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51 Cards in this Set
- Front
- Back
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Calcium and Phosphate: Actions--
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*Diverse role
-Bone structure (~99% total Ca; 85% total P) -Cellular functions (~1 % total Ca; ~15% total P) -Muscle contraction -Coagulation, other enzyme activities (P critical for ATP) -Regulation of hormone secretion -Nerve conduction *Extracellular [Ca] tightly regulated (0.1% total Ca) -50% free AKA ionized Ca -40% bound to protein (90% albumin) -9% complex with anions (e.g., citrate, phosphate) *Extracellular [P] (~1% total P): less tightly regulated -Two forms: HPO4, H2PO4 |
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What organs and hormones regulate calcium?
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Describe the role of Bone, Kidney, and the intestines in regulating Ca:
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*Bone
-Principal reservoir of Ca and P -Major crystalline salt: hydroxyapatite -Ca, P mineralization necessary for structural integrity *Kidney -Filters both Ca and P -Re-absorbs 99% filtered Ca -Excretes P over a certain threshold -Site of activation of Vitamin D (25-OH D to 1,25-OH D) *Intestine -Intake ~1000 mg/day of each: P absorption > Ca (~35%) -Absorption of dietary Ca (active), P (active and passive) -Fecal excretion of Ca, P is significant |
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Describe mineral levels in mineralized bone, bone fluid, and the central canal:
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Describe the makeup of Bone Components: Cells and Matrix--
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*Matrix
1. Type I Collagen fibers organized in triple helix structure with other proteins (osteocalcin and osteonectin which bind Ca++) polymerize to form osteoid 2. Ca deposition in osteoid converted to hydroxyapatite (calcium phosphate crystals) *Cells 1. Osteoblasts: bone-forming cells that produce matrix; receptors for E2, PTH, Vit D; following calcification, cells become osteocytes 2. Osteoclast: bone-remodeling cells that are multinuclear macrophages: bone resorption by acid, lysosomal enzymes |
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What's the structural organization of bone?
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i feel like i've heard this before
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Describe the balance b/t bone formation and resorption:
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How does bone remodeling happen?
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Describe the critical hormones regulating bone:
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*Parathyroid Hormone (PTH) and Vitamin D
-activate osteoclasts indirectly through secretion of soluble factors from osteoblasts *Estrogen -Activates osteoblasts to produce IGF-I and Osteoprotegerin (OPG) -Inhibits osteoclasts indirectly by suppressing IL-6 and increasing OPG -Loss of E2 at menopause increases resorption *GH directly and indirectly via IGF-I: -Regulates bone turnover and remodeling -Stimulates proliferation of articular chondrocytes and production of matrix |
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How does PTH Regulate Osteoclast Function?
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*Activated osteoblasts express Rank Ligand (RankL) which binds its receptor RANK on osteoclasts, inducing activation
*Osteoblasts secrete Osteoprotegerin (OPG) which acts as a decoy receptor for RankL, preventing osteoclast activation *Hormones and drugs that increase or decrease these proteins control bone resorption by regulating osteoclast activation |
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Biochemical Markers of Bone Turnover:
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Bone formation products come from OBs
Bone resorption products are breakdown products from osteoid |
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What 2 organs does PTH act directly on? How?
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-renal tubule
-bone -acts indirectly on gut |
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Describe PTH Regulation of Calcium (and P):
-discuss PTH-rp -discuss role of Mg with PTH |
*Parathyroid Hormone (PTH)
-84 aa peptide produced in parathyroid gland chief cells -Ca-sensing receptor controls PTH synthesis, release -PTH action via G-protein coupled receptor, cAMP -Bone: increases Ca, P resorption via osteocyte (rapid) and osteoclast (slow: mechanism is indirect) -Kidney: increases Ca absorption, decreases P absorption (rapid); activates 1alpha hydroxylase to convert 25 OH-D to active 1,25 OH-D *PTH-rp: homologous to N-terminal portion of PTH; wide expression (e.g., placenta, cancer); PTH and PTH-rp have common receptor and specific receptors *High [Mg] inhibits; acutely low [Mg] stimulates PTH |
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How does PTH secretion relate to ionized Ca++?
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iCa regulates PTH; very tightly
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What Controls PTH synthesis and release?
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Ca Sensing Receptor
-Ca inhibits PTH via CaSR |
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Describe the Calcium Sensing Receptor, CaR:
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*Increased extracellular Ca++ binds to CaR
*CaR: Gq coupled receptor that signals thru phospholipase C to inhibit PTH *CaR widely distributed in brain, skin, bone, stomach, thyroid C cells, renal distal tubule *Mg required for increased PTH secretion due to low iCa++ *Mutations in CaR can result in calcium sensing defects: e.g., inactivating mutation in parathyroids and kidney leads to “benign” hypercalcemia |
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Describe Regulation of Phosphate:
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*Phosphate resides in bone (85%), cells (14%) and extra-cellular fluid (~1%)
*Kidney is the major site of PO4 homeostasis: Na/P transporters, especially NPT2a mediate PO4 reabsorption in the renal tubule *PTH and FGF23 decrease NPT2a expression to increase PO4 excretion and decrease serum [PO4] *FGF23, a phosphatonin, is synthesized in bone and acts on the kidney to inhibit PO4 absorption and 1,25-OH Vit D production; its cofactor Klotho is required for activation of its receptor, FGFR1 |
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Describe FGF23 Regulation of Phosphate:
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FGF23 increases P excretion in urine; ALSO decreases P absorption in gut
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What does Vit D do for us? What diet sources do we get it from in the U.S.?
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Regulates Bone and Ca
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Describe the structure and synthesis of Vit D:
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Describe regulation of Ca by Vit D:
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*Regulation: Cholesterol derivative Cholecalciferol (D3) converted to STORAGE form (25OH D) in liver, activated by PTH in kidney to ACTIVE form: 1,25(OH)2D
*Metabolism: kidney converts to water-soluble INACTIVE calcitroic acid or 24,25(OH)D if PTH low *Target tissue/Action: Bone: remodeling, mineralization Small Intestine: Ca, P, Mg absorption (increases expression of Ca-binding Protein) Skin: keratinocyte differentiation |
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Describe Vit D's diverse actions via the VDR:
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*VDR+RXR needed for transcription
*Thyroid hormone ALSO binds with RXR |
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Describe the various effects Vit D has on different tissues:
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Describe Calcitonin and its role in Calcium regulation:
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*32 amino acid peptide made in C cells (neural crest derivatives) in the thyroid gland
*Regulated acutely by elevated Ca levels *MINOR role in Ca homeostasis in humans -Decreases resorption of bone due to inhibition of osteoclasts, therefore decreases Ca concentration -Decreases Ca reabsorption in kidney at high levels -No consequences on Ca metabolism if pt is athyroidal *Used clinically for disorders of osteoclasts and hypercalcemia to inhibit bone resorption |
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Describe Ca and PTH levels in various diseases:
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-low Ca, low PTH = 1˚ hypoparathyroidism
-low Ca, high PTH = uremic parathyroidism or Vit D deficiency -hi Ca, low PTH = PTHrp related cancer -high Ca, high PTH = 1˚ hyperparathyroidism |
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Talk about some Metabolic Bone diseases:
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*Osteomalacia: “soft” bones due to poor mineralization of newly formed osteoid; insufficient Ca, P or Vitamin D
*Rickets: osteomalacia of growing bones affects growth plate; soft bones bend *Osteoporosis: low BMD due to decreased bone formation and increased resorption; bone loss *Osteogenesis Imperfecta (OI): mutation in Type 1 collagen leads to abnormal osteoid and increased resorption resulting in fragility; sort of a combo or osteomalacia AND osteoporosis. |
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normal bone vs. osteoporosis vs. osteomalacia:
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Describe general bone structure:
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Skeletal Manifestations of Rickets:
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*Sites of rapid bone growth: Distal forearm, knee and costochondral junction
*Enlargement of the costochondral junction *Enlargement of joints: wrist, knee, ankle *Delay closure of the fontanelles *Craniotabes (soft skull bones) *Parietal and frontal bossing *Bowing: Radius, femur, tibia *Growth failure |
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Signs of Rickets:
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Rickets: skeletal changes at growth plates ("fuzzy")
Inadequate mineralization, cartilage accumulation leads to soft bones |
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Skeletal Manifestations of Osteomalacia in adults:
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Usually asymptomatic; dull bone pain or tenderness
Decrease in bone density Pseudofractures AKA loosers zones Low trauma fractures |
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osteomalacia in an adult
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Vitamin D Deficiency:
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*Deficient intake or absorption
Poor diet or malabsorption Inadequate sunlight exposure PTH high; Ca variable, P low, 1,25 D normal or elevated (b/c PTH is high!) *Defective 25-hydroxylation Liver disease Anticonvulsants - convert to inactive Vitamin D metabolite *Defective 1-alpha hydroxylation (occurs in kidney) Hypoparathyroidism Renal failure Enzyme defect (VDDR-1) *Vitamin D receptor defect (VDDR- 2) |
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Vitamin D-Dependent Rickets Type I:
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*1,25 OH-D deficiency
*1-alpha hydroxylase deficiency -Autosomal recessive disorder -Inactivating mutation in the gene that encodes 1-alpha-hydroxylase -Defect in calcidiol (D 25) to calcitriol (D1,25) conversion *Clinical manifestations -Skeletal findings within the first year of life -Low vitamin D 1,25 -Severe hypocalcemia (with tetany due to increased electrical potential across the cell membrane; hyperventilation alkalosis can cause this, too) -Moderate hypophosphatemia -Enamel hypoplasia |
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Vitamin D-Dependent Rickets Type II:
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*VDR resistance
*Hereditary vitamin D-resistant rickets -Autosomal recessive disorder (50 affected kindreds) -Mutations in the gene encoding the vitamin D receptor *Clinical spectrum -Varies based on mutation and residual receptor activity --> develop rickets within two years of life -ALOPECIA (lack of vitamin D receptor action within keratinocytes) is a marker of disease severity -Elevated 1,25-OH-Vitamin D since VDR is abnormal; can't bind it. |
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Vitamin D Deficiency in Children:
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*Vitamin D Status
-Transferred from the mother prenatally (lasts 3-4 wks) -Ingested or produced by the skin *Nutritional vitamin D deficiency -Occurs when growth rates and calcium needs are high -Associated with breast feeding, inadequate sun, malabsorption, poor diet -Prevention and treatment -Fortified formula/milk -Vitamin D supplements with breastfeeding |
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Vitamin D Deficiency in Adults:
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*Cutaneous production
Declines with age Varies with season, latitude and skin pigmentation *Reduced intake 50% consume <137 IU/d 25% consume <65 IU/d *Treatment Sun exposure Vitamin D intake via diet or supplements |
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Renal phosphate Wasting Syndromes: 3
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*Hypophosphatemic rickets
-X-linked: most common; PHEX mutation increases FGF23 -AD: activating mutations in FGF23 -AR: mutation in Dentin Matrix Protein-1 increases FGF23 -HHRH: mutation in Na/P co-transporter (1,25 doesn't decrease --> hypercalcemia) *Tumor-induced (oncogenic) osteomalacia -Mesenchymal tumors produce FGF23, other phosphatonins -Tumor resection cures urinary phosphate wasting *Fanconi syndrome -Proximal renal tubule defect (inherited or acquired): loss of phosphate, glucose, amino acids, potassium, bicarb, uric acid |
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Describe the differnt types of OI:
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boards love the blue sclera
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Etiology of Osteomalacia/Rickets-- name the big categories: 5
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Ca deficiency
Vit D related Inhibitors of mineralization Phosphate wasting Enzyme deficiency Abnormal matrix |
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Describe Vit D related Osteomalacia/Rickets:
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Vitamin D-related
- Deficient intake or absorption Poor diet or malabsorption Inadequate sunlight exposure - Defective 25-hydroxylation Liver disease Anticonvulsants - Defective 1-alpha 25-hydroxylation Hypoparathyroidism Renal failure Enzyme defect (VDDR-1) - Vitamin D receptor defect (VDDR- 2) |
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Describe inhibitors of mineralization that may cause Osteomalacia/Rickets:
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- Fluoride
- Aluminum, Cadmium - Bisphosphonates |
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Describe Osteomalacia/Rickets due to phosphate wasting:
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*Decreased intestinal absorption
- Vitamin D deficiency - Alcoholism, anorexia, starvation - Antacids *Increased renal losses - 1º or 2º hyperparathyroidism - Hypophosphatemic rickets - Oncogenic hypophosphatemia - Renal tubular defect |
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Describe Osteomalacia/Rickets due to enzyme deficiency and abnormal matrix:
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Enzyme deficiency
- Hypophosphatasia: 5 types, decreased alkaline phosphatase activity Abnormal matrix - Osteogenesis imperfecta - Axial osteomalacia |
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Low Ca and Low P=
Low Ca and High P= High Ca, Low P, low PTH= |
-Vit D problem
-PTH problem -xs Vit D (due to PTHrp); could be cancer related |
