Calcium & Phosphate Homeostasis

Question 1

ground substance of bone is a combination of extracellular fluid and proteoglycans, including ____ and _____

Answer 1

hyaluronic acid and chondroitin sulfate

Question 2

______ is the storage form of the bone salts (calcium and phosphate)

Answer 2

hydroxyapatite

Question 3

osteoblasts produce ______, which stimulates the differentiation of preosteoclasts into osteoclasts

Answer 3

RANK (receptor activator for nuclear factor kB) ligand

RANKL also up-regulates osteoclast activity

Question 4

what is the function of osteoprotegerin?

Answer 4

osteoprotegerin: produced by osteoblasts, decoy receptor for RANKL (also produced by osteoblasts) which lowers its local availability

recall RANKL up-regulates osteoclast activity

so osteoblasts modulate both bone reabsorption and deposition

Question 5

what are the effects of parathyroid hormone (PTH)?

Answer 5

• increase serum Ca2+
• decrease serum PO4

Question 6

PTH increases renal ______ expression, thereby promoting the synthesis of calcitriol, which induces Ca2+ absorption from the intestines

Answer 6

1alpha hydroxylase (CYP27B1)

so PTH raises plasma Ca2+ both indirectly and directly (via decreased renal excretion in distal tubules/collecting ducts)

Question 7

explain how chronic elevation in PTH induces bone reabsorption

Answer 7

osteoblasts express PTH receptors, osteoclasts do NOT

chronic exposure to PTH causes osteoblasts to secrete proteases that digest bone matrix and cytokines (RANKL) which promote osteoclast differentiation/activity [recall osteoblasts module both bone reabsorption and deposition]

[also note that acute PTH elevation increases osteoblast proliferation and bone deposition]

Question 8

what is the effect of calcitriol?

Answer 8

formation of calcitriol stimulated by PTH and hypophosphatemia

predominant effect is stimulating GI absorption of Ca2+ and PO4

also stimulates Ca2+ reabsorption and blocks PO4 excretion within proximal nephron

[however, note PTH is the predominant regulator of Ca2+ and PO4]

Question 9

what is the effect of fibroblast growth factor 23 (FGF23)?

Answer 9

secretion stimulated by hyperphosphatemia and calcitriol —> increases PO4 renal excretion (blocks CYP27B1 expression, impeding calcitriol production), up-regulates 24-hydroxylase in proximal tubule (inactivates calcitriol), blocks PTH secretion (lowers bone reabsorption of PO4/ Ca2+)

Question 10

what is the effect of estrogen (E2) on osteocytes?

Answer 10

blocks apoptosis + stimulates TGF-beta secretion (which blocks osteoclast differentiation)

overall stimulates bone growth and maintains bone density

Question 11

how do glucocorticoids affect osteoblasts/cytes/clasts?

Answer 11

induce apoptosis in osteoblasts and osteocytes

increase survival of osteoclasts and increase production of RANKL - increased ratio of RANKL:osteoprotegerin promotes bone reabsorption

Question 12

how do raloxifene and denosumab, respectively, treat osteoporosis?

Answer 12

raloxifene: SERM (selective estrogen receptor modulator), functions as E2 (estrogen) agonist in bone

denosumab: human mAb against RANKL

Question 13

how does hypercalcemia affect cardiomyocyte function?

Answer 13

recall Ca2+ slowly enters cardiac myocyte during phase 2 depolarization (plateau phase) of action potential, and duration of phase 2 = duration of ST segment

therefore, hypercalcemia causes shorted QT interval

Question 14

what is the effect of hypercalcemia on skeletal muscle function?

Answer 14

excess extracellular Ca2+ raises membrane potential necessary to open motor neuron voltage-gated Na+ channels —> hypo-excitability —> skeletal muscle weakness

Question 15

the most common cause of true hypocalcemia is the loss of ______ synthesis that results from….

Answer 15

the most common cause of true hypocalcemia is the loss of CALCITRIOL synthesis that results from advanced stages of chronic kidney disease

[recall vit. D is activated in nephron to produce calcitriol]

Question 16

what is the effect of hypocalcemia on skeletal muscle and neuron function?

Answer 16

low extracellular Ca2+ increases membrane permeability to Na+ within skeletal muscles and neurons —> hyper-excitability —> cramping and/or tetany, paresthesias

within cardiac muscle, can prolong QT interval

Question 17

what 2 PE signs can be used to diagnose hypocalcemia?

Answer 17

1. Trousseau’s sign: carpal spasm due to loss of brachial artery circulation with sustained inflation of BP cuff above systolic pressure - very specific
2. Chvostek’s sign: ipsilateral facial muscle contraction when facial nerve is tapped anterior to the ear - not as specific

Question 18

most common etiology of hypophosphatemia is…

Answer 18

… increase in PO4 excretion that accompanies hyperparathyroidism

PTH promotes PO4 excretion, and this effect far outweighs effect of intra-renal calcitriol on PO4 reabsorption

Question 19

how is calcitriol linked to rickets/ osteomalacia?

Answer 19

calcitriol deficiency —> increased PTH-dependent elimination of PO4 in urine and inability to reabsorb Ca2+ —> diminished bone density/mineralization