This study investigated the delivery of a model therapeutic protein, namely, osteoprotegerin (OPG), to bone sites in an animal model of osteoarthritis. The OPG was chemically conjugated to a “bone seeking” thiol-bisphosphonate (thiolBP) via a disulfide linkage. The BP conjugates of OPG were shown to display a higher hydroxyapatite affinity in vitro as compared to unmodified OPG. After intravenous injection, the bone uptake of OPG−thiolBP conjugate was increased 2-fold over that of control OPG under conditions of normal bone turnover. Furthermore, the retention of the OPG−thiolBP conjugate was significantly higher after 72 h. When administered to osteoarthritic rats undergoing active bone remodeling, the delivery of OPG−thiolBP conjugate to bone was increased more than 4-fold over that of control OPG after 24 h. These results suggest a significant advantage of BP conjugation as a drug delivery strategy for therapeutic cytokines in osteopenic bone diseases.