2024 Spring Calcium Homeostasis PDF

Calcium Homeostasis Learning Objectives ! Basic principles of calcium homeostasis ! Disorders of calcium homeostasis 1. Hypocalcemia (low blood calcium) 2. Hypercalcemia (high blood calcium) 3. Osteoporosis (porous bone) Hypercalcemia ! Mechanism of actions of each medication for disorders of calciu...

Calcium Homeostasis Learning Objectives ! Basic principles of calcium homeostasis ! Disorders of calcium homeostasis 1. Hypocalcemia (low blood calcium) 2. Hypercalcemia (high blood calcium) 3. Osteoporosis (porous bone) Hypercalcemia ! Mechanism of actions of each medication for disorders of calcium homeostasis. ! Structure-activity relationships of each medication for disorders of calcium homeostasis. PCOL 836B Medicinal Chemistry Course Handouts-Spring 2024 Dr. Daekyu Sun Office: Drachman Hall, Room B211-M4 Tel:626-0323; E-mail: [email protected] Two Tyroid Hormones Responsible for Calcium Homeostasis: Calcitonin and Parathyroid Hormone (PTH) Calcitonin " The tumor necrosis factor (TNF) receptor RANK and its ligand RANKL regulate osteoclast development and bone metabolism. " PTH receptor signaling increases the RANKL in osteoblasts and osteocytes, promoting both osteoclast recruitment and osteoclast activity, and thereby stimulating bone resorption. Parathyroid hormone " Osteoprotegerin (OPG) secreted by osteoblasts binds to RANKL and prevents it from interacting with RANK, protecting the skeleton from excessive bone resorption. Bone Remodeling Cycle: Osteoclast and Osteoblast ! Definition: A physiological process in which old or damaged bone is removed by osteoclasts (bone-resorbing cells), then replaced by new bone formed by osteoblasts (bone-forming cells). Medications to Be Covered in This Lecture ! Active form of vitamin D (Calcitriol): Hypocalcemia, rickets, osteomalacia, and osteoporosis). ! Antiresorptive agents: depress osteoclasts and diminish resorption of bone. 1. Calcitonin (Miacalcin): hypercalcemia and osteoporosis 2. Bisphosphonates: hypercalcemia and osteoporosis 3. Denosumab (Prolia, Xgeva): hypercalcemia and osteoporosis: Antibody against RANK-ligand (osteoclast activator) 4. Estrogens and Selective Estrogen Receptor Modulators (SERMs): osteoporosis ! Calcimimetic agent (Cinacalcet: Sensipar): Hypercalcemia caused by increased by PTH expression and secretion in parathyroid chief cells or caused by parathyroid carcinoma ! Anabolic agents: stimulate osteoblastic bone formation (osteoporosis). 1. Teriparatide (Forteo/Forsteo): PTH analog 2. Abaloparatide (Tymlos): PTHrP analog 3. Romosozumab (Evenity): Antibody against sclerostin (inhibitor of osteoblast and osteocyte) Treatment of Hypocalcemia ! Hypocalcemia: lower-than-average levels of calcium (4.65 to 5.25 mg/dL or 1.16 to 1.31 mmol/L) in the liquid part of the blood, or the plasma. ! Intravenous (10% formulation) calcium gluconate (less tissue necrosis) or calcium chloride (more elemental calcium) for severe or chronic hypocalcemia ! Maintenance doses of both calcium and vitamin-D (often as 1,25-(OH)2-D3, i.e. Calcitriol) Cholesterol " Calcitriol binds primarily to nuclear receptors (VDR) to induce the synthesis of calbindin, which transports calcium ions across intestinal epithelial cells. " Calcitriol also binds to VDRs in the kidneys, promoting renal tubular reabsorption of Ca2+. Treatment of Hypercalcemia ! Hypercalcemia: a serum calcium levels above normal (greater than 2.7mEq/L) caused by accelerated bone resorption, excessive gastrointestinal absorption, or decreased renal excretion of calcium. ! Primary hyperparathyroidism and malignancy are the most common (> 90 %) among all causes of hypercalcemia. RANKL !Medications for Hypercalcemia 1. Calcitonin (Miacalcin): hormone from salmon 2. Cinacalcet (Sensipar): Calcimimetic 3. Bisphosphonates; Intravenous osteoporosis drugs 4. Denosumab (Prolia, Xgeva): antibody against RANKL ! Others: Prednisone is used to treat people with cancer-caused hypercalcemia. Calcitonin Salmon for Treatment of Hypercalcemia ! Human calcitonin is a 32 AA peptide hormone from parafollicular cells (C cells) of the thyroid gland. ! Calcitonin Salmon is a 32 AA peptide hormone differing at 16 residues compared to human calcitonin. ! It reduce blood calcium by opposing the effects of parathyroid hormone (PTH). Bisphosphonates for Treatments of Hypercalcemia ! Bisphosphonates are pyrophosphate analogues with high affinity for bone, especially areas of high bone-turnover; they are taken up by osteoclasts and inhibit osteoclastic bone resorption. " Chemical structure of bisphosphonates is a basis for pharmacological activity " Bisphosphonate group mimics the structure of pyrophosphate, inhibiting activation of enzymes that utilize pyrophosphate. " When R1 is an OH group, binding to bone is enhanced. R2 site determines drug’s effects on binding to hydroxyapatite. Both phosphonate groups act as a “bone hook” essential for both binding to hydroxyapatite. Structures of Bisphosphonates Used in Clinics Two Distinct Molecular Mechanisms of Action of Bisphosphonates VS. Inhibition of farnesyl pyrophosphate synthase Denosumab (Prolia and Xgeva) for Hypercalcemia ! RANK pathway is involved in the activation, differentiation, proliferation, and apoptosis of osteoclasts. ! RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells. ! Denosumab is a human monoclonal antibody that works as a RANK ligand (RANKL) inhibitor. ! Denosumab inhibits the binding of RANKL to RANK, preventing development of osteoclasts. Calcimimetic Cinacalcet (Sensipar) for Hypercalcemia ! Cinacalcet mimics the action of calcium on tissues by allosterically activating the calciumsensing receptor that is particularly expressed on the surface of the chief cell of the parathyroid gland. " The activation of calcium-sensing receptors on parathyroid cells results in the reduction of parathyroid hormone (PTH) levels and thus decrease serum calcium levels. " Cinacalcet is used to treat hyperparathyroidism in patients with chronic kidney disease who are on dialysis. Osteoporosis ! A systemic skeletal disorder characterized by low bone mass and consequent increase in fracture risk # the most common reason for a broken bone among the elderly ! Treatment of osteoporosis " Calcium and vitamin D supplements " Antiresorptive Agents 1. Bisphosphonates are useful in decreasing the risk of future fractures in those who have already sustained a fracture due to osteoporosis. 2. RANK ligand (RANKL) inhibitor: Denosumab (Prolia™) 3. Calcitonin (Fortical®, Miacalcin®) 4. Estrogens and Selective Estrogen Receptor Modulators: Estrogen; Selective estrogen receptor modulators (SERMs): Raloxifene (Evista®); and Tissue Specific Estrogen Complex (TSEC): Duavee® (conjugated estrogens/Bazodoxifene) " Anabolic Agents 1. Parathyroid Hormone (PTH) Analog: Teriparatide (Forteo®) 2. Parathyroid Hormone-Related Protein (PTHrp) Analog: Abaloparatide (Tymlos) 3. Monoclonal antibody Sclerostin Inhibitor: Romosozumab (Evenity) Anabolic Agents: Teriparatide, Abaloparatide, Romosozumab ! Parathyroid hormone (PTH) increases serum calcium by increasing bone resorption in osteoclast. ! The intermittent administration of PTH has a pleiotropic anabolic effect on bone by increasing osteogenesis and bone formation in osteoblast. # a new therapeutic agent for osteoporosis " Teriparatide (Forteo) is a recombinant form of PTH ( first N-terminus 34 amino acids) " Abaloparatide (Tymlos) is a parathyroid hormone-related protein (PTHrP) analog. " Romosozumab (Evenity) is a monoclonal antibody against sclerostin. It is secreted by osteocytes and inhibits the genesis of osteoblasts as a WNT signaling inhibitor, thereby resulting in a decrease in bone formation. Circulating sclerostin levels are higher in postmenopausal than in premenopausal women. $ Unlike Teriparatide and Abaloparatide, Romosozumab increases bone formation by osteoblast and decreases bone resorption by osteoclast. Estrogens and Selective Estrogen Receptor Modulators (SERMs): Raloxifene and Bazedoxifene " Estrogens silence osteoclast activity by inhibiting the expression of local inflammatory interleukins and other cytokines. # Prevention of bone loss and decreases fractures Effect of estrogen and anti-estrogen therapies on bone turnover " Estrogen receptors of different target tissues vary in chemical structure, so SERMs were developed to reap the benefits of estrogen while avoiding the hormone's potential side effects. " Raloxifene as a SERM can act like estrogen on bone, protecting its density, but as an anti-estrogen on breast and the lining of the uterus. # Prevention and treatment of osteoporosis in postmenopausal women and Reduction of the risk of invasive breast cancer in postmenopausal women at high risk or with osteoporosis " DUAVEE® (Estrone sulfate/bazedoxifene): a novel class of agents pairing a selective estrogen receptor modulator (SERM) with 1 or more estrogens # FDA-approved to reduce hot flashes and osteoporosis in postmenopausal women DUAVEE® Agonist and antagonist effects of Raloxifene Estrone sulfate Raloxifene (Evista) Bazedoxifene Medications for Disorders of Calcium Homeostasis ! Calcium, Vitamin D, and Calcitriol: hypocalcemia, rickets, osteomalacia, and osteoporosis ! Antiresorptive agents: effective therapies for the treatment of bone diseases associated with excessive osteoclast activity (hypercalcemia and osteoporosis). 1. Calcitonin (Miacalcin): Inhibition of osteoclast function 2. Bisphosphonates: Decreasing osteoclast progenitor development and recruitment and promoting osteoclast apoptosis 3. Denosumab (Prolia, Xgeva): As a RANK ligand inhibitor, it inhibits osteoclast formation, function and survival. 4. Estrogens and SERMs: Raloxifene and Estrone sulfate/Bazedoxifene ! Calcimimetic agent [Cinacalcet (Sensipar)]: Hypercalcemia caused by increased by PTH expression and secretion in parathyroid chief cells or caused by parathyroid carcinoma ! Anabolic agents: increase osteoblast differentiation and proliferation, which enhances bone mass, quality, strength and composition (oteoporosis). 1. Teriparatide (Forteo/Forsteo): a parathyroid hormone analog 2. Abaloparatide (Tymlos): a parathyroid hormone-related protein analog 3. Romosozumab (Evenity): a sclerostin inhibitor; sclerostin is produced in osteocytes, and its main function is to inhibit bone formation. Review Questions RQ 1. Which of the following is NOT an anabolic agent to stimulate osteoblastic bone formation? A. B. C. D. Calcitonin Teriparatide Abaloparatide Romosozumab RQ 2. Which of following statements is NOT correct regarding bisphosphonates? A. B. C. D. Bisphosphonates are pyrophosphate analogues with high affinity for bone. Non-nitrogen-containing bisphosphonates can be metabolized to non-hydrolyzable ATPs. Alendronate structurally belongs to non-nitrogen-containing bisphosphonates. Nitrogen-containing bisphosphonates target osteoclast farnesyl pyrophosphate synthase.