Osteoporosis pathophysiology: Difference between revisions
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* The role of [[calcitonin]], a hormone generated by the [[thyroid]] that increases bone deposition, is less clear and probably less significant.<ref name=Raisz/> | * The role of [[calcitonin]], a hormone generated by the [[thyroid]] that increases bone deposition, is less clear and probably less significant.<ref name=Raisz/> | ||
* The activation of osteoclasts is regulated by various molecular signals, of which the [[RANKL]] (receptor activator for[[NF-kB|nuclear factor κB]] ligand) is one of best studied. This molecule is produced by osteoblasts and other cells such as[[lymphocyte]]s, and stimulates [[RANK]] (receptor activator of nuclear factor κB). [[Osteoprotegerin]] (OPG) binds RANKL before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to [[tumor necrosis factor]] and its receptors. The role of the [[Wnt signaling pathway|''wnt'' signalling pathway]] is recognized but less well understood. | * The activation of osteoclasts is regulated by various molecular signals, of which the [[RANKL]] (receptor activator for [[NF-kB|nuclear factor κB]] ligand) is one of best studied. This molecule is produced by osteoblasts and other cells such as [[lymphocyte]]s, and stimulates [[RANK]] (receptor activator of nuclear factor κB). [[Osteoprotegerin]] (OPG) binds RANKL before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to [[tumor necrosis factor]] and its receptors. The role of the [[Wnt signaling pathway|''wnt'' signalling pathway]] is recognized but less well understood. | ||
* Local production of [[eicosanoid]]s and [[interleukin]]s is thought to participate in the regulation of bone turnover, and excess or reduced production of these mediators may underlie the development of osteoporosis.<ref name=Raisz/> | * Local production of [[eicosanoid]]s and [[interleukin]]s is thought to participate in the regulation of bone turnover, and excess or reduced production of these mediators may underlie the development of osteoporosis.<ref name=Raisz/> | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Raviteja Guddeti, M.B.B.S.[3]
Overview
The pathophysiology of osteoporosis involves an imbalance between bone resorption and bone formation. Factors that contribute to the development of osteoporosis include advanced age, female sex and hypogonadism.
Pathophysiology
In normal bone, there is constant remodeling of bone matrix; up to 10% of all bone mass may be undergoing remodeling at any point in time. The process takes place in bone multicellular units (BMUs) as first described by Frost in 1963.[1] Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which new bone is deposited by osteoblast cells. [2]
Gross Pathology
- The three main mechanisms by which osteoporosis develops are:
- An inadequate peak bone mass in which the skeleton does not develop sufficient levels of bone mass and strength during growth
- Excessive bone resorption and breakdown by osteoclasts
- Inadequate formation of new bone by osteoblasts
An interplay of these three mechanisms underlie the development of fragile bone tissue.[2]
- Hormonal factors strongly determine the rate of bone resorption. Lack of estrogen, such as during menopause, increases bone resorption, while also decreasing the deposition of new bone that normally occurs in weight bearing bones. The amount of estrogen needed to suppress this process is lower that than the amount normally needed to stimulate the uterus and breast gland. The α-form of theestrogen receptor appears to be the most important in regulating bone turnover.[2]
- In addition to estrogen,calcium metabolism plays a significant role in bone turnover, and deficiency of calcium and vitamin D leads to impaired bone deposition. The parathyroid glands react to low calcium levels by secretingparathyroid hormone (parathormone, PTH), which increases bone resorption to ensure sufficient calcium in the blood.
- The role of calcitonin, a hormone generated by the thyroid that increases bone deposition, is less clear and probably less significant.[2]
- The activation of osteoclasts is regulated by various molecular signals, of which the RANKL (receptor activator for nuclear factor κB ligand) is one of best studied. This molecule is produced by osteoblasts and other cells such as lymphocytes, and stimulates RANK (receptor activator of nuclear factor κB). Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK, and hence suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor and its receptors. The role of the wnt signalling pathway is recognized but less well understood.
- Local production of eicosanoids and interleukins is thought to participate in the regulation of bone turnover, and excess or reduced production of these mediators may underlie the development of osteoporosis.[2]
Microscopic pathology
- Trabecular bone is the sponge-like bone in the center of long bones and vertebrae. Cortical bone is the hard outer shell of bones. Trabecular bone is more active and more subject to bone turnover and to remodeling than cortical bone.
- In osteoporosis not only is the bone density decreased, but the microarchitecture of bone is disrupted.
- In osteoporosis, the weaker spicules of trabecular bone break ("microcracks"), and are replaced by weak bone. Common osteoporotic fracture sites such as the wrist, the hip, and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength, and therefore the intense remodeling causes these areas to degenerate most when the remodeling is imbalanced. This is why fractures most commonly occur at these sites.
References
- ↑ Frost HM, Thomas CC. Bone Remodeling Dynamics. Springfield, IL: 1963.
- ↑ 2.0 2.1 2.2 2.3 2.4 Raisz L (2005). "Pathogenesis of osteoporosis: concepts, conflicts, and prospects". J Clin Invest. 115 (12): 3318–25. doi:10.1172/JCI27071. PMID 16322775.