Background:
Osteoporosis is the most common metabolic bone disease in humans and is characterized by low bone mineral density. Low bone mineral density, or BMD, results in impaired structural integrity of the bone and decreased bone strength, which places the person at risk for fractures. The cortical bone becomes more porous and thinner, making the bone weaker and more prone to fractures. Osteoporosis often progresses silently and is noticed when a fragility fractures occur (McCance & Huether, 2019).
There are 2 types of Osteoporosis:
- Primary or idiopathic, which is the most common.
- Secondary that is caused by other conditions such as endocrine diseases, medications, and other substances.
Endocrine diseases such as hormone imbalances, diabetes, hyperparathyroidism, hyperthyroidism, rheumatoid disease, HIV, malignancies, malabsorption syndromes, or liver and kidney diseases can contribute to secondary osteoporosis. Heparin, corticosteroids, phenytoin, barbiturates, lithium, tobacco, and ethanol are medications and substances are additional risk factors (McCance & Huether, 2019).
Risk factors:
- Genetics/ family history
- Anthropometrics
- Hormonal/Metabolic factors
- Dietary factors
- Lifestyle
- Concurrent diagnosis
- Illness/Trauma
- Liver Disease
- Drugs (McCance & Huether, 2019)
Several Sub-Types of Osteoporosis:
- Postmenopausal osteoporosis
- Regional osteoporosis
- Glucocorticoid induced osteoporosis
- Age-related bone loss (McCance & Huether, 2019)
Stages of Osteoporosis:
Osteoporosis is defined based on bone density:
- Normal bone mass is greater than 833 mg/cm2
- Osteopenia ranges from 833 to 648 mg/cm2
- Osteoporosis is less than 648 mg/cm2 (McCance & Huether, 2019)
Normal physiology:
Normal bone remodeling process occurs when osteoblasts and osteoclasts are working together to maintain balance between bone loss and formation (Hong Kong Baptist University, 2017). Estrogen plays an important role in the bone remodeling process. Osteoprotegerin (OPG) secretion and receptor activator of nuclear factor kB ligand (RANKL) down-regulation are stimulated by estrogen. A balance between OPG, RANKL, and the RANK receptor is necessary for normal bone homeostasis decreasing the likelihood of pathologic diseases such as osteoporosis, immune-mediate bone diseases, or malignant bone disorders (McCance & Huether, 2019).
Pathophysiology:
Osteoporosis develops when the remodeling cycle, the process of bone reabsorption and formation is disrupted, leading to an imbalance in the coupling process.
Reactive oxygen species (ROS) are normal byproducts of aerobic metabolism and serve as signaling molecules for many cell types, such as osteocytes, osteoblasts, and osteoclasts. ROS can cause cell damage with excess accumulation, which can result in oxidative stress (OS) or loss of bone mass and strength (McCance & Huether, 2019).
Post-menopausal osteoporosis is characterized by increased bone resorption relative to the rate of formation, leading to sustained bone loss resulting from estrogen deficiency in men and women (McCance & Huether, 2019).
Bone remodeling is the process by which old bone is replaced by new bone. The normal bone remodeling process consists of five phases: the resting, activation, resorption, reversal, and formation phases.
- In the activation phase of remodeling, osteoclasts are recruited to the surface of the bone.
- In the resorption phase, osteoclasts generate an acidic micro-environment between the cell and the surface of the bone, dissolving or resorbing the mineral content of the bone.
- In the reversal phase, osteoclasts undergo apoptosis and osteoblasts are recruited to the bone surface.
- In the formation phase, osteoblasts then deposit collagen; this is mineralized to form new bone (McCance & Huether, 2019).
In menopause, estrogen deficiency impairs the normal cycle by increasing osteoclastic resorption activity without a corresponding increase in osteoblastic activity. The amount of bone resorbed is greater than the amount deposited, which results in loss of bone. This process was originally described as ‘uncoupling’. Cellular changes that occur in estrogen deficiency are:
- Increased production of Tumor necrosis factor (TNFα)
- Stromal/osteoblastic cells become more sensitive to IL-1 (Interleukin 1)
- IL-1 and TNF stimulate stromal cells/pre-osteoblasts to release several cytokines- IL-6, macrophage colony stimulating factor (M-CSF), IL-11, granulocyte macrophage colony-stimulating factor (GM-CSF), transforming growth factor (TGF).
- RANK ligand (receptor activator of nuclear factor B ligand), which is produced from osteoblasts binds to its receptor RANK on osteoclasts.
- RANKL has a natural antagonist osteoprotegerin (OPG) a soluble receptor stimulated by estrogen is secreted by stromal osteoblast cells.
These factors increase bone resorption by increasing the pool size of pre-osteoclasts in bone marrow and are down regulated by estrogen. The important action of estrogen is to increase OPG secretion and decrease M-CSF and RANK (Tella & Gallagher, 2014).
Effects of Estrogen (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187361/figure/F1/)
Estrogen decreases osteoclastogenesis and increases osteoclast apoptosis. Estrogen reduces osteoclastogenesis by suppressing IL-1 and TNF and increasing the sensitivity of stromal cells/pre-osteoblasts to IL-1, thus suppressing MCSF, RANKL, and perhaps most notably, IL-6. Estrogen also stimulates the production of OPG, the potent inhibitor of osteoclastogenesis; reduces the responsiveness of osteoclast precursors to RANKL; and promotes osteoclastic apoptosis, thereby reducing osteoclast lifespan (Tella & Gallagher, 2014).