Osteoporosis Pathophysiology

What is the role of bones?

• mechanical support for movement

• protects the viscera

• determines body shape and size

• mineral homeostasis

• houses hematopoietic elements

What is the role of collagen in bone?

flexibility, energy absorbing capability

What is the role of minerals in the bone?

calcium hydroxyapatite, gives bone strength and hardness

What can imbalances in the bone components lead to?

impaired bone quality

What are the two types of bone?

cortical bone

trabecular bone

What is cortical bone?

outside shell

80% of bone

long bones

What is trabecular bone?

inside bone with trabeculae, spaces filled with red or white marrow

vertebrae and ends of long bones

remodeled more rapidly than cortical bone

True or False: bone is a dynamic tissue that is continuously resorbed, renewed, and remodeled

true

What processes are a part of the continuous, lifelong bone development and homeostasis process?

balances bone reabsorption and formation

maintains calcium and phosphate balance

osteoblasts and osteoclasts involved

When is peak bone mass acieved?

early adulthood (18-25)

True or False: the higher the peak bone mass, the more bone a person can lose before being at an increased risk of fracture

true

What factors determine peak bone mass?

genetics, nutritional intake, physical activity, adverse lifestyle practices, hormonal status, certain conditions and meds

What are osteoclasts?

specialized for bone resorption

break down bone matrix by secreting collagenase and proteases

What are osteoblasts?

specialized for bone formation

lay down bone matrix (type I collagen) by secreting proteins and proteoglycans

What are osteocytes?

mechanoreceptors; detect strain on bone and signal changes in bone remodeling

Why is bone remodeling triggered?

to repair damage to bone microarchitecture and to support calcium hemostasis

What happens in the resorptive phase of bone remodeling?

osteoclasts resorb bone

What happens in the formation phase of bone remodeling?

osteoblast form bone

What happens in the quiescent phase of bone remodeling?

bone unit inactivity

What is bone remodeling triggered by?

stress, micro-fractures, biofeedback responsive to cytokines and growth factors, and certain medical conditions and medications

What hormones is bone remodeling influenced by?

estrogen, testosterone

What is RANK ligand?

a key regulator of osteoclast differentiation, activation and function

Where is RANKL secreted from?

osteoblasts and osteocytes

What does RANK ligand bind to?

RANK receptor on osteoclast precursor cells

What is osteoprotegerin (OPG)?

protein produced by osteoblasts and osteocytes

What does OPG inhibit?

RANK ligand

What does OPG do?

prevent osteoclast activation and protects the balance of osteoblast/clast activeation

What factors favor osteoclast activity?

inflammatory cytokines

parathyroid hormone

sclerostin

glucocorticoids

What factors favor osteoblast activity?

estrogen

calcitonin

osteoprotegerin

vitamin D

When does the “scale tip” towards bone resorption?

beginning in the 4th decade (30s)

How does destruction of bone microarchitecture occur?

decreased tensile strength, decreased bone mineral density, increased fracture risk

What is osteoporosis?

low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and consequent increase in fracture risk (4-fold)

What is osteopenia?

low bone mass; 1.8x risk of fracture

True or False: osteoporosis is often a silent disease until it is complicated by low-trauma fractures

true

What are common fracture sites for osteoporotic fractures?

hip, wrist, and spine

How do osteoporotic fractures usually occur?

results from a fall from standing height or less

What are the odds for women to experience a fracture?

50% of women over the age of 50 will experience a fracture in her lifetime

What % of men usually experience a fracture?

20

What is the pathogenesis of osteoporosis?

after peak bone mass is attained, a small deficit in bone formation accrues with every remodeling cycle

What is age-related osteoporosis?

age-related bone loss is normal and somewhat predictable; time to significant bone loss depends on peak bone mass

What is post-menopausal osteoporosis?

bone loss increases following menopause; protective effects of estrogen are lost/decreased

What are the three factors that lead to peak bone mass?

genetic factors, nutrition, physical activity

What occurs in menopause that leads to osteoporosis?

decreased serum estrogen, increased cytokines (IL-1, IL-6, TNF levels), increased expression of RANK, RANKL, and increased osteoclast activity

What occurs in aging that leads to osteoporosis?

decreased replicative activity of osteoprogenitor cells, decreased synthetic activity of osteoblasts, decreased biologic activity of matrix-bound growth factors, and reduced physical activity

What differs in postmenopausal and age-related osteoporosis?

site of fracture and selection of treatment (not impacted as much)

What kind of fractures are more common in post-menopausal osteoporosis?

compression fractures of vertebrae

Which medications/therapies inhibit bone resorption/ increase osteoclast acitivty?

bisphosphonates, RANKL inhibitors, estrogen or estrogen like agents, calcitonin, sclerostin monoclonal antibodies

What medications/therapies increase bone formation/stimulate osteoblast activity?

parathyroid hormone analogs, sclerostin monoclonal antibodies

What is the drug target of bisphosphonates?

bind to hydroxyapatite and inhibit osteoclast function

What is the drug target of estrogen agonist/antagonists (EAAs) or tissue specific estrogen complex (TSEC)?

acts as estrogen agonist in bine

What is the drug target of denosumab?

prevents RANKL from activating RANK, inhibiting osteoclast formation

What is the drug target of teriparatide/abaloparatide (synthetic PTH)?

stimulates new bone formation by preferential stimulation of osteoblast activity over osteoclast activity

What is the drug target of romosozumab?

monoclonal antibody against sclerostin, prevents inhibition of bone formation and decreases bone resorption

What are risk factors for osteoporosis?

low BMD, female sex, advanced age, race/ethnicity, history of previous fragility fracture as an adult, low body weight of BMI, premature menopause (<45), current cigarette smoking, alcohol intake of 3 or more drinks/day, low calcium intake, vitamin D insufficiency or deficiency, low physical activity or immobilization, cognitive impairment, recent falls, impaired vision

What medical conditions are associated with osteoporosis?

ovarian failure, testosterone deficiency, hyperthyroidism, primary hyperparathyroidism, diabetes, nutritional disorders, malabsorptive states, vitamin D deficiency, inflammatory diseases, chronic illness (CKD, malignancies, COPD), conditions causing immobility, genetic diseases (cystic fibrosis)

What medications are associated with osteoporosis?

glucocorticoids, antiseizure therapy, aromatase inhibitors, depo shot, heparin (UF> LMWH), PPIs, TZDs, SGLT-2i (canagliflozin)