Treatment with the SERCA2 agonist ISTA or endogenous specific overexpression of SERCA2 in osteocytes was demonstrated to reverse the deterioration in the mechanoresponse of T2D skeletons by rescuing osteocyte Ca2+ dynamics and the osteocyte-mediated regulation of osteoblasts and osteoclasts. The gene discussed is ATP2A2; the disease is type 2 diabetes mellitus.