: The aim of this study was to investigate the relationship between osteoporosis and osteoarthritis by analyzing the DNA methylation in osteoporosis and osteoarthritis. The cancellous bone specimens were collected from a total of 12 hospitalized patients and divided into the osteoporosis group (OA), the osteoarthritis group (OP), the osteoporosis combined with osteoarthritis group (OA & OP), and the normal control group (N). The cancellous bone specimens of each group were detected and the differences in gene expression profiles by the MeDIP-chip technique were compared. Compared with Group OA & OP, the methylation levels in Group OA and Group OP were statistically higher, P < 0.05. In the microarray analysis, a total of 1,222 sites occurred hypermethylation. The analysis targeting the differentially expressed genes between Group OA & OP and Group N revealed that group OA and group OP had 4 common genes: PPIL3, NIF3L1, SMTN, and CALHM2. The level of genomic methylation is lower in the patients with osteoporosis and/or osteoarthritis. The common difference between osteoarthritis and osteoporosis is reflected in some specific promoters, which may participate in the processes of diseases through different pathways.