Vacuolar-type　H　(+)-ATPase　(V-ATPase)　is　a　highly　conserved,　ancient　enzyme　that　couples　the　energy　of　ATP　hydrolysis　to　proton　transport　across　vesicular　and　plasma　membranes　of　eukaryotic　cells.　Previously　reported　mutations　of　various　V-ATPase　subunits　are　associated　with　increased　bone　density.　We　now　show　that　haploinsufficiency　for　the　H　subunit　of　the　V-1　domain　(ATP6V1H)　is　associated　with　osteoporosis　in　humans　and　mice.　A　genome-wide　SNP　array　analysis　of　1625　Han　Chinese　found　that　4　of　15　tag　SNPs　(26.7%)　within　ATP6V1H　were　significantly　associated　with　low　spine　bone　mineral　density.　Atp6v1h(+/-)　knockout　mice　generated　by　the　CRISPR/Cas9　technique　had　decreased　bone　remodeling　and　a　net　bone　matrix　loss.　Atp6v1h(+/-)　osteoclasts　showed　impaired　bone　formation　and　increased　bone　resorption.　The　increased　intracellular　pH　of　Atp6v1h(+/-)　osteoclasts　downregulated　TGF-beta　1　activation,　thereby　reducing　induction　of　osteoblast　formation　but　the　bone　mineralization　was　not　altered.　However,　bone　formation　was　reduced　more　than　bone　resorption.　Our　data　provide　evidence　that　partial　loss　of　ATP6V1H　function　results　in　osteoporosis/osteopenia.　We　propose　that　defective　osteoclast　formation　triggers　impaired　bone　formation　by　altering　bone　remodeling.　In　the　future,　ATP6V1H　might,　therefore,　serve　as　a　target　for　the　therapy　of　osteoporosis.