Bone Practise Questions 2023-03-27 (1).ppt

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Bone Practise Questions 1 What are the two main causes/determinants of bone remodelling? • Calcium homeostasis & Mechanical stress Click to see answer 2 Which of the following is a symptom/sign of acute hypocalcaemia Constipation Fatigue Low mood Muscle spasms Neuromuscular depression • • C...

Bone Practise Questions 1 What are the two main causes/determinants of bone remodelling? • Calcium homeostasis & Mechanical stress Click to see answer 2 Which of the following is a symptom/sign of acute hypocalcaemia Constipation Fatigue Low mood Muscle spasms Neuromuscular depression • • Click to see answer Muscle spasms Hypocalcaemia induces hyper-excitability 3 All of the following are symptom/signs of chronic hypocalcaemia EXCEPT Carpopedal spasm Delayed dentition Scoliosis Short stature Enlarged iliac crest Click to see answer • Enlarged iliac crest 4 Which of the following is a symptom/sign of acute hypercalcaemia Chvostek’s sign Rales Joint pains Diarrhoea Arrhythmias Click to see answer • Arrhythmias 5 Name 5 functions of the skeleton • Maintaining body structure, locomotion, Click to see answer haematopoiesis, ca2+/mineral homeostasis, protection of inner organs, 6 Name three organs that are affected by PTH Click to see answer • Bone, kidney, gastrointestinal tract 7 Name 5 symptoms of chronic hypocalcaemia Click to see answer • Delayed dentition, short stature, pigeon chest, scoliosis, easily fractured bones, etc. 8 Name 5 symptoms of hypercalcaemia • HyPERcalcaemia is associated with neuromuscular depression. And calcium deposition • groans (constipation),Click moans noise), bones to see (psychotic answer (bone pain, especially if PTH is elevated), stones (kidney stones), and psychiatric overtones (including depression and confusion). 9 What is the cause of autosomal dominant osteopetrosis? • bone resorption is reduced compared to mineralisation • This is due to failure Click toof seeosteoclasts answer • Osteoclasts cannot secrete acid • Either acid pump or chloride channel is mutated 10 Name 5 signs of autosomal dominant osteopetrosis AND for each one explain how osteopetrosis leads to this symptom. • increased bone density (compromised bone resorption due to failure of osteoclasts), Deafness (nerves compromised when skull Click to see answer foramina filled), blindness (skull foramina filled), frail bones (bone remodelling is not directional), anaemia (bone spaces for haematopoiesis compromised) 11 How do osteoclasts resorb bone: how do they position themselves, what do they secrete, and why are these two functionally connected? • They create a ruffled border with integrins to surround the region of resorption, they create a lysosome-like space extracellularly where they secrete acid (to digest hydroxyapatite), and Click to see answer proteases (to digest the matrix proteins such as collagen), and the ruffled border is necessary to prevent dilution of the acid and loss/misapplication of the proteases 12 Name 5 differences between osteoblasts and osteoclasts with regard to: mitosis, genetic material, size, overall function, and developmental origin • Blasts cannot divide, are mononucleate, smaller than clasts, lay down bone, and develop from mesenchyme. Clasts multinucleate, can Click toare see answer proliferate, are substantially bigger than blasts, reabsorb bone, and are derived from haematopoietic tissue 13 Name 5 differences between osteoblasts and osteocytes with regard to: location, shape, size/shape, overall function, and developmental origin • Blasts are on endosteal surface, cigar-shaped, the same size as cytes, they lay down bone and they are mesenchymal. Cytes are within to see answer osteoid, they areClick stellate (star) shaped with many extended processes, they maintain osteoid, and they are derived directly from osteoblasts that are trapped inside osteoid 14 Name 5 differences between PTH and vitamin D in terms of: chemical class, origin, effects at bone, effects at GI tract, effects at kidney • PTH is a peptide hormone, origin from parathyroid glands, net effect of resorption, minor effect on increasing GI calcium absorption, increases Ca2+ resorption at kidney. Vitamin D is a broken steroid, it is created in skin and is further modified by Clickfrom to seethe answer enzymatic actions derived liver, and kidney, it indirectly stimulates osteoclasts (via effects on osteoblasts), strong effect on increasing GI absorption of Ca2+. Vitamin D’s effects on Ca2+ resorption at Kidney are controversial. 15 Name 4 classes of molecular constituents in bone matrix • Hydroxyapatite (Ca-phosphate), collagen (and Click to see answer other structural proteins such as elastin), glycosaminoglycans, growth factors, 16 Name 3 symptoms of acute hypocalcaemia • BAD-CATS: Bleeding, Click to see answer Anaesthesia, Dysphagia, Convulsions, Cardiac arrhythmias, latent tetany, spasms, stridor 17 What is this entire microscopic structure in bone called. Also, name the structures A, B and C: Haversian system, or an individual area is an osteon A. Haversian canal Click to see answer B. Osteocyte C. Canaliculus A B C 18 In the illustration below of PTH-induced osteoclast activation and differentiation, which letter represents the following molecules: RANK, OPG, OPGL, PTH, Receptor activator of nuclear factor kappa B, PTH receptor, RANKL. a b osteoblast c d e A = PTH B = PTH receptor C = OPGL = RANKL D = OPG E =Click RANKto= see Receptor answer activator of nuclear factor kappa B osteoclast precursor 19 Draw a negative feedback loop showing how transiently low plasma calcium triggered by lactation can be corrected physiologically by the action of PTH Kidney increases Ca resorption at DCT Enterocytes increase calbindin  Ca absorption Bone mobilises Ca to plasma Plasma Ca increases lactation NEGATIVE Chief cells release PTH FEEDBACK Click to see answer Perturbation: Low plasma Ca2+ Calcium sensitive receptor in parathyroid chief cells detect low calcium 20 Give 3 reasons why you need bone resorption. • Bone resorption is essential for repair of broken bones, remodelling of bones as person grows (ie from child to adult), Click to see remodelling of bone foranswer specific stresses, and plasma calcium homeostasis. 21 How is hydroxyapaptite (e.g. calcium phosphate crystals) resorbed when bone is being remodelled? • Hydroxyapatite is brought into solution by A) acid, which makes calcium phosphate less soluble, B) phagocytosis of calcium Click to see answer phosphate by osteoclasts, and C) digestion of proteins etc that nucleate crystalisation by acid hydrolases (eg by Cathepsin K) 22 What is compressive strength and tensile strength, and what molecules give bone its high values for both? • The compressive strength is resistance to being compressed (ie supporting weight), see answer which is providedClick in to bone by hydroxyapatite. It is very rigid; so when it fails, it cracks. Tensile strength is resistance to stretching (and shearing), which is provided by collagen, which is flexible. 23 What are the structural and functional properties of glycosaminoglycans? • GAGs are repeating polysaccharide units. They typically have high negative charges, which means that they repel each other but attract water and cations. Click to see answerThis makes them viscous and good as lubricators. 24 When an osteoclast is degrading bone, what is the name of the depression around itself that forms? • Howship’s lacuna (or just lacuna) Click to see answer 25 How does the positioning of growth factors in bone matrix contribute to bone turnover? • The demineralisation by osteoclasts exposes and releases growth hormones that stimulate and attract osteoblasts, which will lay down Click to see answer new bone. 26 Name two types of fetal bone formation, and describe how they differ. • Intramembranous bone formation and endochondral bone formation. Endochondral begins with a cartilage structure that is to see answer ossified, while Click intramembranous starts without cartilage. 27 Name the size, cell shape, nuclear morphology, location, and ONE functional activity of osteocytes • osteocytes – embedded in bone matrix. For bone maintenance and detection of environmental & ageing stresses. Long and thin Click to see answer with extensive branches (that travel through canaliculi), the main cell body inside the lacuna (inside bone spicules) is 20 microns x 5 microns, mononucleate. 28 Name the size, cell shape, nuclear morphology, location, and ONE functional activity of osteoblasts and osteoclasts • osteoblasts – 20-25 microns, round and regular in shape, mononucleate. Located on developing bone surfaces. Formation of new bone, release of signalling substances, produce protein component of acellular Click to see answer matrix, regulate bone growth and degradation. • osteoclasts – Giant (40 micron) multinucleate cells. Cube-like, regular often with ruffled border responsible for bone degradation and remodelling bone. Located in Howship’s lacunae at bone surfaces being resorbed. 29 Name the precursor cell lineage for osteocytes, osteoblasts and osteoclasts. • Osteoblasts come from mesenchymal stem cells, osteocytes come from osteoblasts, and osteoclasts develop from the same precursors Click to see answer as monocytes (GM-CFUs) 30 How do osteoclasts resorb bone? • They form a seal with the bone (a ruffled border) with integrin molecules, and into the sealed off region they secrete acids (eg lactate) and enzymes (eg Cathepsin K or TRAP), which Click to see answer solubilise the hydroxyapatite and degrade the collagen and other protein content. The osteoclasts then phagocytose the products. 31 Name THREE ways calcium ions are stored in the body AND for each, state how accessible that store of calcium is. • Bone, inaccessible (at least without osteoclast action) • Sequestered (e.g. inside cells, inside SR), reasonably inaccessible (without activation of ryanodine receptor, etc) • Bound to proteins (e.g. calbindin), somewhat inaccessible (unless free calcium diminishes). For example, protein bound calcium is not filtered by kidneys. Click to see answer • Complexed with anions (e.g. phosphate), reasonably accessible • Free calcium, immediately accessible 32 What percentage of the body’s total calcium resides in the extracellular fluid? <1% Click to see answer 33 For each of the following hormones, state where it is made (including cell type), what chemical class of molecule it is, and its net effect on plasma calcium levels: PTH, vitamin D (calcitriol), and calcitonin. • PTH is made in the chief cells of the parathyroid gland, it is a peptide, and it causes an increase in plasma calcium. • Calcitonin is made by C cells of the thyroid, it is a peptide, and it causes a Decrease in plasma calcium. • Calcitriol (1,25-OH cholecalciferol) has its precursor Click seecells, answer (cholecalciferol) made in to skin this is then metabolised by the liver (hepatocytes) to 25-OH cholecalciferol, and it is finally activated in the kidneys (proximal tubule) to be calcitriol; it is a seco-steroid (ie it is steroid-like) and its net effect is to increase plasma calcium. 34 What are the main effects of PTH on different organs of the body? • PTH reduces the kidney’s secretion (i.e. it increases reabsorption) of calcium (and increases it secretion of phosphate), and PTH stimulates bone to mobilise calcium – it is detected by osteoblasts (and osteocytes) which immediately mobilise sequestered Click to see answer calcium as well as releasing cytokines resulting in increased differentiation and activity of osteoclasts. The net effect is to increase plasma calcium. 35 List THREE causes of hypocalcaemia. • Parathytoid dysfunction. Insufficient intestinal absorption. Insufficient calcium ingestion (eating disorders). Rickets. Renal failure. Alkalosis. Hyperventillation. Drugs (magnesium, Click to see answer anticonvulsants). Pregnancy and Lactation can draw on calcium, but in healthy women these should be compensated for endocrinologically. 36 What are the main effects of 1,25 dihydroxycholecalciferol on the body? • Increases intestinal absorption of dietary calcium by increasing calbindin in enterocytes. It also acts on osteoblasts in bone to release RANKL and thus increase Click to see answer osteoclast differentiation and activity. 37 Give an example of a bis-phosphonate, what it does, and how it works. • Alendronate • Used in osteoporosis to diminish bone resorption by osteoclasts. • Works by interfering with osteoclast’s metabolism – Mimics pyrophosphate Click to see answer – Interferes with reactions dependent on pyrophosphate • Accumulates specifically in bone because it binds to calcium. – Then ingested by osteoclasts 38 List the ways that the production of 1,25 dihydroxycholecalciferol is reduced via negative feedback. • 25-OH cholecalciferol feeds back on the liver to reduce the production of 25-OH cholecalciferol from cholecalciferol. • Calcium feeds back on the parathyroid gland to Click to see answer reduce the production of PTH, and this reduction reduces the kidney’s activation of 25-OH cholecalciferol to 1,25 (OH)2 cholecalciferol. 39 Name 4 phases of bone repair that would occur after a fracture, AND state approximately how long fracture repair would take in a healthy young adult. • • • • • Reactive: Haematoma / Inflammation Soft Callus Formation Hard Callus formation Remodelling Click to see answer Upper body 2-3 weeks, lower body > 4 weeks 40 In the repair of a bone fracture, what is the difference between soft callus formation and hard callus formation? • Soft Callus Formation = woven bone or hyaline cartilage join the fractured pieces of bone – Woven bone has disorganised collagen – This process happens first because it is fast Click to see answer • Hard Callus formation = lamellar bone replaces woven bone / cartilage – Lamellar bone has parallel collagen fibres – Slow process, but results in bone that is much stronger 41 Name THREE pharmacological treatments to reduce osteoporosis AND for each list the drug’s nominal mechanism. • Bisphosphonates – mimic pyrophosphate in bone leading to osteoclast apoptosis or protein trafficking defects. • Intermittent PTH – increases osteoblast activity and anabolic bone formation • Denosumab – Monoclonal antibody that binds to the RANK ligand (mimicking the action of Click OPG), preventing activation and to thus see answer differentiation of osteoclasts. • Teriparatide -- portion of human parathyroid hormone (PTH). Intermittent application activates osteoblasts more than osteoclasts. Encourages osteoblasts to lay down bone 42 Advanced Material 43 Bone is made up of a high percentage of inorganic material (e.g. Calcium, minerals). Why is that unusual in a living system? • Inorganic material cannot be manipulated Click to seeactivity. answer directly by enzymatic 44 How do you get calcium phosphate crystals to form where bone is needed? • Because calcium and phosphate are at a high concentration, they can crystalise out of solution when A) the inhibitors to Clickremoved to see answerand B) where the crystalisation are proteins (ie collagen) provide nucleation points. 45 Why doesn’t calcium phosphate fall out of solution in plasma? • Calcium and phosphate in the plasma are at a high enough concentration to form crystals, but do not because there are crystallization to see answer inhibitors in theClick plasma, e.g. pyrophosphate. 46 Advanced: explain why hypocalcaemia can lead to convulsions, and why hypocalcaemia’s effects on the ECG are “paradoxical”. • • Hypocalcaemia makes membranes “more excitable” and “less stable”. Thus, Na+ entry into cells is increased, and the threshold for action potentials is lowered, which explains latent tetany and its signs. Hypocalcaemia paradoxically increases the QT interval of the ECG. One would expect low extracellular calcium would reduce inward calcium flow during the plateau phase of the cardiac ventricular action potential, thus shortening the QT interval. Instead a long QT interval is observed because the decreased membrane stability allows increased Na+ entry during the plateau phase, which lengthens phase. Note that it does not Clicktotoplateau see answer increase calcium entry dramatically (as there is less extracellular calcium drive to enter cell), so hypocalcaemic prolonged QT syndrome is not usually accompanied by ventricular arrhythmias such as Torsades de pointes. 47 Advanced: If you made a drug to block the activity of each of the following, would it increase (or decrease) bone resorption: OPG, OPGL, PTH, RANK, RANKL • Osteoprogeretin – block would increase resorption • OPGL = RANKL – block would decrease resorption Click to see answer • PTH – block would decrease resorption • RANK – block would decrease resorption • RANK Ligand – block would decrease resorption 48 Name 5 processes that happen during the reactive phase of bone fracture repair • Blood cells enter wound, hematoma forms, (inflammation), fibroblasts and blood vessels aggregate to make granulation tissue, bone Click to see answer making cells are recruited from periosteum, woven bone (or hyaline cartilage) is laid down to join the two broken pieces of bone. 49 Name 2 temporary structures that are created during the repair phase of bone fracture repair AND state briefly how these are created. • The Soft Callus is spongy bone near blood vessels and fibrocartilage further away. It’s made by bone precursor cells (chondroblasts proximally or osteoblasts distally), Click to see answer • Hard callus formation occurs when endochondral ossification takes place (endochondral bone replaces fibrocartilage or woven bone) 50 What 3 events occur during the remodelling phase of bone fracture repair? • Endochondral bone is replaced by trabecular Click to see answer bone, it is remodelled to the correct shape, and where appropriate it is replaced by compact bone 51 Why are bisphosphonates specific for affecting bone cells, and have few adverse effects on other cell types? • • • • • Bisphosphonate-based drugs' specificity comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to bind to calcium ions. Bisphosphonate molecules preferentially "stick" to calcium and bind to it. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration only in bones. Click to see answer Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts. Also the oral bioavailability of bisphosphonates is low because the drug has highly negative charge (associated with phosphate groups) – it is an acid that donates H+ into solution. Almost all oral drugs used in medicine are weak bases because weak bases are taken up by cells more easily. 52 Teriparatide increases PTH activity and decreases demineralisation during osteoporosis. Why doesn’t it increase bone destruction by osteoclasts? • • • • Teriparatide is a PTH fragment that acts as a PTH agonist. Teriparatide increases the PTH-dependent activity of osteoblasts. Osteoblasts have two opposing effects on mineralisation: 1) osteoblasts lay down bone and 2) they activate osteoclast precursors, which become Click to see answer osteoclasts that demineralise bone. PTH applied continuously results in bone loss via increased osteoclast activity, but intermittent PTH results in increased osteoblast number and osteoblast mineralisation activity in osteoporosis; the net effect of intermittent PTH is bone strengthening. 53

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