pharmacology Bone Metabolism and Drugs Used for Treatment of Bone Disorders Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Understand bone structure and composition. Understand different classes of drugs used to treat different types of b...

PHARM 233 Pharmacology Bone Metabolism and Drugs Used for Treatment of Bone Disorders Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Understand bone structure and composition. Understand different classes of drugs used to treat different types of bone disorders. Understand the mechanisms of different drugs used for treatment of bone disorders. Understand the clinical uses and pharmacokinetics of different drugs used for treatment of bone disorders. Understand the side effects and toxicities of different drugs used for treatment of bone disorders. Bone structure and Composition 99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca2+ storage. 10% of total adult bone mass turns over each year during remodeling process. During growth rate of bone formation exceeds resorption and skeletal mass increases. Once adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resorption begins to exceed formation and bone mass slowly decreases. Bone structure and Composition Types of bone cells: There are 3 major types of bone cells: Osteoblasts: the differentiated bone forming cells and secrete bone matrix on which Ca2+ and PO43precipitate. Osteocytes: the mature bone cells are enclosed in bone matrix. Osteoclasts: a large multinucleated cell derived from monocytes whose function is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic matrix is composed primarily of collagen. Turnover of Bone Minerals About 1000 mg of Ca is ingested per day. About 200 mg of this is absorbed into the body. Absorption occurs in the small intestine, and requires vitamin D. The major site of Ca excretion in the body is the kidneys. The rate of Ca loss and reabsorption at the kidney can be regulated. Regulation of absorption, storage, and excretion of Ca results in maintenance of calcium homeostasis. The plasma Ca concentration is regulated by PTH, Vitamin D and calcitonin. Turnover of Bone Minerals Phosphate Metabolism: P is an essential mineral necessary for ATP, cAMP 2nd messenger systems, and other roles. Phosphate absorption is an energy-requiring process regulated by calcitriol. Phosphate deposition in bone, as hydroxyapatite, depends on the plasma concentration of PTH, which, with calcitriol, mobilizes both Ca2+ and phosphate from the bone matrix. Phosphate is excreted by the kidney; here PTH inhibits reabsorption and thus increases excretion. Osteoporosis The total bone mass of humans peaks at 25-35 years of age. Men have more bone mass than women. A gradual decline occurs in both genders with aging, but women undergo an accelerated loss of bone due to increased resorption during menopause. Bone resorption exceeds formation. Reduced bone density and mass: osteoporosis Susceptibility to fracture. Earlier in life for women than men but eventually both genders are affected. Drugs used in Bone Disorders Two types of agent are used for treatment of osteoporosis: 1. Antiresorptive drugs that decrease bone loss, e.g. bisphosphonates, calcitonin, selective estrogen receptor modulators (SERMs), denusomab , calcium. 2. Anabolic agents that increase bone formation, e.g. PTH, teriparatide. Strontium has both actions (antiresorptive and anabolic). Rickets and osteomalacia are treated with vitamin D preparations. Paget's disease is treated by bisphosphonates such as pamidronate or zoledronate and calcitonin 1. Bisphosphonates (BPs) Common Drugs: Aminobisphosphonates: alendronate, risedronate, pamidronate, zoledronate Non-Aminobisphosphonates: etidronate,clodronate 1. Bisphosphonates (BPs) Mechanism of Action: Bisphosphonates (BPs) inhibit osteoclast activity through a variety of mechanisms. Aminobisphosphonates: Disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling. Disruption of the mevalonate pathway interrupts osteoclast function and leads to apoptosis of the osteoclast. Non-Aminobisphosphonates: Increase the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death. 1. Bisphosphonates (BPs) Pharmacokinetics: BPs have very low oral bioavailability (~1%), and their absorption is further reduced by food and by divalent cations such as calcium. It is therefore recommended that BPs be taken on an empty stomach, with plain water. The BPs that are absorbed are highly bound to bone, and are not metabolized. They are eliminated by the kidney. The oral BPs are typically administered once weekly. 1. Bisphosphonates (BPs) Indications: Osteoporosis Paget’s disease of the bone (results in enlarged, deformed bones) Hypercalcemia: Malignancy Primary hyperparathyroidism (continuous parathyroid hormone [PTH] release causes bone demineralization) Bone metastasis causing osteolysis: Multiple myeloma Bone metastases of malignant tumors 1. Bisphosphonates (BPs) Contraindications: Hypocalcemia: BPs have exhibited decreases in serum calcium. It is recommended that deficiencies in calcium be addressed before initiation of therapy. Poor renal function: BPs are eliminated renally. Side Effects: Gastrointestinal: nausea, dyspepsia Esophagitis or esophageal erosion Osteonecrosis of the jaw with higher doses. Aminobisphosphonates also cause fever, flulike symptoms are a transient, typically first-dose phenomenon seen with intravenous administration. 2. Estrogens and Related Compounds Common Drugs: Raloxifene Mechanism of Action SERM, selective estrogen receptor modulators. It stimulates osteoblasts and inhibits osteoclasts. Pharmacokinetics: It is well absorbed in the gastrointestinal tract, and undergoes extensive first-pass metabolism (bioavailability 2%). Raloxifene is concentrated in tissues, and is converted to an active metabolite in liver, lungs, bone, spleen, uterus and kidney. Its half-life averages 32 h and excreted mainly in the feces. 2. Estrogens and Related Compounds Side Effects: Hot flushes, leg cramps, flu-like symptoms and peripheral oedema. Thrombophlebitis and thromboembolism. Raloxifene is not recommended for primary prevention of osteoporotic fractures, but is one alternative to a bisphosphonate postmenopausal women who cannot tolerate a bisphosphonate. 3. Parathyroid Hormone (PTH) Parathyroid hormone, which consists of a single-chain polypeptide of 84 amino acids. Common Drugs: Teriparatide Mechanism of Action PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney. The key effects of PTH are as follows: Increased serum calcium Decreased serum phosphate Increased osteoclast activity in bone (indirect by increase RANKL activity) 3. Parathyroid Hormone (PTH) PTH increases both resorption and formation but the net effect of excess PTH is resorption. Low level of intermittent PTH, increase bone formation. The actions of PTH are largely mediated through the PTH-1 receptor. The anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis. PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, which has anabolic effects on bone. Also, PTH has several effects on the kidney: Increased reabsorption of Ca2+ and Mg2+ Decreased reabsorption of phosphate, amino acids, bicarbonate, Na+, Cl−, and sulfate Stimulation of production of 1,25 dihydroxyvitamin D 3. Parathyroid Hormone (PTH) Pharmacokinetics Teriparatide is administered as a subcutaneous injection once daily. It is both rapidly absorbed and rapidly eliminated, with plasma concentrations reaching their peak at 30 minutes post-injection and falling to undetectable levels after 3 hours. Indications Osteoporosis Severe osteoporosis and/or patients in whom previous therapies, including the BPs, have failed Osteoporosis secondary to corticosteroid use 3. Parathyroid Hormone (PTH) Contraindications Children or young adults with open epiphysis. Hypercalcemia: PTH already raises Ca2+ levels. Active Paget’s disease of bone. Skeletal metastases or skeletal malignant conditions. History of radiation to the skeleton: risk of osteosarcoma Pregnancy and lactation: deleterious effects on fetal bone development are possible. 3. Parathyroid Hormone (PTH) Side Effects Hypercalcemia (mild): PTH increases serum calcium. Leg cramps may occur. Nausea may occur. Orthostatic hypotension: PTH infusions have a vasodilatory effect in animals. 4. Vitamin D Replacement The two major forms of vitamin D replacements are vitamin D2 and vitamin D3. Vitamin D is an important regulator of calcium and phosphate homeostasis and bone metabolism. It works in conjunction with PTH. Common Drugs: Calcitriol, ergocalciferol (vitamin D2), calcipotriene, doxercalciferol, paricalcitol 4. Vitamin D Replacement 4. Vitamin D Replacement Mechanism of action: Vitamin D increase serum calcium concentrations. These effects are mediated via the following: Increased calcium absorption from the intestine Regulation of bone resorption and formation This occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone. Increased calcium reabsorption in the distal renal tubules Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH. Intracellularly, it binds vitamin D receptors (VDRs) and binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and parathyroid gland. 4. Vitamin D Replacement Pharmacokinetics: Calcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicity. Indications: Osteoporosis Hyperparathyroidism Osteomalacia Rickets Side Effects: Symptoms are primarily induced by hypercalcemia, which include GI pain, renal stones, and psychiatric disturbances. 5. RANKL Inhibitors Common Drugs: Denosumab 5. RANKL Inhibitors Mechanism of Action RANKL (receptor activator of nuclear factor kappa ligand) is a cytokine member of the TNF superfamily The binding of RANKL to RANK results in increased bone resorption through the differentiation, activation, and prolonged survival of osteoclasts. Denosumab is a new fully humanized monoclonal antibody that binds RANKL and through binding causes inhibition of RANKL and thus inhibits osteoclast activity. 5. RANKL Inhibitors Pharmacokinetics Denosumab has a very long half-life and is administered once every 6 months via subcutaneous injection. The time to maximum concentration is 26 days. Indication Osteoporosis Side Effects Eczema (small increase in risk) Hypocalcemia Increased risk of infections (ie cellulitis) ONJ and atypical fractures 6. Calcitonin Common Drugs: salcatonin (synthetic salmon calcitonin). Mechanism of Action It decreases the reabsorption of both calcium and phosphate in the kidney; it inhibits bone resorption by binding to a specific receptor on osteoclasts, inhibiting their action. Pharmacokinetics Calcitonin is given by subcutaneous or intramuscular injection. Its plasma half-life is 4–12 min, but its action lasts for several hours. 6. Calcitonin Indication: Hypercalcaemia (e.g. associated with neoplasia). Paget ' s disease of bone (to relieve pain and reduce neurological complications) – but it is much less convenient than an injected high potency bisphosphonate. Postmenopausal and corticosteroid-induced osteoporosis (with other agents). 7. Calcium Salts Common Drugs: Calcium carbonate, calcium citrate, calcium phosphate, calcium acetate, calcium gluconate and calcium lactate. Calcium and Vitamin D are essential nutrients for proper bone health. Vitamin D helps to increase the absorption of calcium, ultimately building stronger bones. It also improves the function of muscles, improving the balance and decreasing the likelihood of falls, which can lead to fractures. 7. Calcium Salts 7. Calcium Salts Side Effects: Oral calcium salts can cause gastrointestinal disturbance. Intravenous administration in emergency treatment of hyperkalemia requires care, especially in patients receiving cardiac glycosides, the toxicity of which is influenced by extracellular calcium ion concentration References Rang & Dale's Pharmacology 8th Edition Applied Pharmacology 1st Edition