Advanced Pathophysiology

Osteoporosis

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Speaker 2: Osteo refers to bones and porosis means pores. So osteoporosis is when there's a higher breakdown of bone in comparison to the formation of new bone, which results in porous bones, meaning a decrease in bone density to the point of potential fracture. Looking at a cross section of a bone, there's a hard external layer known as the cortical bone and a soft internal layer of spongy bone or trabecular bone that is composed of trabeculae. The trabeculae are like a framework of beams that give structural support to the spongy bone. The cortical bone in turn is made up of many functional pipe-like units called osteons, which run through the length of the bone. In the center of these osteons, there are hollow spaces called haversian canals, which contain the blood supply and innervation for the bone cells. Around the haversian canals, there are concentric lamellae, which look a bit like tree rings.

The lamellae have an organic part, which is mostly collagen and an inorganic part called hydroxylapatite, which is mostly calcium phosphate. In between neighboring lamellae, there are spaces called lacunae, which contain bone cells called osteocytes. At first glance bone may appear in nerve and unchanging, but it's actually a very dynamic tissue. In fact, spongy bone is replaced every three to four years and compact bone is replaced every 10 years in a process called bone remodeling, which has two steps, bone resorption when specialized cells called osteoclasts break down bone and bone formation, which is when another type of cells called osteoblasts form new bone. Bone remodeling as a whole is highly dependent on serum calcium levels, which in turn are kept in the normal range by a balance between parathyroid hormone or PTH, calcitonin and vitamin D. Parathyroid hormone is produced by the parathyroid glands in response to low serum calcium, and it increases bone resorption to release calcium into the bloodstream.

On the other hand, calcitonin is produced by the thyroid gland in response to high serum calcium. So it opposes the action of PTH, therefore promoting bone formation and decreasing bone resorption. Finally, vitamin D promotes calcium absorption in the gut. So it increases serum calcium, promoting bone formation and decreasing bone resorption. The balance between these regulatory factors results in a peak bone mass, usually by age 20 to 29. And this usually occurs earlier in females than in males. Factors that determine the peak bone mass or genetics. For example, people of African descent tend to have greater bone mass and nutrition, meaning adequate vitamin D intake increases bone peak mass. Finally, strength training increases peak bone mass, as well as hormones like estrogens and androgens that inhibit bone resorption.

Okay. Now when osteoclasts break down bone faster than the osteoblasts can rebuild it, it results in the lowering of the bone mass and eventually an osteoporosis. If we zoom into a cross section of an osteoporotic bone, it will show normal cells with normal mineralization, which differentiates it from osteomalacia where there's a lack of mineralization. So with osteoporosis, abnormal findings include fewer trabeculae in the spongy bone and thinning of the cortical bone, as well as the widening of the haversian canals. These bone changes increase the risk of fracture, and they're known as fragility or pathologic fractures. Some bones like the vertebrae, shoulder blades and ribs consists mainly of spongy bone. So they're in great risk of fragility fractures.

Factors that accelerate bone mass loss and increase the risk of osteoporosis are low estrogen levels like after menopause and low serum calcium. Additional factors include alcohol consumption, smoking, drugs like glucocorticoids, which decrease calcium absorption from the gut through the antagonism of vitamin D and drugs like heparin and L-thyroxine.

Another factor is physical inactivity as seen in astronauts in a zero gravity environment where they just don't use their musculoskeletal system as hard as when they're on earth. As a result, bone deposition decreases due to a lack of stress while resorption increases. There are also diseases that can cause osteoporosis like Turner syndrome, hyperprolactinemia, Klinefelter syndrome, Cushing syndrome, and diabetes mellitus. Now the two most common types of osteoporosis are postmenopausal osteoporosis and senile osteoporosis.

In postmenopausal osteoporosis, decreased estrogen levels lead to increased bone resorption. With senile osteoporosis on the other hand, it's believed that osteoblasts just gradually lose the ability to form bone while they osteoclasts keep doing their thing unabated. So bone resorption usually overtakes bone formation around the eighth decade of life. People with osteoporosis don't usually have symptoms until a fracture occurs. The most common type of fractures are vertebral fractures, also known as compression fractures. And that occurs when one or more bones in the spine weaken and shatter. Vertebral fractures cause back pain, height loss, and a hunched posture. Femoral, neck fractures and distal radius fractures can also occur and there are often associated with post-menopausal osteoporosis.

Osteoporosis is usually diagnosed with a dual energy x-ray absorptiometry or DEXA scan, which tests for bone density. The test compares an individual's bone density to that of a normal adult, which yields the result or the T score. A T score less than or equal to negative 2.5 is diagnostic of osteoporosis. Treatment for osteoporosis usually relies on bisphosphonate drugs like alendronate and risedronate. If osteoporosis is really advanced, teriparatide, a recombinant parathyroid hormone can be used.

Now, even though parathyroid hormone stimulates bone resorption, it's been found that intermittent injections with teriparatide activates osteoblasts more than osteoclasts, therefore increasing bone formation. Interestingly, a thiazide diuretic like hydrochlorothiazide can be used to treat osteoporosis as well. Hydrochlorothiazide boosts calcium retention in the kidney and directly stimulates osteoblast differentiation, therefore decreasing mineral bone loss. Finally, medications like denosumab, which is a monoclonal antibody that inhibits osteoclasts and raloxifene, which is a selective estrogen receptor modulator can be used for postmenopausal osteoporosis.

All right. As a quick recap, osteoporosis refers to decreased bone density on account of increased bone resorption compared to bone formation. In osteoporosis there's thinning of the cortical bone widening of the haversian canals and a decrease in the number of trabeculae in the spongy bone. There are two common types of osteoporosis. These are senile osteoporosis and postmenopausal osteoporosis. The most common type of fracture in osteoporosis is a vertebral compression fracture. Diagnosis is done with a dual energy x-ray absorptiometry or DEXA scan where a T score equal to or less than negative 2.5 equals osteoporosis. First line treatment relies on bisphosphonate drugs like alendronate and risedronate.

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