Osteoarthritis (OA) currently affects 41 million Americans, and knee OA (KOA) alone causes the highest risk of mobility disability of any medical condition in people 65 years and older. There are no current treatments to reverse the degenerative changes of KOA, and research is aimed at finding biomarkers of KOA progression to aid in the development of effective therapies. Osteophytes are a hallmark feature of KOA and may act as a biomarker of joint space loss and pain progression. MR imaging, which is an accurate and non-invasive method to monitor KOA disease status, may aid in clarifying the role of osteophytes in KOA, especially using semi-automated quantitative software methods to accurately and efficiently calculate osteophyte volume in longitudinal studies. This study investigated the association of osteophyte volume change with joint space narrowing and pain progression in a randomized sample of 505 subjects from the FNIH OA Biomarker Consortium Project, a case-control study based on a larger longitudinal study of patients with KOA. We also aimed to further validate a software method that measured osteophyte volume in MRI. We found a moderate and significant association with osteophyte volume and joint space narrowing, but no significant association with pain progression. The software was further validated as responsive and efficient method to measure KOA osteophyte volume change.