Walter Sisulu University

Faculty of Health Sciences

2023 MBChB II Musculo-skeletal Block Seminar 2

Scenario:

A 65 yr old lady visits her GP complaining of difficulty in walking due to swollen

feet and some bruises in the knee. Physical findings revealed that she is exhibiting
typical postmenopausal symptoms.

1. List SIX essential activities of free fraction of ECF Calcium.

a. Neuromuscular excitability

b. Excitation-contraction coupling

c. Stimulus-secretion coupling

d. Excitation-secretion coupling

e. Maintenance of tight junctions between cells

f. Clotting of blood.

2. What are the effects of parathyroid hormone (PTH) on calcium and phosphate
concentration in the extracellular fluid?

PTH: has two effects on bone: absorption of calcium and phosphate. One
is rapid phase: begins in minutes and increases progressively for several
hours.

Activation of Osteocytes to promote calcium and phosphate absorption.

The second phase is much slower one requiring several hours or even
weeks to become fully developed. It results from proliferation of the
osteoclast followed by osteoclastic reabsorption of the bone.

PTH: immediate effect: Removal of bone salts from two areas in the bone:
from the bone matrix in the vicinity of the osteocytes lying within the bone
itself and in the vicinity of the osteoclasts along the bone surface. PTH can
activate the calcium pump strongly thereby causing rapid removal of
calcium phosphate salts from the bone crystals and transfers the calcium
ions to the ECF.
Slow phase: Activation of osteoclasts. Osteoblasts send a signal to
osteoclasts. Immediate activation of osteoclasts that are already formed
and formation of new osteoclasts.
 PTH: rapid loss of phosphate in the urine by diminishing proximal tubular
reabsorption of phosphate. PTH also increases renal tubular reabsorption
of calcium.

PTH: increases both calcium and phosphate absorption from the intestines
by increasing the formation of 1,25 DIOH CC from Vit D in the kidneys.

3. Discuss the PTH synthesis and storage of Parathyroid hormone.

PTH: Chief cells in parathyroid gland synthesise PTH. It is synthesized in the

ribosomes- preprohormone—prohormone—hormone 84 aas—in ER---stored
in secretory granules--. The final hormone is about 9500 mol wt 84 aas.

Scenario contd: Blood samples were drawn for the measurement of serum
calcium, PTH, Vitamin D and estradiol.

Parathyroid hormone (PTH) : 0.5 pmol/L (normal 1-6)

25-OH Vitamin D: 10 pmol/L (normal 50-150)
Serum calcium : 1.8 mmol/L (normal 2.2-2.56)
Serum Phosphate: 3.9 mmol/L (normal 3.5-5)
Serum estradiol : Very low levels of estrogen

4. What is a RANK ligand (RANKL) and Osteoprotogerin. Discuss their

role in osteoclast development and activity.

Comment on the effect of estrogen on the above two ligands.

Osteoblasts and their immature precursors produce TWO chemical signals

that govern osteoclast development and activity in opposite ways.-RANK
ligand & osteoprotegerin (OPG).

RANK revs up osteoclast action. (Receptor activator of NF-kB).

RANK ligand binds to RANK, a protein receptor on the membrane surface of
nearby macrophages to differentiate into osteoclasts and helps them live
longer by suppressing apoptosis. As a result Bone resorption is stepped up and
bone mass decrease.

Osteoprotogerin (OPG) is secreted by neighbouring osteoblasts. This

suppresses osteoclast activity. OPG acts like s decoy receptor that binds to
RANKL. By doing so tiRANKL is taken out of action so that it can not bind
with its receptors. Hence OPG prevents RANKL from revving up osteoclast
activity. As a result the osteoblasts are able to outpace the osteoclasts and so
bone mass increases.
The balance between RANKL and OPG is an important determinant of bone
density.

Various factors influence both these signals. Estrogen stimulates activity of the
OPG producing gene in osteoblasts and promotes apoptosis of osteoclasts, thus
preserving bone mass. Low levels of estrogen on the contrary will lead to
increased RANKL and so revs up osteoclastic activity leading to osteoporosis.

5. What is an osteocytic-osteoblastic bone membrane. Explain the role of

Fast and slow exchange of calcium across the osteocytic-osteoblastic
bone membrane.

The surface osteoblasts and osteocytes are connected by an extensive network

of small, fluid containing canals, the CANALICULI which allows substances
to be exchanged between osteocytes and the circulation. The gap junctions
permit communication between osteoblasts and osteocytes and also exchanges
materials among the bone cells. This interconnecting network is called
OSTEOCYTIC-OSTEOBLASTIC bone membrane.

The small, labile pool of calcium is in the bone fluid. Fast exchange (labile
pool) of calcium between the bone and plasma is due to Calcium pumps in the
osteocytic-osteoblastic bone membrane that transport calcium from the bone
fluid into these bone cells which transfer calcium into the plasma.

Slow exchange (stable pool) of calcium between the bone and plasma is due
to osteoclast dissolution of bone. Both require PTH for their activation.

Scenario Contd: After a few months the patient returns and now complains of
several symptoms typical of hypocalcemia.

6. Explain these symptoms of hypocalcemia and the physiological basis of

these symptoms.

Hypocalcemia leads to changes in the nervous system excitability. This is due

to increased neuronal permeability to sodium ions, allowing easy initiation of
action potentials. Below normal levels of serum calcium, the peripheral nerve
becomes so excitable that they begin to discharge spontaneously, initiating
trains of nerve impulses that pass to the peripheral skeletal muscles to elicit
titanic muscle contraction. Hypocalcemia therefore causes tetany.
Tetany occurs when calcium levels go below 6 mg/dL. It is usually lethal when
it falls to 4 mg/dL.
Scenario Contd: One of the treatment plans for this patient includes Vitamin
D. Vitamin D has a potent effect to increase calcium absorption from the
intestinal tract. But the active factor of Vitamin D is a different compound.
 7. Name this active component and its role in the regulation of serum
calcium.

Calcitriol (1,25 dihydroxyCC) : promotes intestinal absorption of calcium. It

increases the formation of calcium-binding protein in the intestinal epithelial cells.
This protein function in the brush border of these cells to transport calcium into the
cell cytoplasm and the calcium then moves thro the basolateral membrane of the cell
by facilitated diffusion. The rate of absorption of calcium is directly proportional to
the quantity of the calcium binding protein.

Calcitriol also promotes calcium absorption by forming 1. A calcium-stimulated

ATP ase in the brush border of the epithelial cells and 2. An alkaline phosphatase in
the epithelial cells. The role of these two are still uncertain.