Abstract: Nowadays β-blockers are commonly used for a broad spectrum of diseases including cardiovascular diseases but their effects on the bone are an issue of concern. Animal studies support their protective effects on bone however, human studies are controversial. We followed this issue by conducting a systematic review of all existing materials through all available search engines. Results indicate a major controversy existing among studies. Most of studies are limited to lack of considering pharmacokinetic/pharmacodynamic properties of this class of drugs, Body Mass Index (BMI) as well as physical activity of patients, adequacy of sample size or ability to sub-analyze data, smoking behavior and patients’ lifestyle that all can be a source of bias and cause controversy. Further studies by paying attention to above-mentioned bias sources are highly recommended to help making sure about the safety of this class of medications on bone.