Question 7

College Answer

The main points expected for a pass were:
· The components of plasma calcium are diffusible Ca ( free and complexed ) and nondiffusible Ca ( protein bound). Only the plasma free Ca is physiologically active and regulated by homeostatic mechanisms. Plasma free Ca is also affected by plasma pH and albumin concentration.
· The distribution of Ca in the body and the fact that ECF Ca is less than 0.1% of total body Ca. ECF and hence plasma Ca is the result of a balance between dietary intake, gastrointestinal absorption and excretion, renal excretion and exchange with bone Ca.
· Tight hormonal regulation of GIT absorption, bone exchange and renal excretion mainly by parathyroid hormone and calcitriol.

Also expected were details of the actions of PTH on bone and the kidney and the actions of calcitriol on the gut and bone. No candidates described the feedback control mechanisms involving PTH and calcitriol. Additional marks were given for mention of other hormones that have a lesser effect on plasma Ca concentration.

The second part of the question on the mechanism of action of biphosphonates was poorly answered.

Discussion

• Distribution
  • > 99% of total body calcium is in bone and not easily accessible
  • Less than 1% is in the extracellular fluid (~20-30mmol total)
  • Minimal intracellular concentration (second messenger)
  • In the plasma:
    • 40-45% of calcium circulates bound to albumin
    • 10-15% is bound to other anions such as lactate and phosphate
    • 40-45 % is free and ionised
• Regulation of calcium intake
  • Absorbed by combination of paracellular and transcellular transport in the ileum
  • Transcellular route carefully regulated by hormones
    • intestinal absorption increased by calcitriol and PTH, 
    • decreased by calcitonin
• Regulation of bone resorption of calcium
  • Normal daily flux in and out of bone is 12-13 mmol
  • Bone is reabsorbed by osteoclasts; this liberates calcium
  • Osteoclast activity is increased by PTH and decreased by calcitonin
  • Calcitriol has mixed effects; in vitro increased osteoclast activity, and in vivo protective effects in the treatment of osteoporosis
• Regulation of renal elimination of calcium
  • ​​​​​​​70% is reabsorbed in the proximal tubule
  • 20% is reabsorbed in the thick ascending limb
  • 10% is reabsorbed in the distal convoluted tubule by a mechanism that is regulated by PTH calcitriol and calcitonin:
    • Calcitonin decreases the reabsorption of calcium and phosphate
    • PTH and calcitriol increase the reabsorption of calcium and phosphate 

Bisphosphonate activity, if it were worth 50% of the marks...

• Inhibition of osteoclast and osteoblast activity
  • Bisphosphonates act locally on osteoclasts:
    • Binding to bone apatite crystals and local release during bone resorption
    • Thus, preferential accumulation under osteoclasts
  • Multiple effects:
    • inhibition of osteoclast recruitment and adhesion;
    • shortening of the life span of osteoclasts by being metabolised into toxic ATP analogues
    • inhibition of osteoclast activity by inhibiting several essential parts of the cholesterol synthesis pathway
  • The result is an inhibition of bone resorption as well as new bone formation
• Inhibition of calcification by inhibiting the formation of calcium phosphate salts
  • Mainly seen in high doses
  • A totally physicochemical effect: they bind to the calcium of calcium phosphate
  • The result is inhibition of formation and aggregation of calcium phosphate crystals and inhibition of the transformation of amorphous calcium phosphate into hydroxyapatite.
  • This is useful for diseases of ectopic calcification
  • This also means mineralisation of normal bone (eg. during fracture healing) can be impaired

Mundy, Gregory R., and Theresa A. Guise. "Hormonal control of calcium homeostasis." Clinical chemistry 45.8 (1999): 1347-1352.

Bronner, Felix. "Mechanisms of intestinal calcium absorption." Journal of cellular biochemistry 88.2 (2003): 387-393.

Davies, K. Michael, Karen Rafferty, and Robert P. Heaney. "Determinants of endogenous calcium entry into the gut." The American journal of clinical nutrition 80.4 (2004): 919-923.

Seldin, Donald W. "Renal handling of calcium." Nephron 81.Suppl. 1 (1999): 2-7.

Jeon, Un Sil. "Kidney and calcium homeostasis." Electrolyte & Blood Pressure 6.2 (2008): 68-76.

Fleisch, Herbert, et al. "Bisphosphonates: mechanisms of action." Principles of bone biology (2002): 1361-XLIII.

Rogers, Michael J., Jukka Mönkkönen, and Marcia A. Munoz. "Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton." Bone 139 (2020): 115493.