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JC WCS > Endocrine JC036: Back Pain In An Elderly Woman: Osteoporosis And Related Fractures > Flashcards

Endocrine JC036: Back Pain In An Elderly Woman: Osteoporosis And Related Fractures Flashcards

1
Q

Pathogenesis of osteoporosis

A

Skeleton undergo constant metabolism —> Bone formation vs Bone resorption at the same time

  1. If Resorbed cavity too large + Newly formed packet of bone too small
    —> ***Formation does not match resorption
    —> Increased bone loss
  2. Increased no. of remodeling units at the same time (i.e. ***Excessive remodeling: both formation + resorption too quickly / too many)
    —> Increased bone loss

Remodeling (i.e. Turnover of skeleton): Eating up old bone + Laying down new bone

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2
Q

Bone turnover

A
  1. Trabecular bone
    - 20% of skeletal mass
    - **80% of bone turnover (∵ much greater SA) —> **active metabolising bone
  2. Cortical bone
    - 80% of skeletal mass
    - 20% of bone turnover
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3
Q

Bone remodeling

A

Osteoclast (from **Haematopoietic stem cells)
—> come into remodeling unit
—> eat up old bone
—> forms a **remodeling pit
—> Osteoblast (from **Mesenchymal cells) come into remodeling pit
—> line up over cavity + make new bone
—> uncalcified new bone (i.e. **Osteoid) being mineralised (primarily Ca)
—> hard bone

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4
Q

Regulation of Osteoclast

A

記: OPG同RANK爭RANKL

Osteoclastogenesis:
- Regulated by factors secreted from Osteoblast / Stromal cells: **RANKL, **M-CSF

Osteoblast:
- produce RANKL that bind to RANK (receptor) on Osteoclast precursor
—> Osteoclast precursor differentiate into Mature Osteoclast

To prevent overactivation of Osteoclastogenesis:
- body produce ***Osteoprotegerin (OPG) “Decoy receptor”
—> bind to excessive RANKL to prevent RANKL from interacting with RANK of Osteoclast
—> preventing excessive bone resorption

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5
Q

Regulation of RANKL and OPG by systemic hormones

A

Stimulation of RANKL:
- **Dexamethasone (Exogenous steroids)
- **Calcitriol (1, 25-dihydroxycholecalciferol)
- ***PTH
- PGE2

Inhibition of RANKL:
- ***17β-Estradiol (female hormone)

剛好相反
Stimulation of OPG:
- 17β-Estradiol

Inhibition of OPG:
- Hydrocortisone (Cushing’s (Cortisol) / Exogenous steroids)
- Calcitriol (1, 25-dihydroxycholecalciferol)
- PTH
- PGE2

During menopause:
- ↓ 17β-Estradiol —> ↓ OPG
- Unopposed activation of RANKL
—> Osteoporosis

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6
Q

Role of Sclerostin in Bone metabolism

A

Osteoblast laying down osteoid
—> buried in skeleton
—> become Osteocyte
—> produce **Sclerostin (production ↑ by **Mechanical unloading + ***Estrogen deficiency)

  1. ***Stimulate RANKL expression —> Stimulate Osteoclastogenesis + Activate Osteoclast
  2. ***Inhibit Osteoblast differentiation
  3. ***Reduce mineralisation

Drug:
- Monoclonal Ab against Sclerostin —> Suppress Osteoclastic resorption + Stimulate Osteoblast + New bone formation

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7
Q

Aged-related bone loss / Menopause

A
  1. ***↓ Dietary Ca intake
  2. ***↓ Vit D intake + synthesis (↓ outdoor activity)

1+2:
—> ↓ Ca absorption
—> ↓ Plasma Ca —> ↑ Bone turnover + resorption —> Bone loss
—> ↑ ***PTH secretion
—> ↑ Bone turnover + resorption
—> Bone loss (1% per year)

  1. ***↓ Age-related osteoblastic activity + ↓ Osteoblastic progenitor cells
  2. Menopause: ***Estrogen deficiency
    —> ↑ Bone turnover + resorption
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8
Q

***Secondary osteoporosis

A
  1. Endocrine disorder
    - **Hyperthyroidism
    - **    Hyperparathyroidism
    - Hypogonadism
    - ***Cushing syndrome
  2. Nutritional deficiency
  3. Drug-induced
    - ***Glucocorticoid
    - Immunosuppressant
    - Anticonvulsant
  4. ***Immobilisation
    - e.g. Stroke
  5. Others
    - **RA
    - **    DM
    - Tumours (Myeloma etc.)
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9
Q

Osteomalacia

A

記: Low Vit D, High ALP

  • Equivalent to Rickets in children (same pathogenesis)
  • Uncommon in HK
  • Abnormal histology (distinguish from Osteoporosis): ***Unmineralised osteoid (軟骨症) (vs Osteoporosis: Normal histology / Reduced mineralisation)
    —> Deformed bone + Spontaneous fracture
  • ***Softening of bone (vs Osteoporosis: Reduction of mass of bone)

Cause:
- ***Vit D deficiency / resistant receptor
- Very low level of serum 25-OH Vit D (<10 ng/ml)

New conception:
- Osteoporosis and Osteomalacia is **a continuum of clinical presentation + **Vit D level (difficulty in defining a distinct boundary)
—> many osteoporosis patients have low level of Vit D
—> ∵ cannot take biopsy to confirm whether bone is mineralised (i.e. osteomalacia)

Bone marker:
- **ALP high (∵ it is a metabolic bone disease vs normal in osteoporosis (unless fracture))
—> ∵ ↑ in **compensatory osteoblast activity

(ALP: a marker in bone, placenta, liver
- produced by Osteoblast in bone)

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10
Q

WHO definition of Osteoporosis

A
  • Condition characterised by **Low bone mass + **Microarchitectural deterioration of bone tissue
  • with a consequent ↑ in **bone fragility + ↑ susceptibility to **fracture
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11
Q

***Clinical diagnosis of Osteoporosis

A
  1. Previous fragility fracture (often unnoticed until fracture), common sites:
    - Wrist
    - Spinal
    - Hip
  2. Back pain
    - gradual / acute ∵ spine fracture
  3. Height loss (>2 cm since age 25)
    - ∵ kyphosis
  4. Kyphosis (∵ gradual accumulation of silent morphometric fracture of spine)
    - Occiput-to-wall distance (head unable to touch the wall)
    - Gap between costal margin and iliac crest <3 finger breadths
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12
Q

Detection of Osteoporosis prior to fracture

A

BMD (Bone mineral density) measurement
- prevalence estimate of osteoporosis in a population
- results expressed as SD from mean of young adult Caucasian women (T score) —> overestimation of osteoporosis in Asian (~5%)
- evaluated in postmenopausal Caucasian women
- **1 SD reduction in BMD (T score, using DXA of spine / hip / forearm)
—> correspond to **2 fold increased risk in hip fracture (∵ higher impact than other fractures)

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13
Q

***T-score

A

Young normal adult reference of same ethnicity:
***(Patient’s BMD - Young adult mean BMD) / (1 SD of Young adult BMD)

(a large population SD can affect the T score value)

T scores allow comparison using the same diagnostic criteria for different machines

WHO definition of Osteoporosis
- Normal: T score >= -1
- **Osteopenia: -2.5 < T < -1
- **Osteoporosis: T <= -2.5
- Established osteoporosis: T <= -2.5 + Fracture

Why cutoff at -2.5
- this cutoff value identify ~30% of postmenopausal women as having osteoporosis using measurements made at spine / hip / forearm —> ~ equivalent to lifetime fracture risk at these sites
- ***threshold of treatment

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14
Q

2001 Definition of Osteoporosis

A
  • A skeletal disorder characterised by compromised bone ***strength predisposing a person to an ↑ risk of fracture
  • Bone strength: integration of **bone density (BMD) + **bone quality
    —> ↓ in no. of trabeculae, connectivity

Other determinants of bone strength apart from BMD:
1. **Microarchitecture
2. **Mass (size, geometry)
3. ***Tissue properties
- Mineralisation
- Collagen (structure, cross-links)
- Microdamage

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15
Q

Prevalence of Osteoporotic fractures in HK women

A

60-69: 1 in 6
70-79: 1 in 5
>=80: 1 in 4

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16
Q

Osteoporosis risk factors

A

Non-modifiable:
- **Gender
- **Race (Asian / Caucasian > Black)
- Heredity, Body frame
- Age

Modifiable:
- **Low estrogen
- **Low dietary Ca / Vit D
- Sedentary lifestyle
- Smoking
- Alcoholism
- ***Medications (e.g. Glucocorticoid, Tamoxifen)
(- Surgery: Removal of ovaries (from SpC O&T))

17
Q

Clinical evaluation of patient with established osteoporosis

A
  1. History taking
    - Risk factors
    - ***Evidence for secondary osteoporosis
    - Medications that can cause bone loss
    - Medication / Illness that ↑ chance to fall
    - Family history of low BMD
  2. Physical examination
    - Height, weight
    - Dental exam (loss of teeth, dentures)
    - Hyperthyroidism, Cushing’s disease
    - **Estimate degree of kyphosis, observe posture, site of tenderness
    - **    Factors that influence propensity to fall (agility, hearing, eyesight, postural sway)
    - Gait, mobility muscle strength
  3. Laboratory test
    - Serum Ca, PO4
    - 24 hour urine Ca
    - 25OH Vit D
    - **PTH, TSH (exclude secondary cause of osteoporosis)
    - **    Biochemical markers of bone turnover: ALP (exclude metabolic bone disease)
  4. Radiological evaluations / Non-invasive bone mass quantitations
    - X-ray thoracolumbar spine
    - Dual-energy X-ray Absorptiometry (DXA)
    - CT
18
Q

***Treatment options of Osteoporosis

A

Non-pharmacological
1. Adequate dietary Ca intake
- Ca absorption in stomach, ileum —> if on PPI / other condition —> gastric acid eliminated —> impair Ca absorption —> need to ↑ Ca intake if ***achlorhydria
2. Avoid Vit D deficiency
3. Weight bearing exercise

Pharmacological
Anti-resorptive (Inhibit osteoclastic activity)
1. Estrogen / HRT
2. SERM (not for non-vertebral fractures)
3. Bisphosphonate
4. Calcitonin (***not for non-vertebral fractures)
5. RANKL inhibitor (monoclonal Ab)

Anabolic agent (Stimulate new bone formation)
6. PTH
7. PTH-rP
8. Sclerostin inhibitors

19
Q
  1. Estrogen / HRT
A
  • Inhibit apoptosis of osteoblast
  • Inhibit RANKL / cytokines, Stimulate OPG to prevent activation of osteoclast
  • Promote apoptosis of osteoclast

MOA:
1. Inhibit bone resorption
- ↓ Ca excretion in urine
- ↓ cytokines production by stromal cells

  1. Additional advantage
    - **↓ CVS risk factors e.g. cholesterol, but outcome events (i.e. MI, stroke) not reduced
    - **    ↓ menopausal symptoms

Disadvantage:
- Unopposed estrogen —> **↑ Endometrial cancer (must give additional Progestogens if **uterus intact)
- Slight **↑ Breast cancer
- **↑ Venous thromboembolism

20
Q
  1. SERM (Selective Estrogen Receptor Modulator)
A

Raloxifene

  • Selective action on bone resorption (Avoid SE of Estrogen)
  • ↓ LDL cholesterol
  • Little effect on uterus, breast (∵ little effect of estrogen on uterus)
  • ***↓ ER+ Breast cancer
  • ↓ Vertebral fracture risk by 50% but ***NOT non-vertebral fracture
21
Q
  1. Bisphosphonate
A
  • ***Mainstay of treatment
  • Alendronate, Risedronate, Zolendronate, Etidronate, Ibandronate

MOA:
- Derivatives of pyrophosphate
- Inhibit osteoclast activity, specific inhibition of bone resorption
- Bound onto surface of osteoclast —> inhibit FPPS (farnesyl pyrophosphate synthase) (key enzyme in the mevalonate pathway (HMG-CoA reductase pathway): ∴ some statin can cause osteoporosis —> induce ***osteoclast apoptosis)

Effect:
- ↓ fracture risk (both vertebral + non-vertebral (including hip)) by about 50%

PK:
- **Oral / IV
- **Poor intestinal absorption
- Selective uptake at active bone sites
—> short plasma t1/2
—> no active metabolite
—> ***renal excretion

SE:
- **Erosive esophagitis / gastritis
- First phase reaction (fever, muscle / bone pain)
- Action **persist, may cause adverse effect of oversuppression of bone turnover (action in body for months / years)
—> **Adynamic bone (Frozen bone)
—> Bone too stiff (fracture during twist and turn)
—> Very rare SE: 5 years risk: **Atypical femoral fractures (AFF) + ***Osteonecrosis of jaw (ONJ)

22
Q
  1. Calcitonin
A
  • Anti-resorptive agent
  • Hormone from Thyroid C-cells

MOA:
- Inhibit osteoclast activity

PK:
- ***IM / Intranasal

Effect:
- BMD 2-3%
- ↓ vertebral fracture risk by 30% but **NOT non-vertebral fracture
- Additional benefit of **pain relief

23
Q
  1. RANKL inhibitor (Monoclonal Ab)
A

Denosumab

MOA:
- Human monoclonal Ab to RANKL
- Interfere with RANKL —> ↓ Osteoclast differentiation / activation

PK:
- ***SC injection every 6 months

Effect:
- ↓ Vertebral fracture 50% + ↓ non-vertebral fracture 30%

SE:
- Rash
- Very rare SE: **Atypical femoral fracture + **Osteonecrosis of jaw

24
Q
  1. PTH
A
  • If high level, continuous (e.g. Primary / Secondary hyperparathyroidism):
    —> Predominant effect Bone resorption
    —> Cortical > Trabecular bone
  • If **low dose, intermittent: **Anabolic action

**Teriparatide (PTH 1-34 active peptide):
- 18 months SC daily injection
- ↓ vertebral fracture 70% + ↓ non-vertebral fracture 30%, concern with osteogenic **sarcoma in rats —> ∴ limit use to ***max 2 years in human

PK:
- SC injection daily
- limit use to 2 years

25
Q
  1. PTH-rP
A

***Abaloparatide

MOA:
- Act on PTH receptor
1. Stimulate osteoblastic bone formation
2. Stimulate renal tubular Ca reabsorption
3. but it has ***minimal effect on intestinal Ca absorption

Effect:
- SC daily ↓ new vertebral fracture 80% + ↓ non-vertebral fracture 50%
- ***Limit to 2 years in human
- Not yet available in HK

PK:
- SC daily

26
Q
  1. Sclerostin inhibitors (Monoclonal Ab)
A

***Romosozumab

MOA:
- Monoclonal Ab against Sclerostin (inhibit osteoblastic bone formation through Wnt-signaling pathway)
—> ↑ bone formation + ↓ fracture

Effect:
- ***Most effective agent of all
- Romosozumab SC monthly for 1 year ↓ vertebral fracture 75% + ↓ non-vertebral fracture 25%
- available in HK

SE:
- ↑ CVS risk + **MI
—> Limit use to **1 year
—> CI in recent MI / high CVS risk

27
Q

Biochemical Bone Markers

A

Bone formation:
1. Osteocalcin
2. **ALP (only one available in HA)
- distinguish osteoporosis vs other metabolic / infiltrative bone diseases
3. **P1NP (Type 1 Pro-collagen Peptide)

Bone resorption:
1. Hydroxyproline
2. Deoxypyridinoline
3. Pyridonoline II (PYD)
4. ***C-telopeptides (CTx)
5. Urine N-Telopeptide (NTx)

***: good marker but expensive

28
Q

Usefulness of Biochemical markers

A
  • Study of normal bone metabolism
  • Diagnosis + monitoring of bone disease
  • Evaluate effectiveness of therapeutic agent, monitor ***treatment progress
  • ***Not useful as a screening agent for osteoporosis
    —> but inexpensive test e.g. ALP may help exclude other bone disease e.g. metastasis, osteomalacia
29
Q

Major secondary causes of osteoporosis

A

1 in 5 with low bone mass has secondary cause

Disease —> Investigation
1. Myeloma —> SIEP (Serum Immunoelectrophoresis)
2. **Hyperparathyroidism —> Ca, PTH
3. **Hyperthyroidism —> TSH
4. ***Cushing’s syndrome —> Cortisol, ACTH
5. Hypogonadism —> Estradiol, Testosterone

30
Q

Mechanisms for Steroid-induced Osteoporosis

A
  1. ↓ Osteoblast function, ↓ Bone formation
  2. ↑ Osteoclast resorption
  3. Causes negative Ca balance (by ↓ GI absorption, ↑ Renal excretion)
  4. Induces Hypogonadism (25-50%)
  • Progressive demineralisation
  • Trabecular > Cortical bone
  • Bone loss greatest within ***1st year (can lose up to 20% of trabecular bone)
  • Rate of loss greatest in those subjects with high bone remodeling rates

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