Osteoporosis pathophysiology
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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 basically involves an imbalance between bone resorption and bone formation. Major factors that contribute to the development of osteoporosis include: estrogen deficit, and aging. The main pathway, through which these factors might lead to osteoporosis is reactive oxygen species (ROS) damage to osteocytes. Decreasing the capability of autophagy in osteocytes is another important issue; which make them vulnerable to oxidative stresses.
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. Osteoporosis is a disease could involve all bones of human body; majorly defined as mass loss and also microarchitechtural deterioration in bones. The final destination in osteoporosis is fracture, causing by the predefined mechanisms.[1][2]
- The main mechanism, through which bone mass would be lost, is activation of osteoclastogenic pathway; there are two main cells involved, include: osteoblasts, and osteoclasts. Bone is reabsorbed by osteoclasts, after which new bone is deposited by osteoblasts.The main predictor of final result, rearrangement or loss of bone tissue, are osteoclasts.[2][3]
- Normal balance between osteoblasts and osteoclasts activities, resulted from tissue microenvironment (i.e., affected by macrophages and innate adaptive immunity), may lead to functional bone homeostasis; finally, forming normal bone. Whenever, the balance and its' predictor factors become disturbed, it may lead to increasing the osteoclastic activity compare with osteoblastic activity; deterioration move above construction, and bone mass loss is happened.[2]
- Manolagas in 2010, suggested that main pathogenesis of osteoporosis shift from estrogen-based theory to age-related issue; consist of reactive oxygen species (ROS) as its' main role. He mentioned that loss of estrogen and androgen in body would make bone tissue more vulnerable to ROS; make the osteocytes prone to deterioration.[4]
- When ROS become elevated in bone tissue, several factors would be increased include: T and B lymphocytes, nuclear factor kappa-B (NF-kB), and also osteoclastogenic cytokines (e.g., IL-1, IL-6, IL-7, and receptor activator of NF-kB ligand (RANKL)). On the other hand, androgen may decrease all of them.[5]
- RANKL is thought to be the most important factor need for forming osteoclasts; however, Xiong has challenged the old assumption and found that osteoblast and its progenitor cells are not the main source of RANKL, essential for osteoclast formation and remodeling in adult bones. The main role of matrix resorption belongs to the cells embedded in itself.[6]
- Autophagy is the mechanism, through which osteocytes use to run away from oxidative stresses. The capability of autophagy in cells decrease as they aged; or it better to say it is one of the reasons of aging, indeed. As the osteocytes grow, they lose their ability more; make the bone holes bigger and bone mass lower.[7]
- In addition to estrogen, calcium metabolism plays a significant role in bone turnover; deficiency of calcium and vitamin D leads to impaired bone deposition. The parathyroid glands react to low calcium levels by secreting parathyroid hormone (i.e., parathormone, PTH), which increases bone resorption; ensuring sufficient calcium in the blood.[8]
- The role of calcitonin, a hormone generated by the thyroid that increases bone deposition, is less clear and probably less significant.[3]
- Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK; hence, suppresses its ability to increase bone resorption. RANKL, RANK and OPG are closely related to tumor necrosis factor (TNF) and its receptors. The role of the wnt signalling pathway is recognized, but less well understood.
References
- ↑ Frost HM, Thomas CC. Bone Remodeling Dynamics. Springfield, IL: 1963.
- ↑ 2.0 2.1 2.2 Pagliari D, Ciro Tamburrelli F, Zirio G, Newton EE, Cianci R (2015). "The role of "bone immunological niche" for a new pathogenetic paradigm of osteoporosis". Anal Cell Pathol (Amst). 2015: 434389. doi:10.1155/2015/434389. PMC 4605147. PMID 26491648.
- ↑ 3.0 3.1 Raisz L (2005). "Pathogenesis of osteoporosis: concepts, conflicts, and prospects". J Clin Invest. 115 (12): 3318–25. doi:10.1172/JCI27071. PMID 16322775.
- ↑ Manolagas SC (2010). "From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis". Endocr. Rev. 31 (3): 266–300. doi:10.1210/er.2009-0024. PMC 3365845. PMID 20051526.
- ↑ Weitzmann MN, Pacifici R (2006). "Estrogen deficiency and bone loss: an inflammatory tale". J. Clin. Invest. 116 (5): 1186–94. doi:10.1172/JCI28550. PMC 1451218. PMID 16670759.
- ↑ Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA (2011). "Matrix-embedded cells control osteoclast formation". Nat. Med. 17 (10): 1235–41. doi:10.1038/nm.2448. PMC 3192296. PMID 21909103.
- ↑ Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, Komatsu M, Selig M, Weinstein RS, Zhao H, Jilka RL, Almeida M, Manolagas SC, O'Brien CA (2013). "Suppression of autophagy in osteocytes mimics skeletal aging". J. Biol. Chem. 288 (24): 17432–40. doi:10.1074/jbc.M112.444190. PMC 3682543. PMID 23645674.
- ↑ Fleet JC, Schoch RD (2010). "Molecular mechanisms for regulation of intestinal calcium absorption by vitamin D and other factors". Crit Rev Clin Lab Sci. 47 (4): 181–95. doi:10.3109/10408363.2010.536429. PMC 3235806. PMID 21182397.