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Here we show that<jats:italic>nAchR7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice exhibit increased bone mass due to decreased osteoclast formation, accompanied by elevated osteoprotegerin\/RANKL ratios in serum. Vagotomy in wild-type mice also significantly increased the serum osteoprotegerin\/RANKL ratio, and elevated bone mass seen in<jats:italic>nAchR7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice was reversed in \u03b17nAchR\/osteoprotegerin-doubly-deficient mice. \u03b17nAchR loss significantly increased TNF\u03b1 expression in Mac1-positive macrophages, and TNF\u03b1 increased the osteoprotegerin\/RANKL ratio in osteoblasts. Targeting TNF\u03b1 in<jats:italic>nAchR7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice normalized both serum osteoprotegerin\/RANKL ratios and bone mass. Administration of nicotine, an \u03b17nAchR ligand, to wild-type mice increased serum RANKL levels. 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