Accumulating evidence demonstrates that adipogenic metabolism is intricately connected with bone mass regulation in rodent models and humans. Energy metabolism dysfunction includes diseases such as obesity, insulin resistance, and diabetes. People with these diseases are often accompanied by bone loss and abnormal bone structure and function. Similarly, the incidences of obesity and lipid metabolism disorders are incredibly high after impaired bone formation and bone resorption. Existing studies have reported a deep connection between abnormal lipid and bone metabolism. However, little is known about the underlying molecular mechanisms leading to comorbidity. Herein, bioinformatics and systems biology approaches were utilized to compare clinical datasets of obese subjects to those with bone-related disorders including osteoporosis (OP), osteoarthritis (OA), osteosarcoma (OS), and low osteogenic potential (LOP) to investigate the potential genetic links. A significant number of overlapping differentially expressed genes (DEGs) were involved in regulating the inflammatory and immune processes. As per the biological enrichment analyses, these DEGs were distributed in the biological processes and signaling pathways related to inflammatory responses such as taxis, chemotaxis, leukocyte chemotaxis, regulation of immune response, and leukocyte activation. Protein-protein interaction and gene regulation networks were constructed to understand the potential interaction effects between common DEGs, microRNAs (miRNAs), transcription factors (TFs), and chemical compounds. Drug prediction was used to screen for potential pharmacological therapies against comorbidity between lipid and bone metabolic disorder (CLBD). Together, our findings provide insights into the potential association between abnormal lipid and bone metabolism. Further, it lays the foundation for developing novel therapeutic strategies that apply agents of immune-related diseases to treat CLBD clinically.