Osteoporosis frequently coexists with other chronic diseases and syndromes of aging, and therefore multimorbidity interactions can potentially complicate its evaluation and treatment. This article reviews osteoporosis comorbidity interactions with select common diseases of aging including cardiovascular, neurologic, and geriatric syndromes, and select commonly used medications by older adults. Using depression as a case example, we describe the complex relationship between osteoporosis, mood, and antidepressant medications, and the implications of these interactions for patients and clinicians.