1. ENDOCRINE CONTROL OFCALCIUM HOMEOSTASIS • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia The Body’s Calcium Pools Endocrine Axes in Calcium Homeostasis Synthesis of PTH, Calcitonin & Calcitriol Bone Metabolism Cellular Control of Calcium (& Phosphate) Homeostasis Causes & Consequences of Hypo- & Hypercalcaemia ESR46-01

2. Osteoblasts / Osteoclasts? ESR46-02

3. Osteoblast* Osteoblast* Osteoclast Skeletal Target Cells Target Cell Parathyroid hormone (PTH) Calcitriol Calcitonin *Increased “osteoclast-activating factors” ESR46-03

4. ENDOCRINE CONTROL OFCALCIUM HOMEOSTASIS • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia ESR46-04

5. Cellular Actions of PTH - 1 • Increases mobilisation of hydroxyapatite pool by osteoclasts (indirect) • Increases calcitriol synthesis (hence intestinal calcium uptake) - Increases 1-hydroxylase directly - Increases PO42- clearance so relieves inhibition of 1-hydroxylase ESR46-05

6. Cellular Actions of PTH - 2 • Increases cAMP via GPCR ESR46-06

7. Pseudohypoparathyroidism? • True hypoparathyroidism - insufficient PTH - Adult - loss of PTH - Ca2+ <48h - Symptoms of hypocalcaemia • Pseudohypoparathyroidism - resistance to PTH - Inactive PTH receptor - Decreased expression of PTH receptor ESR46-07

8. Which of the followinghormone concentrations would differ between pseudohypoparathyroidism vs idiopathic hypoparathyroidism? (A) PTH (B) Calcitonin (C) Calcitriol (A) PTH - Elevated vs Suppressed (B) Calcitonin - Suppressed in BOTH (C) Calcitriol - Increased in BOTH ESR46-08

9. Effects of PTH on Phosphate • PTH increases renal [PO42-] clearance - phosphaturia • PTH decreases plasma [PO42-] - Allows 1-hydroxylase activity to increase ESR46-09

10. Cellular Actions of Calcitriol • Increases expression of: - intestinal calcium transporter - osteoclast-activating factors • Acts via nuclear receptor (SKSS) ESR46-10

11. ENDOCRINE CONTROL OFCALCIUM HOMEOSTASIS • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia ESR46-11

12. Symptoms of Hypocalcaemia • Skeletal malformations* - Rickets (in childhood) - Osteomalacia (post-puberty) • Myopathy • Paraesthesia (“pins & needles”) • Epilepsy (only if severe) • Hypocalcaemic tetani ESR46-12

13. Rickets vs Osteomalacia Age-dependent: Failure of endochondrial ossification (rickets) or decreased bone density (osteomalacia) ESR46-13

14. Symptoms of Hypercalcaemia • Renal calculi (Ca2P04) in calyces - Scarring to ureter (haematuria) - Recurrent infection (pyelonephritis) • Impaired renal function - Thirst - Polyuria ESR46-14

15. Acutealkalosis Causes of Hypocalcaemia • Alkalosis ([H+]) - decrease plasma [Ca2+] • May result from CO2 expiration ESR46-15

16. Acutealkalosis Causes of Hypocalcaemia • Hypoparathyroidism • Pseudohypoparathyroidism • Impaired calcitriol biosynthesis - insufficient Vit.D - impaired 1-hydroxylase activity/expression • Defects in Vit.D receptor • Chronic renal failure - impaired renal Ca2+ resorption - decreased calcitriol biosynthesis ESR46-16

17. Medullary carcinomaof the thyroid Calcitonin  =  PTH  =  Calcium  =  Calcitonin  =  PTH  =  Calcium  =  ESR46-17

18. Acuteacidosis Causes of Hypercalcaemia • Acidosis ([H+]) - increase plasma [Ca2+] • May result from decreased CO2 expiration ESR46-18

19. RARE • Acuteacidosis Causes of Hypercalcaemia • Hyperparathyroidism* - hypercalcaemia - hypophosphatemia / phosphaturia • Malignancy-associated hypercalcaemia* • Excessive biosynthesis of calcitriol • Overdosage with Vit.D - “vitamin D intoxication” ESR46-19

20. Causes of hyperparathyroidism • Primaryhyperparathyroidism = benign tumour of the parathyroid glands • Secondaryhyperparathyroidism = chronic renal failure (hypocalcaemia) • Tertiaryhyperparathyroidism = renal transplant ESR46-20

21. Parathyroid hypertrophy in renal failure ESR46-21

22. Malignancy-associated hypercalcaemia • Bone metastases set up local inflammatory response - prostaglandins increase production of “osteoclast activating factors” • Cancerous cells synthesise PTHRP ESR46-22

23. In the face of adequate Vit.D(diet + u/v light)why might there be insufficientcalcitriol to support intestinal calcium absorption? Chronic renal failure: Defective renal metabolism of 25-OH-Vit.D ESR46-23

24. ENDOCRINE CONTROL OFCALCIUM HOMEOSTASIS • The Body’s Calcium Pools • Endocrine Axes in Calcium Homeostasis • Synthesis of PTH, Calcitonin & Calcitriol • Bone Metabolism • Cellular Control of Calcium (& Phosphate) Homeostasis • Causes & Consequences of Hypo- & Hypercalcaemia ESR46-24