Pharmacology Chapter 42: Bone Mineral Homeostasis PDF

Ph-24a (PHARMACOLOGY 2) INSTRUCTOR: DR. KIM ALEXANDRA PEDROSA FINALS CHAPTER 42: AGENTS THAT AFFECT BONE...

Ph-24a (PHARMACOLOGY 2) INSTRUCTOR: DR. KIM ALEXANDRA PEDROSA FINALS CHAPTER 42: AGENTS THAT AFFECT BONE Secondary regulators of calcium and phosphate homeostasis: Calcitonin (plays a role during pregnancy and lactation) MINERAL HOMEOSTASIS Prolactin Growth hormone Insulin LECTURE OUTLINE insulin-like growth factors thyroid hormone I. BASIC PHARMACOLOGY Glucocorticoids II. PRINCIPAL HORMONAL REGULATORS OF BONE MINERAL Sex steroids HOMEOSTASIS III. SECONDARY HORMONAL REGULATORS OF BONE MINERAL PRINCIPAL HORMONAL REGULATORS OF BONE MINERAL HOMEOSTASIS HOMEOSTASIS IV. NONHORMONAL AGENTS AFFECTING BONE MINERAL PARATHYROID HORMONE HOMEOSTASIS - a single-chain peptide hormone composed of 84 amino acids V. ABNORMAL SERUM CALCIUM & PHOSPHATE LEVELS - produced in the parathyroid gland - Clearance: Liver & kidney VI. SPECIFIC DISORDERS INVOLVING BONE MINERAL VII. OTHER DISORDERS OF BONE MINERAL HOMEOSTASIS Mechanisms by which calcium limits the production of PTH: 1. A calcium-sensitive protease capable of cleaving the intact BASIC PHARMACOLOGY hormone into fragments Calcium and phosphate 2. Involves the calcium-sensing receptor (CaSR) which, when - major mineral constituents of the bone stimulated by calcium, reduces PTH production and secretion - most important minerals for general cellular function 3. The parathyroid gland also contains the vitamin D receptor (VDR) and the enzyme, CYP27B1, that produces 1,25(OH)2D, thus enabling circulating or endogenously produced 1,25(OH)2D to suppress PTH production 4. 1,25(OH)2D also induces the CaSR, making the parathyroid gland more sensitive to suppression by calcium PTH 1-34 (teriparatide) - fully active - Treatment of osteoporosis rhPTH 1-84 (Natpara) - full length form of PTH - treatment of hypoparathyroidism MECHANISMS CONTRIBUTING TO BONE MINERAL HOMEOSTASIS PTHrP (abaloparatide) - Analog of rhPTH 1-84 Bone - Treatment of osteoporosis - where approximately 98% of the 1–2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found ❖ PTH regulates calcium and phosphate flux across cellular - serves as the principal structural support for the body and membranes in bone and kidney, resulting in increased serum provides the space for hematopoiesis calcium and decreased serum phosphate ❖ In bone, PTH increases the activity and number of osteoclasts, Abnormalities in bone mineral homeostasis: the cells responsible for bone resorption. However, this stimulation of osteoclasts is not a direct effect. Rather, PTH Cellular dysfunctions acts on the osteoblast (the bone-forming cell) to induce (Tetany, Coma, muscle weakness) membrane-bound and secreted soluble forms of a protein Disturbances in structural support of the body called RANK ligand (RANKL). (osteoporosis with fractures) Loss of hematopoietic capacity RANKL (infantile osteopetrosis) - acts on osteoclasts and osteoclast precursors to increase both the numbers and activity of osteoclasts Intestine (This action increases bone remodelling, a specific sequence - where absorption (principally in the duodenum and upper of cellular events initiated by osteoclastic bone resorption and jejunum) and secretion (principally in the ileum) of calcium followed by osteoblastic bone formation) and phosphate occur Denosumab Kidney - an antibody that inhibits the action of RANKL - In the steady state, renal excretion of calcium and phosphate - developed for the treatment of excess bone resorption in balances intestinal absorption patients with osteoporosis and certain cancers. - where more than 98% of filtered calcium and 85% of filtered phosphate are reabsorbed Sclerostin Principal regulators of calcium and phosphate homeostasis: - one of several proteins that blocks osteoblast proliferation by Parathyroid hormone (PTH) inhibiting the wnt pathway Fibroblast growth factor 23 (FGF23) ❖ Antibodies against sclerostin (eg, romosozumab) are in Vitamin D (via its active metabolite: 1,25-dihydroxyvitamin D clinical trials for the treatment of osteoporosis (1,25[OH]2D) GROUP 11: ABAYAN, ONCE, PURA Ph-24a (PHARMACOLOGY 2) INSTRUCTOR: DR. KIM ALEXANDRA PEDROSA FINALS ❖ Thus, PTH directly and indirectly increases proliferation of Nonclassic actions: osteoblasts, the cells responsible for bone formation regulation of the secretion of PTH, insulin, and renin regulation of innate and adaptive immune function through Recombinant PTH 1-34 (teriparatide and abaloparatide) actions on dendritic cell and T-cell differentiation - treatment of osteoporosis enhanced muscle function proliferation and differentiation of a number of cancer cells ❖ In the kidney, PTH stimulates 1,25(OH)2D production, and increases tubular reabsorption of calcium and magnesium, but FIBROBLAST GROWTH FACTOR 23 reduces reabsorption of phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate. - a single-chain protein with 251 amino acids, including a 24-amino-acid leader sequence VITAMIN D - inhibits 1,25(OH)2D production and phosphate reabsorption - a secosteroid produced in the skin from 7-dehydrocholesterol (via the sodium phosphate co-transporters NaPi 2a and 2c) in under the influence of ultraviolet radiation. the kidney and can lead to both hypophosphatemia and - also found in certain foods and is used to supplement dairy inappropriately low levels of circulating 1,25(OH)2D products and other foods - originally identified in certain mesenchymal tumors, osteoblasts, and osteocytes in bone which appear to be its primary site of production ❖ FGF23 requires O-glycosylation for its secretion, a glycosylation mediated by the glycosyl transferase GALNT3. ❖ FGF23 is normally inactivated by cleavage at an RXXR site (amino acids 176 - 179) ❖ Mutations in this site lead to excess FGF23, the underlying problem in autosomal dominant hypophosphatemic rickets. A similar disease, X-linked hypophosphatemic rickets, is due to mutations in PHEX, an endopeptidase, which initially was thought to cleave FGF23 ❖ FGF23 binds to FGF receptors (FGFR) 1 and 3c in the presence of the accessory receptor Klotho-α. Both Klotho and the FGFR must be present for signaling in most tissues, although high levels of FGF23 appear to affect cardiomyocytes lacking ❖ Vitamin D is a precursor to a number of biologically active Klotho. Mutations in Klotho disrupt FGF23 signaling, resulting metabolites. in elevated phosphate and 1,25(OH)2D levels, a phenotype ❖ Vitamin D is first hydroxylated in the liver and other tissues to quite similar to inactivating mutations in FGF23 or GALNT3 form 25(OH)D, (calcifediol).This metabolite is further ❖ FGF23 production is stimulated by 1,25(OH)2D and phosphate converted in the kidney to a number of other forms, the best and directly or indirectly inhibited by the dentin matrix protein studied of which are 1,25(OH)2D (calcitriol) and 24,25[OH]2D DMP1 found in osteocytes. Mutations in DMP1 lead to (secalciferol), by the enzymes CYP27B1 and CYP24A1 increased FGF23 levels and osteomalacia. A number of analogs of 1,25(OH)2D have been synthesized to extend the INTERACTION OF PTH, FGF23, AND VITAMIN D usefulness of this metabolite to a variety of nonclassic conditions: Calcipotriene (calcipotriol) - used to treat psoriasis (hyperproliferative skin disorder) Doxercalciferol and paricalcitol - approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease Eldecalcitol - Approved in Japan for the treatment of osteoporosis 1,25(OH)2D - most potent stimulant of intestinal calcium and phosphate transport and bone resorption - act on the intestine both by induction of new protein synthesis ❖ Regulation of calcium and phosphate homeostasis is achieved (eg, calcium-binding protein and TRPV6, an intestinal calcium through important feedback loops channel) and by modulation of calcium flux across the brush border and basolateral membranes by processes that do not Calcium all require new protein synthesis It binds to a novel ion recognition site that is part of a Gq - like PTH, 1,25(OH)2D can induce RANKL in osteoblasts to protein–coupled receptor called the calcium-sensing receptor regulate osteoclast activity and proteins such as osteocalcin (CaSR) that employs the phosphoinositide second messenger and alkaline phosphatase, which may regulate the system to link changes in the extracellular calcium conc. to mineralization process by osteoblasts changes in the intracellular free calcium As serum calcium levels rise and activate this receptor, ❖ Specific receptors for 1,25(OH)2D (VDR) exist in nearly all intracellular calcium levels increase and inhibit PTH secretion. tissues, not just intestine, bone, and kidney. As a result much effort has been made to develop analogs of 1,25(OH)2D that Phosphate will target these non-classic target tissues without increasing regulates PTH secretion directly and indirectly serum calcium Its indirect actions are the result of forming complexes with calcium in the serum. Because it is the ionized free conc. of GROUP 11: ABAYAN, ONCE, PURA Ph-24a (PHARMACOLOGY 2) INSTRUCTOR: DR. KIM ALEXANDRA PEDROSA FINALS extracellular calcium that is detected by the parathyroid gland, - a disulfide bond between positions 1 and 7 is essential for increases in serum phosphate levels reduce the ionized biologic activity calcium levels, leading to enhanced PTH secretion. Clearance: Much of the clearance occurs in the kidney by metabolism; ❖ Such feedback regulation is appropriate to the net effect of little intact calcitonin appears in the urine PTH to raise serum calcium and reduce serum phosphate Principal effects: To lower serum calcium and phosphate by actions on levels. bone and kidney ❖ High serum calcium works directly and indirectly by reducing Indication: Paget’s disease, hypercalcemia, and osteoporosis PTH secretion ❖ High serum phosphate works directly and indirectly by ❖ Calcitonin inhibits osteoclastic bone resorption increasing FGF23 levels ❖ In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including 1,25(OH)2D sodium, potassium, and magnesium - directly inhibits PTH secretion (independent of its effect on ❖ Tissues other than bone and kidney are also affected by serum calcium) by a direct inhibitory effect on PTH gene calcitonin transcription ❖ Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing ❖ In patients with chronic renal failure who frequently are secretion of sodium, potassium, chloride, and water in the gut deficient in producing 1,25(OH)2D due in part to elevated FGF23 levels, loss of this 1,25(OH)2D-mediated feedback loop Pentagastrin coupled with impaired phosphate excretion and intestinal - potent stimulator of calcitonin secretion (as is hypercalcemia) calcium absorption leads to secondary hyperparathyroidism. ❖ 1,25(OH)2D also stimulates the production of FGF23. This GLUCOCORTICOIDS completes the negative feedback loop in that FGF23 inhibits 1,25(OH)2D production while promoting hypophosphatemia, - alter bone mineral homeostasis by antagonizing vitamin which in turn inhibits FGF23 production and stimulates D–stimulated intestinal calcium transport, stimulating renal 1,25(OH)2D production. calcium excretion, blocking bone formation, and at least initially stimulating bone resorption. Indication: useful in reversing the hypercalcemia associated with lymphomas and granulomatous diseases such as sarcoidosis (in which unregulated ectopic production of 1,25[OH]2D occurs) or in cases of vitamin D intoxication. ❖ Prolonged administration can cause osteoporosis in adults and can cause stunted skeletal development in children ESTROGENS - can prevent accelerated bone loss during the immediate postmenopausal period and at least transiently increase bone in postmenopausal women - has direct effects on bone remodeling Indication: treatment or prevention of postmenopausal osteoporosis ❖ Prevailing hypothesis: estrogens reduce the bone-resorbing action of PTH ❖ Estrogen administration leads to an increased 1,25(OH)2D level in blood, but estrogens have no direct effect on 1,25(OH)2D production in vitro. The increased 1,25(OH)2D levels in vivo following estrogen treatment may result from decreased serum calcium and phosphate and increased PTH. ❖ However, estrogens also increase DBP production by the liver, which increases the total concentrations of the vitamin D metabolites in circulation without necessarily increasing the free levels Estrogen receptors - found in bone - Case reports of men who lack the estrogen receptor or who are unable to produce estrogen because of aromatase THE HORMONAL INTERACTIONS CONTROLLING BONE MINERAL deficiency noted marked osteopenia and failure to close HOMEOSTASIS epiphyses SECONDARY HORMONAL REGULATORS OF BONE MINERAL Selective estrogen receptor modulators (SERMs) HOMEOSTASIS - developed to retain the beneficial effects on bone while CALCITONIN minimizing deleterious effects on breast, uterus, and the cardiovascular system - secreted by the parafollicular cells of the mammalian thyroid - a single-chain peptide hormone with 32 amino acids and a molecular weight of 3600 - produced from a precursor with a molecular weight of 15,000 GROUP 11: ABAYAN, ONCE, PURA Ph-24a (PHARMACOLOGY 2) INSTRUCTOR: DR. KIM ALEXANDRA PEDROSA FINALS NONHORMONAL AGENTS AFFECTING BONE MINERAL HOMEOSTASIS DENOSUMAB BISPHOSPHONATES Denosumab is a fully humanized monoclonal antibody that targets and inhibits RANKL (Receptor Activator of Nuclear Factor Kappa-Β Ligand), Chemical Structure which is produced by osteoblasts and T lymphocytes. Analogs of pyrophosphate but have a stable P-C-P bond, which is nonhydrolyzable, rather than P-O-P bond, enhancing their stability in the RANKL is crucial for the formation and activity of osteoclasts, the cells body. responsible for bone resorption. By blocking RANKL, denosumab prevents osteoclastogenesis, thereby reducing bone loss. Currently Available Etidronate (rarely used due to lower Indication and Administration Bisphosphonates potency) Pamidronate Postmenopausal Osteoporosis: Helps prevent fractures in Alendronate postmenopausal women. Risedronate Certain Cancers: Used in prostate and breast cancers to limit Tiludronate bone metastases and prevent bone loss from gonadal Ibandronate function suppression. Zoledronate Administered subcutaneously every 6 months Efficacy and its Advantages Absorption and Administration Comparable in effectiveness to potent bisphosphonates in inhibiting bone resorption. Oral bisphosphonates (alendronate, risedronate, ibandronate) Unlike bisphosphonates, denosumab can be used in patients have poor absorption (