Osteoporosis is a chronic disease of low bone mass and fragility. Treatment is frequently compromised by suboptimal medication compliance causing increased morbidity. This review investigates adherence and persistence to parenteral osteoporosis therapies. Findings reveal parenteral medications requiring reduced dosing frequency have higher compliance than oral therapies. This systematic review examines real-world adherence to parenteral osteoporosis therapies. We searched PubMed, Medline, and EMBASE databases for English language observational studies that examined patient adherence and/or persistence to parenteral osteoporosis treatments (teriparatide sc, ibandronate iv, zoledronic acid iv, and denosumab sc) in adults with osteoporosis published up to September 2018. Studies with only self-reported adherence or persistence data and those with less than 20 patients were excluded. Quality assessment of included studies was completed using the Newcastle-Ottawa quality assessment scale (NOS). We identified 40 eligible studies. Teriparatide was examined in 29 studies, with persistence rates of 10–87% (median 55%) at 1 year and 10–69% (median 29.5%) at 2 years, and adherence rates of 21–89% (median 53%) at 1 year and 37–68% (median 40%) at 2 years. Ten studies of zoledronic acid reported persistence rates of 34–73% (median 42%) for second dose and 20–54% (median 35.8%) for third dose. Ten studies of ibandronate adherence reported and 2-year persistence rates of 31–58% (median 47.5%) in 1 year and 13–35% (median 25%) at 2 years, and adherence rates of 21–72% (median 47.3%) and 15–58% (median 36.5%) respectively. Denosumab was reported in 19 studies, with second (1 year) and fourth (2 year) dose persistence rates of 61–100% (median 81%) and 36–99% (median 45.5%). There is substantial heterogeneity in reports of persistence and adherence rates with parenteral osteoporosis therapies. Most of the published data are from short-term studies and evaluations of long-term adherence and persistence with parenteral therapies for osteoporosis are needed.