Case 25 Questions 1-10

Question 1

Which of the following factors secreted by osteoclasts with the purpose of unfixing calcium from bone matrix?

1. Acid phosphatase
2. Alanine Aminotransferase
3. Alkaline phosphatase
4. Hydroxyapatite
5. Osteoprotegerin

The correct answer is option a, Acid phosphatase

Acid phosphatase is the enzyme secreted by osteoclasts to un-fix calcium from mineralised bone matrix. This is the method by which osteoclasts perform bone resorption; the resulting ‘resorption pit’ is the subsequent site of osteoblast activity, where osteoid is deposited and mineralised to form bone. As such, parathyroid hormone (PTH) acts to increase osteoclast number and activity, increasing resorption and therefore releasing calcium ions in the serum.

Alanine Aminotransferase -> (ALT) secreted by liver. This was a red herring as alkaline phosphatase (ALP) is also secreted by the liver; the 2 in combination with GGT are used as biomarkers of liver function.

Alkaline phosphatase -> secreted by osteoblasts to prime osteoid for mineralisation

Hydroxyapatite -> mineralised bone comprising calcium and phosphorous bound to collagen

Osteoprotegerin -> (OPG) is another bone regulatory factor secreted by osteoblasts. NOT ESSENTIAL KNOWLEDGE FOR 2ND YEAR

Question 2

Which of the following is the primary site of bone remodelling in an adult?

1. Cortical bone
2. Haversian canal
3. Trabecular bone
4. Volkmann’s canal
5. Woven bone

The correct answer is option c, Trabecular bone

Trabecular bone (spongy bone) forms the central portion of long bones and represents 20% of their volume. It has a high surface area and is surrounded by blood vessels and marrow. This is where bone remodelling by osteoblasts and osteoclasts primarily occurs -> the high surface area facilitates calcium turnover, while blood vessels allow for hormones such as PTH to act on these cells and for calcium ions to be released into circulation.

Cortical bone -> (compact bone) outer portion of long bones, responsible for structural integrity and mechanical strength. Location of osteocytes.

Haversian canal + Volkmann’s canal -> structural components of long bones which allow for the transition of vessels through mineralised bone.

Woven bone -> immature bone comprising randomly orientated collagen fibres. Flexible with low structural integrity. Matures into secondary, lamellar bone through remodelling. It occurs in foetuses before the 3rd trimester, in fracture repair and (pathologically) in Paget’s disease of the bone. Although woven bone is a site of bone remodelling, it is not the primary site found in adults.

Question 3

Which of the following is the site of parathyroid hormone (PTH) action in the nephron?

1. Ascending limb of Loop of Henle
2. Collecting duct
3. Descending limb of Loop of Henle
4. Distal convoluted tubule
5. Proximal convoluted tubule

The correct answer is option d, Distal convoluted tubule

60% of calcium is present as free ions in the serum; there are filtered at the glomerulus. A majority are reabsorbed in the proximal convoluted tubule and thick ascending limb of the Loop of Henle. Most of the remaining ions are actively reabsorbed in the distal convoluted tubule. PTH acts here to increase reabsorption, thus retaining more calcium and elevating serum levels.

Question 4

Parathyroid hormone (PTH) induces renal secretion of which enzyme, responsible for catalysing 1,25DHCC production from vitamin D3?

1. Aromatase
2. Cholesterol side-chain cleavage enzyme
3. Tryptase
4. 1α-hydroxylase
5. 5α-reductase

The correct answer is option d, 1α-hydroxylase

This is a hard question but it is useful to know the functions of all of these enzymes! PTH acts directly at the distal convoluted tubule and at bone to increase serum calcium concentration. It does not have a direct effect on the gut. However, PTH induces renal secretion of 1α-hydroxylase. This enzyme catalyses the conversion of inactive vitamin D3 into its active form, 1,25 DHCC (calcitriol). 1,25 DHCC acts to increase calcium absorption from the gut, increasing serum calcium concentration over the course of days. In this way PTH has an indirect effect on gut absorption of calcium.

(Additional point for completeness -> impaired 1α-hydroxylase secretion in chronic kidney disease is involved in a disease known as renal osteodystrophy. This is in part caused by inadequate absorption of calcium in the gut due to reduced 1,25 DHCC production)

Aromatase -> conversion of androgens to oestrogens

Cholesterol side-chain cleavage enzyme -> all steroid hormones are produced from cholesterol. This enzyme forms the 1st step in this process.

Tryptase -> enzyme contained in the secretory granules of mast cells and can be used as a biomarker of mast cell activation e.g. in anaphylaxis. (Not to be confused with trypsin)

5α-reductase -> conversion of testosterone (weak androgen) to its most potent form dihydrotestosterone

Question 5

Parathyroid hormone (PTH) is secreted by which cells?

1. Chief cells of the parathyroid gland
2. Follicular cells of the thyroid gland
3. Juxtaglomerular cells of the kidney
4. Oxyphil cells of the parathyroid gland
5. Parafollicular (C cells) of the thyroid gland

The correct answer is option a, Chief cells of the parathyroid gland

All of these cell types exist however PTH is only produced by chief cells in the parathyroid gland. The function of the 2nd parathyroid cell type (oxyphil cells) is currently unclear.

Question 6

Which of the following forms the primary, direct source of vitamin D?

1. Cholesterol
2. Cow’s milk
3. Egg yolks
4. Oily fish
5. Red meat

The correct answer is option a, Cholesterol

Egg yolk, oily fish and red meat are all sources of dietary vitamin D. 90% of vitamin D is derived from cholesterol through the ultraviolet pathway. Only 10% is directly derived from dietary sources (although cholesterol is clearly ultimate derived from diet derived). Cow’s milk in the UK is not a major source of vitamin D.

Question 7

In calcium homeostasis, what is the most important effect of 1,25 DHCC (calcitriol)?

1. Inactivation of calcium binding protein in gut epithelial cells
2. Inactivation of calcium binding protein in renal endothelial cells
3. Induction of calcium binding protein in gut epithelial cells
4. Induction of calcium binding protein in renal endothelial cells
5. Promotion of parathyroid hormone’s (PTH) effect at bone

The correct answer is option c, Induction of calcium binding protein in gut epithelial cells

The most important role of 1,25 DHCC in calcium homeostasis is its action at the gut to increase calcium absorption from the lumen. This is done by inducing the production of intracellular calcium binding proteins in gut epithelial cells. These proteins bind calcium when it is transported across the cell membrane; this limits its intracellular effects and maintains the concentration gradient between the lumen and the cell. Increasing calcium binding proteins increases this gradient, thus increasing calcium absorption.

While 1,25 DHCC does have renal effects, they are far weaker than its effect at the gut. 1,25 DHCC also has a mild promotional effect on PTH’s action at the bone.

Question 8

Which of the following is the 1st line intervention in osteoporosis

1. Falls risk assessment and prevention
2. Hormone replacement therapy
3. Intravenous bisphosphonate
4. Oral bisphosphonate
5. Teriparatide

The correct answer is option a, Falls risk assessment and prevention

Oral bisphosphonates are the 1st line pharmacological intervention in osteoporosis however, falls assessment and prevention is the 1st line intervention. Alendronic acid is the most common bisphosphonate used.

Hormone replacement therapy -> Severe risk in post-menopausal women. Can only be used for prevention of osteoporosis.

Intravenous bisphosphonate -> Reserved for specialist use

Teriparatide -> Reserved for severe risk in post-menopausal women.

Question 9

Which of the following is an effect of parathyroid hormone (PTH) at bone?

1. Inhibition of collagen secretion by osteoblasts
2. Inhibition of osteoclast activity
3. Promotion of calcium precipitation on osteoid
4. Promotion of osteoblast activity
5. Osteocyte necrosis

The correct answer is option a, Inhibition of collagen secretion by osteoblasts

PTH acts to increase serum calcium concentrations. At bone, this occurs through enhancement in the number and activity of osteoclasts and through inhibition of osteoblast collagen secretion -> overall resorption is increased while bone formation is reduced. The middle 3 options would decrease bone resorption. Osteocyte necrosis is completely unrelated to day to day calcium homeostasis.

Question 10

Calcium binding protein production is upregulated by which of the following hormones?

1. Calcitonin
2. Parathyroid hormone
3. Vitamin D3
4. 1a-hydroxylase
5. 1,25 DHCC

The correct answer is option e, 1,25 DHCC

1α-hydroxylase catalyses the conversion of inactive vitamin D3 into its active form, 1,25 DHCC (calcitriol). 1,25 DHCC acts to increase calcium absorption from the gut, increasing serum calcium concentration over the course of days.