Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone
microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporotic bones are more at risk of fracture.
Osteoporosis represents a major and increasing public health problem with the aging of population :
the incidence of osteoporotic fractures is higher in whites or Asiatic ethnicity than in blacks , and higher in women than in men .
- Idiopathic : children and adolescents with normal function of gonads
- Type I : postmenopausal women with excess loss of cancellous bone and relative sparing of cortical bone .
- Type II : men and women > 75 years with loss of both cortical and cancellous bone .
Osteoporosis is called "the silent disease" beacuse it's asymptomatic until the onset of
fractures ; its clinical manifestation are due to wrist , hip , humerus and tibia fractures but vertebral ones are
the most important . They cause an intense pain , limitation of motion , deformity with loss of
stature : in the thoracic spine this is associated with a progressive increase in the degree of
kyphosis and in the lumbar spine this is associated with progressive flattening of the lordotic
curve . The course of disease could not have been foreseen .
- Clinic : loss of stature , local pain ( non specific )
- bone-metabolism markes
- genetic test
PATIENT RISK FACTORS
- Familial prevalence
- Cigarette use
- Low physical activity
- Excessive proteinic diet ( increase of acids)
- Heparin-use as anti-coagulant
- Parathyroid Hormone = stimulates bone resorption indirectly because the osteoclasts does not have PTH receptos ; it can stimulate and inhibit bone collagen or matrix syntesis .
- Calcitonin = inhibits bone resorption but is does not modify bone formation .
- Insulin = causes a marked stimulation of bone matrix syntesis and cartilage formation ; necessary for bone mineralization .
- Growth Hormone
- Vitamin D = similar functions to PTH ; direct effects on the osteoblasts enhancing the synthesis of osteocalcin ( bone Gla protein ) .
- Vitamin K = enhaces the synthesis of osteocalcin ; inhibits trasformation cells in osteoclasts and promotes osteoblasts differentiation .
- Glucocorticoids = their long-term effect on bone collagen synthesis is inhibitory probably due to a marked decrease is preosteoblastis cell replication .
- Sex steroids = estrogens decrease bone resorption ; decrease the synthesis of IL-6 which is present in the bone microenvironment and plays a role in the stimulation of bone resorption .
- Thyroid Hormones = in contrast to their important role on cartilage and linear growth , they stimulate bone resorption .
- Local Factors
- Insulin-Like Growth Factors = enhance bone collagen and matrix synthesis ; stimulate the replication of cells of the osteoblast lineage ; they are regulated by PTH , Prostaglandin E2 and inhibit by Glucorticoids .
- TGF-beta = beta 1 , 2 , 3 stimulate the replication of precursor cell of the osteoblast lineage and it also has a direct stimulatory effect on bone collagen synthesis ; decrease bone resorption .
- FGF = stimulate bone cell replication capable of synthesizing bone collagen ; they are important in the process of healing and bone repair .
- PDGF = stimulates bone resorption and bone cell replication .
- Cytokines = IL-1 , IL-6 , macrophages , TNF , stimulate bone resorption either directly or by enhancing the recruitment of osteoclasts .
Scheme showing possible interactions between estrogen, statins, EFAs, NO, HMG-CoA reductase activity, BMPs, and osteoporosis. - indicates inhibition of activity.
Nitric Oxide as the Mediator of the Antiosteoporotic Actions of Estrogen, Statins, and Essential Fatty Acids 2002
Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. 2009
Papers microRNA ostoporosis
Polymorphisms in predicted miRNA binding sites and osteoporosis. 2010
J Bone Miner Res. 2010 Jul 16.
Lei SF, Papasian CJ, Deng HW.
- MicroRNAs (miRNAs) regulate posttranscriptional gene expression usually by binding to 3'-untranslated regions (3'-UTRs) of target message RNAs (mRNAs). Hence, genetic polymorphisms on 3'-UTRs of mRNAs may alter the binding of miRNAs to target 3'-UTRs, thereby altering translational regulation of target mRNAs and/or degradation of mRNAs, leading to differential protein expression of target genes. Based on a database that catalogues predicted polymorphisms in miRNA target sites (PolymiRTS), we selected 568 polymorphisms within 3'-UTRs of target mRNAs, and performed association analyses between these selected PolymiRTSs and osteoporosis in 997 Caucasians that were genotyped by Affymetrix Human Mapping 500K arrays. Initial discovery (in the 997 subjects) and replication (in 1,728 Caucasian subjects) association analyses identified three PolymiRTSs (rs6854081, rs1048201, and rs7683093) in the FGF2 (Fibroblast Growth Factor 2) gene that were significantly associated with femoral neck bone mineral density (BMD). These three PolymiRTSs serve as potential binding sites for 9 miRNAs (e.g., miR-146a, miR-146b). Further gene expression analyses demonstrated that the FGF2 gene was differentially expressed between subjects with high vs. low BMD in three independent sample sets. Our initial and replicate association studies and subsequent gene expression analyses support the conclusion that these three polymorphisms of the FGF2 gene may contribute to susceptibility to osteoporosis, most likely through their effects on altered binding affinity for specific miRNAs. © 2010 American Society for Bone and Mineral Research.
OSTEOPOROSIS AND CARDIOVASCULAR DISEASES
CALCIFICATION IS A DEFENCE PROCESS IN CHRONIC INFLAMMATION :
The inflammatory cytokines of the immune system , specifically IL-1 and IL-6 , can cause calcium to be pulled from bone . When we are under stress , our stress hormone cortisol is secreted . Cortisol release signals the T-helper-2 cells to secrete IL-1 and IL-6 . As well , when cortisol levels go up , our anti-aging and immune regulating hormone DHEA decreases .
Osteoporosis can also be influenced by an overactive immune system . When macrophages eat invaders in the course of their daily surveillance , they release nitric oxide and IL-1 . Nitric oxide in small amounts protects against bone loss.But when the immune system is fighting infection (immune dysfunction) , macrophages release nitric oxide in large amounts , promoting the breackdown of bone . In this case there is an increase of others cytokines :
- TNF-alfa : enhances bone resorption via stimulating osteoclasts development and activity as well as bone formation .
- C-reactive protein
Among the factors released by osteoblast (IL-6,TNF-alfa,..) , M-CSF ( "Macrophage colony stimulating factors" ) has an important role : the CSF binds to its osteoclast receptor C-fms which associates with and activates phosphatidylinositol-3-kinases ( PI-3-KS ), important in osteoclast differentation and attachment . Na/P(i) cotransporters in the osteoclast plasma membrane provide P(i) for ATP synthesis and that the osteoclast may utilize part of the P(i) released from bone resorption for this purpose .
COMMON RISK FACTORS WITH CARDIOVASCULAR DISEASES : Age , Estrogen deficiency , Vit.D , Chronic Inflammation and oxidative stress .
THE MACROPHAGE IS A KEY PLAYER IN BOTH TISSUES : BIOLOGICAL LINKAGES
COMMON THERAPY : statins , nitrogen-containg bisphosfonates, Denosumab
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