Osteoporosis pathophysiology

The pathophysiology of osteoporosis consists of an imbalance between bone resorption and bone formation. Major factors contributing to the development of osteoporosis include estrogen deficit and aging. The main mechanism, by which these factors might lead to osteoporosis is reactive oxygen species (ROS) induced damage to osteocytes. Decreased capability of osteocyte autophagy is another important issue; which makes them vulnerable to oxidative stresses. Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups namely, osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes.   

Osteoporosis is mainly defined as bone mass loss and micro-architectural deterioration in bones. The final outcome of osteoporosis is fracture.

• In normal bone, there is constant remodeling of bone matrix. The process takes place in bone multicellular units (BMUs).^[1][2]

• The process through which loss of bone mass occurs is the activation of osteoclastogenic pathway.

• The two main cells involved in osteoclastogenic pathway are osteoblasts and osteoclasts.
• Bone resorption is caused by osteoclasts, after which new bone is deposited by osteoblasts.
• Osteoclasts determine the final outcome of bone resorption.^[2][3]
• Normal balance between osteoblast and osteoclast activities within a bone is influenced by macrophages and innate adaptive immunity. This leads to the formation of a normal bone.
• Whenever there is a disturbance of this balance leading to increased osteoclastic activity relative to osteoblastic activity, the result is resorption, and eventual bone mass loss.^[2]

• In addition to estrogen, calcium 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 (parathormone, PTH) increasing bone resorption in a bid to ensure adequate calcium levels in the blood.^[4]
• The role of calcitonin, a hormone produced by the thyroid that increases bone deposition, is less clear and probably less significant.^[3]

• Manolagas in 2010, suggested that main pathogenesis of osteoporosis shifted from estrogen-based theory to age-related issue.
• The theory consists of reactive oxygen species (ROS) as the main factor involved in the osteoporosis.
• According to Manolagas theory, loss of estrogen and androgen in the body would make bone tissue more vulnerable to ROS, making the osteocytes prone to deterioration.^[5]
• 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.^[6]
• RANKL is thought to be the most important factor needed for formation of osteoclasts.

• Xiong proposed that osteoblast and its progenitor cells are not the main sources of RANKL essential for osteoclast formation and remodeling in adult bones.
• Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK thereby suppressing 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 signaling pathway is recognized, but not clearly understood.

Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups. Mutation in any of these genes can lead to the development of some rare diseases. These genes include:

• Osteoblast regulatory genes
• Osteoclast regulatory genes
• Bone matrix elements genes
• Hormone/receptor genes.

• Wnt pathway is a critical pathway in developing various organs, such as extremities, central nervous system (CNS), osteoblasts and chondrocytes.
• The downstream protein after Wnt/LPR5/LPR6 activation is β-cathenin.
• Some extracellular proteins like Dickkopf (Dkk) could bind to LPR5 and LPR6, decreasing and inhibiting the Wnt signaling pathway.
• OPPG is osteoporosis along with blindness due to vitreous opacity while HBM is an abnormal increase of bone mineral density (BMD).^[7][8][9]

• The major family of TGF-β plays an important role in cell differentiation before and after birth.
• The most important member of the family in bone and fibrous tissues is TGF-β1, encoded by TGF-β1 gene.
• TGF-β1 plays the main role in determining osteoporosis susceptibility.
• If TGF-β gene becomes inactivated, it may result in major inflammation and severe osteoporosis.
• Polymorphisms within the intron 4 of the TGF-β1 gene has been shown to be the main cause of severe osteoporosis.
• Mutations in TGF-β1 gene causes Camurati-Engelmann (CED) disease, which is a rare disease of hyperostosis and sclerosis of long bones metaphysis.^[10][11]

• BMPs are also members of the superfamily of TGF-β proteins.

• Various changes in different codon location among the gene sequence have been proved to cause low bone mineral density (BMD) and also osteoporosis in patients.^[12]

• Sclerostin is a protein with cysteine contained knots in its structure that share some homologous sequences with anti-BMP proteins.

• SOST gene has a major role in BMD regulations, while the patient with heterozygous mutation may be asymptomatic they usually have higher BMD.
• Decrease in BMD following SOST over expression may be due to inhibitory effects of sclerostin on Wnt signaling pathway, through binding and interacting LPR5 and LPR6 proteins.
• The mutations in the SOST gene may lead to van Buchem and Sclerosteosis bone dysplasias. These diseases are mainly severe osteosclerosis of skull, mandible, or any other trabecular bones.
• Sclerosteosis is more severe than van Buchem disease and mainly involves the upper extremity bones.^[13][14][15]

• CBFA1 is a major gene in bone formation. Laboratory animals with a mutated version or without the wild version of CBFA1 gene have failure of development of bone.

• The major role of the gene is to differentiate osteoblasts in order to construct the bones.
• Lack of the CBFA1 gene in the human body may lead to cleidocranial dysplasia (CCD), a disease in which patient has clavicular hypoplasia or complete aplasia, patent fontanels, short stature, teeth abnormalities, and other skeletal deformities.^[16]

• A mutation in cathepsin K gene may cause Pycnodysostosis syndrome that is a rare syndrome of bone dysplasia along with osteosclerosis and short stature.^[17]

• It seems that this gene has some role in the regulation of bone mineral density (BMD).
• The majority of recessive forms of osteopetrosis are caused by inactivation of TCIRG1 gene.^[18]

• It controls the acidification of the environment and facilitate the resorption of the bone.
• Inactivation mutations of the gene may lead to severe forms of osteopetrosis.^[15]

• Collagen type 1 gene is one of the most important genes in osteoporosis as collagen type 1 is the major conforming element in the bones.
• mutation in the collagen type 1 gene may cause osteogenesis imperfecta, in which the bone mineral density (BMD) is increased and the bones become fragile.^[19]

• Aging
• Anorexia nervosa
• Calcium abnormalities
• Chronic corticosteroid use
• Chronic renal failure
• Deep vein thrombosis (DVT)
• Fractures
• Gonadal dysgenesis
• Hyperparathyroidism
• Hypophosphatemic rickets
• Immobility
• Menopause
• Multiple myeloma
• Mixed connective tissue disease
• Paget’s disease of bone
• Primary hypoparathyroidism
• Short stature

• Bone with osteoporosis shows increased number of osteoclasts and decreased number of osteoblasts under the microscope.
• Autophagy is the mechanism through which osteocytes evade oxidative stress.
• The capability of autophagy in cells decreases as they age, a major factor of aging.
• As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.^[21]

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