Rheumatology - Osteoporosis Flashcards
Define Osteoporosis
Systemic skeletal disease characterized by:
- Low bone mass
- Microarchitectural deterioration of bone tissue
- Increase in bone fragility and susceptibility to fracture
Compare difference between Trabecular bone and cortical bone
Normal bone is composed of:
□ Trabecular bone: 20% of mass, 80% of bone turnover
□ Cortical bone: 80% of mass, 20% of bone turnover
Describe bone remodeling units and physiological processes
□ 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
Major regulation factors from Osteoblasts to control osteoclastogenesis
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
Normal physiological action of OPG and RANKL
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
Stimulatory and inhibitory factors of RANKL and OPG
Increase RANKL and decrease OPG»_space;»> Bone resorption
- Dexamathasone
- Dihydroxyvitamin D
- PTH (high concentration)
- PGE2
Decrease RANKL and increse OPG»_space;»> Block bone resorption
- 17β-estradiol
Role of sclerostin in bone metabolism
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
Action of estrogen on bone remodeling
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
Pathophysiology of age-related bone loss
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
Pathophysiology of glucocorticoid on osteoporosis
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
Recommended Ca intake
800mg/d in adults
1000mg/d for >50y (F) or >70y (M)
Normal changes in bone density over lifetime
Peak bone mass attained in age 20-40y
Gradual age-related bone loss after 40y (~1%/y)
2 clinical types of Osteoporosis
□ 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
Causes and RF of primary osteoporosis
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
Causes and RF of secondary osteoporosis
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
One major Ddx of osteoporosis
Causes
Test to differentiate
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)
Clinical presentation of Osteoporosis
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
Diagnosis of Osteoporosis
□ 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
Morbidity and mortality of OP-related hip fractures and vertebral fractures
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
Formula for BMD T-score
Outline history-taking for OP
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
Outline specific physical exams for OP
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
List panel of lab investigations for OP
Non-pharmacological treatment of OP
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
Calcium intake
1) Example of food with high Ca
2) Calcium supplements
- Examples
- S/E
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)
Vitamin D intake
- Recommended level
- Source of Vit. D
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
Weight bearing exercises
- Examples
- Benefits
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
2 classes of pharmacological agents for OP with examples
□ Antiresorptives:
oestrogen (HRT), SERM, bisphosphonate, RANKL inhibitor
□ Anabolic agent:
teriparatide/ Abloparatide (PTH), romosozumab (anti-sclerostin Ab)
Standard treatment regiment for OP
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
HRT for OP
- Indication
- MoA
- S/E
- 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
SERM
- Example
- Indication
- MoA
- Effect
- S/E
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**
Bisphosphonates **
- Examples
- MoA
- Effect
- Precautions
- S/E
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)
RANKL Antibody
- Example
- MoA
- Effect
- S/E
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
PTH for OP
- Examples
- MoA
- Effect
- S/E
- C/O
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
Calcitonin for OP
- MoA
- Effect
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
Define atypical femoral fracture
- Location
- Features
- Risk factors
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)
Define osteonecrosis of jaw
Risk factors of ONJ
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)
Anti-sclerostin Ab
- Example
- MoA
- S/E
- C/O
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
Management of osteoporotic fractures
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
