This study aims to systematically review, critically appraise and identify from the published literature, the most effective interventions to improve medication adherence in osteoporosis. A literature search using Medline, EMBASE, Cochrane library, and Cumulative Index to Nursing and Allied Health Literature was undertaken to identify prospective studies published between January 1, 1999 and June 30, 2012. We included studies on adult users of osteoporosis medications that tested a patient adherence intervention (e.g., patient education, intensified patient care, different dosing regimens) and reported quantitative results of adherence. The Delphi list was modified to assess the quality of studies. Of 113 articles identified, 20 studies fulfilled the inclusion criteria. The most frequent intervention was education (n = 11) followed by monitoring/supervision (n = 4), drug regimens (n = 2), drug regimens and patient support (n = 1), pharmacist intervention (n = 1), and electronic prescription (n = 1). Although patient education improved medication adherence in four studies, two large-scale randomized studies reported no benefits. Simplification of dosing regimens (with and without patient support program) was found to have a significant clinical impact on medication adherence and persistence. Monitoring/supervision showed no impact on medication persistence while electronic prescription and pharmacist intervention increased medication adherence or persistence. In conclusion, this review found that simplification of dosing regimens, decision aids, electronic prescription, or patient education may help to improve adherence or persistence to osteoporosis medications. We identified wide variation of quality of studies in the osteoporosis area. The efficacy of patient education was variable across studies, while monitoring/supervision does not seem an effective way to enhance medication adherence or persistence.