ARTHRITIS & RHEUMATISM Vol. 54, No. 4, April 2006, pp 1255–1261 DOI 10.1002/art.21735 © 2006, American College of Rheumatology Low Vitamin K Status Is Associated With Osteoarthritis in the Hand and Knee Tuhina Neogi, 1 Sarah L. Booth, 2 Yu Qing Zhang, 1 Paul F. Jacques, 2 Robert Terkeltaub, 3 Piran Aliabadi, 4 and David T. Felson 1 Objective. Poor intake of vitamin K is common. Insufficient vitamin K can result in abnormal cartilage and bone mineralization. Furthermore, osteophyte growth, seen in osteoarthritis (OA), may be a vitamin K–dependent process. We undertook this study to de- termine whether vitamin K deficiency is associated with radiographic features of OA. Methods. We conducted an analysis among 672 participants (mean age 65.6 years, 358 women) in the Framingham Offspring Study, a population-based pro- spective observational cohort. Levels of plasma phyllo- quinone (the primary form of vitamin K) had previously been measured in these participants, for whom we also had bilateral hand and knee radiographs. The main outcomes were 1) prevalence ratios (PRs) of OA, osteo- phytes, and joint space narrowing (JSN) per quartile of plasma phylloquinone level for each joint, adjusting for correlated joints using generalized estimating equa- tions, and 2) adjusted mean number of joints with each feature per quartile of plasma phylloquinone level. Analyses were conducted in hands and knees separately and adjusted for age, sex, body mass index, total energy intake, plasma vitamin D, and femoral neck bone min- eral density. Results. The PRs for OA, osteophytes, and JSN and adjusted mean number of joints with all 3 features in the hand decreased significantly with increasing plasma phylloquinone levels (P < 0.03 for all). For example, as plasma phylloquinone levels rose, the PR for hand OA decreased from 1.0 to 0.7 (P  0.005). For the knee, only the PR for osteophytes and the adjusted mean number of knee joints with osteophytes decreased significantly with increasing plasma phylloquinone lev- els (PR decreased from 1.0 to 0.6, P  0.01). Conclusion. These observational data support the hypothesis of an association between low plasma levels of vitamin K and increased prevalence of OA manifes- tations in the hand and knee. Vitamin K is an essential cofactor in the post- translational -carboxylation of glutamic acid to form -carboxyglutamic acid (Gla) residues, which confer functionality to these Gla proteins (1). In addition to coagulation factors, this family includes the growth factor Gas-6 and the skeletally expressed extracellular matrix proteins osteocalcin and matrix Gla protein (MGP) (2–4). Vitamin K–dependent Gla proteins have high affinity for calcium and phosphate and can bind to the hydroxyapatite crystal surface of mineralized tissue (4,5). Hence, vitamin K is an important regulator of bone and cartilage mineralization. Vitamin K also reg- ulates growth plate cartilage calcification, as revealed by effects of vitamin K antagonism by warfarin (6–10). Genetic deficiencies of MGP in humans and mice have been linked to skeletal abnormalities, including prema- ture epiphyseal calcification and shortening of long limb bones, reflecting endochondral bone formation (11–14). Osteoarthritis (OA) is characterized by alter- ations in chondrocyte viability and subchondral bone, by Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the US Department of Agriculture. Supported by the NIH (grants AG-14759, AR-47785, AG- 18393, and P01-AGO-7996), the Veterans Administration Research Service, the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (NHLBI/NIH contract N01-HC-25195), and the US Department of Agriculture (agreement 58-1950-4-401). Dr. Neogi’s work was supported by the Arthritis Foundation Postdoctoral Fellowship Award and the Abbott Scholar Award in Rheumatology. 1 Tuhina Neogi, MD, FRCPC, Yu Qing Zhang, DSc, David T. Felson, MD, MPH: Boston University School of Medicine, Boston, Massachusetts; 2 Sarah L. Booth, PhD, Paul F. Jacques, DSc: Tufts University, Boston, Massachusetts; 3 Robert Terkeltaub, MD: Univer- sity of California at San Diego; 4 Piran Aliabadi, MD: Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Tuhina Neogi, MD, FRCPC, Clinical Epidemiology Research and Training Unit, 715 Albany Street, A203, Boston, MA 02118. E-mail: tneogi@ bu.edu. Submitted for publication September 6, 2005; accepted in revised form December 30, 2005. 1255