Osteoporosis is a systemic bone disease, characterized by low bone density and micro-architectural deterioration of bone that lead to increased bone fragility and increased risk of fractures. It is the most common metabolic bone disease. In those aged more than 50years, 1 in 2 of women and 1 in 5 of men eventually will have osteoporotic fractures. It is a preventable but neglected and under treated disease mainly because it is clinical silent till an insufficiency fracture occurs. Only less than on third of those who sustain a fragility fracture are diagnosed and treated for osteoporosis.

WHO Definition

Bone mineral density or BMD is a measure of amount of minerals mainly Calcium and Phosphorus in a cubic centimeter of bone. It is used as an indirect indicator of osteoporosis and fracture risk. BMD varies depending on the age, sex, anatomic region and type of bone tissue. Average BMD is 1500kg/m3, for the spine region it is 1000-1200kg/m3, for cortical bone 1900kg/m3 and for forearm is 700-800kg/m3. BMD measurement at the lumbar spine and proximal femur using dual energy X-ray absorptiometry (DEXA) is the current gold standard for the diagnosis of osteoporosis. Definition of osteoporosis by the WHO is based on the BMD data in young white women.

Standard score in statistics means how many standard deviations a person’s individual measurement is above or below the mean for the population. It is derived by subtracting population mean from an individual’s measurement and dividing that value by standard deviation of the population. It is expressed in standard division units.

T score is expressed in standard deviation units from a given mean for the population. It is obtained by subtracting mean BMD of young white women at peak bone mass from BMD of an individual, and then divided by standard deviation of measurement in the young white women. It gives an idea regarding the BMD of and individual in comparison to BMD of young white women when they have peak bone mass. It is used to detect osteoporosis in post-menopausal women and men over 50 years. It should not be used in premenopausal women and men below 50 years. In premenopausal women and in men below 50 years, Z score should be used for diagnosis of osteoporosis and should not be based on densitometry criteria alone. Z score is adjusted for the age, sex and ethnicity. It gives an idea about the BMD of an individual in comparison with the mean BMD of individuals of same sex, age and ethnicity. Z scores -2 or lower is reported as below expected range for age & ethnicity and Z scores above -2 is within expected range for age and ethnicity.

As per WHO definition of osteoporosis in post-menopausal women and men over 50 years
Normal – T scores of -1 standard deviations or higher
Osteopenia – T scores between -1 and -2.5 standard deviations
Osteoporosis – T scores of -2.5 or lower standard deviations
Established osteoporosis – T scores of -2.5 or lower standard deviations with fracture

It is a good predictor of fracture risk with each standard deviation decline increasing the fracture risk one fold. But approximately half the fractures occur in the osteopenic group; hence diagnosis and treatment should not be based on BMD measurements alone. In addition DEXA is limited in availability and costly. Hence other methods such as fracture risk assessment (FRAX) tool has been developed by the WHO based on clinical risk factors.

Normal Bone Metabolism

The mechanical property of bone is determined by the composition and architecture of bone. Bone is composed of cells and extracellular matrix. Types of bone cells are osteoblasts, osteocytes and osteoclasts. Extracellular matrix is formed by mineralized and non-mineralized components. Collagen framework of bone provides tensile strength and mineralized matrix provides the compressive strength. The composition of cancellous bone and cortical bone are same, but the architecture is different.

Bone is continuously being formed and removed in a finely balanced and orderly fashion called remodeling. Remodeling occurs at discrete areas and bone resorption and formation are coupled. Bone is formed by the osteoblasts and removed by the osteoclasts, these cells are interdependent. Osteoblasts mature into osteocytes. Osteoblasts are derived from haemopoetic cells and osteoclasts are derived from mesenchymal cells.

Final common pathway of bone remodeling at the molecular level is the RANKL/RANK/OPG system. RANKL or receptor activator of nuclear factor-kappa B ligand is produced by osteoblasts which bind to RANK or receptor activator nuclear factor-kappa B cytokine in osteoclasts. OPG or osteoprotegerin is a soluble decoy receptor that binds and sequesters RANKL to inhibit the RANKL/RANK system.

Each year 25% of cancellous bone and 3% of cortical bone is recycled. Osteoclasts take few weeks to remove bone, but osteoblasts take many months to form new bone. The bone mineral density of an individual increases each year till peak mineral density is achieved in the third decade, and then it comes down each year. The peak mineral density is influenced by heredity, gender, physical activity levels and nutrition. After menopause the decrease in bone mineral density accelerates in females.

Pathophysiology of osteoporosis

Decreased bone mass is the hallmark of osteoporosis. It may be due to failure to achieve peak bone mass or loss of bone mass. Loss of bone mass may be due to increased resorption or decreased formation of bone. Aging and sex hormone level decrease are the most important causes of osteoporosis. Senile osteoporosis of aging is due to decreased bone formation and postmenopausal osteoporosis due to estrogen deficiency is due to increased bone resorption. Women lose 30-40% of their cortical bone and 50 % of their cancellous bone over their life when compared to lifetime loss of 15-20% of cortical bone and 25-30% cancellous bone in men. 60% of extracellular matrix is formed by minerals and 40% by organic molecules mainly collagen. In osteoporosis the mineral to organic ratio is normal. But in osteomalacia, mineral content is low.
Estrogen deficiency in postmenopausal women leads to increased RANKL release and decreased osteoprotegerin release by the osteoblasts; which lead to up-regulation of bone resorption due to increased osteoclasts. Estrogen sensitizes the bone to the effects of parathormone. In addition estrogen increases transforming growth factor-beta production which increases apoptosis of osteoclasts. In the absence of estrogen, T cells increase osteoclasts by osteoclast recruitment, differentiation and prolonged survival through interleukin 1(IL 1), interleukin 6 (IL6) and tumor necrosis factor alpha (TNF). T cells also inhibit osteoblast formation and increases osteoblast apoptosis.

Calcium deficiency and vitamin D deficiency leads to secondary hyperparathyroidism which leads to bone loss. Vitamin D3 and parathormone act on the osteoblasts through the RANKL/RANK pathway. Osteoclasts do not have PTH or vitamin D3 receptors.

In osteoporosis, bone strength is decreased below the fracture threshold. Insufficiency fractures or fragility fractures occur due to low energy trauma. This is mainly seen in the vertebral bodies, proximal femur and distal radius. These areas are rich in trabecular bone or cancellous bone. Trabecular bone has vertical trabeculae to support compressive forces. The ability of vertical trabeculae to withstand compressive stresses is increased by the presence of interconnected horizontal trabeculae called horizontal trabecular cross bracing system. Osteoporosis increases fracture risk due to decreased bone mass and decreased interconnectivity of trabeculae.

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Copyright @Dr Rajesh Purushothaman, Associate Professor, Government Medical College, Kozhikode, Kerala, India

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