Bone Physiology Flashcards

Question

What affects the biochemical homeostasis of calcium?

Answer 1

Input ————————> blood ————————> output GI absorption || Urinary of Ca after || excretion absorption || of Ca Internal reservoir = bone (Not directly measurable) Hypercalcaemia: - Increased (input) GI absorption - Increased bone resorption (into circulation) - Decreased bone mineralisation (what goes into resovoir) - Decreased urinary excretion (little output) Hypocalcaemia: - Decreased GI absorption (low ca diet) - Decreased bone resorption (cant deminarilise) - Increased bone mineralisation (hungry bone syndrome) - Increased urinary excretion (nephrotic diseases)

Answer 2

Increased GI Absorption: - Elevated Vitamin D - Excess exogenous (therapeutic) - Excess endogenous (e.g. sarcoidosis) - Elevated PTH - increased activation - Hypophosphataemia - Milk-alkali syndrome ``` Increased bone resorption: - Increased net bone resorption - Elevated PTH - Malignancy - Increased bone turnover - Paget’s disease - Hyperthyroidism - body is increased metabolically so functions happen at a higher rate ``` Decreased bone mineralisation: - Elevated PTH - Aluminium toxicity - used to happen in dialysis patients, causing deposition in bone Decreased urinary excretion: - Thiazide diuretics - Elevated Vitamin D - Elevated PTH

Answer 3

Common Causes: - Primary hyperparathyroidism (99% ambulant patients) - Single adenoma (80%) (double is rare) - Hyperplasia (15%) - Double adenoma (2%) - Carcinoma (<1%) - Malignant disease (99% of ill patients) - Metastases and myeloma - PTHrp secreting - Lymphoma - PTH secreting (v. rare) Uncommon Causes: - Vitamin D excess - Tertiary hyperparathyroidism - often occurs post transplant - Hyperthyroidism Rare Causes: - Familial hypocaliuric hypercalcaemia - low 24 hour urine sample

Answer 4

Discovered in 1987 when studying the mechanism by which certain cancers produce humoural hypercalcaemia of malignancy The N-terminal shows homology with PTH with 8 of first 13 AA matching Remainder of molecule shows little homology - so first 8/13 must be key for interacting with receptors. So tumours act as PTH. Turnaround time for assay is too long to have clinical importance = research tool The common N-terminal explains how PTHrP can interact with PTH/PTHrP receptors, mimicking biological actions of PTH in target tissues such as bone and kidney Like PTH, PTHrP causes hypercalcaemia and hypophosphataemia and increases urinary cAMP

Answer 5

``` Decreased GI absorption: - Poor dietary intake - Impaired absorption of Ca - Vitamin D deficiency - Poor dietary intake of Vit D - Malabsorption - Decreased conversion of Vitamin D - Liver failure - Renal failure - Low PTH - Hyperphosphataemia - tend to maintain each other in opposite direction ``` Decreased bone resorption / Increased bone mineralisation - Hypoparathyroidism - PTH resistance (pseudohypoparathyroidism) - Vitamin D deficiency - Hungry bone syndrome - metabolic process where bone sucks in all Ca and P - Osteoblastic metastases Increased urinary excretion: - Low PTH - Thyroidectomy - I131 treatment - Autoimmune hypoparathyroidism - PTH resistance - Vitamin D deficiency

Answer 6

Always exclude EDTA contamination (causes high K, low Ca and low Mg due to collation - less common with coated tubes) Multiple transfusions with citrated blood products (stop coagulation) = often see post op Common causes: - Acute or chronic renal failure - Hypoparathyroidism - Hypomagnesaemia - Vitamin D deficiency Parathyroid Causes: - Parathyroid agenesis - Isolated - Part of complex developmental anomaly eg DiGeorge Syndrome - Parathyroid destruction - Surgery - Radiation - Infiltration: eg haemochromatosis, Wilson’s - Autoimmune - Isolated - Polyglandular - Reduced parathyroid function - PTH gene defects - Hypomagnesaemia - Neonatal hypocalcaemia - Hungry bone disease ``` Non-parathyroid Causes: - Vitamin D deficiency - Vitamin D resistance - Altered vitamin D metabolism eg phenytoin (reduce 1-Alpha hydroxylation), ketoconazole - PTH resistance - Pseudohypoparathyroidism - Magnesium deficiency - Bisphosphonates - Acute pancreatitis - flair up causes calcium to bind = don't give Ca to patient! - Acute rhabdomyolysis ```

Answer 7

Neuromuscular irritability: - Tetany - Carpopedal spasm - Muscles cramps - Seizures – all types - Prolonged QT interval on ECG - Bronchospasm - Laryngospasm Effect of Ca on muscles and nerves! ``` Longterm hypocalcaemia: - ectopic calcification eg in basal ganglia causing extrapyramidal neurological symptoms - Cataract, papilloedema - Abnormal dentition ```

Answer 8

Formation of: - High energy compounds e.g. ATP, creatinine phosphate - Second messengers e.g. cAMP, inositol phosphates Component of: - DNA/RNA - Phospholipid membranes - Bone Phosphorylation (activation/inactivation) of enzymes - activates/deactivates pathways Intracellular anion (not a representation of the stores in a serum collection)

Answer 9

85% is within the skeleton and teeth 14% is located within the cells Only 1% is present in the extracellular fluids - what we measure Present as organic (phosphoproteins, phospholipids) and inorganic (phosphate) - Inorganic phosphate component is what we measure (0.70-1.40 mmol/L) - Mild deficiency 0.35 – 0.70 mmol/L - Severe deficiency <0.35 mmol/L - especially in recovery from DKA and refeeding syndrome

Answer 10

Intracellular redistribution ⬇️⬆️ Delayed separation ⬇️⬆️ Refeeding Rhabdomyolysis ⬇️⬆️ Recovery from DKA Renal failure, etc. ⬇️⬆️ Alkalosis, etc. ⬇️⬆️ Input ————————> blood ————————> output GI ⬇️⬆️ Urinary absorption Mineralisation ⬇️⬆️ resorption excretion of PO4 ⬇️⬆️ of PO4 Internal reservoir = bone (Not directly measurable) Hyperphosphatemia: - Increased GI absorption - Increased bone resorption - Decreased bone mineralisation - Decreased urinary excretion Hypophosphataemia: - Decreased GI absorption - Decreased bone resorption - Increased bone mineralisation - Increased urinary excretion

Answer 11

Pseudohyperphosphataemia: - Haemolysed specimen - Myeloma - Delayed separation / Old sample Increased Phosphate Input: - IV PO4 - Rectal PO4 - Cell death - Tumour lysis syndrome - cells break down - Rhadbomyolysis - Jordan muscle trauma, or someone falling and lying in the same position - crushing muscle cells - Malignant hyperpyrexia - due to heat - Heat stroke Reduced phosphate excretion: - Reduced eGFR - Acute renal failure (AKI) - Chronic renal failure Increased renal tubule reabsorption: - Physiological - Recovery from Vit D def - Lactation - Pathological - Reduced PTH or PTH resistance - Vitamin D toxicity - Thyrotoxicosis - Acromegaly

Answer 12

Inadequate phosphate absorption: - Low dietary intake (v rare) - Phosphate binders (dialysis patients - causes phosphate to transiently drop) - Phosphate binding antacids (rare due to new therapies for peptic ulcers) Abnormal urinary phosphate loss: - Primary and secondary hyperparathyroidism - Osmotic diuresis e.g. hyperosmolar hyperglycameic state HHS - equivalent of DKA - Diuretics - Fanconi syndrome - Genetic conditions e.g.X-linked hypophosphataemia Shifts of phosphate from extracellular fluid into cells: - <1% in extracellular space - Recovery from DKA - Treatment with insulin causes phosphate to move back into cells - Refeeding syndrome - Starving or chronically malnourished patients are refed or given IV glucose - carbohydrates (initiate glycolysis and pentose phosphate pathways) stimulate insulin which drives phosphate and glucose intracellularly - Cells switch to anabolic state resulting in further depletion of P - use give IV phosphate during refeeding - Respiratory alkalosis - Activating phosphofructokinase which stimulates intracellular glycolysis - Increased muscle intake - Hepatic encephalopathy - Salicylate toxicity - Acute leukaemia - Rapid growing malignancies may consume phosphate preferentially

Answer 13

Increased significance in regulation of serum phosphate and 1,25 (OH) Vitamin D (active) Secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased 1,25(OH)D (active) In CKD, FGF23 sensitive biomarker of abnormal renal phosphate handling increasing during early stages - can treat before develop serious disease Raised FGF23 increases fractional phosphate excretion (via NPT2 Na-PO4 cotransporter), reducing phosphate levels FGF23 suggested to suppress 1α-hydroxylase activity, reducing ability to activate vitamin D Responsiveness to FGF23 declines as number of intact nephrons reduces - FGF23 therefore cannot reduce PO4 as effectively and exerts other off-target effects including premature mortaility - Lowering PO4 through binding agents reduces FGF23 and may improve patient outcomes

Answer 14

Cofactor for 300+ enzymes Mg-ATP complex is a substrate for many ATP requiring enzymes Critical role for DNA replication, transcription and translation Maintenance of structure of ribosomes, nucleic acids and some proteins Interacts with calcium, required for PTH activation Affects permeability of excitable membranes and their electrical properties - ECF depletion of Mg causes hyperexcitability - Post op given Mg, so expect to see high levels in certain wards. Deliberately raised to prevent hyperexcitabilty for short time

Answer 15

Predominantly intracellular cation Serum Mg inaccurate way to assess total body Mg stores and can be misleading Hypomagnesaemia symptoms include: - Loss of appetite - Nausea and vomitting - Fatigue - Weakness & numbness - Tingling - Muscle cramps - Seizures - Personality changes - Hypokalaemia - Hypocalcaemia Effects nerves, muscles and gut = same as Ca

Answer 16

Symptoms usually not apparent unless > 2mmol/L Concomitant HypoCa, HyperK or uraemia exaggerate symptoms of hyperMg Non-specific symptoms include nausea, vomiting and flushing Neuromuscular symptoms - Blockage of neuromuscular transmission Conduction system symptoms - Mild decrease in blood pressure - Higher concentrations lead to symptomatic hypotension - Heart block >7mmol/L Hypocalcaemia

Answer 17

Decreased intake +/- absorption - Starvation (protein calorie malnutrition) - Malabsorption syndrome - Prolonged gastric suction - Inadequate parenteral nutrition Loss from body - Extra renal - Diarrhoea - Laxative abuse - Gut fistula - Excessive lactation (rare) Misc - Acute pancreatitis - Multiple transfusions, through chelation - Insulin therapy - Hungry bone syndrome ``` Renal : - Alcoholism - Interstitial nephropathy (anything that affects loop of Henle) - Diuresis e.g. DKA, post ATN - Drugs e.g. loop diuretics, cis-platinum (65-75% reabsorbed in Loop of Henle) - Hypercalcaemia - RTA - Bartter’s syndrome, Gitelman’s - Endocrine e.g. hypoparathyroidism, primary hyperaldosteronism, hyperthyroidism - K depletion - PO4 depletion - Post renal Tx - Primary renal Mg wasting ```

Answer 18

Significant hypermagnesaemia is uncommon as readily excreted in urine Cardiac conduction is affected at concentration >2.5-5.0 mmol/L Very high concentrations >7.5 mmol/L cause respiratory paralysis and cardiac arrest ``` Generally either - Impaired renal function - Large Mg load - IV Contamination - Post cardiac surgery or in pre-eclampsia where it is used to decrease neuromuscular excitability - Enema / laxative abuse ``` Rare causes include - Excessive tissue breakdown - Lithium therapy (↓ renal excretion) - Hypothyroidism - Addison’s disease - Familial hypocalciuric hypercalcaemia - tubular defect