The effect of bisphosphonates in specific knee osteoarthritis subpopulations


Changes in subchondral bone turnover play a role in knee osteoarthritis (OA) pathogenesis and are a promising target for treatment. Yet, randomized clinical trials to date investigating the effectiveness of bisphosphonates in knee OA have found divergent results, with no superiority of these drugs over placebo in a recent meta-analysis. The aim of this study is to investigate the effect of bisphosphonates in specific knee OA subpopulations, based on possible distinct rates of subchondral bone turnover, to identify whether particular patient subgroups are more likely to benefit from this therapy than others. A systematic literature search will be conducted for randomized clinical trials comparing bisphosphonates with other control treatments in individuals with symptomatic knee osteoarthritis. Authors of original trials will be contacted to obtain individual patient data from each study.


The primary outcomes will include pain and radiographic minimum joint space width loss (mm) in the index knee. Outcomes will be grouped into three main time points of outcome assessment: short-term (≤3 months), intermediate-term (>3 months; ≤12 months); and long-term (>12 months). Potential treatment effect modifiers to be examined in the subgroup analyses include: gender, menopausal status, body mass index, radiographic disease stage, baseline knee pain severity, presence of bone marrow lesions on MRI, and baseline levels of systemic biochemical markers of bone turnover (serum and/or urinary). Regression models will be used adding an interaction term for each subgroup of interest to determine possible subgroup effects.


This is an ongoing project and the protocol is in preparation.

Protocol and publications


L. (Leticia) A. Deveza 1
S. (Sita) M.A. Bierma-Zeinstra 2, 3
W. (Willem) E. van Spil 4
W. (Win) Min Oo 1
B. (Bruno) T. Saragiotto 5, 6
T. (Tuhina) Neogi 7
M. (Marienke) van Middelkoop 3
D. (David) J. Hunter 1

1. Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, Sydney, NSW Australia
2. Department of Orthopedic Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
3. Department of General Practice, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
4. Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
5. School of Public Health, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
6. Centre for Pain, Health and Lifestyle, Australia
7. Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts, USA.