Osteoporosis

Question 1

What is osteoporosis?

Answer 1

Decreased bone mass due to loss of bone cells, matrix and trabeculae

Question 2

What are complications of osteoporosis?

Answer 2

Pathological fractures and microfractures

Question 3

What are the risk factors/etiology of osteoporosis?

Why?

Answer 3

Increasing age - decreased production, increased destruction

Genetic factors, certain ethnicities

post-menopause (oestrogen withdrawal) - loss of oestrogen results in increased RANK + RANKL, decreased survival of oestoblasts, decreased OPG, increased increased inflammatory cytokines

Failure to reach peak bone mass in development - less bone mass to begin with

Decreased physical activity - muscles pull on bones stimulating remodelling to strengthen bone & form new bone

Cushing’s disease/iatrogenic effects of steroids - increased cortisol & other steroids increases RANKL and decreases OPG

Inadequate calcium & vitamin D - decreases calcium intake, more Ca loss from bone for homeostasis, less Vit D less Ca GIT absorption

Question 4

What are the 2 categories of pharmacological treatments for osteoporosis?
What are the main therapies within each?

Answer 4

1. Antiresorptive (aim to reduce osteoblast activity)
   Bisphosphonates, RANKL inhibitor, selective oestrogen receptor modulators
2. Bone anabolic agents
   PTH*, calctitonin, Vit D, Ca

Question 5

What are bisphosphonates?
How do they treat osteoporosis?
What are their adverse effects?

Answer 5

Aldendronate
Pyrophosphate analogue - toxic to osteoclasts
Weekly dose as it accumulates (not related to half life)

Incorporated into the bone matrix & accumulates, when osteoclasts destroy bone they disrupt it and die - therefore reduces bone resorption

Can cause reflux and oesophagitis
Increased risk of oesophageal cancer and atypical fractures

Question 6

What are RANKL inhibitors?
How do they treat osteoporosis?
What are their limitations?

Answer 6

Denosumab
RANKL inhibitors are monoclonal Abs that bind to RANKL

Binding to RANKL reduces RANKL-RANK interactions between osteoblasts & osteoclasts, reducing the maturation and activity of osteoclasts - reduces bone resorption

Very expensive

Question 7

What are SERMs?

How do they treat osteoporosis?

Answer 7

Selective oestrogen receptor modulators
Ralixofene

Selectively act as agonists at oestrogen receptors at the bone & CV tissue
At the bone they increase activation of oestrogen receptors, leading to decreased RANK/RANKL, increased OPG, prolonged osteoblast survival - increased osteoblast activity and decreased osteoclast activity

Act as antagonists at oestrogen receptors in mammary & uterine tissue

Question 8

How do calcitonin and PTH treat osteoporosis?
How are they administered?
When else is calcitonin used?

Answer 8

Calcitonin reduces bone resorption and is administered intravenously or nasally
Only sometimes used for osteoporosis, mainly used to treat hypercalcaemia (paraneoplastic)

PTH has a paradoxal effect
Administered intravenously
Small infection favours anabolism of bone
Large, continuous doses favour catabolism - increase RANKL, decrease OPG

Question 9

When and why are Calcium & Vitamin D used to treat osteoporosis?
What other conditions is Vitamin D used?
What adverse effects can calcium cause?

Answer 9

Increased calcium available for serum homeostasis so less required from bone, therefore less bone mobilisation
Can cause GIT upset

Vitamin D increases absorption of calcium in the gut
Also used in deficiency to prevent osteomalacia (adults) and rickets (children), in hypoparathyroidism (reduced PTH would reduce activation of Vit D by kidneys) and chronic renal failure (reduced activation of Vit D)