Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis of osteoporosis. Different cytokines from activated macrophages can regulate or stimulate the development of osteoclastogenesis-associated bone loss. The fusion of macrophages can form multinucleated osteoclasts and, thus, cause bone resorption via the expression of IL-4 and IL-13. Different cytokines, endocrines, and chemokines are also expressed that may affect the presentation of macrophages in osteoporosis. Macrophages have an effect on bone formation during fracture-associated bone repair. However, activated macrophages may secrete proinflammatory cytokines that induce bone loss by osteoclastogenesis, and are associated with the activation of bone resorption. Targeting activated macrophages at an appropriate stage may help inhibit or slow the progression of bone loss in patients with osteoporosis.