S4: Hormones, Skeleton and HRT

Question 1

List synthetic hormones with skeletal effects

Answer 1

• Oestrogen.
• Parathyroid hormone (PTH).
• Vitamin D (1,25-(OH)2 Vit D3).
• Calcitonin.
• FGF-23 (released by osteocytes),

Question 2

What are osteons?

Answer 2

Long cylindrical column that make up cortical bone.

Question 3

Describe two lineages of bone cells

Answer 3

• The osteoclasts are essentially a type of macrophage derived from the haematopoietic stem cell. These secrete acid and enzymes that degrade and resorp the bone matrix and mineralisation.
• The osteoblasts are derived from mesenchymal stem cells, these lay down bone by secreting osteoid (mainly contains type 1 collagen) and involved in the mineralisation of that matrix which is necessary for it to be strong and hard.
• How much these two cells differentiate from their precursors depends on various local and systemic factors that promote or inhibit their differentiation and promote or inhibit their apoptosis which then affects their life cycle.

Question 4

Describe the lacunar-canicular network

Answer 4

Osteoblasts that get stuck in the matrix and do not undergo apoptosis terminally differentiate into the osteocyte. The osteocytes sit within lacunae in the bone matrix and may live for decades. The lacunae is like a little hole in the bone that the osteocyte sits in, they then project off dendrites (cellular processes) that pass through little tunnels in the bone matrix called canaliculi. They communicate with these dendrites. This is referred to as the lacunar-canalicular network, this enables communication between osteocytes and other cells on the bone surface.

Question 5

Describe function of osteocytes

Answer 5

• The role of the osteocyte is being continuously researched, they do have an important regulatory role of the balance between osteoblasts and osteocytes. They are therefore thought to regulate bone modelling in response to both mechanical stimuli (that is strain on the bones) and endocrine stimuli (circulating hormones).
• The osteocytes also function as endocrine cells themselves, secreting FGF23, via the canalicular network it gets into the systemic circulation. FGF23 increases phosphate excretion in the kidneys and decreases 1-alpha-hydroxlase activity to reduce active vitamin D.

Question 6

What is bone remodelling?

Answer 6

Skeletal health depends on continual turnover of bone tissue. This is called remodelling. It depends on a delicate balance between eating away old bone and laying down new bone.An adequate balance between osteoblasts and osteoclasts is essential for healthy bone. Anything that tips the balance one way or the other will therefore lead to overall loss or gain of bone mass.

Question 7

Control of bone remodelling

Answer 7

• Mechanical factors that favour resorption are lack of use (unloading), things like bedrest or being in zero-gravity.
• Mechanical factors that favour formation of bone are load bearing exercise that put stress on bone
• There are also then endocrine and paracrine control of bone remodelling.
• Cellular/molecular signalling in remodelling involves complex auto/para/endocrine network involving multiple cell types.

Question 8

How is bone a metabolic organ?

Answer 8

· Bone turnover serves homeostasis of serum calcium, phosphate, in conjunction with parathyroid hormone, vitamin D, calcitonin and FGF-23.

Question 9

Role of PTH in calcium homeostasis + bone

Answer 9

• Maintains a very tight control of serum Ca2+ between 2.2 - 2.6mmol/L, this is through a negative feedback mechanism, by which if Ca2+ starts getting too high PTH production immediately will turn off.
• Decreases in plasma Ca2+ will stimulate PTH release.
• PTH stimulates bone remodelling, it has both anabolic and catabolic effects on bone (depends on situation, generally catabolic) due to -ve feedback in related to calcium homeostasis.
• PTH stimulates conversion of hormonal vitamin D in the kidney to active calcitriol via stimulating 1-alpha hydroxylase.
• Increases Ca2+ reabsorption in the DCT of the kidney.

Question 10

Role Vitamin D (1,25-dihydroxy D3) in calcium homeostasis +bone

Answer 10

• Increases Ca2+ absorption from the gut.
• It promotes differentiation of osteoclast and osteoblasts.
• Inhibits PTH (to ensure one doesn’t become hypercalcaemic).
• Inhibits 1-alpha hydroxylase (inhibits its own synthesis, feedback inhibition).

Question 11

Role of calcitonin in calcium homeostasis + bone

Answer 11

• Is released in response to rises in Ca2+ and functions to lower serum Ca2+ but its importance in Ca2+ homeostasis is doubtful (as if you remove thyroid gland, thus calcitonin release stops, doesn’t seem to have much of an effect).
• Directly inhibits osteoclasts (has been used to treat osteoporosis).

Question 12

Role of oestrogen in calcium homeostasis + bone

Answer 12

Regulates life cycle of osteoblasts and osteoclasts:

• Osteoclasts: shorten (promote apoptosis).
• Osteoblasts: lengthen (protect from apoptosis).
• Indirectly inhibit osteoclast differentiation.
• May be necessary for new bone formation in response to mechanical stress.

Question 13

Describe molecular control of bone remodelling

Answer 13

It is very complex and involves multiple cell types utilising auto/para and endocrine mechanisms.
One mechanism involves the induction of osteoclast differentiation by RANK ligand.
- RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation.
- RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation.
- OPG (osteoprotogerin): decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK.
- As osteocytes produce both RANk ligand and OPG it has different effects under different conditions.
- Therefore this process of osteoclast differentiation and therefore bone resorption is controlled by a balance between RANK ligand and OPG.
- PTH binding to osteoblasts causes them to increase release of RANK ligand and decrease release of OPG, so you get more osteoclast differentiation and more resorption of bone.

Question 14

Describe osteoblast differentiation

Answer 14

• Osteocytes also regulate bone formation via the secretion of modulators of the Wnt signaling pathway. PGE2, NO, and ATP act to activate Wnt signaling, whereas sclerostin, DKK1, and SFRP1 all inhibit Wnt signalling.
• WNT pathway is how osteoblasts differentiation.
• Sclerostin expression can alter the balance between bone formation and re-absorption. It is a brake on bone formation and mechanical stress can take this brake off. It is also a brake on osteoblast differentiation.

Question 15

Describe osteoporosis and osteomalacia

Answer 15

• The most common metabolic bone disease is osteoporosis which is a loss of bone mass leading it to becoming brittle, this may be due to endocrine disorders (e.g. hyperparathyroidism), malignancy, drug induced, renal disease, nutritional.
• Osteomalacia is different, it is a loss of bone mineralisation resulting in soft bones.

Question 16

Endocrine causes of osteoporosis

Answer 16

• Hypogonadism -> Most notably any cause of oestrogen deficiency, this is seen after the menopause which is why postmenopausal osteoporosis is common.
• Excessive glucocorticoids -> May be endogenous (cortisol) or exogenous, they have a catabolic effect on bone leading to bone loss.
• Hyperparathyroidism.
• Hyperthyroidism.

Question 17

Describe diagnosis of osteoporosis

Answer 17

• To diagnose osteoporosis involves measuring the bone mineral density (BMD) and we do this by doing a DEXA scan (dual energy x-ray absorptiometry).
• This gives us a T score which is the no. of standard deviations below the average peak bone mass for a young adult.
• One is normal if they have a T score of -1 or above, so they lie within 1 S.D. of the normal.
• Osteopenia or low bone density is diagnosed if they have a T score of lower than -1 but greater than 2.5.
• Osteoporosis if T score lower than -2.5.
• Severe osteoporosis if T score lower than -2.5 and presence of at least one fragility fracture.
• A Z score is essentially the same thing but rather than being no. of S.D. from a young adult at peak bone mass it is age matched to that individual (may also match gender, ethnicity etc.).

Question 18

How does bone density in women change at different ages?

Answer 18

The bone density of women declines over life, peak bone mass is achieved between 25-30 and then after 30 it declines. Especially after the menopause when there is a big decline in oestrogen levels which increases rate of decline in bone mass. Bone loss is a natural part of ageing.

Question 19

Treatment for osteoporosis

Answer 19

• First line: Ensure adequate calcium and vit D intake (diet), appropriate exercise.
• Oestrogen - effects well established but safety of long term treatment has been questioned. It is not current first line treatment.
• Bisphosphonates: inhibit function of osteoclasts function e.g. risedronate, alendronate.
• Long term use associated with atypical fractures due to brittle bone.
• PTH analogues: paradoxially work. Long term elevated PTH levels –> osteoporosis (inevitable in hyperparathyroidism). Remember PTH is both anabolic and catabolic. Low dose intermittent PTH is used for osteoporosis.
• Denosumab: antibody against RANK ligand (since 2010) thus preventing osteoclast differentiation.

Question 20

Features of menopause

Answer 20

The menopause is the permanent cessation of the menstruation and the average age for it is 51. There are various signs and symptoms associated with it for example dry vagina and hot flushes.
The most common (early?) manifestation of the menopause is vasomotor symptoms, basically hot flushes!
Later on accelerated bone loss is seen and osteoporosis due to the low oestrogen levels.