Recently, a new receptor for RANKL, LGR4, was discovered. When RANKL binds to LGR4, unlike RANKL–RANK signaling, it inhibits the translocation of NFATc1, thereby inhibiting osteoclastic activity. In previous studies, an LGR4 agonist derived from RANKL, which does not bind to RANK but binds to LGR4, inhibited osteoclastogenesis. However, a structure similar to that of RANKL has a weakness in that it can be scavenged by osteoprotegerin (OPG). Therefore, in this study, a novel mutant of RANKL with a low affinity for OPG was introduced for LGR4 signaling to inhibit osteoclast activity, and its applicability as a treatment for osteoporosis was investigated. The binding affinities of RANK–RANKL and OPG–RANKL were measured using microscale thermophoresis. The generation and activation of osteoclasts were assessed by tartrate-resistant acid phosphatase staining, bone resorption pit formation, real-time polymerase chain reaction, western blot, and nuclear translocation of NFATc1 to determine the novel mutant RANKL candidate. Radiographic and histological analyses were performed to confirm the inhibitory effect on bone resorption in RANKL-induced and ovariectomized mice. As a result, the novel mutant RANKL, as a LGR4 agonist that has low affinity with OPG, stimulated LGR4 signaling, resulted in the inhibition of NFATc1 translocation to the nucleus through the GSK-3β signaling pathway, and showed an inhibition of osteoclastogenesis. In addition, the novel RANKL mutant considerably inhibited bone resorption in RANKL-induced and ovariectomized mice. These results suggest that the development of a novel mutant RANKL with a low affinity for OPG could be an innovative strategy to treatment of osteoporosis.