Apr 5, 2005 - Sweet roll, coffee cake, or other pastry home baked (1 serving). Pie, homemade (1 slice). Pie, ready made (1 slice). Jam, jelly, preserves, syrup, ...
UNIVERSITY OF CINCINNATI April 5, 2005 Date:___________________
Henna Muzaffar I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of:
Master of Science in:
Department of Nutritional Science It is entitled: Combined Effects of Diet and Exercise Intervention on Self-Reported
Knee Pain Associated with Osteoarthritis
This work and its defense approved by:
Shanil Juma, PhD. Chair: _______________________________ Sarah Couch, PhD, RD. _______________________________ Rose Smith, DPT, MEd, ATC, SCS _______________________________
_______________________________ _______________________________
Combined Effects of Diet and Exercise Intervention on SelfReported Knee Pain Associated with Osteoarthritis By Henna Muzaffar March, 2005
Bachelor of Science, Nutrition Science Master of Science, Nutrition science Department of Nutritional Science College of Allied Health Science
Shanil Juma, PhD Committee Chair
ABSTRACT
Combined Effects of Diet and Exercise Intervention on Self-Reported Knee Pain Associated with Osteoarthritis BY Henna Muzaffar Background: Osteoarthritis ranks among the top three health care problems in the developed world. It is a leading cause of disability in the elderly population and the relative economic impact of this condition has reached 2.5 percent of the gross national product. Lifestyle changes including nutrition and physical activity are now recommended as the first line of treatment for osteoarthritis. Vitamin A, C, D, and E have shown beneficial effects because of their anti-oxidant capacity and role in the metabolism of bone and cartilage. The American College of Rheumatology recommends moderate intensity exercise as it helps to decrease pain, increase muscle strength and improve physical function. However, the combined impact of dietary and exercise intervention needs to be investigated further. Methods: A total of 60 subjects were randomly assigned to either the dietary modification only group or the dietary modification/exercise regimen group for a period of three months. They made two visits to the assessment laboratory where anthropometric measurements were taken, five questionnaires were administered, and subjects received relevant counseling. Results: After three months of intervention, the nutrition and exercise intervention had a significant effect on extension (P= 0.041). There was no difference in flexion from baseline to final in either of the treatments groups or between the treatment groups. The nutrition and exercise intervention in comparison to nutrition alone was also associated with a greater reduction in pain from baseline to follow up (p= 0.02). Conclusion: In summary, the findings of this study suggest that lifestyle modifications which focus on changes in dietary and exercise behaviors can improve joint mobility via positive changes in the range of motion and pain of the knee afflicted with osteoarthritis.
Acknowledgements I would like to express my gratitude and appreciation to my thesis advisor Dr Shanil Juma, Assistant Professor, Department of Nutritional Sciences in the College of Allied Health at the University of Cincinnati, Ohio. I would not have been able to compile my thesis without his assistance and guidance. I would also like to thank Dr Sarah Couch, Associate Professor; Department of Nutritional Sciences and Dr. Rose Smith, Assistant Professor, Department of Rehabilitation Sciences for their professional guidance and dedication of time to this research. My appreciation to Dr. Linda Levin, Department of Environmental Health for conducting the statistical analysis of the thesis data and Ms. Becky Gardener and Mr. Eric Marsli for their help with data entry and patient visits.
Table of Contents Introduction Literature Review Epidemiology and prevalence Classification of osteoarthritis Composition of cartilage Changes in the diseased joint Osteoarthritis of the knee Estrogen and osteoarthritis Biochemical markers in osteoarthritis Current treatments and therapies for osteoarthritis Methods Subject recruitment and selection Screening Data collection methods Treatment protocol Statistical analysis Results Tables Discussion Implications Bibliography
1 3 3 4 5 7 9 12 13 16 32 32 32 33 34 36 37 39 44 49 50
Appendix Medical history questionnaire Physical activity questionnaire Pain assessment questionnaire Food frequency questionnaire Supplement use questionnaire
56 57 61 66 72 80
Tables Table 1: Characteristics of Study Participants
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Table 2: Range of Motion in Left and Right Knees
40
Table 3: Levels of Pain of Study Participants
41
Table 4: Consumption of Main Food Groups by Study Participants
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Table 5: Intake of Fluids by Study Participants
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Introduction Osteoarthritis ranks among the top three health care problems in the developed world. At present, it affects 20 billion Americans and is expected to exceed 59 billion by 2020 because of aging of the American population.1 Under age 50, men have a higher prevalence of osteoarthritis; but after age 50, women experience a dramatic increase in the incidence of osteoarthritis.2 The incidence of osteoarthritis increases with age, as data from the Framingham Heart study population indicates that the percentage of people who have mild, moderate, or severe radiographic changes indicative of osteoarthritis increase from less than 5% in individuals younger than 25 years of age to more than 80% in individuals more than 75 years of age.3,4 Obesity is a well recognized and modifiable risk factor associated with knee osteoarthritis. The risk for osteoarthritis increases by 15% for each additional unit of body mass index above 27.5 Both animal and human studies provide evidence in favor of moderate and even strenuous regular activity because they do not cause or accelerate the development of osteoarthritis.6,7 More specifically, cyclic type activities stimulate matrix synthesis whereas prolonged static activity or the absence of loading and motion causes degradation of the matrix and the joint.8,9 Lifestyle changes including exercise and nutrition are now being touted as the first line of treatment in the management of symptoms of osteoarthritis.10 Vitamin C, D, and E have shown beneficial effects on retarding the progression of this disease through maintenance of optimal bone mass and antioxidant and anti-inflammatory actions.2,5,11 Diet therapies also have an indirect effect by decreasing body weight, thus reducing the weight bearing stress on the joints and increasing mobility.12 However, aging slows down
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body’s metabolism thus limiting the effect of diet alone on body weight. Thus, a combined dietary and physical activity intervention will be more beneficial in reducing symptoms related to pain in knee OA by maintaining ideal body weight, increasing lean body mass, and improving joint mobility.
Hypothesis and Objectives: The central hypothesis of this thesis proposal is to evaluate the combined effects of dietary modification and an exercise regimen on reducing symptoms of pain related to knee OA. Objective 1: To examine the effects of diet modification and an exercise regimen in comparison with diet modification alone on reducing symptoms of self-reported knee pain associated with osteoarthritis. These symptoms include frequency and severity of pain, and limited range of motion
Objective 2: To determine the effect of diet modification and an exercise regimen in comparison to diet modification alone on body weight, body composition, and anthropometric measurements in individuals with self-reported knee pain associated with osteoarthritis before and after treatment period.
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Literature Review Osteoarthritis Epidemiology and Prevalence: Osteoarthritis is the leading cause of disability in the elderly population and is listed eighth as a worldwide cause of disability.13 Seventy-five to eighty-five percent of people over the age of 55 years have osteoarthritis, thus making osteoarthritis a universal affliction in older people. The prevalence of osteoarthritis increases with age, which is further aggravated by the lack of treatment for this musculoskeletal disorder. Currently 20.7 million Americans have this chronic disorder and this figure is expected to exceed 59 million by year 2020, because America’s oldest old are increasing at a rapid rate both numerically as well as a proportion of the total population.1,13 Osteoarthritis ranks among the top three health care problems of the developed world because it exhausts a major portion of the health care dollars. The relative economic impact of musculoskeletal conditions is increasing rapidly, having reached 2.5 percent of the gross national product in 1992.14 The financial impact of musculoskeletal and associated conditions is equivalent to a chronic severe recession, lending importance to finding ways to decrease the clinical and financial impact of OA.14 The prevalence of osteoarthritis is not consistent across genders. Before the age of 50, men have a higher prevalence; but this trend reverses after age 50, with more women afflicted than men. Women have a greater number of affected joints as compared to men and have more osteoarthritis of the hand. On the other hand, men have a higher prevalence of hip osteoarthritis.13 The epidemiologic definition of osteoarthritis includes symptoms, disability, and structural changes associated with it. It is characterized by loss of cartilage at the joints and is a
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metabolically active process with anabolic and catabolic activity occurring. The structural changes that can be seen on radiographic examination include narrowing of the joint space, osteophyte production or the growth of small bony projections on joint surfaces, and bone reformation around the joint.13 The most widely accepted system for grading the severity of the radiograph is known as the Kellgren-Lawrence grading system.13,15 This grading system assesses the severity of osteoarthritis by defining the degree of osteophyte formation from 0-4 but does not take narrowing of the joint space and bone formation around the joint into account.
Classification of Osteoarthritis: Osteoarthritis is classified into two broad categories which include primary and secondary osteoarthritis.16 In primary or idiopathic osteoarthritis, aging and wear and tear of the tissue is responsible for the degeneration of articular cartilage and alterations in single or multiple joints. These changes lead to loss of structure and function of the articular cartilage, causing pain and loss of motion.6 Primary osteoarthritis most commonly involves the joints of the hands, knees, hips, cervical and lumber spine, and the metatarsophalangeal joint of the great toe. On the other hand, secondary osteoarthritis develops as a sequel to diverse endocrine and metabolic disorders or inflammatory joint disease. In these conditions, chondrocytes lose their capacity to maintain a normal matrix, joint congruity is affected, or the biomechanical properties of the cartilage or subchondral bone are altered.17 In both types of osteoarthritis, articular cartilage suffers a progressive loss which is accompanied by attempted repair of the cartilage, remodeling and sclerosis of the underlying bone and in many cases the formation of bone cysts and marginal
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osteophytes. The diagnosis of osteoarthritis is confirmed by the presence of signs and symptoms which include joint pain, restriction of motion, crepitus with motion, joint effusions, and deformity.18 Primary osteoarthritis is more common than secondary osteoarthritis, which develops due to trauma, underlying joint disorders, systemic metabolic disorders, endocrine disorders, or neuropathic disorders.16 There is a strong association between the prevalence of primary osteoarthritis and increasing age. In contrast, the age of onset of secondary osteoarthritis depends on the underlying cause, thus it can develop at any age.19 Osteoarthritis can affect any synovial joint but is most prevalent in the foot, knee, hip, spine, and hand joints. The tools to diagnose osteoarthritis have numerous limitations which include difficulty in defining and establishing the diagnosis and in evaluating more than a few synovial joints in each individual.20,21,22
Composition of Cartilage The hyaline cartilage in synovial joints has a firm slick surface that resists deformation.23 It is composed of mainly hydrated extracellular matrix and specialized cells called chondrocytes.24 Chondrocytes are responsible for synthesizing and maintaining the extracellular matrix.24 Morphologically, the articular cartilage has a highly intricate and ordered structure and the integrity of the tissue is maintained by a variety of complex interactions between the chondrocytes and the protein matrix.
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Chondrocytes: Chondrocytes are spheroidal in shape and synthesize type II collagen, large aggregating proteoglycans, and specific non-collagenous proteins to form cartilaginous matrix.25,26 A variety of stimuli including chemical mediators and mechanical stimuli alter the metabolic rates of chondrocytes.27 Maintenance of the articular surface involves the continuous replacement of degraded matrix components and alteration in the macromolecular framework of the matrix in response to the use of the joint.28 Chemical mediators such as proteoglycans, pH, oxygen tension, local calcium concentration, growth hormone, injury, prostaglandins, insulin, and thromboxin can alter the uptake of amino acids and synthesis of extracellular matrix.27 Mechanical stimuli such as exercise may stimulate chondrocyte metabolism, increasing proteoglycan synthesis.27
Matrix and Collagen Framework: The matrix of articular cartilage is composed of tissue fluid and a framework of structural molecules, which include proteoglycans, collagens and non-collagenous proteins. The tissue fluid and the structural molecules give the cartilage its mechanical properties of stiffness and resilience.29 Collagen is the primary fibrous protein component of the articular cartilage. There are multiple genetically distinct collagen types and the structural organization of these throughout the tissue provides tensile stiffness and strength.30,31 Proteoglycans are a heterogenous group of macromolecules which make up most of the remainder of extracellular matrix. These molecules are composed of a protein core and one or more glycosaminoglycan chains. The principal glycosaminoglycans in
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the articular cartilage are chondroitin sulphate, heparin sulphate, dermatan sulphate, and keratan sulphate.27
Cartilage Metabolism: Cartilage metabolism is an active process involving each component of the cartilage. The remodeling is not uniform because of the variable turnover of different areas of the articular surface. Chondrocytes play an important role in cartilage metabolism because of their synthetic and degradative capabilities.27 Synovial fluid is the source of nutrition for the chondrocytes, which diffuses via a double barrier, first in the synovial tissue and then the cartilage matrix. The passage of materials through the matrix depends on both the size and the charge of the materials.32 In different stages of skeletal growth, the activity of chondrocyte varies. New tissue is produced to expand and model the articular cartilage surface in growing individuals.33 However in mature adults, the volume of the tissue does not change, but the chondrocytes mainly replenish the degraded macromolecules and minimal remodeling of the articular surface continues.7,34 Once growth ceases, the chondroytes do not divide under normal conditions and the rate of metabolic activity and matrix synthesis also declines.27 The number, size, and composition of aggregan molecules also changes with aging.27
Changes in the Diseased Joint Osteoarthritis involves all the tissues that form the joint; which comprises the cartilage, synovium, perichondrium and bone. However, the disease process centers in the cartilage. It is a dynamic disease with both anabolic and catabolic activity occurring
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simultaneously.35 The structural changes associated with osteoarthritis include degradation of the cartilage, narrowing of the joint space, osteophyte production or the growth of small bony projections on joint surfaces, and stiffening of subchondral bone. The symptoms of pain and discomfort are not caused by the primary disease but rather by the secondary effects.13 In osteoarthritis of the knee, the cartilage cushion is reduced in thickness and in some patients completely absent. Bare bones grind against each other and cause mechanical pain. Inflammation is a second source of pain which can be caused by fragments of cartilage floating in the joint. Up to this date, the correct order of these events has not been confirmed because degeneration of articular cartilage and remodeling of subchondral bone are both present by the time the person develops signs and symptoms of osteoarthritis. Many of the mechanisms responsible for progressive cartilage degeneration remain unknown. However, this process is usually divided into three overlapping steps. In step I, injury, genetics or unknown stimulus disrupt or alter the cartilage matrix. Step 2 is the response of the chondrocytes to try to repair the damaged cartilage. This stage results in a cycle of anabolism and catabolism that ultimately leads to cartilage erosion. The final step is the decline of the chondrocyte response to restore the damaged cartilage, thus leading to loss of articular cartilage.35 The failure to stabilize or restore the tissue leads to the third step in the development of osteoarthritis.36 This step results in progressive loss of articular cartilage and a decline in the chondrocytic anabolic and proliferative response. Mechanical damage and death of chondrocytes can cause this decline but the response of chondrocytes to anabolic cytokines is also downregulated.37 This may be due to synthesis
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and accumulation of molecules in the matrix that bind anabolic cytokines and other molecules that can affect cytokine function.37 The subchondral bone undergoes marked proliferation as the disease progresses, And therefore results in dense bone. The bone remodeling occurs either directly beneath the weight-bearing surface or at the margins of the joint, the latter called osteophytes. This in turn leads to remodeling of the bone-calcified cartilage interface with excursion into the articular cartilage, which produces thinning of the cartilage and eventual exposure of smooth dense bone on the articular surface. Other changes in the subchondral bone are microfractures of the bone trabeculae which play a potential role in the progression of osteoarthritis. Enchondral bone formation is also characteristic of progressive osteoarthritis, which when occurs at the margins of the joint leads to osteophytes. 38 Osteophytes are usually palpable and may appear to be tender and in all joints they can restrict motion and contribute to pain with motion.39 Synovium is one of the most common periartcular soft tissues involved in osteoarthritis. Inflammation of the synovium is accompanied by fibrosis which is characterized histologically by a mild infiltrate composed primarily of lymphocytes and mononuclear cells.38
Osteoarthritis of the Knee Incidence and Gender differences: Osteoarthritis of the knee has profound physical and economic impact. It is the most common form of arthritis and accounts for more dependency and disability of the lower extremity than any other diseases. The prevalence of this musculoskeletal condition
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increases with age. It increases from 25-30% in people aged 45-64 years of age to more than 85% in individuals older than 65 years of age.40 Epidemiological surveys have suggested sex-associated differences related to age and disease severity.41,42 Before the age of 50 years, men have a higher prevalence and incidence of knee osteoarthritis. However, after age 50, women have a higher incidence and prevalence.40 Women also appear to be affected with greater severity and in both the knee joints. In the Framingham Heart study, 2% of women developed radiographic knee osteoarthritis as compared to 1.4% men. Similarly in a population based study in Holland, the incidence of knee osteoarthritis was twice as high in women compared to men.16
Clinical Features: The most common clinical complaints of knee osteoarthritis are pain and stiffness in and around the affected joint along with some limitation of function. In mild to moderate osteoarthritis cases, pain worsens with the use of the affected joint and is relieved with rest and pain at rest is a feature of severe osteoarthritis. Morning stiffness lasting less than 30 minutes is also common in severe cases.14,17,43 Patients with osteoarthritis of the knee often have difficulty descending stairs or stepping off curbs because of instability or buckling. Crepitus which is a grinding noise or sensation within a joint is another frequent sign of knee osteoarthritis. It is felt on passive range of motion due to irregularity of opposing cartilage surfaces. Inflammation is not a necessary component except in the advanced stages of the disease. Radiographs are useful to confirm the diagnosis of the disease but the findings are usually non-specific. The two most common radiographic features of the disease include narrowing of the joint space
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and the presence of new bone or osteophytes. Many joints with pathologic or radiographic evidence of this disease remain asymptomatic, thus the association between joint pain and the radiographic features of osteoarthritis is not constant.14,17,43
Risk Factors: Many of the reviews of osteoarthritis have treated risk factors as uniform for all the joints, despite joints having different biomechanics, different types of injuries, and different rates of developmental deformities.44,45,46,47 One of the strongest consistent risk factor associated with osteoarthritis is aging, but this may not be a key factor in the development of osteoarthritis because of the slowing down of the processes of OA at ages above 75.44 This suggests that factors other than aging also contribute to the development of osteoarthritis. It is well accepted that certain level of loading is necessary to maintain healthy cartilage. However, prolonged heavy loading, if repetitive, can produce osteoarthritic lesions. Osteoarthritis is more common in females as compared to males, especially of the hands and knees. This suggests the possible role of estrogens or other sex hormones in the pathogenesis.44 Occupational kneeling and squatting, and previous knee surgery and injury are another set of risk factors for knee osteoarthritis. The Framingham Heart study confirms that heavy physical occupational and leisure activity, particularly in obese people, predisposes to subsequent osteoarthritis of the knee.45 Population based studies; both cross-sectional and longitudinal, indicate a positive association between obesity and knee osteoarthritis. One possible explanation for the association could be an increased load on the joint surface secondary to obesity. These studies suggest that the effect is stronger in women and can increase the risk upto 4-5 fold
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in obese individuals.46 Epidemiological studies provide evidence for increased incidence of knee osteoarthritis with increasing bone mineral density. However, among women who already have knee osteoarthritis, those with low bone mineral density and who are losing bone faster experience more rapid progression of the disease than those with high bone mineral density and who are losing bone more slowly.47
Estrogen and Osteoarthritis Sex hormones have been thought to affect the occurrence and progression of osteoarthritis. Osteoarthritis incidence and prevalence increases with age. Furthermore this condition which is more common in males before the age of 50 becomes much more prevalent in females after age 50.48 Women are also more likely to get generalized diseases as compared to men. All these pieces of evidence suggest that hormonal changes that occur around menopause may modulate this disease.48,49 A large body of epidemiologic studies suggests that women on hormone replacement therapy have a lower prevalence of osteoarthritis. One of the largest studies conducted by Nevitt et al., which evaluated 4366 women, found that women on hormone replacement therapy had threefold reduction in the risk of knee osteoarthritis.50 This protective effect was greater among long term users. These results are consistent with study conducted by Hannan et al., who examined the data of the Framingham study.51 Samanta and colleagues found a 70% lower risk of osteoarthritis among estrogen users.51 In addition to these cross-sectional studies, one longitudinal study found that women on estrogen replacement therapy at the study onset had a lower rate of disease progression than women not on estrogen replacement therapy. On the other hand, studies conducted
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by Sahyoun et al. and Spector et al. failed to show protective effects of estrogen use.52 However, these studies had three important limitations. Initially, there was a potential for detection bias because estrogen users would be more likely to visit physicians and, therefore, are more likely to be diagnosed. Secondly, age was not adjusted and estrogen users are older than non-users. Lastly, at least 3 years of estrogen use is required to see a demonstrable effect and these studies did not take duration of estrogen use into account.50,51,52,53 Several possible protective mechanisms make estrogen beneficial for delaying the onset and progression of oestearthritis. Estrogen may affect articular cartilage by modulating the synthesis of the cartilage matrix and the production of matrix enzymes.50 Estrogen may also influence cartilage metabolism via cytokines and secondary messengers.48 Additionally, estrogen may influence the development of osteoarthritis through its effects on bone metabolism, by dampening subchondral bone remodeling.50 The data from cross-sectional and cohort studies of estrogen use are compelling; and because few treatments are available for osteoarthritis, clinical trials must be conducted to evaluate the effect of estrogen therapy on osteoarthritis. Additionally, longitudinal studies are needed in which estrogen users and non-users are followed and carefully characterized.48
Biochemical Markers in Osteoarthritis Serum and Synovial Markers: The diagnostic technique currently used to clinically diagnose osteoarthritis is evaluation of plain weight bearing radiographs, which show joint space narrowing in the
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tibiofemoral joint. However, radiographic changes are not detectable till the disease process has reached advanced tissue alterations. Even magnetic resonance imaging and arthroscopic inspection cannot detect the early pathologic process in the cartilage. One reasonable alternative is to quantify cartilage macromolecules or fragments thereof released into the synovial fluid in joint damaging process.54 These macromolecules then enter the circulation via the lymphatics and are eliminated from the body by the liver and kidneys. Cartilage markers such as keratin sulphate, chondroitin sulphate, and collagen propeptides; and bone markers such as osteocalcin and alkaline phosphatase have been measured in serum and synovial fluid.55 The major limitation of measuring markers in the serum is that they can also be affected by variables such as age, sex, disease duration, and clearance rate in addition to being altered by the disease process. The evidence for the role of inflammation in osteoarthritis has come from studies which have demonstrated increases in inflammatory proteins in these patients.55
Serum C-Reactive Protein (CRP): C-reactive protein is an acute phase protein whose levels are increased in lowgrade inflammation. In women with early knee osteoarthritis, CRP levels increase, which suggests that low-grade inflammation may be a significant aspect of early osteoarthritis. A study by Spector et al. has demonstrated that CRP levels are modestly but significantly increased in women with knee osteoarthritis and can also predict the disease progression in the next four years.52 These results are in compliance with the results obtained by Loose et al. in a similar study.56 Cytokines stimulate the production of CRP which is also increased in the disease process. Interleukin-6 is most important in this respect. The
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minor acute phase response in patients with osteoarthritis suggests tissue damaging processes within the joints. The CRP levels do not increase in osteoarthritis to the same extent as in classic inflammatory diseases, infections, and most tissue damaging conditions.52 CRP levels have stronger association with osteophyte production than with joint narrowing. One reasonable explanation is that narrowing is a weak measure of disease in population studies because of positioning problems and large numbers of false positives. Thus, for now if the nonspecific nature of acute phase response is recognized, other intercurrent diseases are sought and excluded, and a sensitive and precise CRP assay is used, increased CRP levels can help to identify individual who are at risk of disease progression.52
YKL-40 Production by Chondrocytes: YKL-40 is synthesized by articular chondrocytes and synovial cells. It has been proposed to be a useful marker of disease activity in osteoarthritis.57 Normal human articular cartilage shows no or very low numbers of YKL-40 positive chondrocytes and thus no significant amount of YKL-40 in the extracellular matrix. In osteoarthritis, the articular cartilage and chondrocytes secrete increased amounts of YKL-40. Consequently, YKL-40 levels are elevated in synovial fluid and serum of patients with severe osteoarthritis compared with normal subjects.58 Majority of the degradation of components of the extracellular matrix in osteoarthritis occurs in the middle and superficial layers of arthritic cartilage, the same layers where YKL-40-positive chondrocytes are found. Changes in the extracellular matrix environment appear to be the major stimulator of YKL-40 production. Cytokines and growth factors are important
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regulators of secretion of most proteins in chondrocytes. Interleukin-1 and transforming growth factor-Beta suppress YKL-40 production and interleukin-6, 17, & 18 stimulate YKL-40 production. However, the regulation of YKL-40 by cytokines and growth factors is weak and tissue injury appears to be the main stimulus for YKL-40 production.58
Current Treatments and Therapies for Osteoarthritis Surgical Treatments for Osteoarthritis: There are four main surgical treatments used for patients with osteoarthritis, which include osteotomy, debridement, arthrodesis, and arthroplasty or total knee replacement. The choice of surgical intervention depends on the severity and pattern of pain, functional impairment, anatomic abnormalities, individual patient ability to cooperate with the treatment plan, general health of the patient, age, risk/benefit, and cost/benefit ratio.59 Osteotomy: Osteotomy is one of the earliest surgical procedures used for the treatment of osteoarthritis. In this procedure a wedge of bone is removed from a damaged joint where the cartilage is healthy to tilt the body weight to the healthier part of knee cartilage. It is mainly done to relieve pain and to slow or prevent the progression of the disease. The procedure does not cure the disease but relieves pain, improves function, and helps to maintain physiologic joint motion and stability. It is usually done on young active individuals who have normal articular cartilage. The recovery period for this procedure is about three months. The expected duration of improvement after this procedure is variable and depends on the preoperative extent of osteoarthritis.59,60
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Debridement: Debridement is an attractive surgical approach for patients with early osteoarthritis. It helps to smooth irregular joint surfaces and remove loose bodies and inflamed synovium that lead to disease progression.59 Debridement usually gives impressive pain relief but some joint mobility may be lost after surgery. This procedure has a 75% success rate and maximal improvement is seen twelve months postoperative. The results of debridement can be improved by continuous passive motion in the postoperative rehabilitation phase.59 Arthrodesis: Arthrodesis is still used for surgical management of patients with severe osteoarthritis. It is usually done on young, active healthy patients with single joint involved with osteoarthritis. Arthrodesis also becomes an attractive alternative when bone stock is deficient and motor power is inadequate. The pain improves significantly and the functional improvement is also excellent. The expected duration of improvement can be for lifetime. Total joint replacement is the only option left if this procedure fails.59 Total Joint replacement: Total joint replacement is the procedure of choice if severe pain and disability are present. This is the most expensive procedure but consistent in its results and dependable operative technique used for the treatment of osteoarthritis patients. Any joint can be replaced but this procedure is usually done on hips and knees. Advancement in technology has allowed improving implant designs and fixation methods with more
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successful outcomes. Any degree of obesity (BMI> 30) has a negative effect on the outcome of this procedure. The most common complication of this procedure is wear and tear of the articulating surfaces which can ultimately result in loosening of the implant with significant loss of the bone. However, 80-90% of patients have excellent results at 10-year follow-up.59,61,62
Pharmacological Management of Osteoarthritis: Analgesics: The 1995 American College of Rheumatology guidelines suggests using simple analgesics up to a full dose as first-line therapy, after failure with nonpharmacological interventions. If simple analgesics are not effective then topical agents such as capsaicin should be used alone or with analgesics. This is because a significant number of patients suffer only pain without inflammation and thus might benefit from analgesics alone.63 Analgesics can be given up to a dose of one gram four times a day.2 Simple analgesics are associated with fewer side effects as compared to non-steroidal anti-inflammatory drugs.64 Non-Steroidal Anti-Inflammatory Drugs (NSAIDS): NSAIDS should be given as a second-line therapy, starting first with low doses and then escalating to higher doses if needed. Numerous NSAIDS are available, all of them having equal analgesic potency but some NSAIDS have been shown to have lower gastrointestinal, renal or hepatic toxicity than others. Multiple NSAIDS should not be used concurrently because of risk of toxicity. Most of the standard NSAIDs are cyclooxygenase-1 (COX-1) inhibitors, which is expressed in many tissues including the
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stomach and the kidney.65 Recently, cyclo-oxygenase-2 (COX-2) selective inhibitors are increasingly used. They have equal efficacy to standard NSAIDS but the incidence of endoscopically detected ulcers is lower with this new class of drugs. Adverse upper GI events are reduced by 50% with these selective COX-2 inhibitors.66 However, COX-2 inhibitors may cause the loss of antiplatelet activity which could lead to cardiovascular complications.2 Rofecoxib and celecoxib are the two most commonly used COX-2 inhibitors. A clinical trial comparing these two drugs conducted by Geba et al. has shown Rofecoxib to be better than Celecoxib for rest and night pain and for WOMAC pain and stiffness domain.64 COX-2 specific inhibitors have a more favorable benefit/risk ratio as compared to standard NSAIDS, so they should be given to the patient before starting them on a standard NSAID. A prophylactic therapy such as misoprostol, a proton pump inhibitor, or high-dose hydrogen receptor antagonists should be given to patients who are prescribed NSAIDS and are an increased risk for NSAID induced gastrointestinal adverse event.63 Intra-articular corticosteroids: Injections of corticosteroids such as triamcinolone hexacetonide or methylprednisone give significant short term benefits of two to four weeks over placebo. However, these injections should be used in disease flares only. The American College of Rheumatology suggests limiting the use of these injections to no more than 3-4 times per year.2 The injections are more beneficial if a joint effusion is present in the knee, which indicates an active inflammatory phase of the disease. Common side effects with these injections include skin atrophy and dermal pigmentation, especially with long acting preparations. Infections can develop, but it is a rare complication.2
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Treatment with Nutritional Supplements: Commonly nonsteroidal anti-inflammatory drugs (NSAIDS) and analgesics are used to treat arthritic symptoms. Although these medications are effective in relieving the symptoms, they can cause serious side effects including peptic ulcers and less commonly hepatic and renal failure. Secondly these medications cannot inhibit or slow the progression of the disease. Consequently, the American College of Rheumatology recommends using two nutritional supplements, glucosamine sulphate and chondroitin sulphate to treat patients with osteoarthritis.67,68 Glucosamine Sulphate: Glucosamine occurs naturally in the human body, where it is used as a substrate in the biosynthesis of glycosaminoglycans, proteoglycans and hyaluronan. Glucosamine is first acetylated and sulphated and then incorporated in keratan sulphate, heparan sulphate and hyaluronan. Specifically, keratan sulphate and hyaluronan are important for building cartilaginous matrix and for maintaining the structural and functional integrity of articular cartilage. These molecules also help cartilage in the joints to absorb pressure forces by binding water.67 Thus, glucosamine sulphate when given as a nutritional supplement is beneficial for patients with joint diseases. It has very little direct antiinflammatory effect and no analgesic effect. However, it stimulates the synthesis of proteoglycans, inhibits the degradation of proteoglycans, and stimulates the regeneration of cartilage. Proteoglycans are needed to stabilize the cell membranes and increase intracellular ground substance. This allows glucosamine sulphate to stop the progression of the disease process and to promote the regeneration of joint matrix.69
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Various other clinical trials conducted by Reichelt et al., Tapadinhas et al., and Rovati have shown the effect of glucosamine sulphate to be more favorable in comparison to a placebo.69 When compared to nonsteroidal anti-inflammatory agents (NSAIDS), glucoasmine sulphate has similar efficacy in relieving symptoms.69 NSAIDS provide a prompt reduction in clinical symptoms but the symptoms reappear as soon as the treatment is discontinued. On the other hand, patients exhibit slower response to glucosamine sulphate but the favorable response remains for up to three months after the treatment is stopped.69 The typical dosage of glucosamine sulphate given to patients with osteoarthritis is 500 mg three times daily orally for at least 6 weeks. 88% of the subjects do not report any side effects with glucosamine, and those who do report have very mild side effects which reverse when the treatment is stopped. Moreover glucosamine sulphate does not interfere with either the course of the illness or treatment with medications. Continuous administration or repetitive courses of administration are also safe because of its safety profile.69 Chondroitin Sulphate: The most abundant glycosaminoglycan in the cartilage is chondroitin sulphate, which is part of the proteoglycan molecule. Proteoglycans together with collagen and non-collagenous glycoproteins makes cartilage resilient. Shark and bovine cartilage is used to manufacture chondritin sulphate supplements.67 Chondroitin sulphate is capable of preserving cartilage by providing substrates for proteoglycan synthesis and decreasing collagenolytic activity. Secondly, it helps to reduce pain and increase overall mobility of the patients. Thirdly, chondroitin sulphate
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can stabilize the medial femoro-tibial joint space which is a good predictor of cartilage thinning and compression of the medial compartment of the knee. Lastly, it alters the expression of various markers of bone and cartilage metabolism. Specifically, it decreases the levels of serum antigenic keratan sulphate, serum osteocalcin and urinary deoxy-pyridinoline. Keratan sulphate is a marker of cartilage turnover and the latter two indicate bone turnover.70 The typical oral dosage of chondroitin sulphate is either 400 mg twice daily or a single dose of 800 mg per day. The beneficial effects of chondroitin sulphate are not permanent, so repeated cycles of administration are needed to provide continuous relief. Chondroitin sulphate is well tolerated and does not cause any serious side effects or any signs of toxicity. Only 3% of individuals experience mild dyspeptic symptoms or nausea.69 To date, the choice of using glucosamine sulphate, chondroitin sulphate or both is a matter of individual preference. More studies and clinical trials are needed to compare the relative efficacy of glucosamine sulphate with chondroitin sulphate or compare the effectiveness of the combination of these two compounds to either compound alone.68
Dietary Management of Osteoarthritis: Laboratory and observational studies support the hypothesis that certain nutritional factors influence the course of osteoarthritis. These dietary factors include vitamins A, C, E and D, and boron.71 They can influence the course of the disease in four ways: protection from oxidative damage, modulation of the inflammatory response, cellular differentiation, and biological actions related to bone and collagen synthesis.5
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(Sowers., 2001). The studies do not provide any definitive answer but emphasize the importance of nutrition as an area for further research to fully evaluate its role in the etiology, progression and possible treatment of osteoarthritis.11,71 Antioxidant Role of Vitamins (Vitamins A, E, and C): Reactive oxygen species are continuously formed in the tissues by both endogenous and exogenous mechanisms. They cause damage to many macromolecules including cell membranes, lipoproteins, proteins and DNA. This damage accumulates with age and is implicated in the pathophysiology of many diseases, including osteoarthritis. Additionally, there is evidence that cells within the joints, specifically chondrocytes, are also capable of producing reactive oxygen species. Chondrocytes can produce hydrogen peroxide and superoxide anions which can adversely affect the collagen structure and depolymerize synovial fluid hyaluronate.11,71 The human body attempts to defend itself by antioxidant defense systems. Antioxidant enzymes including superoxide dismutase, catalase and peroxidase provide the intracellular defense. Extracellular defense is provided by the micronutrients vitamin E, Vitamin A and vitamin C whose blood concentration is determined by dietary intake. The concept of extracellular defense has led to the hypothesis that high dietary intakes of these micronutrients might protect against age related disorders, including osteoarthritis.11 In the Framingham Heart study cohort, the association of reported dietary intake of anti-oxidant micronutrients with knee osteoarthritis was evaluated.71No significant association was found with any micronutrient for the incidence of osteoarthritis. However, these nutrients were found to be beneficial for delaying the progression of the
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disease. Vitamin C provided the most benefit by reducing the risk of progression threefold for those in the middle and highest tertiles of vitamin C intake. The risk of progression was also decreased by high intakes of vitamins A and E, but these results were less consistent, and vitamin E effect was only seen in men.11 A privately- sponsored six week double-blind placebo controlled trial has provided the most rigorous evidence for the beneficial effect of vitamin E in osteoarthritis patients. These patients showed improvements in every efficacy measure including pain at rest, pain on movement and the use of analgesics.11,71 The study of antioxidants in osteoarthritis patients is complicated by a number of problems. First of all, there is no test currently available to measure oxidative activity in the joints. Also, very little is known about the tissue distribution and bioavailability of these vitamins within the joints.11 Non-Antioxidant Roles of Antioxidant Vitamins (Vitamin C and E): Vitamin C has several important biochemical functions in the body which might be important in osteoarthritis. Lysylhydroxylase is a vitamin C dependent enzyme which is required for the posttranslational hydroxylation of of prolyly and lysyl residues in procollagen to convert it to mature collagen fibril. Vitamin C is also required for glycosaminoglycan synthesis by acting as a carrier for the sulphate groups. Furthermore, vitamin C also has some effect on growth factors by modulating the production of binding proteins for these factors.11 These biochemical functions of vitamin C are supported by animal studies conducted by Schwartz et al. and Sandell et al. who found decreased proteinase activity, increased proteoglycan biosynthesis, and increase in type II procollagen mRNA, in the presence of ascorbic acid.11
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Short-term arthritis trials suggest that vitamin E might have positive effects on inflammation associated with osteoarthritis. Vitamin E could modulate the inflammation by blocking the formation of arachidonic acid from phospholipids and inhibiting lipoxygenase activity.11 Role of Vitamin D in osteoarthritis: In addition to cartilage, bone is also involved in the pathophysiology of osteoarthritis, which is indicated by the development of osteophytosis, subchondral sclerosis, and cyst formation in osteoarthritis patients. Radin et al. have demonstrated that patients who have abnormalities in their bone seen on scanning have a high rate of disease progression, suggesting that quality of periarticular bone may influence the course of osteoarthritis.72 The skeletal expression of the disease may also be influenced by bone mineral density which appears to be inversely related to osteoarthritis.72 Vitamin D is important for the normal metabolism of bone. Low levels of vitamin D intake can affect calcium metabolism, osteoblastic activity, matrix ossification and bone density. Thus, low levels of vitamin D can impair the ability of the bone to respond to the pathophysiologic processes in osteoarthritis and consequently predispose people to disease progression. Vitamin D can also affect articular cartilage by stimulating the synthesis of proteoglycans by mature articular.11,72 A prospective observational study was conducted on the participant in the Framingham Heart study to evaluate the role of vitamin D in osteoarthritis patients. This study suggests that suboptimal levels of vitamin D have a greater effect on disease progression than on incidence.5 In accordance with the hypothesis, low vitamin D levels decreased the ability of bone to respond to changes in the arthritis joint. High Vitamin D
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intake and high level in the serum can reduce the risk of progression by three times as compared to low levels.5,11,72 Role of Boron in Osteoarthritis: Numerous epidemiologic and controlled animal and human experiments provide evidence for the use of boron as a safe and effective treatment for some forms of osteoarthritis. Boron is found naturally in apples, legumes, leafy vegetables, carrots, grains, nuts, pears, grapes, and drinking water (in certain areas). An analytical study showed that the concentration of boron is lower in femur heads, bones and synovial fluid of osteoarthritis patients as compared to normal joints. Moreover, surgeons have observed that the bones of patients using boron supplementation are harder to cut than patients not using these supplements. The incidence of osteoarthritis ranges from 20 to 70% in the areas where boron intake is low as compared to 0-10% incidence in the areas of the world where boron consumption is high.73 The most convincing evidence for the use of boron for osteoarthritis patients comes from a double-blind placebo-boron supplementation trial conducted in Australia. The subjects were put on boron supplementation for a period of eight weeks. The group on boron supplementation improved significantly as compared to the placebo group. The beneficial response was better in the patients who had been suffering from osteoarthritis for a shorter period of time. Younger patients responded better than older patients and also responded quickly. None of the subjects showed any side effects with boron supplementation.73
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To date the findings suggest that boron is safe and beneficial for preventing and treating osteoarthritis. Thus, efforts should be made to increase the consumption of this important element especially in areas of the world where boron intakes are low.73
Lifestyle Factors Influencing Osteoarthritis: Currently, osteoarthritis patients are treated primarily to control their pain, improve or preserve joint function and mobility, and improve health related quality of life. The pharmacological treatments are effective in reducing symptoms like pain, but are accompanied with detrimental side effects such as liver or kidney failure and GI abnormalities. Thus non-pharmacological options for treatment are gaining popularity.74 The two most popular lifestyle approaches to combat this disease are losing weight in obese adults and/or incorporating exercise to improve health related quality of life. Exercise as an Intervention: Moderate intensity exercise is believed to be beneficial for patients with osteoarthritis, especially of the knee. The American College of Rheumatology recommends using exercise as a vital component of therapy. Therapeutic exercises decrease pain, increase muscle strength, increase range of motion, increase endurance and aerobic capacity, and improve physical function and quality of life.75,76 Exercise is also believed to be advantageous because it increases the circulation of synovial fluid, which provides nutrients to the articular cartilage and helps to maintain periarticular muscle strength.77
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In the recent past, studies have been conducted to evaluate the beneficial effects of exercise on knee osteoarthritis. A study conducted by Focht et al. suggests that exercise can increase pain transiently, especially in sedentary adults, but in the long run the pain dissipates. This is an important finding and educating patients about the possibility of transient increase in pain with exercise can increase their compliance to the exercise regimen, and consequently help them in achieving the long term benefit of pain reduction with exercise training. This study was conducted in patients having mild to moderate intensity pain so the results cannot be generalized to people with severe pain. The exercise regimen used in this study consisted of walking at 50 to 70% of heart rate reserve and resistance exercise. Future research is needed to evaluate the effects of alternative modes of activity, particularly non-weight-bearing forms of exercise, on pain perception in osteoarthritis patients.78 A twelve week study by Minor and Colleagues demonstrated that an exercise program of either aquatics or walking improved physical function and pain symptoms.79 A six-month pilot study conducted by Messier et al. suggested that combined dietary weight loss and exercise treatment had consistent positive effects on self-reported disability, functional limitations, and pain.80 Miller et al. conducted a follow up study to assess the beneficial effects of combined dietary weight loss and exercise treatment.80 The exercise intervention was a combination of both cardiovascular fitness and resistance training. This was one of the fewer studies which offered the flexibility to participate in either a facility based exercise program, a home-based program, or a combination of the two. The findings of this study suggest that lifestyle modifications can improve health related quality of life in obese adults who have knee osteoarthritis.80 The combined
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dietary and physical activity intervention produced most consistent and positive outcomes as compared to either intervention alone.79,80 A clinical trial was designed to determine whether a home-based exercise program can improve the symptoms of knee osteoarthritis patients.81 This two-year exercise program was devised to maintain and improve the strength of muscles acting around the knee, the range of motion at the knee joint, and the locomotor function. The exercise group showed highly significant reductions in knee pain as compared to the control group.81 Pain reduction was greater in patients who were more compliant to the exercise regimen. This study demonstrated that home based exercise program for two years can produce significant reduction in knee pain. The subjects showed significant improvements even at six months and sustained the improvement, suggesting that following the subjects for more than six months might not be necessary.81 More research is needed to answer some important questions related to exercise intervention for osteoarthritis patients. More specifically, studies are required to determine the type of exercise activity which would be most beneficial to osteoarthritis patients. Investigation is required to determine the optimal duration of exercise, so that the beneficial effects of exercise are realized without further compromising functional status. Also, the advantages of home-based versus facility-based exercise programs need to be compared to see if similar benefits can be obtained. Since most of the studies have been conducted in obese subjects, it would be important to see the effects of exercise in normal weight subjects.78,79,80
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Weight Loss in Osteoarthritis Patients: Obesity is a primary risk factor for osteoarthritis, especially knee osteoarthritis. Individuals with a BMI greater than 30 are four times more likely to have knee osteoarthritis than people in the normal BMI range. The risk of developing knee osteoarthritis is greater for obesity at an early age than obesity later in life.80 Obesity increases the risk of developing bilateral knee osteoarthritis in individual having unilateral knee osteoarthritis. Additionally, overweight persons with knee osteoarthritis are at a higher risk of experiencing progressive disease.5,71 The primary mechanism which predisposes obese individuals to osteoarthritis is mechanical. While walking, an individual can exert three to six times the body weight across the knee during the single leg stance. Thus, any increase in weight multiplied by this factor reveals the excess force exerted across the knee when an overweight person walks.71 The metabolic mechanisms involved the production of tumor necrosis factoralpha, the interleukins, or leptin from the adipose tissue, which affect the cartilage and the bone, predisposing them to osteoarthritis.80 The weight control programs which focus on decreasing body fat and increasing physical activity appear to be more important in providing symptomatic relief than programs which focus only on weight loss or decreasing other indices of obesity.71 A study conducted by Toda et al. demonstrated that reductions in body fat were correlated with changes in radiographic knee osteoarthritis and changes in the body weight were not associated with any improvements.80 Felson et al. in their study provide evidence for reduction in the risk of subsequent symptomatic knee disease with weight loss. The data from Framingham study suggests that a weight loss of 5 kg decreases the risk of
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developing knee osteoarthritis by over 50%.71 An epidemiologic study by Davis et al. also suggests a positive association of body mass index with knee osteoarthritis. However, unlike the strong association of central body fat pattern with cardiovascular and gallbladder diseases, they were not able to find any consistent pattern of association of body fat distribution with knee osteoarthritis.82 Miller et al conducted a study in which they compared the beneficial effects of weight loss, exercise intervention, and the combination of two interventions. The subjects in the combined weight loss and exercise intervention group showed greater improvements than either intervention alone.79 Obesity is the strongest modifiable risk factor for both the incidence and progression of osteoarthritis. To date, no large randomized controlled trial has been conducted to examine the beneficial effect of weight loss on physical disability in knee osteoarthritis patients. Hence, more research is needed to evaluate the relative benefits of weight loss, alone or in combination with exercise.80
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Methods Subject Recruitment and Selection: A total of 63 subjects, between the ages of 45-69, with a mild to moderate degree of self-reported knee pain associated with joint osteoarthritis, regardless of sex, ethnicity, and race, were recruited. The screening criteria for the subjects included appropriate age, no history of severe liver and kidney disease, agreement not to start on any new prescribed medication for knee pain during the three months of intervention, willingness to modify diet and/or incorporate an at-home exercise program, and commitment to make two visits to the Human Assessment Laboratory in the Department of Nutritional Sciences. At the first visit, subjects were provided with a verbal and written description of the project and with answers to any questions regarding their participation in this study. The potential subject was assured that his/her participation is completely voluntary and was then asked to sign an informed consent form. A copy of the signed consent form was also made available to the subject to take home. The subjects were randomly assigned to either the dietary modification only group or the dietary modification/exercise regimen group for a period of three months. They were followed up by two monthly calls and then they made a final visit in the third month.
Screening: A trained graduate student screened potential subjects over the phone by conducting a short medical history questionnaire. The questionnaire helped to identify subjects who were interested and met the inclusion criteria of age, health status, and knee pain status. The subjects were then asked to come to the UC medical center. All
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measurements and questionnaires were conducted in the Human Assessment laboratory located in the first floor of the French east building.
Data Collection Methods: Anthropometric data: Anthropometric data including height, weight, and body composition were determined at both the initial and the final visit. Body weight was measured using an electronic scale (Tanita Best Weight; Cincinnati, OH) with an accuracy of +/- 0.5 lbs. Height was obtained at baseline and at the end of study using a stadiometer (Health-OMeter; Cincinnati, OH). The stadiometer measures height in inches with an accuracy of +/- 0.1 inch. Bioelectrical impedance (RJL Systems; Clinton Twp, MI) which is a widely used and an acceptable method of measuring body composition was used at baseline and at the end of the three months. It provides correlations in the range of 0.75-0.92 for total body weight and 0.46-0.79 for extra cellular water. The results were then analyzed using analysis software available at the manufacturer’s website http://interactive.rjlsystems.com. Questionnaires: A medical history questionnaire was completed at the first visit for each of the study participants. This questionnaire was used to further support our prescreening of individuals who were excluded due to certain chronic and acute conditions. The physical activity questionnaire, pain assessment questionnaire, food frequency questionnaire, and the vitamin/mineral supplement use questionnaire were conducted at both the initial and the final visit. All the questionnaires have been validated for using with osteoarthritis
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patients. Physical activity was evaluated using the Five-City Project Physical Activity Recall. The pain assessment questionnaire used in this study was a modification of the McGill Pain Questionnaire and SF-36 health survey questionnaire. McGill Pain Questionnaire is used for both assessment and monitoring of pain status. It provides quantitative measures of clinical pain that encompass its sensory, affective and other qualitative components and allows statistical analysis of data collected (http://www.qolid.org/public/MPQ.html). The SF-36 health survey questionnaire can detect the subtle changes in health that follow an intervention and produces reliable and valid results. It is easy to understand and relevant to most people’s lives (http://www.bupa.co.uk/healthsurvey/html/why/sf36.html). The food frequency questionnaire and a vitamin and mineral supplement questionnaire adapted for studies on osteoarthritis patients were conducted to assess the nutritional status of the subjects and to find any relationship between intake of specific food groups as well as fluid intake and the severity and progression of osteoarthritis.
Treatment Protocol: Subjects in both groups received individual counseling to modify their dietary intake of fat, cholesterol, and sodium, and to reduce the overall intake of calories. Additionally, study participants were provided with dietary guidelines for Americans, established by the United States Department of Agriculture (USDA), to increase their fruit and vegetable intake to increase the intake of antioxidant vitamins and minerals. Research suggests that increased antioxidants in the diet help to decrease the inflammatory process associated with cartilage degeneration.
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Subjects in the dietary modification/exercise regimen group were also be provided with counseling to incorporate an at-home exercise program to their daily routine. This exercise program was designed by Dr Smith P.T. and is a modification of an exercise program recommended by the orthopedic surgeons/rheumatologists focused on knee OA. The exercise program was designed to improve the strength of muscles acting around the knee, the range of motion at the knee joint, and the locomotor function. The participants were encouraged to do the exercise regimen daily with both legs for 20-30 minutes. The exercise program was self paced and the participants were advised to make it more challenging by increasing the number of repetitions of each exercise. The exercise program was taught to the participants in the assessment laboratory by trained graduate students. To help subjects follow the exercise program at home, they were provided with a thera band device, a video tape of the exercise regimen, and a schematic presentation of the individual exercises. The thera bands were used to increase the resistance against which the muscles worked. Study participants were also provided with a three month calendar to assess their compliance to the exercise protocol at the end of the study. All the subjects were followed up by two monthly phone calls to address issues or problems related to the study treatments. These follow-up phone calls were also utilized to evaluate the compliance of study participants. The subjects returned for their final visit approximately 90 days after the initial visit. During the final visit, all of the measures obtained at baseline were repeated to evaluate the effect of the treatment.
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Statistical Analysis: Descriptive statistics including means, standard deviations, standard errors, minima and maxima, were determined for all variables. Distributions of the response variables were examined to determine if statistical tests of hypothesis based on the assumption of normality are appropriate, or whether transformed data or non-parametric tests should be used. An unpaired t-test was performed on all the data to compare the improvement following three months of both the interventions. After satisfying the assumption of normality, a student t-test was used to compare the baseline values of body weight, body mass, and anthropometric measurements and relevant covariates such as age were compared for the two groups. The baseline values of pain and stiffness assessments were compared to the after treatment values among the two groups using the test for ordinal data. Spearman correlation test was performed to determine if any relationship exists between the four pain parameters for each individual. Logistic regression analysis was used to compare the effect of treatments on the four pain parameters for the subjects in both the intervention groups. The logistic regression analysis included adjustment for body weight, fat and fat free mass because the baseline values of weight, fat and fat free mass differed between the two intervention groups. Tests of fixed effects were performed on the data for range of motion (extension and flexion), which provided with the p-values and 95% confidence intervals for the effect of treatment on flexion and abduction. It was tested using a random effects model as well. All the data are reported as mean +/- standard deviation, with pmile/hr;
