Endocrine JC036: Back Pain In An Elderly Woman: Osteoporosis And Related Fractures Flashcards
Pathogenesis of osteoporosis
Skeleton undergo constant metabolism —> Bone formation vs Bone resorption at the same time
- If Resorbed cavity too large + Newly formed packet of bone too small
—> ***Formation does not match resorption
—> Increased bone loss - 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
Bone turnover
- Trabecular bone
- 20% of skeletal mass
- **80% of bone turnover (∵ much greater SA) —> **active metabolising bone - Cortical bone
- 80% of skeletal mass
- 20% of bone turnover
Bone remodeling
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
Regulation of Osteoclast
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
Regulation of RANKL and OPG by systemic hormones
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
Role of Sclerostin in Bone metabolism
Osteoblast laying down osteoid
—> buried in skeleton
—> become Osteocyte
—> produce **Sclerostin (production ↑ by **Mechanical unloading + ***Estrogen deficiency)
- ***Stimulate RANKL expression —> Stimulate Osteoclastogenesis + Activate Osteoclast
- ***Inhibit Osteoblast differentiation
- ***Reduce mineralisation
Drug:
- Monoclonal Ab against Sclerostin —> Suppress Osteoclastic resorption + Stimulate Osteoblast + New bone formation
Aged-related bone loss / Menopause
- ***↓ Dietary Ca intake
- ***↓ 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)
- ***↓ Age-related osteoblastic activity + ↓ Osteoblastic progenitor cells
- Menopause: ***Estrogen deficiency
—> ↑ Bone turnover + resorption
***Secondary osteoporosis
- Endocrine disorder
- **Hyperthyroidism
- **Hyperparathyroidism
- Hypogonadism
- ***Cushing syndrome - Nutritional deficiency
- Drug-induced
- ***Glucocorticoid
- Immunosuppressant
- Anticonvulsant - ***Immobilisation
- e.g. Stroke - Others
- **RA
- **DM
- Tumours (Myeloma etc.)
Osteomalacia
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)
WHO definition of Osteoporosis
- Condition characterised by **Low bone mass + **Microarchitectural deterioration of bone tissue
- with a consequent ↑ in **bone fragility + ↑ susceptibility to **fracture
***Clinical diagnosis of Osteoporosis
- Previous fragility fracture (often unnoticed until fracture), common sites:
- Wrist
- Spinal
- Hip - Back pain
- gradual / acute ∵ spine fracture - Height loss (>2 cm since age 25)
- ∵ kyphosis - 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
Detection of Osteoporosis prior to fracture
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)
***T-score
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
2001 Definition of Osteoporosis
- 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
Prevalence of Osteoporotic fractures in HK women
60-69: 1 in 6
70-79: 1 in 5
>=80: 1 in 4
Osteoporosis risk factors
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))
Clinical evaluation of patient with established osteoporosis
- 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 - 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 - 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) - Radiological evaluations / Non-invasive bone mass quantitations
- X-ray thoracolumbar spine
- Dual-energy X-ray Absorptiometry (DXA)
- CT
***Treatment options of Osteoporosis
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
- Estrogen / HRT
- 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
- 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
- SERM (Selective Estrogen Receptor Modulator)
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
- Bisphosphonate
- ***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)
- Calcitonin
- 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
- RANKL inhibitor (Monoclonal Ab)
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
- PTH
- 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
