Osteoporotic Of The Subchondral Bone In Early Stage Of Osteoarthritis On Knee Joint

Mochammad Rifki Maulana, S.ked Bekasi City General Hospital, Faculty Of Medicine Trisakti University Rifkimaulana91@yahoo.com

Abstract Osteoarthritis (OA) is a degenerative disease whose incidence increases with age. Despite much research into this condition, the etiology of OA is unknown, but it is generally agreed to be multifactorial. Studies have reported that subchondral bone changes preceded cartilage lessions and could be responsible for the evolution of tissue lession. There is now substantial evidence in human and experimental animal OA that there is a change in the metabolism of the bony skeleton, and in particular at the subchondral area. Because these changes in bone density and metabolism precede cartilage fibrillation, it is likely that bone metabolism in general, and subchondral bone density in particular, are involved in the pathogenesis of osteoarthritis. Piezoelectrical current, and mechanotransduction involved in this process, so it makes the subchondral bone to be hypomineralized. Keywords : osteoarthritis, piezoelectrical current, mechanotransduction, hypomineralized of the subchondral bone. I. Introduction Osteoarthritis (OA) is the most common joint disease in the world with an age-related increase in both incidence and prevalence. 1 In the US, OA is the single largest reason for disability among those over 18. This has more than double the number of people disabled by cardiac disease. 2 OA affects predominantly older adults, and by the year of 2020 the population 65 and over in developed country is projected to be increase by 71%.3 OA represents a major cause of disability, particularly among the aging population; indeed, OA is the most common form of joint disease. 4 Despite much research into this condition, the etiology of OA is unknown, but it is generally agreed to be multifactorial. OA is invariably described as a loss of articular cartilage, with joint space narrowing accompanied by secondary bone changes. Consequently, the main thrust of research into OA has focused on the cartilage, the loss of which is believed by many to represent the initial event responsible for joint destruction, pain, and disability. Therefore, biochemical analysis of the underlying bone tissue has received scant attention despite the well known changes that occur, such as the formation of osteophytes and subchondral cysts, which are striking characteristics of the disease.5 Further, early histological analyses6 provided some indication of unusual bone remodeling in OA, in particular that matrix deposition exceeded mineralization. Changes within the subchondral bone have been reported by Radin and his colleagues7 who postulated that a thickening of the

underlying bone was a consequence of healing microfractures, which in turn resulted in disease development, but direct biochemical evidence was not available. 8 the increased bone uptake of technetium-labeled bisphosphonate correlating with disease severity in terms of joint space narrowing. Although of value in describing tissue changes in OA, these scintigraphic analyses extend only to the inorganic phase of bone; what peculiarities there might be to the collagenous scaffold into which the mineral is impregnated remain unknown. The major component of joint tissues is bone, the metabolism and composition of which are fundamental to the biomechanical competence and overall health of the joint. Fibrous type I collagen is the major structural component of bone, accounting for 90% of the organic matrix. The function of the small amount of type V collagen (3%) is uncertain, but based on the retention of its aminoterminal propeptide, it may be involved in regulation of type I collagen fiber size. 9 In addition to its important supportive role, collagen provides a means of cellular communication, notably to the osteoblasts and osteocytes, a main function of which is believed to be the transduction of mechanical stimuli, which has important consequences for the regulation of bone mass. 10 II. Discussion

A. Hypomineralized matrix of subchondral bone Radin et al, 7 suggested that changes in the bone might be a cause for osteoarthritis. Since that time, there has been substantial evidence provided from preclinical and clinical studies that changes in the methabolism of the bony skeleton, and in particular at the subchondral bone area, are an integral part of the disease process. Recent advances of this field of research have clearly shown the global involvement in osteoarthritis of all of major tissue of the joints : namely, cartilage, synovial membrane, and subchondral bone. In addition of cartilage loss, which is mainly related to matrix degradation, the participation and the role of synovial inflamation in the progression of the structural changes of this disease are now widely accepted. 11 Studies have reported that subchondral bone changes preceded cartilage lessions and could be responsible for the evolution of tissue lession. Articular cartilage is bordered at its base by the subchondral bone plate, which is a very thin cortical bone structure. The trabecular subchondral bone is situated under this thin end plate zone. It contains fatty bone marrow and trabecular bone. The thickness of the subchondral bone end

plate varies also as the vascular supply with age, body weight, location, functions and genetics. However, it is generally much thicker in the central weight bearing area. In normal joint articular tissue, the subchondral bone is composed of large trabecules with small trabecular space. Contrasting, in early osteoarthritis there is a thinning of the subchondral bone plate, excessive resorption with reduction of trabeculae thickness, and increased of the trabecular space.

forces to provide articular cartilage protection. The mechanism responsible for osteophyte formation in OA have not yet been known. However, in the murine knee joint it was shown that TGF- and interleukin-1 might be implicated.14 It is also of note that TGF- levels are elevated in osteoarthritic subchondral bone compared to normal and that in vitro osteoarthritic osteoblas release more TGF-1 than normal osteoblast. B. Piezoelectrical effects Piezoelectric is the electrical current that occurs due to the load or pressure on the bones, which according by law wolff, if the bone is given pressure, there will be a piezoelectric currents will increase osteoblast activity. Bone is a connective tissue made up of 70% calcium phosphate mineral materials which are often called hydroxyapatite (HA) and 30% organic material that is 90% in the form of collagen type 1, both materials would generate an electric potential that induce and control the growth and bone regeneration. Hydroxyapatite positive charge applies as semi-conductors in the bone. collagen in bone acts as a semiconductor negative charge, which is a piezoelectric material. when a piezoelectric material is placed under mechanical stress, a shift in the center of positive and negative charges in the material takes place, which then produces an electric current. Subchondral bone in some parts there are not exposed to mechanical stress, it will impose harmony on the surface of the joint, so that the underlying subchondral bone piezoelectric not produce enough, so that the activity of osteoclasts become more active than osteoblasts. C. Mechanotransduction on bone remodelling

Density fractionation (12) have demostrated that subchondral cortical bone and trabecular bone of osteoarthritic patient are less mineralized than age-matched or younger control subjects. The bone density in osteoarthritis would actually decrease, not increase. The possible explanation of this decrease could be that bone remodelling is increased in osteoarthritis such that bone does not have the oportunity to fully mineralize. Moreover, the trabecular bone underlying the subchondral bone plate shows decreased trabecular number and increased intertrabecular spacing. When considering the contribution of bone in OA, we cannot underestimate the role of the subchondral cortical bone plate and the subchondral trabecular bone as the key players of the patophysiology of the disease. To test the hypothesis that increased increased subchondral bone turnover is a determinant of the progression of OA, Bettica et al. (13) conducted a study in which the level of urinary N-terminal type 1 collagen telopeptides (NTX) and C-terminal type 1 collagen telopeptides (CTX-1) which are elevated in bone resorption- were measured at three different time points in patients with knee OA. The result of this study demostrate that over time bone resorption is increased in patients with progressive knee OA, and it is not in those with non progressive OA. The increased bone resorption biomarkers seen in patients with progressive knee OA had a similar profile as the one observed in patients with osteoporosis. The exact roles of subchondral bone remodelling and osteophyte formation, which are well recognized manifestations of OA, remain largely unknown. It is suggested that osteophyte formation may play a compensatory role in the redistribution of biomechanical

Bone remodeling is the turn of old bone tissue with the new one. This condition mostly occurs in the adult skeleton to maintain bone mass. This process includes the formation and bone resorption simultaneously. Remodelling is a dynamic process including bone replacement and recharging. This process occurs continuously to maintain bone mass as well as the integrity and function of the skeleton. The process is complex and controlled by the central nervous system through hormones and by mechanical stresses. This process relies on the mechanism of osteoblasts, osteocytes and osteoclasts. Mechanotransduction, or the conversion of biophysical forces into cellular responses, is an important mechanism for a wide range of physiological functions that allow organisms to live face mechanical environment. In this case the bone mechanotransduction include 4 things: 1. Mechanocoupling, the transduction of mechanical forces on bone to local mechanical signal received by the sensor cells. 2. Biochemical coupling, the local mechanical signal transduction into biochemical signals and gene expression or activation of a protein. 3. Transmission of signals, from sensor to effector cells. Ie, cells that will form or remove bone, and 4. The effector cell response, the appropriate tissue-level response. 1. Mechanocoupling

When loads are applied to the bone, the tissue deforms causing local strains. During mechanical usage, osteocytes are stretched to the same amount as the bone tissue. Also, the pressure gradients in bone tissue caused by bending forces create extracellular fluid flow across the

osteocytes. The issue is forther complicated by the fact that strains in bone tissue cause piezoelectrical effects and stress generated fluid flow cayses electric fields in bone, clled streaming potentials. Each of these tissue-level effects of mechanical loading plays some role in mechanotransduction, as bone cells in culture have been shown to respond to mechanical strain, fluid flow, and electric fields. Each of these signals, mechanical and electrical may play a role in mechanotransduction. (15) 2. Biomechanical coupling There is now evidence of several mechanochemical transduction pathways within bone cell. One involves a mechanotransducer that resides in the cell membrane. This transducer is G protein-linked and also interacts with a stretch-activated cation channel, the inositol triphospate messenger pathway, and constituitive isoforms of cyclooxygenase (COX) and nitric oxide synthase (NOS). The second pathway involves a direct linkage between the transmembrane integrins, the actin cytoskeleton, and the nuclear transcription machinery. The inducction of COX is dependent upon this pathway. In bone cell culture mechanical loading or fluid shear stress increases intracelluler calcium levels and production of prostaglandins and nitric oxide within minutes. This stimulation of prostaglandins can be blocked by 70% to 80% by G protein inhibitors GDPS and pertussis toxins, indicating that a G protein associated mechanotransducer attached to the cell membrane may be responsible for prostaglandin production. Constitutive isoforms of COX and NOS are typically bound to the cell membrane, and thus would be available for mechanochemical trasnduction involving G proteins. The movement of extracelluler calcium ions across the cell membrane also appears to play a role in mechanitransduction, as does calcium release from intracellular stores. One way in which extracellular calcium can pass across the cell membrane is through a stretchactivated cation channel. Increase in intracellular calcium occurs within minutes in osteoblasts exposed to fluid shear stresses, and this response is partially blocked by GdCl3, which blocks the stress activated calcium channels in the cell membrane. Compression of cartilage results in tissue changes including matrix and cell deformation, hydrostatic pressure, fluid flow, content of matrix, osmotic pressure, ion concentration and bone density. Chondrocytes can recognize changes and activation of signaling pschochemical cascade to stimulation of receptors that initiate cell mechanotransduction in chondrocytes. G proteins associated with cell surface receptors. Coupled G proteins play an important role in the development of cartilage and is associated with several different intracellular signaling cascade. G proteins interact with adenyl cyclase which catalyzes the synthesis of cAMP second messenger signaling and activation of protein kinase A. Cyclic AMP is derived from ATP which activates protein kinase A and a mechanical stimulus in response chondrocytes. 3. Transmission of signals

sensors of mechanical stimuli, however, because it osteocytes cannot form or crushing bone, they should send a signal to effector cells (osteoblasts and osteoclasts) before changes in bone structure can begin. The most likely play a role in communication between cells and effector cell sensor here is prostaglandins and nitric oxide (NO). (15) 4. Effector response

Bone formation in response to mechanical loads involving non-proliferating and proliferating cell osteoprogrenitor Populations. Mechanical load induce early bone formation response in 48 hours involving osteoblasts from bone or preosteoblast cell layer. Osteoprogrenitor cell proliferation also in excitatory by mechanical load, the cells differentiate into osteoblasts in 72-96 hours after a mechanical stimulus. The possibility of mechanical signal sensor including osteocytes and bone lining cells, and the number of cell types decreased with increasing age. (15) D. microscopic bone structure Three types of cells involved in bone remodeling process is osteocytes, osteoblasts, and osteoclasts. Osteocytes are the group most cells in the bone tissue. They are located in the cytoplasm lakuna and have some that are in a lot of canaliculi that is used for nutrition and bleeding. Osteocytes in touch with each other by using a gap junction. Therefore, the information from the sensor (osteocytes) is transmitted to the osteoblasts and osteoclasts. Osteoblasts contributes to bone formation, collagen synthesis and control of calcification. They receive signals from osteocytes, and then carry out their duties. Osteoblasts placed on the internal surface of the bone they create a consistent barrier, which limits access to the next cell, the osteoclast. Osteoclasts contribute to bone destruction by bone demineralization. E. patophysiology of OA Cartilage is a unique tissue with viscoelastic and compressive properties which are imparted by its extracellular matrix, composed predominantly of type II collagen and proteoglycans.

Osteocytes and bone lining cells are composed of more than 95% of all cells from osteoblast attached to the bone. These cells are interconnected by gap junctions, that responsive to local mechanical stimuli. For this reason, it is commonly assumed that the cells (osteocytes) that act as

Under normal conditions, this matrix is subjected to a dynamic remodeling process in which low levels of degradative and synthetic enzyme activities are balanced, such that the volume of cartilage is maintained. In OA cartilage, however, matrix degrading enzymes are overexpressed, shifting this balance in favor of net

degradation, with resultant loss of collagen and proteoglycans from the matrix.

cleavage in order to become activated. Once activated, MMPs become susceptible to the plasma-derived MMP inhibitor, alpha-2-macroglobulin, and to tissue inhibitors of MMPs (TIMPs) that are also secreted by synovial cells and chondrocytes. In OA, synthesis of MMPs is greatly enhanced and the available inhibitors are overwhelmed, resulting in net degradation. Interestingly, stromelysin can serve as an activator for its own proenzyme, as well as for procollagenase and prostromelysin, thus creating a positive feedback loop of proMMP activation in cartilage.

One candidate for inducing metalloprotease synthesis is interleukin-1 (IL-1). IL-1 is a potent pro-inflammatory cytokine that, in vitro, is capable of inducing chondrocytes and synovial cells to synthesize MMPs. Presumably in response to this loss, chondrocytes initially proliferate and synthesize enhanced amounts of proteoglycan and collagen molecules. As the disease progresses, however, reparative attempts are outmatched by progressive cartilage degradation. Fibrillation, erosion and cracking initially appear in the superficial layer of cartilage and progress over time to deeper layers, resulting eventually in large clinically observable erosions. OA, in simplistic terms, therefore, can be thought of as a process of progressive cartilage matrix degradation to which an ineffectual attempt at repair is made.

A critical question is whether OA is truly a disease or a natural consequence of aging. Several differences between aging cartilage and OA cartilage have been described, suggesting the former. For example, although denatured type II collagen is found in both normal aging and OA cartilage, it is more predominant in OA. In addition, OA and normal aging cartilage differ in the amount of water content and the in ratio of chondroitin-sulfate to keratin sulfate constituents. The expression of a chondroitin-sulfate epitope (epitope 846) in OA cartilage, that is otherwise only present in fetal and neonatal cartilage, provides further evidence that OA is a distinct pathologic process. A final but important distinction is that degradative enzyme activity is increased in OA, but not in normal aging cartilage.

The primary enzymes responsible for the degradation of cartilage are the matrix metalloproteinases (MMPs).

Furthermore, IL-1 suppresses the synthesis of type II collagen and proteoglycans, and inhibits transforming growth factor- stimulated chondrocyte proliferation. The presence of IL-1 RNA and protein have been confirmed in OA joints. Thus, IL-1 may not only actively promote cartilage degradation, but may also suppress attempts at repair, in OA. In addition to these effects, IL-1 induces nitric oxide production, chondrocyte apoptosis, and prostaglandin synthesis, which further contribute to cartilage deterioration. Under normal conditions, an endogenous IL-1 receptor antagonist regulates IL-1 activity. A relative excess of IL-1 and/or deficiency of the IL-1 receptor antagonist could conceivably result in the cartilage destruction that is characteristic of OA. It is likely that other cytokines or particulate material from damaged cartilage may also contribute to this inflammatory, degradative process.

These enzymes are secreted by both synovial cells and chondrocytes and are categorized into three general categories: a) collagenases; b) stromelysins; and, c) gelatinases. Under normal conditions, MMP synthesis and activation are tightly regulated at several levels. They are secreted as inactive proenzymes that require enzymatic

Growth factors are produced locally in cartilage and synovium and are likely to contribute to local cartilage remodeling by stimulating the de novo synthesis of collagen and proteoglycans. Transforming growth factor (TGF) is the best characterized and most potent of the chondrocyte growth factors. Not only does TGF stimulate de novo matrix synthesis, but it also counteracts cartilage degradation by down regulating IL-1 receptor expression and by increasing IL-1 receptor antagonist release and TIMP expression. Insulin-like growth factor (IGF-1) and basic fibroblast growth factor (b-FGF) are also present in OA cartilage and likely to contribute to reparative attempts, although, as noted, degradation ultimately outstrips repair in OA cartilage. (16)

F. Clinical symptoms Osteoarthritis is a disease of the joints. Unlike many other forms of arthritis that are systemic illnesses (conditions that affect multiple areas of the body or the entire body), such as rheumatoid arthritis and systemic lupus, osteoarthritis does not affect other organs of the body. The most common symptom of osteoarthritis is pain in the affected joint(s) after repetitive use. Joint pain of osteoarthritis is usually worse later in the day. There can be swelling, warmth, and creaking of the affected joints. Pain and stiffness of the joints can also occur after long periods of inactivity (for example, sitting in a theater). In severe osteoarthritis, complete loss of the cartilage cushion causes friction between bones, causing pain even at rest or pain with limited motion. Symptoms of osteoarthritis vary greatly from patient to patient. Some patients can be debilitated by their symptoms. On the other hand, others may have remarkably few symptoms in spite of dramatic degeneration of the joints apparent on X-rays. Symptoms also can be intermittent. It is not unusual for patients with osteoarthritis of the finger joints of the hands and knees to have years of pain-free intervals between symptoms. Osteoarthritis of the knees is often associated with excess upper body weight, with obesity, or a history of repeated injury and/or joint surgery. Progressive cartilage degeneration of the knee joints can lead to deformity and outward curvature of the knees, which is referred to as being "bowlegged." People with osteoarthritis of the weight-bearing joints (such as the knees) can develop a limp. The limping can worsen as more cartilage degenerates. In some patients, the pain, limping, and joint dysfunction may not respond to medications or other conservative measures. Therefore, severe osteoarthritis of the knees is one of the most common reasons for total knee replacement surgical procedures in the United States. (17)

function overtime. Quadriceps sthrengtening has formed the cornerstone of traditional OA exercise therapy, and clinical trials of various types of quadriceps sthrengtening exercise have consistently found significant reduction in pain and improvements in physical function. (19) 2. Hamstring muscle strenghtening Weakness of the hamstring muscles has been found in patients with knee OA. Thus, if the hamstring muscle are weakthis could reduce the ability to resis external loads applied to the knee and increased symptoms of knee instability. (20) 3. Hip muscle strengthening It has been proposed that strengthening the hip muscle responsibly for controlling pelvic position in the frontal plane may reduce knee loads and slow disease progresion. During walking, the hip abductor and adductor muscles stabilize the pelvis on the hip joint. Weakness may cause drop in the level of the pelvis, thereby shifting the center of mass and increasing the knee AM. Less is known about the hip adductor muscles in relation of knee OA, but they may assist inresisting the knee AM. 4. Patient education Patient education is important in doing because osteoarthritis is a disease that can not be cured. Education in doing so does not increase the severity of osteoarthritis 5. Weight loss Significant weight loss is important to do, because osteoarthritis is closely associated with body weight, due to the joint affected by osteoarthritis are weight bearing joints, where the weight gain is in line with an increased incidence of osteoarthritis. 6. Aerobic exercise Aereobic exercise makes decreased knee pain, improve physical function, increased respiratory capacity and decreased joint tenderness. 7. Transcutaneus electrical nerve stimulation Transcutaneous electrical nerve stimulation (TENS) currently is one of the most commonly used forms of electroanalgesia. Hundreds of clinical reports exist concerning the use of TENS for various types of conditions, such as low back pain(LBP), myofascial and arthritic pain, sympathetically mediated pain, bladderincontinence, neurogenic pain, visceral pain, and postsurgical pain. Because many of these studies were uncontrolled, there has been ongoing debate about the degree to which TENS is more effective than placebo in reducing pain. (21) B. Pharmacological treatment

F. Treatment The ultimate goal in the treatment of OA is to improve or preserve the patients joint structure by preventing the destruction of the articular tissue including cartilage and bone. As knee osteoarthritis (OA) is essentially an incurable condition, temporary management has centered on the alleviation of symptoms and the maintenance or improvement of physical function. Treatment options for knee OA may be classified as nonpharmacologic, pharmacologic or surgical. Given their relatively low toxicity and cost, nonpharmacological strategies (such as physical therapy, including exercise) are reccomended by clinical guidelines as the first line treatment of OA. (18) A. Nonpharmacological treatment

Physical therapy focuses on those that may be able to change the disease course by enhancing muscle function and neuromuscular control, by minimizing instability or by by attenuating load and improving load distribution. 1. Quadriceps muscle strengthening Muscle weakness (particulary on quadriceps) is a well recognized impairment in people with knee OA. It has been associated with increased pain and greater deterioration in

The nonsteroidal antiinflammatory drug (NSAID) class of medication includes non selective agents, selective cyclooxygenase 2 inhibitors (coxib) and aspirin. All members of this class inhibits cyclo oxygenase (COX) the group of enzymes that initiate metabolism of arachidonic acids into various eicosanoids, including prostaglandin E2, thromboxane A2, prostacyclin, prostaglandin D2, and prostaglandin F2, these eicosanoid play critical tissuespesific function in almost every system of the body. The ability of NSAIDs to inhibit pain, lower fever, and reduce inflammation makes them one of the most important classes of medications.

Clasically, it has been described that the prostaglandins produced via the COX-1 pathway are involved in housekeeping functions in that they mediate physiologic responses. COX-2 is expressed by cells involved in inflammation and during disease state, such as malignancy. NSAIDs vary in their potency, duration of action, how they are eliminated from the body, how strongly they inhibit COX-1 and their tendency to cause ulcers and promote bleeding. The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding. One NSAID, celecoxib (Celebrex), blocks COX-2 but has little effect on COX-1, and is therefore further classified as a selective COX-2 inhibitor.Selective COX-2 inhibitors cause less bleeding and fewer ulcers than other NSAIDs. Most NSAIDs inhibit the clotting of blood for only a few hours. Ketorolac (Toradol) is a very potent NSAID and is used for moderately severe acute pain that usually requires narcotics. Ketorolac causes ulcers more frequently than other NSAID. Therefore, it is not used for more than five days. Although NSAIDs have a similar mechanism of action, individuals who do not respond to one NSAID may respond to another. C. Surgery When patients with knee OA have failed medical treatment and remain pain with limited physical function and reduced quality of life, patients must be reconciled with a total arthroplasty. This is an operation which is very effective in relieving pain and improving function in most patients. A total knee replacement is a surgical procedure whereby the diseased knee joint is replaced with artificial material. The knee is a hinge joint which provides motion at the point where the thigh meets the lower leg. The thighbone (or femur) abuts the large bone of the lower leg (tibia) at the knee joint. During a total knee replacement, the end of the femur bone is removed and replaced with a metal shell. The end of the lower leg bone (tibia) is also removed and replaced with a channeled plasticpiece with a metal stem. Depending on the condition of the kneecap portion of the knee joint, a plastic "button" may also be added under the kneecap surface. The artificial components of a total knee replacement are referred to as the prosthesis. The posterior cruciate ligament is a tissue that normally stabilizes each side of the knee joint so that the lower leg cannot slide backward in relation to the thighbone. In total knee replacement surgery, this ligament is either retained, sacrificed, or substituted by a polyethylene post. Each of these various designs of total knee replacement has its benefits and risks.

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OA is a degenerative disease that can affect anyone. Current research has shown that there has been hypomineralized of the subchondral bone on the early stage of osteoarthritis. This can happen because of the current piezoelectrical, in accordance with the law wolff, where if the bone is given then there is pressure or load current will activate the piezoelectric and osteoblasts. OA treatment is currently concentrating on to improve or preserve the patient's joint structure by preventing the destruction of the articular cartilage and bone tissue. To achieve this goal in patient, we can choose nonpharmacologic therapy, pharmacologic or surgical.

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