Appendix A: The U.S. Longitudinal Studies of Osteoarthritis

Population-based

Patient-based

Baltimore Longitudinal Study of Aging (BLSA)

PI: Marc C. Hochberg, MD, MPH, University of Maryland School of Medicine (mhochber@umaryland.edu)
with Jeffrey Metter, MD, Gerontology Research Center, National Institute on Aging

Population studied: Healthy, community-dwelling, middle to upper-middle class volunteers ages 40 to 89. Men enrolled since 1958; women since 1978. Longitudinal analysis includes 300 subjects with 10-year x-rays. Includes symptomatic and asymptomatic individuals.

Endpoints: Radiographic OA, global score; in some cases, total knee replacement.

Accessibility of data: Data are available with an analysis plan submitted and reviewed for approval by GRC/BLSA protocol review committee.

Joints evaluated:___Knee and hand

Specimens: Frozen serum, some frozen fibroblasts for DNA taken contemporaneously with visits every 2 years. Specimens stored at -70 C. No synovial fluid, no urine.

Imaging studies: Bilateral posteroanterior hand radiographs taken every 4 years since inception. Bilateral standing anteroposterior tibiofemoral knee radiographs. Knee radiographs taken between 1985 and 1991, then follow-up in small subset (n=300) in 1997-98. No lateral or skyline views of knee to assess patellofemoral joint.

Status: Active and closed.

Summary of strengths and limitations:
Strength: This represents a potential data set for surrogate markers of OA with long-term follow-up, standard radiographic outcomes, and data on risk factors for OA.
Limitations: samples may not be contemporaneous with x-rays and may not be available on all subjects. Subjects are not a random population sample. Power for progression is limited due to small number with follow-up x-rays. No urine or synovial fluid specimens.

Major findings:

  • There is an association between OA in hand sites and the knee. The strength of association increases with increased disease severity (Hirsch 1996).

Relevant references:
Hirsch R, Lethbridge-Cejku M, Scott Jr WW, Reichle R, Plato CC, Tobin J, Hochberg M C. Association of hand and knee osteoarthritis: evidence for a polyarticular disease subset. Ann Rheum Dis 1996;55:25-29. [UI: 96164829]

Framingham Osteoarthritis Cohort Study (FOS)

PI: David T. Felson, MD, MPH, Boston University School of Medicine (dfelson@bu.edu)

Population studied: A population-based observational study of two cohorts, both include symptomatic and asymptomatic individuals:

1. Elderly white men and women, first enrolled in 1948-51. The OA component of the study began in 1983 with questions about musculoskeletal disease and radiography of bilateral hands and anteroposterior knee (original n=1434). At 10-year follow-up, in 1992-93, 869 individuals (mean age 78 yrs) received follow-up lateral and AP knee radiography. Hand radiographs also obtained in 1992-93 and represent 25-year follow-up to hand radiographs obtained in 1967-69.

2. Offspring: sons and daughters of the original cohort and spouses of these sons and daughters (n=1779) were x-rayed in 1993-94 (mean age mid-50s). Weight-bearing knee x-rays (AP and lateral) and hand radiographs obtained on all subjects.

Endpoints: Radiographic (osteophytes and joint space narrowing) and symptomatic OA (pain, function). Also looked at BMI, injury, ERT use, chondrocalcinosis. Extensive risk factor data available.

Accessibility of data: Not accessible, except in special, negotiated circumstances.

Joints evaluated: Knee, hand

Specimens: Blood samples were collected from original cohort during 1987-89. Urine also collected. No synovial fluid. Similar specimens collected from offspring.

Imaging studies:

Cohort 1. Baseline radiograph of right hand in 1967-69. Follow-up radiographs of both left and right hands performed 25 years later, 1992-93. Standing AP knee radiograph in 1983-85. In 1992-93 each participant received a standing AP and standing lateral knee radiographs of each knee flexed to about 30 degrees by placing the foot on a raised step.

Cohort 2. In 1993-94, bilateral hands and weight-bearing knees and lateral knees.

Status: Follow up of offspring is pending. Original cohort is not likely to be restudied.

Summary of strengths and limitations:
Strengths: Useful for information on late-onset knee OA. This is a large longitudinal dataset. Offspring group, if followed, will represent middle- and older-age onset of disease.
Limitations: (possible) Although Framingham policy prohibits data sharing, it is negotiable on a case-by-case basis.

Major findings:

  • A Mendelian form of transmission of generalized OA is likely. The occurrence of disease is affected by other factors, such as other contributory genes or environmental or personal factors that might induce OA (Felson 1998). 
     
  • Symptomatic knee OA (defined as pain on most days plus positive findings on radiograph of the symptomatic knee) occurs in 6.1% of adults ages 30 and over. Symptomatic hip OA occurs in 0.7-4.4% of adults (Lawrence 1998).
     
  • Of those disease-free at baseline, 83% developed radiographic OA in at least one right hand joint at 24-year follow-up. Women had more disease than men in most all hand joints, but the joints most frequently affected were the same in both sexes. Baseline OA in one joint in a row of the hand markedly increased the risk of developing OA in other joints in the same row (same joint in 4 or 5 digits). Baseline OA in a joint in a ray (multiple joints in the same digit) similarly increased risk in that ray (Chaisson 1997).
     
  • Risk Factors: Women were at higher risk for OA than men. Elderly people at risk of developing radiographic knee OA included obese persons, nonsmokers, and those who were physically active. The direction of weight change correlated directly with the risk of developing OA (Felson 1997). 
     
  • The pathogenesis of tibiofemoral OA and patellofemoral OA and a combination of the two compartments of the knee do not differ substantially with respect to BMI, age, sex, chondrocalcinosis, and knee injury; BMI, in particular, is a potent risk factor for all three (McAlindon, J Rheumatol 1996). 
     
  • Persons with low intake and low serum levels of vitamin D are approximately three times more likely to have progression of established knee OA than are persons with high intake and high serum levels. However, the researchers found no evidence that low intake and low serum levels of vitamin D influenced the risk of developing OA in a previously normal knee (McAlindon, Ann Internal Med 1996).
     
  • Rates of incident disease in an 8-year follow-up were 1.7 times higher in women than in men, and progressive disease occurred slightly more often in women, but rates did not vary by age. Approximately 2% of women per year developed incident radiographic disease, 1% per year developed symptomatic knee OA, and about 4% per year experienced progressive knee OA (Felson 1995).
     
  • Weight loss reduces the risk for symptomatic knee osteoarthritis in women (Felson 1992).
     
  • Obesity or as yet unknown factors associated with obesity cause knee osteoarthritis. The link is stronger in women than men. The link between obesity and subsequent osteoarthritis persisted after controlling for serum uric acid level and physical activity. Obesity at examination 1 was associated with the risk of developing both symptomatic and asymptomatic osteoarthritis 36 years later (Felson 1988). 
     
  • Symptomatic knee OA occurs in 9.5% of persons age 63-94. Prevalence is higher in women (11.4%) than in men (6.8%) (Felson 1987).

Relevant references:
Felson DT, Couropmitree NN, Chaisson CE, Hannan MT, Zhang Y, McAlindon TE, LaValley M, Levy D, Myers RH. Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis. Arthritis Rheum 1998;41:1064-71. [UI: 98288705]

Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-99. [UI: 98248143]

Chaisson CE, Zhang Y, McAlindon TE, Hannan MT, Aliabadi P, Naimark A, Levy D, Felson DT. Radiographic hand osteoarthritis: Incidence, patterns, and influence of pre-existing disease in a population-based sample. J Rheumatol 1997;24:1337-43. 
[UI: 97371869]

Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman B, Aliabadi P, Levy D. Risk factors for incident radiographic knee osteoarthritis in the elderly. Arthritis Rheum 1997;40:728-33. [UI: 97244308]

McAlindon T, Zhang Y, Hannan M, Naimark A, Weissman B, Castelli W, Felson D. Are risk factors for patellofemoral and tibiofemoral knee osteoarthritis different? J Rheumatol 1996;23:332-7. [UI: 97036394]

McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Wilson P, Jacques P. Relation of dietary intake and serum vitamin D to progression of osteoarthritis of the knee among participants in the Framingham study. Ann Intern Med 1996;125:353-9. [UI: 96332130]

Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman BN, Aliabadi P, Levy D. The incidence and natural history of knee osteoarthritis in the elderly. The Framingham osteoarthritis study. Arthritis Rheum 1995;38:1500-05. [UI: 96017448]

Felson DT, Zhang Y, Anthony JB, Naimark A, Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Internal Med 1992;116:535-9. [UI: 92181042]

Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis: the Framingham study. Ann Internal Med 1988;109:18-24.
[UI: 88239258]

Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly; the Framingham Osteoarthritis Study. Arthritis Rheum 1987;30:914-8. [UI: 87326533]

Dynamics of Health, Aging, and Body Composition (Health ABC)

Project Officer: Tamara Harris, MD, National Institute of Aging (harrist@gw.nia.nih.gov)

Population studied: This is a study of change in body composition in relation to incident disability and weight-related health conditions. It is a seven-year, population-based cohort study of men and women ages 70 to 79 at entry (mean age 73), selected largely from Medicare enrollment files (n=3075); 33% of men and 46% of women are African American. At baseline (1997-98), all participants reported themselves free of disability in activities of daily living and free of functional limitations (defined as difficulty walking a quarter of a mile or difficulty walking up 10 steps without resting). Recruitment centers are in Pittsburgh, PA, and Memphis, TN. Individuals are asymptomatic and symptomatic (at baseline, about one third reported frequent knee symptoms; 20% had both symptoms and radiographic knee OA).

Endpoints: Self-reported disability, measures of physical function (including walking, rising from a chair, balance), isometric and isokinetic measures of muscle strength, and walking endurance. Joint symptoms assessed using questions adapted from NHANES studies, Framingham OA study, and WOMAC.

X-rays read with semiquantitative scoring of individual radiographic features and quantitative measurement of minimal joint space. MRI reading includes semiquantitative whole organ scoring system: Five articular surface features (cartilage, marrow edema, subarticular cysts, bone attrition, osteophytes) and seven other features (medial and lateral menisci, anterior and posterior cruciate ligaments, medial and lateral collateral ligaments, synovium, and effusion).

Physical exam of knee, hip, and hands at baseline OA visit (Year 2 of study) measures crepitus in the knee, bony swelling of interphalangeal joints, and impaired internal and external rotation of the hip with goniometric measurement of hip internal rotation.

Accessibility of data: Researchers are actively seeking to augment the scientific yield of the study, particularly for weight-related health conditions. Studywide policies exist for ancillary studies, publications, and collaborations with outside investigators.

Joints evaluated: ___Knee (hip and hands are physical exam only)

Specimens: Plasma, serum, and urine specimens collected at baseline. Plasma and serum collected annually. Specimens stored at -70�C. Analysis of plasma IL-6, TNF-alpha, and C-reactive protein in progress for entire cohort.

Imaging studies: Bilateral, weight-bearing PA semi-flexed radiographs of the knee and weight-bearing axial (skyline) views of the knees, were obtained at the Year 2 visit (baseline for OA studies) in all subjects (n=900) reporting knee symptoms on most days of a month in the past year, or who reported at least moderate pain on activity. These subjects will be invited for follow-up knee radiograph in Year 7. Bilateral MRI of the knee was obtained for 70% of subjects with knee symptoms. Bilateral MRIs also obtained on a random sample of 500 subjects who did not have knee symptoms and in 50% of these subjects, knee radiographs were also obtained.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: Peak age for incidence of knee OA. Breadth and depth of relevant longitudinal measurements. Largest sample of knee MRI; MRI library could be reanalyzed by other investigators. Large population of African-American men and women who are weight representative. Availability of stored biologic specimens. Plasma inflammation measurements being done on full cohort. Muscle measurements include both x-ray and strength testing. Repeat radiographs in those with baseline knee symptoms provide measures of radiographic progression outcome in these subjects. 
Limitations: Funding for repeat MRI scanning has not been obtained. Those with mobility disability excluded at baseline. Imaging studies exist for only a subset of subjects without symptoms, so ability to study incidence or progression of knee OA defined exclusively by radiograph is lacking. In-depth clinical examination for subjects with OA would need to be added at time of a repeat MRI.

Major findings: 
Papers to date are methodologic papers relevant to assessment of body composition.

Indiana University Multipurpose Arthritis and Musculoskeletal Diseases Center (IUMAMDC): Muscle Strength in the Development of Knee Osteoarthritis

PI: Kenneth D. Brandt, MD, Indiana University, Indianapolis (kbrandt@iupiu.edu)

Population studied: Population-based sample of 465 men and women ages 65 and older from central Indiana. Study began in 1996 with a 3-year duration, cohort is still being followed. Individuals are asymptomatic and symptomatic.

Endpoints: Incident and progressive radiographic changes of OA (Kellgren & Lawrence criteria) knee pain and function (WOMAC), BMD, lower extremity lean tissue mass (DEXA), quadriceps/hamstring strength.

Accessibility of data: Accessible with approval of IUMAMDC Director

Joints evaluated: Knee

Specimens: None

Imaging studies: Extended view and lateral knee radiographs at baseline and 3 years. DEXA at baseline and 3 years.

Status: Active and closed

Summary of strengths and limitations:
Strengths: Population-based sample.
Limitations: Conventional radiography. No specimens.

Major findings:

  • Quadriceps weakness is present in OA patients who do not have knee pain or decreased lower extremity muscle mass, suggesting that the weakness may be due to muscle dysfunction rather than disuse atrophy (Slemenda 1997)
     
  • Longitudinal data suggest that quadriceps weakness may be a risk factor for incident knee OA (Slemenda 1998, Brandt 1999). 
     
  • In cross-sectional analysis of subjects who had knee pain but a normal knee radiograph at baseline and 3 years, depression scores were high, suggesting that pain in those individuals may have been due to depression, rather than OA (Brandt, in press).

Relevant References:
Slemenda C, Brandt KD, Heilman DK, Mazzuca S, Braunstein EM, Katz BP, Wolinsky FD. Quadriceps weakness and osteoarthritis of the knee. Ann Intern Med 1997;127:97-104. [UI: 97357983]

Slemenda CW, Heilman DK, Brandt KD, Katz BP, Mazzuca SA, Braunstein EM, Byrd D. Reduced quadriceps strength relative to body weight: a risk factor for knee osteoarthritis in women? Arthritis Rheum 1998;41:1951-9. [UI: 99027174]

Brandt KD, Heilman DK, Slemenda CW, Katz BP, Mazzuca SA, Braunstein EM, Byrd D. Quadriceps strength in women with radiographically progressive osteoarthritis of the knee and those with stable radiographic changes. J Rheumatol 1999;26:2431-37.
[UI: 20022832]

Brandt KT, Heilman DK, Slemenda C, et al. A comparison of lower extremity muscle strength, obesity and depression scores in elderly subjects with knee pain and without radiographic evidence of knee osteoarthritis. J Rheumatol. In press.

Johnston County Osteoarthritis Project (JCOP)

PI: Joanne M. Jordan, MD, MPH, University of North Carolina at Chapel Hill (Joanne_Jordan@med.unc.edu)

Population studied: Population-based sample of African-American and Caucasian men and women ages 45 and older in rural North Carolina (mean age 60). Population (n=3200) is two thirds white, one third African American. Recruited between 1991-97. Includes symptomatic and asymptomatic individuals.

Endpoints: Incidence and progression. Looking at Kellgren-Lawrence (functional measures described in literature); joint space narrowing; and individual radiographic features, plus knee, hip, hand, foot, low back, and other joint pain. Also evaluating functional and work disability (Health Assessment Questionnaire, WOMAC, AUSCAN, 8-foot walk, repeated chair stands, grip strength, pinch strength), and psychosocial data (CES-D, anxiety, social support, rheumatology attitudes index, intrinsic optimism).

Accessibility of data: Process needs to be put in place to approve use of data, including consultation with CDC technical advisors. Jordan's group would need to be very involved in any research with their data.

Joints evaluated: Knee, patellofemoral, and hip; added hand at follow-up.

Specimens: Serum collected at baseline and stored at -80� C. At 5-year follow-up, collecting serum, plasma, buffy coat, and urine. Samples of these specimens still exist.

Imaging studies: Anterior radiography of the knees with weight bearing, sunrise patellofemoral joint, and AP pelvis at baseline. At 5-year follow-up, getting all those plus posterior anterior semi-flexed knee films and hand films (both hands). Also getting bone mineral density assessments: peripheral DEXA and full body DEXA.

Status: Active and closed

Summary of strengths and limitations: 
Strength: This is the largest study of OA involving African Americans. OA is characterized at more than one joint: knee and hip, and now hand. Have data on symptoms of other joint areas, as well as pain and disability data.
Limitations: Only had AP knee films, patellofemoral, and hip at baseline. Additional knee and hand films taken only at 5-year follow-up. No urine or DNA collected at baseline.

Major findings:

  • In a population-based sample, cartilage oligomeric protein (COMP) levels can distinguish an OA-affected subgroup from an unaffected subgroup and can reflect disease severity and multiple joint involvement in OA (Clark 1999). 
     
  • OA radiographic severity contributed little useful information beyond that of knee pain in determining subject difficulty in performing 20 activities. Mild and moderate/severe knee pain were associated with difficulty performing tasks requiring work by the lower extremities as well as the upper extremities (Jordan 1997). 
     
  • Participants used a variety of alternative and conventional remedies, with prayer being the most widely used. Prescription medicine was used by 60%. Differences in remedy use included European Americans making greater use of conventional remedies and African Americans making greater use of some alternative remedies. Those with greater functional disability were more likely to have used alternative remedies, but they still used prescription medicine (Acrury 1996). 
     
  • Differences in proportions of African Americans and Caucasians in reporting difficulty in performance of Health Assessment Questionnaire (HAQ) tasks were minimal, but risk factor profiles for difficulty appeared to vary by ethnicity. Obesity appeared an important part of the risk factor profiles for difficulty performing tasks of transfer, mobility, and instrumental activities of daily living in African Americans, while age > 75 and female gender were more often part of the risk factor profiles for difficulties reported by Caucasians (Jordan 1996, Ethnic differences...). 
     
  • Knee pain severity was more important than radiographic knee OA in determining disability. Obesity was independently associated with disability and compounded disability from knee pain (Jordan 1996, Self reported functional status...).
     
  • African Americans are not spared from hip OA (Jordan 1995).

Relevant references:
Clark AG, Jordan JM, Vilim V, Renner JB, Dragomir AD, Luta G, Kraus VB. Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity. Arthritis Rheum 1999;42:2356-64. [UI: 20021502]

Jordan J, Luta G, Renner J, Dragomir A, Hochberg M, Fryer J. Knee pain and knee osteoarthritis severity in self-reported task specific disability: The Johnston County Osteoarthritis Project. J Rheumatol 1997;24:1344-9. [UI: 97371870]

Jordan, JM, Luta G, Renner JB, Dragomir A, Hochberg MC, Fryer JG. Ethnic differences in self-reported functional status in the rural south: The Johnston County Osteoarthritis Project. Arthritis Care Res 1996;9:483-91. [UI: 97282045]

Jordan JM, Luta G, Renner JB, Linder GF, Dragomir A, Hochberg MC, Fryer JC. Self-reported functional status in osteoarthritis of the knee in a rural southern community: The role of sociodemographic factors, obesity, and knee pain. Arthritis Care Res 1996;9:273-8. [UI: 97151983]

Acrury TA, Bernard SL, Jordan JM, Cook HL. Gender and ethnic differences in alternative and conventional arthritis remedy use among community-dwelling rural adults with arthritis. Arthritis Care Res 1996;9:384-90. [UI: 97151995]

Jordan JM, Linder GF, Renner JB, Fryer JG. The impact of arthritis in rural populations. Arthritis Care Res 1995;8:242-50. [UI: 96193481]

Michigan Bone Health Study (MBHS)

PI: MaryFran Sowers, PhD, University of Michigan (mfsowers@umich.edu)

Population studied: A population-based longitudinal study of white, premenopausal women ages 25-45 (mean age 37) in Tecumseh, MI. Osteoarthritis component began in 1992/93 (n=601). Hand and knee x-rays and bone mineral density measures were taken in 1992/93 and 1995/6 and 1998 for 482 women. Cohort includes asymptomatic and symptomatic women.

Endpoints: X-ray measures (osteophytes, joint space narrowing), bone mineral density, body composition, hormone levels, exercise capacity, diet, markers of cartilage and bone turnover, pain, injury, joint symptoms, function, and activity level (Stanford Five-City Study instrument), and genotyping.

Accessibility of data: Database is available to selected collaborators who have ability to protect confidentiality, demonstrate respect for the interests of current collaborators, and not involve activities that will compromise the integrity or retention of the cohort.

Joints evaluated: Sixteen joints of the dominant hand and both knees (weight bearing) were evaluated in three exams (1992-3, 1995-6, 1998).

Specimens: Serum and urine collected and frozen at -80�C at each information gathering contact, rather than at disease diagnosis. Collected in fasted state and during days 3-7 of menstrual cycle for those still menstruating.

Imaging studies: Anterior-posterior radiographs of dominant hand and both knees at baseline (either 1988 or 1992) and 8 years later.

Status: Active and closed. A follow-up in 2000 is funded to include x-rays, bone densitometry, and biochemical markers.

Summary of strengths and limitations: 
Strengths: This may be a good age cohort for studying emerging OA disease. There is longitudinal assessment of the cohort beginning at a disease-free state.
Limitation: Women only.

Major findings:

  • Women with radiographically defined knee OA had greater BMD than women without knee OA and were less likely to lose that higher level of BMD. There was less bone turnover among women with hand OA and/or knee OA (Sowers, Lachance 1999). 
     
  • Sex hormone genes may be important contributors to the variation in bone mineral density among pre- and perimenopausal women (Sowers, Willing 1999). 
     
  • Mid-aged women who develop radiographically-defined OA of the knee had greater bone mineral density (at all sites) than women without OA of the knee. Women with knee OA did not lose as much bone density over 3 years as did women without knee OA. Women with knee OA and or hip OA had lower bone turnover and less change in bone turnover, as measured by osteocalcin, than women without OA. Mid-aged women with OA had a differential response of bone forming cells with time (presented at NIH Conference: Stepping Away from OA, 7/99 [https://www.nih.gov/niams/reports/oa/oareport.htm].
     
  • Prevalence was low in perimenopausal population (2.8% hand OA, 3.6% knee OA). History of knee injury had significant impact on prevalence of knee OA. Increased prevalence of hand OA occurred with older age, greater bone density, and lower serum testosterone levels. Knee OA increased with older age, greater BMI, greater BMD, and current use of replacement hormones (Sowers 1996).

Relevant references: 
Sowers MF, Lachance L, Jamadar D, Hochberg M, Crutchfield M, Jannausch ML. The association of bone mineral density and bone turnover markers with osteoarthritis of the hand and knee in pre- and peri-menopausal women. Arthritis Rheum 1999;42:483.
[UI: 99186632]

Sowers MF, Willing M, Burns T, Deschenes S, Hollis B, Crutchfield M, Jannausch M. Genetic markers, bone mineral density, and serum osteocalcin levels. J Bone Min Res 1999;14:1411-19. [UI: 99388222]

Sowers MF, Hochberg M, Crabbe JP, Muhich A, Crutchfield M, Updike S. The association of bone mineral density and sex hormone levels with osteoarthritis of the hand and knee in premenopausal women. Am J Epidemiol 1996;143:38-47.
[UI: 96129939]

National Health and Nutrition Examination Survey (NHANES)

Contact for OA section: Rosemarie Hirsch, MD, MPH, National Center for Health Statistics, CDC (rrh7@cdc.gov)

Focus here is NHANES-III, conducted 1988-94. It is most recent NHANES study with OA exam, x-rays, and interview questions.

Population studied: Cross-sectional, nationally representative, population-based survey of a stratified, random, noninstitutionalized civilian sample of the U.S. population. Radiographs available on 5000 individuals ages 60 and older; interview-related arthritis data available on 3479 women and 3117 men (n=6596). Older age groups (60+) and minorities (non-Hispanic Blacks and Mexican Americans) were oversampled. Includes symptomatic and asymptomatic individuals.

Endpoints: Since non-weight bearing films, osteophytes and individual radiographic features excluding joint space narrowing; interview and lab information that can be used to construct OA definitions based on ACR classification criteria. Disability measured with HAQ-like instrument and physical performance measures.

Accessibility of data: Database is accessible to other researchers via cd-rom, however, radiographs have not been read (in process). Specimens are available. Sera that have not been thawed are available from CDC bank with justification.

Joints evaluated: Knee, hand

Specimens: Serum collected at study entry, stored at -70� C (some may have been through at least two freeze-thaw cycles).

Imaging studies: PA radiograph of hands, non-weight bearing AP radiograph of knees done at study entry.

Status: Closed. May be a passive follow-up (medicare match on endpoints like joint replacement) or a longitudinal follow-up including interview and possible exam (probably will not include radiographs, but may include serum sampling).

Summary of strengths and limitations:
Strengths: Nationally representative population with minority representation. This population could serve as the referent group for the expected value of biomarkers in the population, even if NHANES III radiographs not studied for biomarker associations. Multiple collateral data on disability, including performance measures and HAQ-like questionnaire information. 
Limitations: X-rays were non-weight bearing, so assessment of joint space narrowing not useful. No longitudinal x-rays. No x-rays for younger age groups.

Major findings: 
None published.

Relevant references:
Plan and Operation of the Third National Health and Nutrition Examination Survey, 1983-94. National Center for Health Statistics. Vital Health Stat. 1(32) 1994.

San Antonio Longitudinal Study of Aging (SALSA)

PI: Helen Hazuda, PhD, University of Texas Health Science Center at San Antonio
(hazuda@uthscsa.edu)

Population studied: Population-based sample of Mexican-American (53%) and European-American elderly men and women ages 65 and older who originally participated in San Antonio Heart Study. Sampled from three diverse neighborhoods -- low, middle, and high income. Began data collection in 1992. N=749. Individuals are asymptomatic and symptomatic.

Accessibility of data: May be accessible with appropriate agreement with PI and IRB review.

Endpoints: Endpoints are impairment, functional limitations, and disability. Looking at pain (McGill Pain Questionnaire and Map) as well. In all three, using performance and self-report measures.

Joints evaluated: Knee, hand, hip, shoulder, elbow.

Specimens: Baseline serum contingency sample (2ml) collected on majority of subjects and stored at -70� or -80� C. If follow-up study is funded, additional contingency samples will be taken. No plans to analyze them for OA.

Imaging studies: No radiography at baseline. At follow-up, will do radiographs of hips, knees, and hands. Hips and knees will be supine.

Status: Completed baseline study in 1996. Anticipate funding to begin April 2000 follow-up, longitudinal study, evaluating subjects every 18 months over a 5-year period (3 visits).

Summary of strengths and limitations: 
Strengths: Unique access to Mexican-American population. There are plans to do use existing serum for genetic analyses and biomarkers of aging, could include biomarkers of OA. They have serum on at least 60% of the population, may have it on remainder as well. 
Limitations: No x-rays at baseline. Follow-up x-rays of knee will be supine.

Major findings:

  • Most community-dwelling elderly people have a flexion range (FR) of the hips and knees that can be considered functional. There was a significant association between each hip and knee joint and its contralateral mate and ipsilateral partner joint. Rising BMI and female sex were independently associated with reduced flexion range of both hips and knees, a Mexican American ethnic background was associated with decreased hip FR, and knee pain was associated with decreased knee FR (Escalante 1999, first on list).
     
  • The great majority of community-dwelling elderly have a flexion range of shoulder and elbow joints that can be considered functional. Diabetes mellitus and obesity are two potentially treatable factors associated with reduced flexion range of these two functionally important joints (Escalante 1999, second on list).

Relevant references:
Escalante A, Lichtenstein MJ, Dhanda R, Cornell JE, Hazuda HP. Determinants of hip and knee flexion range: results from the San Antonio Longitudinal Study of Aging. Arthritis Care Res 1999; 12:8-18. [UI: 99442976]

Escalante A, Lichtenstein MJ, Hazuda HP. Determinants of shoulder and elbow range of motion: results from the San Antonio Longitudinal Study of Aging. Arthritis Care Res 1999;12:277-86. [UI: 20154582]

Study of Osteoporotic Fractures (SOF)

PI: Michael C. Nevitt, PhD, University of California at San Francisco (Mnevitt@psg.ucsf.edu)

Population studied: Multicenter, population-based study of 9704 white, elderly women (65 and older; mean age 71 at baseline) recruited between 1986 and 1988 in Baltimore, MD, Minneapolis, MN, Portland, OR, and the Monongahela Valley near Pittsburgh, PA. Excluded were nonambulatory women and those with bilateral hip replacement. Follow-up occurred at 8 years. Includes symptomatic and asymptomatic individuals.

Endpoints: Radiographic hip OA, both incident and progressive, with data on joint space narrowing, osteophyte development, and other radiographic features. Also evaluated BMD, pain, function, and activity (modified Paffenbarger survey).

Accessibility of data: Access is through study publication guidelines. Data would be available with steering committee approval, which would likely involve Nevitt's group's participation in approved study. Only about half of subjects gave consent for use of samples in genetic studies.

Joints evaluated: Hip, spine, and hand. Longitudinal data available for hip and spine only.

Specimens: Serum, urine, genetic samples collected at baseline and stored at -80� C on all subjects. All stored at Roche Biosciences, which is doing genetic studies with them.

Imaging studies: Hand x-ray at baseline only. Bilateral supine anteroposterior radiograph of the pelvis with hips in 15-30 degrees of internal rotation taken at baseline and about 8 years later. Serial x-rays are available on over 6000 participants.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: large sample size with radiographic follow-up and concurrent information on pain and function.
Limitations: For serum markers, specific processing requirements for serum marker studies may be different than those used for this study, since their samples were not obtained to study markers of OA. For example, samples are not fasting. Also, longitudinal data are not available for hands. No knee radiographs.

Major findings:

  • Elderly women with low serum levels of 25-vitamin D are nearly three times as likely to develop incident radiographic hip OA characterized by joint space narrowing, as are elderly women with serum levels in the highest tertile (Lane 1999).
     
  • Postmenopausal estrogen replacement therapy may protect against OA of the hip in elderly white women (Nevitt 1996).
     
  • Elderly caucasian women with moderate to severe radiographic hip OA had higher bone mineral density in the hip, spine, and appendicular skeleton than did women without hip OA. These findings are consistent with a role of elevated BMD in the pathogenesis of hip OA (Nevitt 1995).
     
  • Radiographically-defined hand OA was associated with radiographic changes of definite hip OA. The existence of a disease subset of polyarticular radiographic OA supports the continued search for underlying metabolic and genetic factors in the etiopathogenesis of OA (Hochberg 1995).

Relevant References:
Lane NE, Gore LR, Cummings SR, Hochberg MC, Scott JC, Williams EN, Nevitt MC. Serum vitamin D levels and incident changes of radiographic hip osteoarthritis. Arthritis Rheum 1999;42:854-60. [UI: 99255019]

Nevitt MC, Cummings SR, Lane NE, Hochberg MC, Scott JC, Pressman AR, Genant HK, Cauley JA. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1996;156:2073-80. [UI: 97015418]

Nevitt MC, Lane NE, Scott JC, Hochberg MC, Pressman Ar, Genant HK, et al. Radiographic osteoarthritis of the hip and bone mineral density. Arthritis Rheum 1995;38:907-16. [UI: 95336484]

Hochberg MC, Lane NE, Pressman AR, Genant HK, Scott JC, Nevitt MC. The association of radiographic changes of osteoarthritis of the hand and hip in elderly women. J Rheumatol 1995;22:2291-4. [UI: 96432498]

Study of Women Across the Nation (SWAN)

PI: MaryFran Sowers, PhD, University of Michigan (mfsowers@umich.edu)

Population studied: Population-based, longitudinal study of 543 African-American and European-American women in perimenopause (ratio of African American to white is 2:1), includes a study of osteoarthritis. Enrollees derived from household census of two communities near Detroit, MI. Enrollees were ages 42-52 (mean age 46), had menstruated within the previous 3 months, and were not using hormone replacement therapy. Radiography study was implemented in 1996.

Endpoints: Osteophytes, joint space narrowing, BMD, body composition, hormones, exercise capacity, diet, markers of cartilage and bone turnover, pain, and injury. Function measured by grip strength, gait, stair climbing, and SF-36.

Accessibility of data: The database is accessible for very selective collaborations. They should reflect an ability to protect confidentiality, demonstrate respect for current collaborators, and not involve activities that will compromise the integrity or retention of the cohort or the overall SWAN study.

Joints evaluated: Sixteen joints of the dominant hand and both knees (weight bearing) evaluated in 1996, 1998, and planned for 2000.

Specimens: Serum and urine collected at each contact time, linked with information gathering, not disease diagnosis. Stored at -80� C. Collected at fasted state and in days 2-5 of menstrual cycle, for those menstruating.

Imaging studies: X-rays of dominant hand, and weight-bearing x rays of both knees taken in 1996, 1998, and planned for 2000.

Status: Active and closed.

Summary of strengths and limitations:
Strength: Can be combined with Michigan Bone Health Study to form a cohort of 1050. 
Limitations:

Relevant References: 
Papers have been submitted or are in press.

Women's Health in Aging Study (WHAS)

PI: Linda P. Fried, MD, MPH, Johns Hopkins University School of Medicine

Population studied: Population-based recruitment of 1002 moderately to severely disabled women, community-dwelling in Eastern Baltimore (ages 65 and older). Includes symptomatic and asymptomatic individuals. Population is 28% African American; women 85+ were oversampled. If symptomatic knee pain in past year, invited to have x-rays. Data collected from 1992 to 1995 and included 6-month follow-up interviews at home every 6 months for 3 years and annual telephone interviews at years 4 and 5.

Endpoints: Progression in symptomatic patients. OA determined using ascertainment algorithm for presence of hand, hip, and knee OA based on symptoms, examination, radiograph, and physician questionnaire info (ACR classification criteria). Kellgren-Lawrence scale and individual radiographic feature scale of hip and knee OA. Hand photographs scored for bony prominence and deformity.

Accessibility of data: Database is accessible by contacting J. Guralnik at the National Institute on Aging. Longitudinal assays of blood from follow-up years 1 and 2 are possible. DNA are available, though discussions are ongoing with Hopkins IRB regarding what can be done with the samples.

Joints evaluated: Knee, hand, hip

Specimens: Serum collected at baseline. Blood samples have been saved from follow-up year 1 and year 2.

Imaging studies: Standing PA radiograph taken at baseline or within 3 years prior to study baseline. AP radiograph of pelvis taken at baseline or 3 years prior. Photographs of hands. No longitudinal radiographs planned.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: Population based, making control selection easy. For testing biochemical markers, this population enriched for disease severity, moderately to severely disabled, may be useful. Films already read for individual radiographic features; OA information available on multiple sites. 
Limitations: Radiographs were not available on all participants; no longitudinal radiographs planned; not all radiographs were study films, some taken in clinical settings (i.e., not all done via same radiograph protocol.) No data on women younger than 65; no urine or DNA.

Major findings:

  • Severe pain in the lower back, hips, knees or feet was reported by 48.5% of the women in the study; 78.8% were using analgesic medications, though 41.2% were using less than 20% of the maximum analgesic dose. The authors conclude that additional, more effective, and safe analgesic treatments are needed for controlling pain in older persons (Pahor 1999).
     
  • Arthritis was the most common condition reported by women in the WHAS. It affected multiple joints and frequently caused knee pain. More than one half of women had pain or stiffness in the hands or wrists and in the knees in the past month, and about 40% had pain in the hips and feet during the previous month. On physical exam, more than 80% of women had patello-femoral crepitus on flexion and extension of their knees, the most common physical finding in patients with knee OA; about 35% had tenderness or pain on motion, 42% had bony enlargement of the knees, and 17% had either a valgus or varus deformity of the knee (Guralnik 1995).

Relevant references:
Pahor M, Guralnik JM, Wan JY, Ferrucci L, Penninx BW, Lyles A, Ling S, Fried LP. Lower body osteoarticular pain and dose of analgesic medications in older disabled women: The Women's Health and Aging Study. Am J Public Health 1999;89:930-4.

Guralnik JM, Fried LP, Simonsick EM, Kasper JD, Lafferty ME, eds. The Women's Health and Aging Study: Health and Social Characteristics of Older Women with Disability. Bethesda MD: National Institute on Aging, 1995; NIH Pub. No. 95-4009. (http://www.nia.nih.gov/HealthInformation/Publications/Reports/WomensHealthAgingStudy.htm)

Boston Osteoarthritis of the Knee Study (BOKS)

PI: David T. Felson, MD, MPH, Boston University School of Medicine (dfelson@bu.edu)

Population studied: A natural history study of 349 men and women (34%) with knee OA (10% African American). Mean age is 66. Study began in 1997 and includes follow-up every 15 months.

Endpoints: Joint space narrowing, symptomatic OA, meniscal subluxation, weight, pain.

Accessibility of data: Available with approval.

Joints evaluated: Knee

Specimens: Serum and urine at baseline and every 15 months, stored at -80�C.

Imaging studies: X-rays include fluoro-positioned semilflexed knee films and skylines. MRI done also. Both x-rays and MRI done every 15 months.

Status: Active and closed.

Summary of strengths and limitations: 
Strengths:
Limitations:

Major findings:

  • Meniscal subluxation is highly associated with symptomatic knee OA. In subjects with OA, increasing meniscal subluxation on MR correlates with the severity of joint space narrowing (Gale 1999).

Relevant References:
Gale DR, Chaisson CE, Totterman SMS, Schwartz RK, Gale ME, Felson D. Meniscal subluxation: association with osteoarthritis and joint space narrowing. Osteoarthritis Cartilage 1999;7:526-32. [UI: 2002780]

Indiana University Multipurpose Arthritis and Musculoskeletal Diseases Center (IUMAMDC): Progression of Osteoarthritis

PI: Kenneth D. Brandt, MD, Indiana University, Indianapolis (kbrandt@iupiu.edu)

Population studied: Volunteer sample of 253 men and women from central Indiana with mild-to-moderate knee OA (i.e., K&L; grade II and medial joint space width > 2.0mm). Study recruitment occurred from 1997-99; duration is 30 months.

Endpoints: Medial tibiofemoral joint space narrowing, incident and progressive radiographic changes of OA (K&L; criteria), knee pain and function (WOMAC) after NSAID/analgesic washout.

Accessibility of data: Available with approval of IUMAMDC Director. Specimens availability to be decided by a panel of experts to be named at a later date.

Joints evaluated: Knee

Specimens: Serum and urine at baseline, 16 months, and 30 months. Synovial fluid when obtained for clinical reasons.

Imaging studies: Bilateral PA hand radiograph at baseline only. Semiflexed AP radiograph and supine lateral radiograph at baseline, 16 months and 30 months. Hughston (patellofemoral) view at baseline, 16 and 30 months.

Status: Active and closed

Summary of strengths and limitations: 
Strengths: Highly reproducible indicator of radiographic OA progression (JSN)
Limitations: Only three data collection points.

Major findings/Relevant references: 
Study in progress

Mechanical Factors in Arthritis of the Knee Study (MAK)

PI: Leena Sharma, MD, Northwestern University (l-sharma@nwu.edu)

Population studied: 300 men and women with knee OA recruited from the community (ages 33-96). Subjects required to meet radiographic definition of OA and have at least "a little" difficulty with at least 2 WOMAC physical function items. Baseline data collected in 1997.

Endpoints: Radiographic and functional status (WOMAC and performance measure) outcomes

Accessibility of data: Collaboration is possible with involvement of MAK investigators. Specimens are being examined within ongoing collaborations; supply is very limited.

Joints evaluated: Radiographic assessment of knee, non-radiographic assessments of other joints, including hand and hip.

Specimens: Serum and urine at baseline, 18 months, and 36 months, stored at -80� C on all subjects.

Imaging studies: Knee radiographs (weight-bearing semi-flexed view of tibiofemoral compartments with fluoroscopic confirmation and weight-bearing skyline/axial view of patellofemoral compartment) at baseline, 18 months, and 36 months.

Status: Active and closed.

Summary of strengths and limitations: 
Strength: Novel emphasis on mechanical factors, radiographic protocols, examination of functional status outcomes. 
Limitations: Small sample, not population-based, no MRI data.

Major findings:

  • Varus-valgus laxity may precede the development of knee OA and become worse with progression of the disease (Sharma, Lou 1999).
     
  • Varus-valgus laxity was associated with a decrease in the magnitude of the relationship between strength and physical function in knee OA (Sharma, Hayes 1999). 
     
  • BMI was related to OA severity in those with varus knees, but not valgus knees. Much of the effect of BMI on OA severity was explained by varus malalignment (Sharma, in press).
     
  • Proprioception declined with age, and was further impaired in elderly patients with knee OA. Poor proprioception may contribute to functional impairment in knee OA (Pai 1997).
     
  • Proprioception was comparably impaired in arthritic and nonarthritic knees of unilateral OA patients vs. controls, suggesting that the impairment is not exclusively a local result of disease (Sharma 1997).

Relevant references:
Sharma L, Lou C, Felson DT, Dunlop DD, Kirwan-Mellis G, Hayes KW, Weinrach D, Buchanan TS. Laxity in healthy and osteoarthritis knees. Arthritis Rheum 1999;42:861-70. [UI: 99255020]

Sharma L, Hayes KW, Felson DT, Buchanan TS, Kirwan-Mellis G, Lou C, Pai YC, Dunlop DD. Does laxity alter the relationship between strength and physical function in knee osteoarthritis? Arthritis Rheum 1999;42:25-32. [UI: 99116738]

Sharma L, Lou C, Cahue S, Dunlop DD. The mechanism of the effect of obesity in knee osteoarthritis: the mediating role of malalignment. Arthritis Rheum. In press.

Pai YC, Rymer WZ, Chang RW, Sharma L. Effect of age and osteoarthritis on knee proprioception. Arthritis Rheum 1997;40:2260-5. [UI: 98077348]

Sharma L, Pai YC, Holtkamp K, Rymer WZ. Is knee joint proprioception worse in the arthritic knee versus the unaffected knee in unilateral knee osteoarthritis? Arthritis Rheum 1997;40:1518-25. [UI: 97402370]

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