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Khurram Mahmood Assistant ProfessorHormonal Regulators of Bone Mineral Homeostasis: Hormonal Regulators of Bone Mineral Homeostasis Principal Parathyroid hormone (PTH) Vitamin D Fibroblast growth factor 23 (FGF23) Other hormones Calcitonin, prolactin, GH, Insulin, Thyroid hormone, Glucocorticoids & sex steroidsParathyroid Hormone (PTH): Parathyroid Hormone (PTH) Single chain peptide hormone composed of 84 AAs Produced in PTG in a precursor form (115 AAs) Metabolic clearance – rapid (within minutes), mostly occurs in the liver & kidney Regulates Ca++ and phosphate flux across CMs in bone & kidney resulting in increased serum Ca++ and decreased serum phosphateParathyroid Hormone (PTH)…: Acts on G protein coupled receptors to increase cAMP in bone and the renal tubule At high doses, the hormone increases blood calcium and decreases phosphorus by increasing net bone resorption Low doses (physiologic levels), PTH can increase net bone formation 1-34 teriparatide, a synthetic PTH analog (recombinant) – treatment of osteoporosis Parathyroid Hormone (PTH)…Vitamin D: Vitamin D Secosteroid; Produced in the skin from 7-dehydrocholesterol under the influence of UV radiation 2 forms D 3 cholecalciferol - animal D 2 ergocalciferol – plant Vit D – a prohormone, serves as a precursor for a large no of active metabolitesVitamin D…: Vitamin D… Natural met – calcifediol, calcitriol Synthetic met – calcipotriene (psoriasis) doxercalciferol & paricalcitol ( sec hyperparathyroidism in pts with RF) Other analogs investigated for Rx of malignancies Regulation is complex; involving Ca, PO4 & other hormones PTH stimulates & PGF23 inhibits production of 1,25(OH) 2 by the kidneyFibroblast growth factor 23 (FGF23): Fibroblast growth factor 23 (FGF23) Sinle chain protein with 51 AAs Inhibits 1,25(OH) 2 D 3 production and phosphate reabsorption Requires O-glycosylation for its secretion Inactivated by cleavageVitamin D Deficiency: Vitamin D DeficiencyInteraction of Parathyroid hormone & Vitamin D : Interaction of Parathyroid hormone & Vitamin DCalcitonin: Calcitonin Single chain peptide hormone secreted by TG Decreases bone resorption and serum Ca++ and phosphate Used in conditions in which an acute reduction of serum Ca++ is needed (paget’s disease, hypercalcemia) R x of osteoporosis Secondary Hormonal RegulatorsGlucocorticoids: Glucocorticoids Alter bone mineral homeostasis Ch. Systemic adm leads to osteoporosis (adults) and stunted skeletal development (children) Useful in reversing the hypercalcemia associated with lymphomas and granulomatous diseases (sarcoidosis or in Vit D intoxication)Estrogens: Estrogens Estrogens and Selective Estrogen Receptor Modulators (SERMs e.g. raloxifene) Prevent or delay bone loss in post-menopausal women Disorders of bone mineral homeostasisNon-hormonal Agents Affecting Bone Mineral Homeostasis: Non-hormonal Agents Affecting Bone Mineral HomeostasisBiphosphonates: BiphosphonatesBiphosphonates: Biphosphonates Analogs of pyrophosphate Etidronate, pamidronate, alendronate, risedronate, tiludronate and zoledronate Reduce both the resorption and formation of bone by an action on the basic hydroxyapatite crystal structure They localize to regions of bone resorption & so exert their greatest effect on osteoclasts Etidronate, pamidronate cause bone mineralization defects & loose their effectiveness over 12 months alendronate, risedronate cause fewer bone problems, effectiveness for 5 yearsTherapeutic uses: Therapeutic uses Rx of osteoporosis Alendronate in combination for hormone replacement therapy, increase bone mass in menopausal pts Oral BA – low, food impairs their absorption, should be taken alongwith plenty of water to minimize esophageal irritationPlicamycin (Mithramycin): Plicamycin (Mithramycin) Cytotoxic antibiotic Used to reduce bone resorption in paget’s disease and hypercalcemia, dose is 1/10th Risk of severe toxicity is not commonly usedThiazides: Thiazides Rx of bone mineral disorders –reducing renal Ca++ excretion May increase the effectiveness of PTH Useful in reducing hypercalciuria and incidence of stone formationFluoride: Fluoride Accumulated by bones & teeth, stabilize the hydroxyapatite crystals Effective for prophylaxis of dental caries Under investigation for the treatment of osteoporosis Excess leads to mottling A/Es – N., V., GIT blood loss, arthralgia & arthritisStrontium Ranelate: Strontium Ranelate Composed of organic iron,ranelic acid, bound to two atoms of strontium Appears to block osteoclast differentiation while promoting their apoptosis & thus inhibiting bone resorption Also promotes bone formationCalcimimetics : Calcimimetics Cinacalcet Activates calcium sensing receptor (CaR) Wide distribution with greatest conc in PTG Treatment of sec hyperparathyroidism in ch kidney disease & Rx of PT carcinomaSlide 28: Summary of Hormones that Act on Bone Hormone Regulated by Actions PTH produced in the parathyroid gland Serum Calcium serum calcium Primarily act at low concenctrations by stimulating osteoblasts to promote bone deposition At high concentrations PTH stimulates bone resorption by indirectly acting on osteoclasts Causes Ca reabsorption from the kidney Causes Phosphate dumping (phosphaturia) in the kidney Stimulates 1 hydroxylase in the kidney to promote formation of 1,25(OH) 2 D FYI John Glenn used the subcutaneous PTH 1-34 injections to prevent bone loss when he went on his last shuttle mission 1,25(OH) 2 D produced in the kidney PTH others? serum calcium primarily acts by promoting Ca and P absorption from the gut acts on bone by stimulating osteoblasts to produce bone mineraliztion proteins (such as osteocalcin) suppresses ostesclasts indirectly by stimulating RANK ligand production in osteoblasts At supraphysiologic levels can cause bone resorption acts on kidney to reabsorb Ca and P (less impt than gut effect) high levels act directly on the parathyroid gland to suppress PTH production Calcitonin produced in parafollicular (C) cells of thyroid gland not discussed serum calcium predominately acts by directly inhibiting the osteoclast some evidence suggests it promotes Ca deposition in bone, but this has not been provenClinical pharmacology: Clinical pharmacology Bone & kidney – bone mineral homeostasis Effects on bone – osteoporosis, osteomalacia, osteitis fibrosa Early indicators of renal involvement – polyuria, nocturia & hyposthenuria Late indicators – radiologic evidence of nephrocalcinosis & stonesPrinciple Cells Regulating Bone Metabolism:: Principle Cells Regulating Bone Metabolism: Osteoblasts Bone forming cells derived from fibroblast precursors Synthesize and secrete collagen (mainly Type I) and other matrix proteins such as osteocalcin (this is a good serum marker of bone formation; it requires Vit K as a cofactor but this isn’t impt ) Synthesizes and secretes alkaline phosphatase (AlkPhos is a marker of bone turnover, it will be increased in pts w/ a fracture or w/ lytic bone lesions; ¾ comes from liver and ¼ comes from bone so bone-specific alk phos or BAP is a better marker of bone turnover) Governs bone mineral deposition- Produce RANK ligand (an analog of TNF) that activates osteoclasts - Produce osteoprotegrin (OPG) that is a free floating RANK ligand receptor (binds RANK ligand to prevent over stimulation of osteoclasts Control of Osteoblasts: 1) Mesenchymal stem cells differentiate into osteoblasts 2) Osteoblasts have receptors for PTH and growth stimulating cytokines (IGF-1 and others) that cause proliferation of osteoblast and cause activity of osteoblasts to synthesize bone matrix: - Produce RANK ligand (an analog of TNF) that activates osteoclasts - Produce osteoprotegrin (OPG) that is a free floating RANK ligand receptor (binds RANK ligand to prevent over stimulation of osteoclasts Control of Osteoblasts: 1) Mesenchymal stem cells differentiate into osteoblasts 2) Osteoblasts have receptors for PTH and growth stimulating cytokines (IGF-1 and others) that cause proliferation of osteoblast and cause activity of osteoblasts to synthesize bone matrixPlasma – 0.2 g (0.02%) where 55% is bound to protein and 45% is ionic (this is the form that affects excitability of membranes) ECF – 0.1 g (0.01%) ICF – 0.1 g (0.01%) Bone – 1.1 kg (99% of body store): Plasma – 0.2 g (0.02%) where 55% is bound to protein and 45% is ionic (this is the form that affects excitability of membranes) ECF – 0.1 g (0.01%) ICF – 0.1 g (0.01%) Bone – 1.1 kg (99% of body store) Distribution of Body CalciumSlide 34: What does Ca do? It is responsible for muscle contraction, acts as a 2nd messenger for horomones, and responds to neural stimulation to release neurotransmitters. Hypocalcemia = low ionized Ca muscle & nerve firing, cardiac excitability (if very low tetany & seizures/coma) Hypercalcemia = high ionized Ca muscular excitability, GI motilityHYPERCALCEMIA: HYPERCALCEMIA Causes hyperparathyroidism & cancer with or without bone metastases, thiazide therapy hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency and immobilization Effects CNS depression including coma - lethalTreatment / Approaches: Treatment / Approaches Saline diuresis Rehydration with saline & diuresis with Furosemide For prolonged R x Biphosphonates Calcitonin Gallium nitrate Plicamycin Phosphate GlucocorticoidsHYPOCALCEMIA: HYPOCALCEMIA Features NM – tetany, paresthesias, laryngospasm, muscle cramps & convulsions Causes hypoparathyroidism, Vit D def, RF, malabsorption, large infusions of citrated blood R x Calcium & Vit DCalcium: Calcium I/V, I/M or Oral use I/V therapy : Ca-gluceptate, Ca-gluconate, Ca-chloride Ca-gluconate preferred, less irritating to veins Oral therapy ; Ca-carbonate, Ca-lactate, Ca-phosphate, Ca-citrate Ca-carbonate preferred, high % of Ca, easy availability, low cost & antacid propertiesVit D : Vit D What does Vit D do? Cholecaliferol possesses very little biological activity; Calcidiol is considered biologically active, but is not nearly as active as calcitriol Calcitriol primarily stimulates Ca (and PO4) absorption from the gut; it also Ca resorption from bone Calcitriol acts on osteoblasts to formation of bone mineralization proteins such as osteocalcin; it also causes synthesis of RANK Calcitriol can act on the kidney to reabsorb Ca and PO4 (less impt than intestinal action) Calcitriol also feeds back on the parathyroid gland to PTH productionHYPERPHOSPHATEMIA: HYPERPHOSPHATEMIA Frequent complication of RF Found in all types of hypoparathyroidism Vit D intoxication Syndrome of tumoral calcinosis R x dialysis glucose and saline infusion in general : restriction of dietary phosphate, use of phosphate binding gelsHYPOPHOSPHATEMIA: HYPOPHOSPHATEMIA Hypoparathyroidism, Vit D def, idiopathic hypercalciuria, Vit D resistant Rickets, forms of renal phosphate wasting (Fanconi’s synd), ext use of phosphate binders & parenteral nutrition with inadequate phosphate content Effects proximal muscle weakness and abnormal bone mineralizationSpecific disorders involving the bone mineral regulating hormones: Specific disorders involving the bone mineral regulating hormones Primary hyperparathyroidism Hypoparathyroidism Nutritional rickets CRF Intestinal osteodystrophy Osteoporosis X-linked & autosomal dominant hypophosphatemia Vit D dependent Rickets Types I & II Nephrotic Syndrome Idopathic HypercalciuriaOther Disorders of Bone Mineral Homeostasis: Other Disorders of Bone Mineral Homeostasis Paget’s Disease of bone Enteric OxaluriaSlide 44: Lab findings in hypocalcemic disorders Serum Ca Serum P iPTH 25 OHD 1,25(OH) 2 D Hypoparathyroidism b/c not resorbing Ca b/c not excreting P b/c not making PTH no effect on 25OHD no PTH to stim. production Pseudo-hypoparathyroidism b/c not resorbing Ca b/c not excreting P b/c gland making PTH, but tissues resistant no effect on 25OHD no PTH to stim. production Magnesium Deficiency b/c Mg PTH secretion &efficacy b/c not excreting P or depends on how low Mg really is no effect on 25OHD enough PTH to stim production Vit D Deficiency or depends on severity of D deficiency b/c not resorbing P trying to compensate for low D lack of intake or sun exposure; mal-absorptive disease will be low in very severe deficiency Renal Failure lack of 1,25(OH) 2 D absorption b/c can’t excrete via kidney b/c serum Ca is low no effect on 25OHD kidney can’t synthesizeSlide 45: Thank you for your attention You do not have the permission to view this presentation. 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