What are the main types of bone?
- Trabecular (cancellous)
What are the different cell types in bone?
- Osteoblast (4-6%)
- Osteoclast (1-2%)
- Osteocyte (90-95%)
- Possibly old osteoblasts (?)
Describe the process of bone turnover (remodeling).
How long does it take?
- Reversal: osteoclasts start process of resorption
- Formation: ostebolasts lay down bone matrix
- Mineralization: osteoid mineralized by deposition of Ca and other minerals
Process is typically 4-8 mo duration
Describe osteoclast features/characteristics?
- CAII produces bicarb and H
- H-ATPase pump sends H out into bone to break up material
Describe osteoblast/osteoclast communication and feedback
RANKL = receptor activator of nuclear factor Kappa-B ligand
- Expressed by osteoblast
- Osteoblast stimulates monocytes to differentiate into osteoclasts
RANK = receptor activator of nuclear factor Kappa
- Expressed by osteoclast
Osteoprotogerin (OPG) can bind RANKL and stop resorption process
- OPG is a decoy receptor that prevents osteoclast activation
- Expressed by osteoblast (?)
T/F: Optimal bone strength occurs within physiologic window of bone turnover?
- Weaker if too much or too little turnover
What are high bone turnover diseases?
- Paget's disease
What is osteoporosis?
A systemic skeletal disease characterized by:
- Low bone mass and microarchitectural deterioration
- Compromised bone strength with a consequent increase in bone fragility and susceptibility to fracture
What are common fracture sites of osteoporosis?
- Spine: wedge compression deformity
- Hip: fracture typically at neck of femur
- Wrist: typically distal 1/3 of the radius
- Osteoporotic Fracture Syndrome (Dowager's hump)
- Multiple compression deformities leading to significant kyphosis
Describe the gain, maintenance, and loss of bone throughout life
- Gain of bone until age 20-30
- Slight loss in 30s-40s (but not much)
- Estrogen deficiency in post-menopausal women corresponds to steep decline in bone density
Fracture risk most strongly corresponds to ____
Fracture risk most strongly corresponds to bone mass
What are risk factors for fracture?
- Medical Hx
- 2ndary causes
Age (biggest risk)
- Low BMD
- High bone turnover
- Low body weight
- Risk of falls
- Excessive alcohol consumption
- Prior fracture
- Family history
Some secondary causes of osteoporosis
Lack of estrogens or testosterone (sex hormones)
- Rapid decline of bone mass in women within 1st 5 yrs following menopause
How is osteoporosis diagnosed? Treatment?
Diagnosed by bone density scan
- Fracture risk assessment model (FRAX) determines probability of major osteoporotic fractures
- Only cost effective to treat osteoporosis if high FRAX risk (would go ahead and treat someone who has fragile bones, not just this early decreased bone density)
Factors leading to fracture
Low bone density
- Low peak bone mass
- Increased bone loss
- Other risk factors
- Propensity to fall
- Poor bone quality
Describe the incidence of osteoporotic fractures by age in men vs. women?
Men: really picks up around age 65
Women: starts picking up around 45 yo
- Get big spike in Colles' fracture at 60 yo
T/F: there is increased remodeling after menopause?
True (measure of how bone turnover/osteoclatic activity)
What is seen here?
Increased porosity in micro-architecture of osteoporosis (right pic)
Diagnosis and evaluation of Osteoporosis
- Diagnosis obvious if fragility fractures present (e.g. falling from stool)
- BMD (bone mineral density) assessment in high risk patients; DEXA (dual x-ray absorption)
- Lab tests to rule out secondary causes
- Labs usually normal in primary osteoporosis
- Biochemical markers of bone turnover?
Describe the diagnostic categories for osteopenia and osteoporosis based upon bone density measurements
- Low bone mass (osteopenia)
- Severe (established) osteoporosis
- BMD within 1 SD of young adult female reference mean
Low bone mass (osteopenia)
- BMD 1-2.5 SDs below reference mean
- BMD 2.5+ SDs below reference mean
Severe (established) osteoporosis
- BMD > 2.5 SDs below reference mean in the presence of 1+ fragility fractures
What is osteopenia?
Low bone mass (less severe than osteoporosis)
What is T score? Z score?
- Compare pt's BMD to young adult of same gender (comparing pt with optimal)
- (Recall 20-30 yo adult has max bone mass; minimum fracture risk)
- Compare pt's BMD with age and gender matched average person
- Low Z score means losing more bone than your peers
Treatment for osteoporosis?
- Vitamin D
Reduction of non-vertebral fractures with Ca and Vitamin D by almost 50%
What are anti-resorptive treatments for osteoporosis?
Bisphosphonates (first line!)*
- Alendronate (oral)
- Ibandronate (1/mo)
- Zoledronic acid (15 min infusion once/yr)
- Selective estrogen receptor modulators
- Estrogen agonist effect on the bone (and antagonist effect on the breast!)
- Not as potent as bisphosphonates
HRT: (Estrogen) Hormone Replacement Therapy
- Breast cancer risk; no longer used as treatment option for osteoporosis
- Not very potent
- Good effect on pain (acute fracture scenario)
- Human monoclonal Ab against the RANKL (works like OPG)
What is the mechanism of bisphosphonates?
- Blocks GTPase binding; GTPase free from cell membrane
- Prevents ruffled border formation of osteoclast (flattened border)
What are concerns with bisphosphonates?
- Osteonecrosis of jaw
- Atypical femoral fractures
What are anabolic agents that may be used to treat osteoporosis?
What is the effect of Teriparatide?
- How best combined with bisphosphonates?
- Duration of treatment
- Reduces vertebral and non-vertebral fracture risk
- Can NOT be used with bisphosphonates
- Best data for Teriparatide for vertical issues (poor lumbar spine density or history of lumbar fracture)
- Teriparatide can only be used ~ 2 yrs (once done, THEN start bisphosphonates)
Do corticosteroids increase or decrease bone mass?
Corticosteroids (glucocorticoids) decrease bone mass
- Induce osteoporosis
Describe glucocorticoid induced osteoporosis
- Rate of bone loss
- Route of administration
- Bone loss rapid during the early months of therapy
- Any route of administration: risk
- Alternate day delivery: does not decrease risk
- Pathophysiology: Multiple mechanisms
- Bisphosphonates for treatment
Describe Paget's disease
- Cells involved
- Extent (systemic vs. local)
- Lab markers
- Osteoclasts are extremely hyperactive
- Localized bone disorder (unlike osteoporosis)
- Overactive osteoclastic bone resorption increase in osteoblastic new bone formation
- Usually asymptomatic
- Alkaline phosphatase (bone formation marker) is increased
- Urinary and serum N-telopeptide (markers of bone resorption) are increased
What is seen here?
What is treatment for Paget's disease?
What is a disease of low bone turnover?
- Osteopetrosis: osteoclasts do not "eat"
- Osteoclast/blast function
- Elevated levels of what
- Loss of osteoclastic bone resorption; normal osteoblastic bone formation
- Osteoclast-derived tartrate-resistant acid phosphatase (TRAP) is elevated
- Generalized symmetric increase in bone mass with thickening of both cortical and trabecular bone
What is seen here?
- Marble bone disease
- Albers-Schonberg disease