Immobilization is one major risk factor for osteoarthritis as longer periods of unloading can initiate catabolic processes and cause cartilage degeneration. Bed rest studies are an excellent standardized model for simulating not only the effects of spaceflight but also to investigate the impact of longer periods of immobilization and possible countermeasures to prevent articular cartilage degeneration. Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of the study was to investigate 1) the effect of 21 days of immobilization on a broad spectrum of serum cartilage biomarkers and 2) the efficiency of a resistive vibration exercise protocol with and without nutritional supplements as countermeasures over 21 days bed rest to avoid changes in cartilage metabolism.