The RANKL pathway is known to be an important aspect of the pathogenesis of oestrogen deficiency-induced bone loss. RANK deletion specifically in neuropeptide Y (NPY) neurones has been shown to enhance the ability of the skeleton to match increases in body weight caused by high-fat diet feeding, likely via the modulation of NPY levels. In the present study, we used ovariectomy in female mice to show that RANK deletion in NPY neurones attenuates bone loss caused by long-term oestrogen deficiency, particularly in the vertebral compartment. Ovariectomy led to a reduction in NPY expression levels in the arcuate nucleus of NPYcre/+;RANKlox/lox mice compared to NPYcre/+;RANKlox/+ controls. Because NPY deficient mice also displayed a similar protection against ovariectomy-induced bone loss, modulation of hypothalamic NPY signalling is the likely mechanism behind the protection from bone loss in the NPYcre/+;RANKlox/lox mice.