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Rowan T. Chlebowski is a primary author.
Rowan T. Chlebowski, Karen C. Johnson, Dorothy Lane, Mary Pettinger, Charles L. Kooperberg, Jean Wactawski-Wende, Tom Rohan, Mary Jo O'Sullivan, Shagufta Yasmeen, Robert A. Hiatt, James M. Shikany, Mara Vitolins, Janu Khandekar, and F. Allan Hubbell are contributing authors who have reviewed and approved the final manuscript.
Low 25 hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms.
Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women's Health Initiative Calcium plus Vitamin D clinical trial.
25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling.
The 25(OH) D levels were commonly low with 53% having deficient (< 50 nmol/L) and only 17% having sufficient (> 72 nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake (R =0.29, P<0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score (P=0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile.
Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials.
While 25-hydroxyvitamin D (25(OH) D) concentration is an accepted marker for vitamin D status in humans , the association between total vitamin D intake (diet and supplements) and 25(OH) D concentrations has been somewhat inconsistent . Low 25(OH) D levels are associated with musculoskeletal disorders, with severe deficiency resulting in the clinical syndrome of osteomalacia . Some [4, 5, 6] but not all , cohort studies have associated low 25(OH) D levels with increased risk of radiographic worsening of osteoarthritis. However, few studies have evaluated associations between 25(OH) D levels with clinical joint symptoms.
Using data from a subset of women participating in the Women's Health Initiative (WHI) Calcium plus Vitamin D (CaD) clinical trial, in post hoc analyses we compared 1) serum 25(OH) D concentrations with total vitamin D intake (diet and supplement) and 2) serum 25(OH) D concentrations with joint symptoms including joint pain and joint swelling.
Women participating in the Women's Health Initiative hormone trials (HT) [8, 9] or the dietary modification (DM)  trial (N=68,132) were invited to enroll in an additional randomized, placebo-controlled trial evaluating calcium plus vitamin D supplementation (CaD) at their first or second annual follow-up clinic visit for the main trials . Details of the eligibility and conduct of the HT and DM trials, conducted at 40 clinical centers across the United States, have been reported [8, 9, 10] as have the influence of the interventions on major study outcomes [12, 13, 14]. A total of 36,282 women were eligible for and agreed to participate in the CaD trial.
Three nested case-control studies were conducted within the CaD clinical trial to examine associations between baseline 25(OH) D concentrations and colorectal cancer, breast cancer and facture incidence, respectively [12, 13, 14]. These included 2792 case patients with colorectal, breast cancer or hip fracture and 1993 matched control subjects. The control subjects were matched to the cancer and fracture patient cases on age, ethnicity/race, sample collection date and clinic center. The associations between 25(OH) D concentrations and total vitamin D intake include these 1993 subjects while associations between 25(OH) D concentration and joint symptoms include 1931 of these subjects with both determinants.
At entry in the HT or DM trial, information on demographics, disease risk factors, family and medical history and lifestyle factors were obtained by questionnaire. Medication use was assessed by interview- administered questionnaire. Physical measurements (height, weight) were made at the baseline clinical trial clinic visit.
Joint pain and swelling was assessed by questionnaire at entry into the CaD trial. Joint pain was assessed as; (yes/no), if yes (mild/moderate/severe) and joint swelling (as yes/no), if yes (mild/moderate/severe). The joint pain and swelling severity scores were calculated as an average of range from 0 (none) to 3 (severe).
At entry into the WHI HT or DM trials, a self-administered food-frequency questionnaire (FFQ) specifically designed for WHI  was used to access usual dietary intake over the previously 3 months including vitamin D intake from foods. Participants in the DM trial also had the FFQ administered at year 1, coinciding with sample collection for 25(OH) D concentrations. For non DM participants, the baseline dietary vitamin D intake at entry into the HT trial was used for association analyses. For DM trial participants, dietary vitamin D intake reported at baseline was closely comparable to that reported at year 1 (0.59, Pearson correlation coefficient, P<0.0001) . Information on current supplement use including dose and duration was collected by interviewer-administered questionnaire at entry into the CaD trial. Total vitamin D intake included both daily dietary intake (largely from dairy products and fatty fish) and the average daily intake of vitamin D supplements.
The 25(OH) D assays were conducted on frozen samples stored at -80 degrees C as previously described . Samples were collected at the time of CaD trial randomization after a 12 hour overnight fast. The DiaSorin Liason chemoluminescent immunoassay (DiaSorin Laboratories, Stillwater, MN) was used to determine 25(OH) D concentrations. Samples were run in batches that included blinded quality control samples with a coefficient of variation of 11.8 percent . While there is no consensus on optimal 25(OH) D concentrations, levels < 50 nmol/L, 50 to 72 nmol/L, and > 72 nmol/L were considered deficient, insufficient and sufficient, respectively, based on physiological evidence in a recent review .
All clinical trials had institutional review board approval and written informed consent was obtained from all participants. Statistical analyses and data management were conducted at the WHI Clinical Coordinating Center.
Analyses examining cross-sectional relationships between 25(OH) D concentration and total vitamin D intake (diet plus supplement) and joint symptoms involved linear regression models. The analysis for association with total vitamin D intake included all 1993 women having both 25(OH) D concentration and dietary and supplement intake information available. Average joint symptom scores were also compared by baseline 25(OH) D concentrations using unadjusted and adjusted linear regression models incorporating age, race/ethnicity, BMI and physical activity. In addition, effect modification by BMI, physical activity, and current menopausal hormone therapy use (based on hormone therapy trial randomization group or personal hormone use) on the association between joint symptoms and 25(OH) D levels was examined by including interaction terms in adjusted linear regression models. In these models, the level of 25(OH) D was treated as both linear and categorical terms (< 28.9 nmol/L, the cut off for the lowest of six equal groups, vs ≥ 28.9 nmol/L). All reported P-values are two-sided.
The baseline characteristics of the study sample with available 25(OH) D concentrations are outlined in table 1 and generally reflect the characteristics of the overall WHI CaD trial population (Chlebowski 2008). Overall, the 25(OH) D levels were commonly low, with 53% having deficient (<50 nmol/L) and only 17% having sufficient (> 72 nmol/L) levels.
Individual values for total vitamin D intake from both food and supplements are shown in relation to 25(OH) D concentration in figure 1. Total vitamin D intake was significantly but modestly associated with 25(OH) D concentrations (R=0.29, P<0.0001). Considerable variability in 25(OH) D concentrations for a given total vitamin D intake is seen.
Joint symptoms (any and mean) are shown by serum 25(OH) D sextiles in Table 2. Linear regression models were performed both unadjusted and adjusted for age, race/ethnicity, BMI and physical activity. The linear trend in the joint swelling score was statistically significant in the unadjusted model but not after adjustment (p=0.42). In contrast, joint pain score was significantly related to 25(OH) D concentrations in both unadjusted and adjusted models with lower 25(OH) D levels associated with higher pain score (linear trend after adjustment, p=0.01).
Higher mean joint pain scores are apparent mainly in the lowest 25(OH) D concentration sextile with 25(OH) D concentration < 28.9 nmol/L). When potential interaction with BMI, physical activity and menopausal hormone therapy on the association between joint symptoms and 25(OH) D concentrations was examined, a significant interaction with physical activity was seen. Women with low physical activity and low 25(OH) D (< 28.9 nmol/L) concentrations had higher joint pain scores compared to women with higher levels of physical activity (P=0.01). A similar relationship was not seen with joint swelling.
In a large population of postmenopausal women, low 25(OH) D levels and relatively high frequency of joint symptoms were commonly seen. There was only a modest association between total vitamin D intake, including both diet and supplement use, with considerable overlap in 25(OH) D concentrations for a given vitamin D intake. The frequency and severity of joint pain was related to 25(OH) D concentration with symptoms more commonly seen in women with the lowest 25(OH) D concentrations.
By one standard , these postmenopausal women had relatively low 25(OH) D levels with only 17% considered to have sufficient levels. However, there is no consensus regarding optimal 25(OH) D levels. Even for fracture risk, recent evidence-based reviews suggest that it is difficult to define an optimal 25(OH) D level for bone health [2, 16].
While there was a statistically significant trend in linear regression model analyses associating lower 25(OH) D concentrations with higher pain scores, an apparent difference was seen mainly in women with the lowest 25(OH) D concentrations (< 28.9 nmol/L). These findings on joint symptoms are non-specific since details of the nature of the joint symptoms including location and impact on daily function were not collected. However, osteoarthritis is a likely contributor since it is the most common cause of joint pain in postmenopausal women. Two reports have associated low 25(OH) D concentrations with higher frequency of radiographic hip osteoarthritis [17, 18]. In addition, several studies have associated low serum 25(OH) D concentrations with development of radiographic knee osteoarthritis [4, 5, 6]. However, Felson and colleagues  reported no association between 25(OH) D concentrations and radiographic progression of osteoarthritis after 9 years follow-up. Any role for vitamin D in osteoarthritis development or progression may be mediated through its effect on supporting cartilage [19, 20] as loss of cartilage volume is a component of osteoarthritis progression .
To our review only two randomized trials have reported on vitamin D influence on joint symptoms in adults. Warner and Arnsbiger  randomized 50 patients with diffuse musculoskeletal pain who had 25(OH) D concentrations < 20 ng/ml (about 50 nmol/L) to receive placebo or vitamin D2 (ergocalciferol) 50,000 IU once weekly for three months. Vitamin D supplementation at this high level had no effect on musculoskeletal pain. In a post-hoc analyses in the WHI calcium and vitamin D trial which entered 36,282 postmenopausal women, those assigned to 1000 mg of elemental calcium with 400 IU of vitamin D3 daily had no change in joint symptoms compared to placebo after seven years with findings based on a randomly identified 6% sample (N=1911) of participants who had serial assessment of symptoms . Future studies could benefit from precise determination of the target disease state (such as incorporating serial change in radiograph-determined osteoarthritis), identification of 25(OH) D levels for eligibility that are most highly correlated with joint symptoms, and use of appropriately targeted vitamin D dosage.
Our finding of only a modest association between total vitamin D intake and 25(OH) D levels is in agreement with other reports. Inconsistent associations between vitamin D dose and subsequent 25(OH) D concentrations have been described in a review summarizing numerous randomized trials . In this regard, an attempt to develop a model to account for individual differences in 25(OH) D concentrations found that nearly 80% of the difference in levels between individuals were not explained by sunlight exposure and/or total vitamin D intake .
Differences in body mass index and physical activity represent potential confounding factors for the association between 25(OH) D and joint pain seen. Lean and physically active women more commonly have higher 25(OH) D concentrations [14, 25] and lower joint pain. In the current report the association between 25(OH) D and joint pain was seen even in analyses controlled for these variables.
Study strengths include the size of the well characterized, diverse study population, measurement of the serum 25(OH) D concentrations with standard assay, and ability to control for both BMI and physical activity in analyses. Study limitations include the cross sectional nature of the analyses, participants identified as control subjects for fracture, breast cancer and colorectal cancer cases, and that the joint pain and joint swelling scale used has not been compared to other instruments or undergone formal validation.
We conclude that joint symptoms are commonly reported by postmenopausal women and lower 25(OH) D concentrations are associated with higher joint pain scores. In cross section analyses total vitamin D intake from both diet and supplement was only modestly associated with 25(OH) D concentrations. Taken together, these results can inform the design of future studies of the relationship between 25(OH) D and joint symptoms.
The WHI program is funded by the National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services.
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Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan, Nancy Geller, Leslie Ford.
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Ronald Prineas, Michelle Naughton; (Medical Research Laboratories, Highland Heights, KY) Evan Stein, Peter Laskarzewski; (San Francisco Coordinating Center, San Francisco, CA) Steven R. Cummings, Michael Nevitt, Lisa Palermo; (University of Minnesota, Minneapolis, MN) Lisa Harnack; (Fisher BioServices, Rockville, MD) Frank Cammarata, Steve Lindenfelser; (University of Washington, Seattle, WA) Bruce Psaty, Susan Heckbert.
Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman; (Baylor College of Medicine, Houston, TX) Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, Paul Bray; (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn Manson, J. Michael Gaziano, Claudia Chae, Kathryn Rexrode, Caren Solomon (Brown University, Providence, RI) Annlouise R. Assaf, Carol Wheeler, Charles Eaton, Michelle Cyr; (Emory University, Atlanta, GA) Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley A.A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Robyn Andersen; (George Washington University, Washington, DC) Judith Hsia, Nancy Gaba, Joao Ascensao; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski, Robert Detrano, Anita Nelson, Michele Geller; (Kaiser Permanente Center for Health Research, Portland, OR) Evelyn Whitlock, Victor Stevens, Njeri Karanja; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan, Stephen Sidney, Geri Bailey Jane Hirata; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard, Lucile Adams-Campbell, Lawrence Lessin, Monique Rainford, Gabriel Uwaifo; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, Carol Rosenberg; (Rush University Medical Center, Chicago, IL) Henry Black, Lynda Powell, Ellen Mason; Martha Gulati; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, Sally Mackey; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina; (The Ohio State University, Columbus, OH) Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, Michael Blumenfeld; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis, Albert Oberman, James M. Shikany, Monika Safford, Mona Fouad; (University of Arizona, Tucson/Phoenix, AZ) Cyndi Thomson, Tamsen Bassford, Marcia Ko, Ana Maria Lopez, Cheryl Ritenbaugh; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, June Chang; (University of California at Davis, Sacramento, CA) John Robbins, S. Yasmeen; (University of California at Irvine, CA) F. Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk; (University of California at Los Angeles, Los Angeles, CA) Howard Judd, David Heber, Robert Elashoff; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, Matthew A. Allison; (University of Cincinnati, Cincinnati, OH) Margery Gass, Suzanne Wernke; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson;1 (University of Hawaii, Honolulu, HI) J. David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Santosh Sharma; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Jennifer Robinson; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis, Peter McGovern;(University of Miami, Miami, FL) Mary Jo O'Sullivan, Linda Parker, Timothy DeSantis, Diann Fernandez, Pat Caralis; (University of Minnesota, Minneapolis, MN) Karen L. Margolis, Richard H. Grimm, Mary F. Perron, Cynthia Bjerk, Sarah Kempainen; (University of Nevada, Reno, NV) Robert Brunner, William Graettinger, Vicki Oujevolk, Michael Bloch; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller, Jane Cauley, N. Carole Milas; (University of Tennessee Health Science Center, Memphis, TN) Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Stephanie Connelly, Fran Tylavsky; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, Charles Mouton; (University of Wisconsin, Madison, WI) Gloria E. Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, Barbara Loevinger; (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds, Greg Burke, Robin Crouse, Mara Vitolins, Scott Washburn; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix, Michael Simon, Gene McNeeley.
Former Principal Investigators and Project Officers:
Baylor College of Medicine, John Foreyt, Ph.D., Emory University, Dallas Hall, M.D., George Washington University, Valery Miller, M.D., Kaiser, Oakland, Robert Hiatt, M.D., Kaiser, Portland, Barbara Valanis, Dr.Ph., National Cancer Institute, Bethesda, Maryland, Carolyn Clifford2, University of California, Irvine, Frank Meyskens, Jr., M.D., University of Cincinnati, James Liu, M.D., Nelson Watts, University of Miami, Marianna Baum, Ph.D., University of Minnesota, Richard Grimm, M.D., University of Nevada, Sandra Daugherty, M.D.2, University of North Carolina, Chapel Hill, David Sheps, M.D., Barbara Hulka, M.D., University of Tennessee, Memphis, William Applegate, M.D., University of Wisconsin, Catherine Allen, Ph.D.2