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MBBS IV - Junior Clerkship WCS > JC36 (Medicine) - Osteoporosis > Flashcards

JC36 (Medicine) - Osteoporosis Flashcards

1
Q

Define Osteoporosis

A

Systemic skeletal disease characterized by:

  • Low bone mass
  • Microarchitectural deterioration of bone tissue
  • Increase in bone fragility and susceptibility to fracture
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2
Q

Compare difference between Trabecular bone and cortical bone

A

Normal bone is composed of:
□ Trabecular bone: 20% of mass, 80% of bone turnover
□ Cortical bone: 80% of mass, 20% of bone turnover

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3
Q

Describe bone remodeling units and physiological processes

A

□ Site: remodeling units containing osteoclasts, osteoblasts and osteocytes within cavity

□ Process:
Osteoclastic absorption (30-40d):
- Osteoclast derived from haematopoietic cells resorb bone → form bone remodeling pit
- Osteoclast signals osteoblast to arrive

Bone formation (150d):
- Osteoblast derived from mesenchymal cells lay down osteoid → later becomes mineralized to form normal bone structure
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4
Q

Major regulation factors from Osteoblasts to control osteoclastogenesis

A

osteoclastogenesis regulated by factors from osteoblast/stromal cells

→ RANKL stimulate osteoclast differentiation by binding to RANK on osteoclast precursors
→ Osteoprotegerin act as competitive inhibitor of RANK-RANKL interaction
→ M-CSF stimulate differentiation of osteoclast precursors

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5
Q

Normal physiological action of OPG and RANKL

A

OPG = decoy receptor to RANK
OPG normally binds to RANKL expressed by osteoblasts to stop activation of RANK receptor on osteoclasts > stop osteoclastogenesis > decrease bone resorption and osteoclast differentiation

RANK produced by osteoblasts > bind to RANKL receptor on osteoclast precursor > maturation and differentiation of osteoclast > Increase bone resorption

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6
Q

Stimulatory and inhibitory factors of RANKL and OPG

A

Increase RANKL and decrease OPG&raquo_space;»> Bone resorption

  • Dexamathasone
  • Dihydroxyvitamin D
  • PTH (high concentration)
  • PGE2

Decrease RANKL and increse OPG&raquo_space;»> Block bone resorption
- 17β-estradiol

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7
Q

Role of sclerostin in bone metabolism

A

Output:

  • Stimulate RANKL expression from osteocytes > increase osteoclastogenesis and bone resorption
  • Inhibit osteoblast differentiation > decrease bone formation
  • Reduce mineralization of osteoblasts

Stimulating factors:

  • Estrogen deficiency
  • Bone mechanical unloading
  • Release by Pre-osteoclasts
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8
Q

Action of estrogen on bone remodeling

A

Oestrogen: acts to ↑bone formation and ↓bone resorption by

↓osteoblast apoptosis by ↓TGF-β secretion

↓osteoblast-induced osteoclastogenesis by ↓cytokine secretion and ↓RANKL expression

↑osteoclast apoptosis by ↑TNF-α secretion

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9
Q

Pathophysiology of age-related bone loss

A

Increased rate of bone remodeling in both cancellous and cortical bone
> Increase number of remodeling units
> Resorbed cavities too large and newly formed pocket of bone too small
> Increased bone loss and negative remodeling balance

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10
Q

Pathophysiology of glucocorticoid on osteoporosis

A

1) Decrease calcium absorption and resorption + Increase PTH secretion > Increase RANKL + Decrease OPG > Osteoclastogenesis; increase osteoclast survival; cancellous osteoclasts > Bone resorption
2) Decrease osteoblastogenesis and induce apoptosis > decrease bone formation
3) Decrease muscle mass and mechano-sensing > Increase apoptosis and canalicular circulation of osteocytes > Poor bone quality
4) Decrease sex steroids > Increase RANKL + Decrease OPG > Osteoclastogenesis and bone resorption

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11
Q

Recommended Ca intake

A

800mg/d in adults

1000mg/d for >50y (F) or >70y (M)

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12
Q

Normal changes in bone density over lifetime

A

Peak bone mass attained in age 20-40y

Gradual age-related bone loss after 40y (~1%/y)

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13
Q

2 clinical types of Osteoporosis

A

□ Type 1 osteoporosis: occurs ≤15-20y post-menopause, hormonal-related

□ Type 2 osteoporosis: occurs in M+F >75y, ageing-related

Both involve:
□ Defect in attaining peak bone mass
□ Accelerated bone loss

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14
Q

Causes and RF of primary osteoporosis

A

Race: Asians, White
Body habitus: short stature, ↓BMI
Family history of OP or fragility fracture
Low oestrogen states: post-menopausal, amenorrhoea >6mo, multiparity
Dietary: low dietary calcium or vitamin D
Lifestyle: smoking, drinking, sedentary lifestyle

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15
Q

Causes and RF of secondary osteoporosis

A

Endocrine: hyperthyroidism, hyperparathyroidism, hypogonadism, Cushing’s syndrome, prolactinoma

Drugs: glucocorticoids, anticonvulsants, PPI, heparin, aromatase inhibitor

Malignancy: multiple myeloma, leukaemia

Inflammatory: IBD, RA

GI: gastrectomy, malabsorption, Primary biliary cirrhosis

Renal: renal osteodystrophy

Others: prolonged immobilization, osteogenesis imperfecta, homocystinuria, Turner syndrome, scurvy

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16
Q

One major Ddx of osteoporosis
Causes
Test to differentiate

A

osteomalacia: Abnormal bone histology with unmineralized osteoids

Causes:

  • Vitamin D deficiency
  • Defective vit D activation
  • Vitamin D resistance
  • Phosphate deficiency
  • Other mineralization defects

Notably ↑ALP in osteomalacia (compensatory ↑osteoblast activity)
vs normal ALP in osteoporosis (osteoblast activity suppressed)

17
Q

Clinical presentation of Osteoporosis

A

Asymptomatic: presented with incidental finding of XR osteopenia or by screening

Fragility fractures: fractures occurring with low energy trauma (eg. fall from level ground)
□ Vertebral collapse: acute mechanical LBP ± radiation with height loss and kyphosis
□ Trochanter/neck of femur, usually upon fall landing on buttock
□ Distal forearm: distal radius/ulna
□ Neck of humerus, pelvic (pubis, sacrum), rib

18
Q

Diagnosis of Osteoporosis

A

□ Previous Low-trauma/ Low-energy fracture in postmenopausal/ elderly patient
□ T-score ≤-2.5 based on BMD measurement by DXA

Device: dual energy X-ray absorptiometry (DEXA) at spine and hip (best predictor of fracture risk)
Interpretation (WHO 1994):
→ Normal = T score ≥ -1
→ Osteopenia = T score <1 and >-2.5
→ Osteoporosis = T score ≤-2.584
→ Established osteoporosis = T score ≤-2.5 with fracture

Note that by 60y, ~1/2 of women will have low bone mass or osteoporosis

19
Q

Morbidity and mortality of OP-related hip fractures and vertebral fractures

A

Hip fracture:
One-year morality: 20-30%
Permanent mobility limitation - 40-60%
Assistant with at least one ADL - 20-60%

Vertebral fracture:
Excess mortality 5-years post-fracture - 20%
Acute and chronic back pain
Deformity and height loss with respiratory compromises
Lower QoL

20
Q

Formula for BMD T-score

A
21
Q

Outline history-taking for OP

A 
Aim:
□ Identify risk factors
□ Evidence for secondary osteoporosis
□ Medications/illnesses that ↑risk of fall and OP 
□ Family Hx

Past health:

  • History of fractures
  • Fall risk
  • Low estrogen state: age of menopause, multiparity… etc
  • GI disease/ Malabsorption syndromes
  • Anorexia nervosa
  • Type I DM

Drug history:

  • OP: glucocorticoids, PPI, anticonvulsants, TZDs
  • Fall risk: hypnotics, sedatives…etc

Social:

  • Smoking and alcohol (RFs)
  • Sedentary lifestyle

Family Hx:
- OP or fragility fractures

22
Q

Outline specific physical exams for OP

A

Height and weight, any recent acute changes (vertebral fracture, Cushing’s syndrome)

Dental exam for loss of teeth and dentures (early signs of osteoporosis, risk of osteonecrosis of jaw)

Evidence of secondary osteoporosis:
→ Signs of endocrine diseases, eg. hyperthyroidism, Cushing’s disease
→ Signs of myeloma, eg. anaemia, hypercalcemia
→ Signs of hypogonadism

Clinical effects of osteoporosis:
→ Observe posture and estimate degree of kyphosis
→ Examine for site of tenderness

Fall assessment: critical in elderly
→ Agility, hearing, eyesight, postural sway
→ Gait
→ Mobility muscle strength

23
Q

List panel of lab investigations for OP

A
24
Q

Non-pharmacological treatment of OP

A

Adequate dietary Ca, vitamin D intake:
→ Recommended intake: 1000mg Ca, 600IU vit D (M or premenopausal F); 1200mg Ca, 800IU vit D (post-M F)
→ Role of supplementation: not much evidence, only in inadequate dietary intake (esp vegans, lactose intolerance)
→ Note that PPI use can ↓calcium absorption

Regular weight bearing exercise

Smoking cessation and moderate alcohol consumption

Regular exposure to sunlight esp in institutionalized patients

25
Q

Calcium intake
1) Example of food with high Ca

2) Calcium supplements
- Examples
- S/E

A

Cheese, Sardine, Almond, Yogurt, Tofu

Ca supplements (Calcium carbonate, Calcium citrate)

  • Taken with food, gastric acidity promote calcium absorption
  • S/E: Dyspepsia and constipation (increase fluid and fiber intake to mitigate)
26
Q

Vitamin D intake

  • Recommended level
  • Source of Vit. D
A

Requirement: target 25 hydroxyvitamin D level at 30ng/mL

  • Mean Vit. D requirement: 1000IU/day
  • 2000IU /day for obese, limited sun exposure, malabsorption

Sources:
- Synthesis of cholecalciferol (Vit. D3) in the skin under UV light
10-15 minutes sunlight exposure every day over face, hands, arms
- Food/ supplements

27
Q

Weight bearing exercises

  • Examples
  • Benefits
A

Examples:
- Brisk walking, jogging, stair climbing, Tai Chi, Dancing

Benefits:

  • Retard bone loss
  • Increase muscle mass and strength
  • Improve balance, reduce fall risk
  • Improve QoL
28
Q

2 classes of pharmacological agents for OP with examples

A

□ Antiresorptives:
oestrogen (HRT), SERM, bisphosphonate, RANKL inhibitor

□ Anabolic agent:
teriparatide/ Abloparatide (PTH), romosozumab (anti-sclerostin Ab)

29
Q

Standard treatment regiment for OP

A

1st line: oral bisphosphonate (+ raloxifene or HRT if under 65 without hip fracture)
→ Raloxifene: generally less effective, more for lower risk pt who prefer to ↓CA breast risk
→ HRT: NO longer indicated for osteoporosis ALONE, can be used if vasomotor symptoms

Add-on therapy:
→ IV bisphosphonate: if refractory to GI S/E of oral form
→ Denosumab: refractory to bisphosphonate, poor compliance or CKD
→ Anabolic agent: severe osteoporosis, fractures or unresponsive to other Tx

30
Q

HRT for OP

  • Indication
  • MoA
  • S/E
A
  • Indication: Young woman with Early menopause, concurrent decrease menopausal symptoms, reduce cholesterol
  • MoA:
    ↓bone resorption, ↓urinary Ca excretion, ↓stromal cell cytokine production → ↓osteoclastogenesis
  • S/E:
    ↑risk of CA endometrium → must add progestogen if uterus intact
    ↑risk of CA breast and CA cervix
    Venothrombolic disease
31
Q

SERM

  • Example
  • Indication
  • MoA
  • Effect
  • S/E
A

Selective estrogen receptor modulators (SERMs), eg. raloxifene

Indication: Young post-menopausal women with low risk of hip fracture

MoA:
Estrogen-agonist effect in bone: Decrease bone resorption
Estrogen-antagonist effect on breast and endometrium: ↓ER+ breast cancer, no risk of endometrial CA

Effect:
↓vertebral fracture risk by 50% but not non-vertebral fracture

S/E:
Venous thromboembolism
Hot flushes
Leg cramps

** Discontinue if prolong immobilization**

32
Q

Bisphosphonates **

  • Examples
  • MoA
  • Effect
  • Precautions
  • S/E
A

Examples: Etidronate, alendronate, risedronate, Zoledronate (IV)

MoA: Anti-resorptive
Pyrophosphate derivative
→ binds to bone surface and absorbed by Osteoclasts
→ competitive inhibitor of PPi-requiring farnesyl pyrophosphate synthase (FPPS) reaction
→ inhibition of mevalonate pathway (i.e. steroidogenesis pathway)
→ specific inhibition of bone resorption + induce apoptosis of osteoclasts

Effect:
↓fracture risk by 50% in both vertebral and non-vertebral fractures (incl. hip)

Precautions:

  • Poor intestinal absorption, take 30min before meal
  • C/O Poor renal function (eGFR<30)
  • Avoid Ca or Vit D supplements >1h before bisphosphate (affect absorption)

S/E
→ Upper GI disturbance (~5%), eg. oesophagitis
→ Flu-like illness (fever, malaise, generalized myalgia) esp at 1st exposure
→ Oversuppression of bone turnover due to persistent action
→ Require drug holidays if undergo dental work (remind pt to ensure good dental hygiene)
→ Atypical femoral fracture due to excessive bone formation
→ Osteonecrosis of jaw due to limited bone healing following trauma (eg. dental work)

33
Q

RANKL Antibody

  • Example
  • MoA
  • Effect
  • S/E
A

RANKL Ab, eg. denosumab

MoA: human mAb vs RANKL → interferes with RANKL → ↓osteoclast differentiation and activation

Effect: ↓vertebral fracture by 50%, ↓non-vertebral fracture by 30%

S/E: rash, atypical femoral fracture (very rare), hypocalcemia, osteonecrosis of jaw (very rare), sudden vertebral collapse if abrupt withdrawal

Can use for poor renal function, unlike bisphosphonate

34
Q

PTH for OP

  • Examples
  • MoA
  • Effect
  • S/E
  • C/O
A

PTH, eg. teriparatide (SC low-dose PTH analogue). Abaloparatide

Biphasic action of PTH on bone:
→ Low dose, intermittent → anabolic action eg. daily IMI can ↑BMD and ↓vertebral fracture risk by 70%
→ High dose, continuous → catabolic action with resorption of cortical > trabecular bone

Effect: ↓vertebral fracture by 70%, ↓non-vertebral fracture by 30%

S/E:
Mild leg cramps
Injection site pain and bruising
Hypercalcaemia

C/O

  • Long-term use (osteosarcoma risk)
  • History of skeletal malignancies/ metastases
  • History of radiation to bone
35
Q

Calcitonin for OP

  • MoA
  • Effect
A

MoA: inhibit osteoclast activity (as same as intrinsic ligand)

Effect:
↑BMD by 2-3%, ↓vertebral fracture risk by 30% but not non-vertebral fracture
Short-term use for post-osteoporotic fracture pain relief

36
Q

Define atypical femoral fracture

  • Location
  • Features
  • Risk factors
A

Fracture at subtrochanteric region/ diaphysis of femur

Radiological features:

  • Predominant transverse fracture line
  • Periosteal callus formation
  • Minimal comminution

Risk factors:

  • Long-term bisphosphonate (>7 years, rare)
  • Denosumab use (rare)
37
Q

Define osteonecrosis of jaw

Risk factors of ONJ

A

Definition:
Area of exposed bone in maxillofacial region
Does not heal within 8 weeks after identification
In patient receiving or exposed to bisphosphonate
With no history of radiation therapy to craniofacial region

RF: 
Age >65 
Periodonititis 
Bisphosphonate use > 2 years 
Smoking 
DM 
Invasive bone procedures (e.g. tooth extraction)
38
Q

Anti-sclerostin Ab

  • Example
  • MoA
  • S/E
  • C/O
A

Romosozumab

MoA:
Humanized monoclonal Ab against Sclerostin
1. Sclerostin cannot bind to LRP-5 and LRP-6 receptors and cannot inhibit downstream Wnt pathway > Uninhibited activation of Wnt signaling pathway and bone formation
2. Decrease RANKL expression
3. Uninhibit osteoblast differentiation and mineralization

S/E:
Injection site reaction
Hypocalcaemia
ONJ, AFF

C/O:

  • Cardiovascular risk
  • Recent MI/ Stroke
39
Q

Management of osteoporotic fractures

A

Non-operative:

  • Manipulation and cast application for 4-6 weeks
  • Conservative wait for symptom improvement in 6 weeks

Operative:

  • Vertebral body augmentation procedures
  • Open surgery if significant neurological deficit/ kyphotic deformity/ pain

MBBS IV - Junior Clerkship WCS (131 decks)

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