Muskuloskeletal - Osteoporosis

Question 1

What is the principle of pathophysiology of osteoporosis?

Answer 1

Imbalance in bone formation and resorption (formation<resorption)
Increased osteoclasts activity (bone resorption)
Decreased osteoblasts activity (bone formation)

Question 2

What is the pathophysiology of osteoporosis?

Answer 2

Physiological Bone resorption
* Osteoblasts sense microcracks
* Osteoblasts produce receptor activator of nuclear factor κβ ligand (RANKL)
* RANKL binds to RANK rece on nearby monocytes –> monocytes fuse tgt –> multinucleated osteoclast
* Osteoclasts secre lysosomal enzymes (mainly collegenase)
- Digest collagen in organic matrix –> drill pits in bone surface aka Howship’s lacunae
* Osteoclast produces HCl which dissolves hydroxyapatite –> Ca2+ & PO4^3- (ions released into bloodstream)

• Scattering of osteocytes trapped in bony matrix
• Phagocytosed when released from dissolving bone or undergo apoptosis

To keep resoprtion under control
* Osteoblasts release osteoprotegerin which binds to RANKL
- Prevents RANK rece activation –> slow activation of osteoclasts
* Osteoblasts secre osteoid seam (sub mainly made up of collagen) to fill in lacunae created by osteoclasts
* Osteoblasts create bone material, get trapped in tiny lacunae or bony matrix and turned into osteocytes

Question 3

Describe the drug induced aetiology of osteoporosis?

Answer 3

Parathyroid hormone
GCs
Immunosuppressants: ciclosporin, tacrolimus
Chemotherapy/Radiation therapy
Cytotoxicity drugs
Heparin
ASM: PB, PHT

Question 4

What are risk factors for osteoporosis?

Answer 4

Age
Post menopausal women
Men >50y.o.
Low Ca dietary intake (<500mg/d)
Drugs
Low body wt
Sedentary lifestyle
Endocrine disorders: Cushing’s syndrome, adrenal insuff, hyperprolactinemia, hypothyroidism, DM
Alc >2units/d
Smoking
Ht loss >=2cm in last 3y

Question 5

Describe the screening for osteoporosis.

Answer 5

OSTA
- Based on age and body wt
- Adjusted for gender (cut off -1)
- Post menopausal women
Mild risk index: -1, Mod risk index: -1 to -4, High risk index: <= -4
- Asian men (50-70y.o.)
Mild risk index: -1, Mod risk index: -1 to -6, High risk index: <= -6
- At cut off, refer to polyclinic, say they underwent OSTA screening for osteoporosis and want to see Dr for further testing to evaluate whether anti osteoporosis xt needs to be started

DXA score
T-score <= -1 SD check (-1 SD to -2.5 SD = osteopenia, <= -2.5 SD = osteoporosis) check FRAX score
- T-score compares pt against normal ref pt pop, Z-score compares pt to ref pop of same age and gender as them)

FRAX
- 10y # risk
- Start osteoporosis tx if
1. Major osteoporotic # >= 20%
2. Hip # >3%

Question 6

What are the signs and symptoms of osteoporosis?

Answer 6

Signs:

Symptoms:
Asymptomatic until fragility # (low impact, from standing)

Question 7

What are the branches of pharmacological agents used in osteoporosis?

Answer 7

1. Anti resorptive agents
2. Anabolic agents

Question 8

What are the antiresorptive agents?

Answer 8

Bisphosphonates - PO risedronate, alendronate, IV zoledronic acid
RANKL inhib - SC denosumab
Oestrogen agonist/antagonist - raloxifene

Question 9

What are the anabolic agents?

Answer 9

PTH hormone - Teriparatide
Sclerostin inhib- Romosozumab

Question 10

What are the principles of pharmacological management of osteoporosis?

Answer 10

1st line: PO Bisphosphonates risedronate, alendronate

2nd line: IV Bisphosphonates zoledronic acid, RANKL inhib denosumab

Others:
Oestrogen rece agonist/antagonist raloxifene
PTH hormone teriparatide
Sclerostin inhib romosozumab

Question 11

Describe the MOA of bisphosphonates

Answer 11

Bisphosphonates increase osteoclasts cell death
Inhib bone resorption
Increase BMD

Question 12

Describe the dosing of bisphosphonates

Answer 12

Risedronate 35mg BD once weekly (or Q1mo)
Alendronate 70mg once weekly
Zoledronic acid 5mg/kg Q1y as 15-30min IV infusion

Question 13

What are the side effects associated with bisphosphonates and denosumab?

Answer 13

Common S/E
GI: NV, abdo cramping
MSK: severe bone, muscle, joint pain

Denosumab: slight tiredness, increased cholesterol

Rare but srs S/E
Endocrine: hypocalcemia
Atypical femoral #
- At shaft not neck of femur (NOF) or intertrochanteric
- Uneven distr of osteoclasts and osteoblasts
- Bone meta put stress under mechanical stress & P
- Activity of osteoblasts and clasts uneven

ONJ
- Risk factors:
Invasive dental procedures, poor PO hygiene, Concomitant agents of angiogenesis inhib, GCs, chemothera, bisphosphonates>denosumab, anaemia, malignancy, coagulopathy, infection, dental or peridontal disease

• Management:
  Good PO hygiene, tell dentist you are on agent (hold off ini until after dental procedures), smoking cessation

Bisphosphonates: iritis, uevitis

IV bisphosphonates: flu like symptoms (sore throate, runny nose, congested nose)

Denosumab: angioedema, srs infections (cellulitis, TB, pneumonitis, diverticulitis, appendicitis)

Question 14

Describe the MOA of denosumab

Answer 14

RANKL inhib
Inhib maturation of pre-osteoclast to osteoclast (curbs replacement)
Prevent processes that lead to survival of osteoclast –> increased osteoclast death

Question 15

Describe the dosing of denosumab

Answer 15

SC Q6mo
Coadmin Ca 1000mg + >=400 IU/d vit D
(More hypocalcemic than bisphosphonates)

Question 16

How do we counsel for administration of bisphosphonates?

Answer 16

Choose a day which is easiest for you to rmb to take
Take first thing in the morning before any food or drinks. Take with at least 240 mL of plain water (NOT mineral water). Wait at least 30minutes to eat any other food or drinks. Stay upright for these 30mins

If forget to take dose, take it the next day and continue the following dose on the original scheduled day. Do not double dose.

Question 17

How do we counsel for the administration of denosumab?

Answer 17

Do not miss doses, abruptly stop tx. Results in increased risk of vertebral column #

Question 18

What are the DDI assoc w denosumab?

Answer 18

Increased immunosuppression of GCs, immunosuppressants

Question 19

What are the DDI assoc w bisphosphonates?

Answer 19

PPI, polyvalent ions: Decreased absorption. Space 2h

PTH: interferes w Ca normalisation, CI

Question 20

What are the cautions w bisphosphonates and denosumab?

Answer 20

Hypocalcemia
Severe renal impairment
- PO bisphosphonates: CrCL < 30 mL/min
- IV bisphosphonates: CrCL< 35 mL/min
- Denosumab: CrCL<10 mL/min
Pregnancy and Lactation

Bisphosphonates:
GI abnormalities (erosive esophagitis, PUD, uncontrolled GERD)
Aspiration risk
Unable to stay upright for min 30min
Caution for risk factors of ONJ, active upper GI disease

Denosumab:
Vit D def
Eczema

Question 21

Describe the MOA of raloxifene

Answer 21

Mixed agonist and antagonist of oestrogen

Question 22

Describe the dosing of raloxifene

Answer 22

60 mg once daily

Question 23

What are the S/E assoc w raloxifene?

Answer 23

Common S/E
CVS: HTN, peripheral oedema
CNS: headache
MSK: arthralgia, MSK pain
Endocrine: hot flashes
Infection: infection
Flu like symptoms: congested, runny nose, sore throat

Rare but srs S/E
CVS: DVT, PE

Question 24

What are the cautions assoc w raloxifene?

Answer 24

DVT, PE
Pregnancy and lactation
Severe renal impairment <30mL/min
Severe hepatic impairment

Question 25

What are the DDI assoc w raloxifene?

Answer 25

Decreased thera effect of: warfarin

Increase toxic effects of:
HRT

Decreased absorption of raloxifene:
cholestyramine

Question 26

Describe the MOA of teriparatide

Answer 26

Physio PTH
Increases activation of vit D –> increased Ca absorption from GIT, increased bone resorption (Ca mobilisation into bloodstream)

Therapeutic
Intermittent high doses of PTH favours bone growth, suppresses bone resorption

Question 27

Describe the dosing of teriparatide

Answer 27

20mcg once daily SC

Question 28

What are the S/E assoc w teriparatide?

Answer 28

Common S/E
GI: NV
CVS: orthostatic hypotension

Rare but srs S/E
Endocrine: HYPERcalcemia
Malignancy: osteosarcoma

Question 29

What are the DDI assoc w teriparatide?

Answer 29

No sig DDI

Question 30

What are the cautions assoc w teriparatide?

Answer 30

Severe renal impairment < 30mL/min
Unexplained elevation of ALP
Paget’s disease, radiation thera to bone
Skeletal malignancies or bone metastases e.g. osteosarcoma
Prev implant
Pregnancy
Hyperparathyroidism
HyPERcalcemia
Hypersensitivity

Question 31

What is the duration of tx of teriparatide be used?

Answer 31

24mo

Question 32

Describe the MOA of romosozumab

Answer 32

Physio sclerostin
Inhib maturation of pre-osteoblast –> osteoblasts
Inhib the Wnt pathway that reg bone meta

Therapeutic
Removes inhib on canonical Wnt pathway
Increased maturation of pre-osteoblast –> osteoblast
Increase bone formation, decrease bone resorption

Question 33

Describe the dosing of romosozumab

Answer 33

SC Q1 mo for 12mo

Question 34

What are the S/E assoc w romosozumab?

Answer 34

Common S/E
MSK: arthralgia

Rare but srs
Endocrine: hypocalcemia
CVS: MI, increased risk of CV death
CNS: stroke
Hypersensitivity

Question 35

What are the cautions assoc w romosozumab?

Answer 35

Pregnancy and lactation
Severe renal impairment: CrCL 30ml/min
Hx of MI, stroke (within last 1y)
Uncorrected hypocalcemia
Hypersensitivity

Question 36

What is the duration of therapy for bisphosphonates?

Answer 36

Low # risk
PO: 5y
IV: 3y

High # risk
PO: 10y
IV: 6y

Wait 2y to check BMD. If desirable –> drug hol. Monitor Q2y, if BMD falls 4-5% or meet tx criteria agn, restart

Question 37

What are the Ca considerations in osteoporosis?

Answer 37

Reco 1000mg elemental Ca dietary intake. Suppl if <700mg daily

Question 38

What are the 25(OH)vit D considerations in osteoporosis?

Answer 38

Reco
50-70y.o. 600 IU/d, >70y.o. 800 IU/d
Suppl 800 IU/d cholecalciferol if hv or at risk of vit D def

Question 39

What are the non-pharm reco for osteoporosis?

Answer 39

Muscle strengthening, wt bearing, balance exercises –> strengthen muscle, promote bone growth
E.g. Tai Chi, brisk walking, elastic band exercise

Smoking cessation
Alc consumption in moderation (<=2 units/d)

Educate on fall risk at home
- Lights on at night when toileting
- Instal railings, antislip mats, hv dry floors