Disorders of bone homeostasis (osteoporosis - OP)

Question 1

What cells are involved in bone homeostasis? (what do?)

Answer 1

Osteoblasts = bone-forming cells —> secrete collagen, derived from bone marrow precursors

Osteoclasts = bone resorbing cells
- resorb old bone

Osteocytes = derive from osteoblasts, embed during bone formation

Question 2

List the hormones involved in bone homeostasis and their function

Answer 2

PTH - parathyroid gland
- Inc bone resorption, dec excretion of Ca2+ in urine

Calcitonin from thyroid gland - respond to inc Ca2+
- dec bone resorption, dec reabsorption of Ca2+

Vitamin D - dietary Vit D2, D3 generated in skin
- Inc bone resorption and inc absorption of Ca2+ in gut

Oestrogen
- maintain bone integrity
- menopause/withdrawal –> osteoporosis

Endogenous glucocorticoids
- req for osteoblast differentiation to osteoclast

Question 3

What is the homeostatic response to rising Ca2+ in blood?

Answer 3

Inc Ca2+ –> thyroid gland release calcitonin –> calcitonin stim kidneys and bone –> inc deposition of Ca2+ into bone, dec Ca2+ reuptake by kidney –> Ca2+ lvls in blood dec

Question 4

What is the homeostatic response to dec Ca2+ in blood?

Answer 4

Dec Ca2+ in blood –> parathyroid gland –> release of PTH –> bones release more Ca2+, kidney stimulate Ca2+ uptake whilst converting Vit D to active form (inc in gut absorption of Ca2+) –> Ca2+ lvls in blood rise

Question 5

What is osteoporosis?

Answer 5

Systemic condition of altered bone quantity and quality
- low bone mass and microstructure deterioration

Enhanced bone fragility and inc facture risk

Diagnosed by bone density test = measure density at hip and spine
- T-score <-2.5 = osteoporosis
- T-score between -1 and -2.5 = osteopenia

Question 6

What are some unmodifiable risk factors for osteoporosis?

Answer 6

Age, sex

Fam hx

race

body frame

Question 7

What are some modifiable/other risk factors for osteoporosis development?

Answer 7

Conditions affecting hormones = menopause, hypogonadism, excessive thyroid hormones, excessive PTH or adrenal hormones, amenorrhoea

Nutritional = inadequate vit D/Calcium, anorexia nervosa, malabsorption syndrome

Medications = corticosteroids, anticonvulsants, thiazolidinedione, lithium, SSRIs, frusemide, gastric-acid lowering agents, warfarin, antiretrovirals, chemo

Lifestyles = smoking, excessive alcohol, inactivity, immobilisation

Question 8

Why is osteoporosis less common in men vs women?

Answer 8

Men tend to have more testosterone which is converted to oestrgen later in life to make more/help with bones

Men tend to also accumulate/have greater bone density since they are bigger –> decline in bone density is a lot slower/less noticeable

However, OP has higher incidence in first nations peoples and they experiences fractures earlier

Question 9

What is the prognosis of someone who has had a OP fracture

Answer 9

Falls prevention programs = not super useful

After OP fracture/fall = 15-20% mortality w/in 12 months

> 50% of people are left w/ sig functional limitations

Length of stay 8 days, cost >20K each

Question 10

What is calcium absorption dependent on and which calcium salts are better?

Answer 10

Absorption depends on:
- daily Ca intake
- intestinal transit time
- age
- oestrogen levels in females
- PTH and vit D activity

Which salt? - Calcium carbonate better absorbed when gastric acidity high, less when taken w/ protein. Other salts are less dependent on gastric acidity

Question 11

How much Vit D supplementation is needed for someone at risk of deficiency? (for under 70 y/o, over 70 y/o, high risk people)

Answer 11

under 70 y/o = 600 iu

over 70 y/o = 800 iu

high risk 1000-2000iu/day

Question 12

Summarise the main treatments for OP

Answer 12

Oestrogen supplements

SERMs - established post-menopausal

Bisphosphonates = corticosteroid induced OP/OP in age >70

Denosumab = OP in >70

Teriparatide = men and women, any reason - severity

Question 13

How/when/for how long is hormone replacement therapy used in OP treatment? (pros/cons)

Answer 13

Used in post-menopausal women - reduces bone turnover and prevents bone loss, improves BMD by 4-7%

Most benefit seen after 4-5 yrs of use
- greatest incidence of CV events in 1st yr of HRT, inc cancer risk after 5 yrs

Bone loss resumes when tx stopped

Inc BC, stroke, VTE

Question 14

How does Raloxifene treat OP? (when used, benefits)

Answer 14

Oestrogen agonist on bone and lipid profile

Antagonistic on breast and uterus –> confer some BC risk reduction

Used in early post-menopausal OP, reduces risk of vertebral fractures (not others though)

Inc VTE and fatal stroke risk for those with coronary heart disease

Question 15

What bisphosphonates are used to treat OP? (what are their doses)

Answer 15

Alendronate = 70mg, once weekly

Risedronate = 35mg once weekly OR 150mg once monthly

Zoledronic acid = 5mg IV once a year

Question 16

What do bisphosphonates do to to treat OP? (when used?)

Answer 16

Alendronate, risedronate, zoledronic acid = effective for primary prevention (vertebral) and effective of secondary prevention (all sites)

Work by inhibiting osteoclast activity

Oral agents, safety after 10 yrs not known so assess after 5-7 yrs
- alendronate maintain bone density for 1-2 yrs after ceasing
- risendronate decline can occur more rapidly

Zoledronic acid IV

Question 17

How are bisphosphonates administered?

Answer 17

To reduce GI irritation - w/ water

Mindful of those w/ GI absorption issues

Question 18

What are some C/I and ADRs of bisphosphonates?

Answer 18

C/I = hypocalcaemia –> will drive more Ca2+ into bone –> further deplete serum Ca2+

ADRs
- oesophagitis (inc erosion)
- gastritis (ulcers)
- iritis, scleritis
- muscle pain

Serious ADR
- osteonecrosis of jaw –> common in IV use and cancer patients

Question 19

When/how is denosumab used to treat OP?

Answer 19

Its a monoclonal antibody –> dec formation and activity of osteoclasts –> reduce bone resorption (inhibits RANKL)

Indication = established OP (BMD or fracture due to minimal trauma), prevention of skeletal event from bone metastases

Question 20

How is denosumab administered? (long term effects? C/I?)

Answer 20

Sub cut every 6 months - long term effect unknown

Rare incidence of osteonecrosis of jaw

C/I = hypocalcaemia, may also cause hypocalcaemia in renally impaired people

Question 21

How is PTH (teriparatide) used to treat OP? (how/when used?)

Answer 21

Action = promotes bone formation and inc BMD

Subcut injection once a day - max 18 months

Indication = severe OP or when factures occurring despite other therapy (both men and women)

Break recommended between alendronate and teriparatide

Question 22

How is strontium ranelate used to treat PO?

Answer 22

Action = inc bone formation by inc osteoblast precursor replication and collagen synthesis
- reduces bone resorption by altering osteoclast structure and dec resorbing activity
- promotes calcium uptake into bone –> improve density but quality uncertain

PBS approved when other therapies not available

*Do not administer w/ food

Question 23

What are some risks to strontium ranelate use for OP?

Answer 23

Inc VTE risk

Inc MI risk

Question 24

What is paget’s disease (osteitis deformans)?

Answer 24

Focal disorder of bone remodelling characterised by excessive bone resorption together with a compensatory but disorganised inc in bone formation

Question 25

What are the manifestations of Paget’s disease?

Answer 25

Manifestation:
- soft, poorly mineralised bone, hypercalcaemia, limb deformities, fractures, deafness, neurological problems

- bone pains at rest, esp at night - dull, nagging in nature and has localised heat. Can become constant 

Advanced disease = leg bowing and/or temporal skull enlargement/pain

Rarely spinal or brain stem compression

Question 26

Does paget’s disease require tx? If so, summarise available drugs/drug classes

Answer 26

Many don’t require treatment

1st line = bisphosphonates –> dec osteoclast activity and dec pain
- indicated for those w/ sx or those w/ ALP 2* ULN

IV pamidronate or oral bisphosphonate = higher doses than for OP

Analgesics and NSAIDs for bony pain

Question 27

What bisphosphonates are used in treatment of Paget’s disease (dose? freq administration?)

Answer 27

Zoledronic acid = 5mg IV

Alendronate = 40mg oral, daily –> lower than for OP

Risedronate = 30mg daily

Pamidronate = 60mg IV

Tiludronate = 400mg orally, daily

Question 28

What are the main differences in bisphosphonate dosing between OP tx and Paget’s disease tx?

Answer 28

OP = usually once weekly/monthly/yearly treatment at higher dosing on empty stomach

Paget’s Disease = usually once daily, smaller doses on empty stomach