The soluble decoy receptor osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function and survival. We investigated OPG gene therapy as a means of ameliorating chronic osteoarticular disease using a mouse ovariectomy (OVX) model of estrogen deficiency-induced osteoporosis (Mol Ther 2001, 3:1–9). Young adult female mice injected once with an adenoviral (Ad) vector carrying a human fusion protein combining the OPG ligand-binding and immunoglobulin constant domains (hOPG-Fc) developed serum OPG levels that exceeded the threshold needed for efficacy (as assessed by a marked increase in bone density) for over 12 months. The extent of OPG production and skeletal enhancement was titer-dependent. Mice subjected to OVX or sham surgery and then treated with Ad-hOPG-Fc had significantly more bone volume and fewer osteoclasts in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector expressing β-galactosidase or vehicle had significantly less bone than did comparably treated, sham-operated mice. This study confirms that a single Ad gene transfer can produce persistent high-level OPG expression and shows that OPG gene therapy may prove useful in treating osteoporosis. We anticipate that OPG gene therapy will offer similar promise as a bone-sparing agent in chronic arthritis since we have shown previously that injected OPG significantly inhibits skeletal erosion in the Lewis rat model of mycobacterial-induced adjuvant arthritis (Nature 1999, 402:304–309).