1. PATHOPHYSIOLOGY
1.1. • Osteoporotic changes occur in diaphysis and metaphysis of bone • Greatest losses occur in areas containing abundant cancellous bone, e.g. spine & femoral neck (common sites for fractures) • Fractures occur due to spongy bone trabeculae becoming thin & sparse / compact bone becoming porous[3].
1.1.1. MENOPAUSE
1.1.1.1. Serum oestrogen
1.1.1.2. Osteoclast activity
1.1.1.3. Osteoblastic activity
1.1.1.4. Cytokines levels
1.1.1.5. - Interleukin-1, interleukin-6, tumour necrosis factor (IL-1, IL-6, TNF) bind to receptor on osteoclast precursor cells & stimulates their activation, production & proliferation - Bone decoy creates decoy receptor for cytokine. - If cytokine binds to decoy receptor, no effect on osteoclasts. - Thus, balance between cytokine amounts, receptor numbers & decoy receptor numbers determines rate of bone resorption. - Any alteration to balance = osteoporotic changes[3].
1.1.1.6. - Serum androgens may also influence bone density in women, as they are stimulants of bone formation. - Other hormones most commonly implicated in osteoporosis are: parathyroid hormone, cortisol, thyroid hormone & growth hormone[3]
1.1.1.7. - Oestrogen helps osteoclast apoptosis - Decreased levels manifest as survival of osteoclasts, loss of cancellous bone & predisposition to fractures -Testosterone deficiency may contribute to bone loss in men with senile osteoporosis [1]
1.1.2. AGE RELATED
1.1.2.1. Serum growth hormone & insulin-like growth factors
1.1.2.2. Binding of cytokine to osteoclast precursor cells
1.1.2.3. Production of decoy receptor[3]
1.1.2.4. Diameter of bone enlarges with age, causing outer supporting cortex to become thinner - Loss of trabeculae from cancellous bone - Thinning of cortex to extent that minimal stress causes fractures [1].
2. CLINICAL MANIFESTATIONS
2.1. • Most common manifestations: pain & bone deformity (depends on bones involved)
2.2. • Develops insidiously - individuals typically asymptomatic early in disease; manifestations occur only in advanced disease state[3].
2.3. • First symptom often dull, constant, aching bone pain, particularly back & chest[6].
2.4. • Fractures occur with minimal or no trauma - vertebral compression fracture or fractures of the hip, pelvis, humerus, or any other bone. Most common sites: distal radius (forearm), humerus, spine, ribs, femur, neck of femur (hip)[2] [3]
2.5. • Fatal complications of fractures: Fat or pulmonary embolism, pneumonia, haemorrhage, shock, surgical complications[3]
2.6. • Reduction in height & kyphosis (from Greek kyphos, meaning hump), resulting from wedging & collapse of vertebrae / multiple compression fractures of spine
2.7. • Systemic symptoms, e.g. weakness, weight loss (suggest osteoporosis may be caused by underlying disease)
3. DIAGNOSIS
3.1. CLINICAL EVALUATION OF RISK FACTORS
3.1.1. Includes oestrogen / androgen deficiencies, hyperthyroidism, nulliparity, chronic malnutrition, long-term lack of calcium intake, sedentary lifestyle, immobility, familial history, underlying skeletal disease[6], age, gender, height, weight, ethnicity, smoking / alcohol intake & prior fracture history.
3.1.2. Tests for serum calcium, phosphorus & alkaline phosphatase levels, protein electrophoresis[3]
3.1.3. Bone turnover tests: Serum & biochemical markers
3.1.4. Measurement of serial heights
3.1.5. Bone mineral density (BMS) test: DXA (dual X-ray absorptiometry) is gold standard technology: • Measures bone density, determines rate of bone loss, confirms diagnosis of osteoporosis, monitors effects of treatment[6] • Preferred sites hip and lumbar spine [2] • Osteoporosis detected as increased radiolucency (translucency) of bone[3]
3.1.5.1. Gives results as: • T scores: Measures by how many standard deviations patient's BMD differs from that of healthy young control • Z scores: Measures by how many standard deviations patient's BMD differs from that of age-matched control
3.1.6. To summarize: DIAGNOSTIC PROCESS USING DXA 1. Clinical risk factors for osteoporosis or fragility fracture 2. Measure BMD at spine and hip 3. Normal (T score > -1.0) Mild osteopenia (T score –1.0 to –2.0) Moderate osteopenia (T score –2.0 to –2.5) Osteoporosis (T score < -2.5)[2]
4. RISK FACTORS
4.1. ADVANCED AGE
4.1.1. After maximal bone mass is attained at around 30 years, rate of bone loss for both sexes is approximately 0.7 % per year; increases to around 1 % per year or more in postmenopausal women[1]. Age-related bone loss reflects diminishing hormone levels, decreased osteoblast activity & increased osteoclastic activity.
4.2. SEX (FEMALE)
4.2.1. Postmenopausal osteoporosis occurs due to: • Low peak bone mass • Accelerated bone loss after menopause & with ageing • A combination of both factors Males: Maintain bone mass longer than women[3].
4.3. FAMILY HISTORY
4.3.1. Nutritional status: Poor nutrition / excessive phosphate intake (interferes with phosphate / calcium balance) / deficiencies of calcium, vitamins D & C, magnesium, boron[7] / age-related decrease in intestinal absorption of calcium due to deficient activation of vitamin D / both excesses & deficiencies in protein[3] this contributes to development of osteoporosis [3].
4.4. SEDENTARY LIFESTYLE
4.4.1. Exercise (particularly weight-bearing variety) helps increase peak bone mineral density during growth periods. Lack of exercise contributes to development of osteoporosis[3].
4.5. NATIONALITY
4.5.1. Bone mass positively correlates with amount of skin pigmentation, Caucasians have the least bone mass, African American the most[1].
4.6. STATURE AND OTHER GENETIC FACTORS
4.6.1. Account for up to 80% of population variance in peak bone mass & other fracture risk determinants (e.g. bone turnover, bone size). Polymorphisms identified in several genes that contribute to pathogenesis: e.g. oestrogen / vitamin D receptors, collagen type I [2].
4.7. POSTMENOPAUSAL / HORMONAL FACTORS
4.7.1. Gonadal (oestrogen / testosterone) levels; other hormones (e.g. cytokines) & chemical messengers. Highest risk is in postmenopausal women, due to decreased oestrogen levels[3].
4.8. ENVIRONMENTAL FACTORS
4.8.1. Risk increases with/in: • Lack of exercise • Low calcium intake (particularly during growth & adolescence) • Premature & low-birth weight infants • Smoking • Corticosteroid drugs • Hypogonadal states (e.g. anorexia nervosa, 'female athlete triad': disordered, amenorrhea, osteoporosis) [3].
5. WHAT IS OSTEOPOROSIS
5.1. A metabolic bone disorder that represents an increased loss of total bone mass due to an imbalance between bone absorption & bone formation, most often related to: • Decreased oestrogen levels in postmenopausal women • The ageing process[1]
5.1.1. CHARACTERIZATION OF OSTEOPOROSIS
5.1.1.1. Reduced bone mineral density
5.1.1.2. Micro-architectural deterioration of bone tissue
5.1.1.3. An increased risk of fracture[2]
5.1.2. SUBDIVISIONS OF OSTEOPOROSIS
5.1.2.1. Post-menopausal osteoporosis: primarily caused by oestrogen deficiency.
5.1.2.2. Age-associated (senile) osteoporosis: mostly caused by calcium deficiency & ageing skeleton
5.2. HOW DOES IT OCCUR?
5.2.1. In adult skeleton, bone modelling proceeds in cycles that involve resorption of old bone by Osteoclasts. Subsequently formation of new bone by Osteoblasts[1]
5.2.1.1. BONE MODELLING
5.2.1.1.1. Ideally, replaced bone = absorbed bone. As aging occurs, bone resorption & formation are no longer perfectly coupled leading to net loss of bone mass = Osteoporosis
5.2.1.1.2. These processes activated by many hormonal stimuli, including:
5.2.1.2. BONE REMODELING
5.2.1.2.1. 3 factors influence bone remodelling: • Mechanical stress: Stimulates osteoblastic activity and formation of the bone's organic matrix.
5.2.1.2.2. • Hormones, local growth factors & cytokines: Differentiation and function of Osteoblasts & Osteoclasts regulated by chemical messengers, including colony-stimulating factors (CSF) & other cytokines[1].
5.2.1.2.3. • Extracellular calcium and phosphate levels: Bone serves as a storage site for extracellular calcium and phosphate ions. Regulated by PTH & calcitonin [5] PTH: promotes bone resorption Calcitonin: Inhibits bone resorption
6. AETIOLOGY
6.1. MAIN CAUSES OF PRIMARY OSTEOPOROSIS
6.1.1. Post-menopausal lack of oestrogen
6.1.2. Inactivity: Lack of physical stress on the bones
6.1.3. Malnutrition / deficiencies
6.1.4. Advancing age [4]
6.2. POST-MENOPAUSAL OSTEOPOROSIS
6.2.1. Primarily caused by oestrogen deficiency.
6.2.2. Post-menopause, almost no oestrogen secreted by ovaries, a deficiency leading to:
6.2.3. Osteoclastic activity in bones (bone resorption)
6.2.4. Biological activity of matrix-bound growth factors
6.2.5. Calcium & phosphate deposition [4]
6.3. AGE ASSOCIATED (SENILE) OSTEOPOROSIS
6.3.1. Primarily caused by calcium deficiency, diminishing hormones/other functional factors & ageing skeleton
6.3.2. Advancing age contributes to osteoporosis due to:
6.3.3. Growth hormone & other growth factors
6.3.4. Physical activity
6.3.5. Nutrient intake &/or absorption
6.3.6. Decreased protein anabolism function leads to lowered biological activity of matrix-bound growth factors Bone matrix cannot be deposited satisfactorily[4].
6.3.7. Osteoblast synthetic activity (bone formation)
6.3.8. Osteoclastic activity in bones (bone resorption)