We provide a proof-of-concept demonstration that a rationally designed AAV9 capsid can deliver an artificial microRNA (amiR) that silences the expression of RANK (OC survival/differentiation) or CTSK (OC resorption activity) in OCs to reverse bone loss and improve bone mechanical properties in mouse models of postmenopausal and senile osteoporosis, while detargeting transduction to non-relevant tissues. The gene discussed is TNFRSF11A; the disease is osteoporosis.