Background Cadmium is a well-characterized bone toxic agent and can induce bone damage via inhibiting osteogenic differentiation. However, only a few studies have addressed the mechanism on cadmium-associated bone damage and none of them has used a panel of sensitive and specific biomarkers for the detection of cadmium-associated bone damage. BMP/SAMD signaling pathway can mediate osteogenic differentiation, but the association between cadmium and BMP/SAMD signaling pathway is yet to be illuminated. Methods We treated human bone marrow mesenchymal stem cells (BMSCs) with CdCl2 in vitro to to detect the expression of BMPs and SAMDs. And we also enrolled 67 cases of bone damage and 67 cases without bone damage. Urinary cadmium concentration and the concentrations of BMP-2 and BMP-4 of subjects were detected. Mediation analyses was used to estimate the influence of urinary cadmium and BMP-4 on bone damage, adjusting for a set of confounders. Results Cd exposure significantly promoted adipogenic differentiation of hBMSCs, and inhibited its' osteogenic differentiation by inhibiting the expression of BMP-2/4, SAMD4, and p-SAMD1/5/9 complex. BMP-4 mediated 22.92% (95%CI 6.37, 46.00) of the total association between cadmium and the risk of osteoporosis. Conclusions We found BMP-4 can be a diagnostic biomarker and therapeutic target of cadmium-associated bone damage.