AUTHORS [REFERENCE]	YEAR	EFFICACY	SAFETY	CONCLUSION
Cosman et al[@177268]	2016	The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), an international, randomized, double-blind, placebo-controlled, parallel-group trial demonstrated that in postmenopausal women with osteoporosis, ROMO was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to DENO, at 24 months. The lower risk of clinical fracture that was seen with ROMO was evident at 1 year.	NA	Women were randomly assigned, in a 1:1 ratio, with the use of an interactive voice-response system, to receive ROMO in a blinded fashion at a dose of 210 mg or placebo. Randomization was stratified according to age (<75 years vs. ≥75 years) and prevalent vertebral fracture (yes vs. no). ROMO or placebo was administered subcutaneously once monthly for 12 months, followed by open-label DENO at a dose of 60 mg (Prolia, Amgen), which was administered subcutaneously every 6 months for an additional 12 months.
Saag et al[@177273]	2017	This phase 3, multicenter, international, randomized, double-blind trial demonstrated that in postmenopausal women with osteoporosis who were at high risk for fracture, ROMO treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone.	NA	Women were randomly assigned, in a 1:1 ratio to receive monthly subcutaneous ROMO (210 mg) or weekly oral alendronate (Merck; 70 mg) for 12 months.
Markham[@177271]	2019	NA	NA	This article summarized the milestones in the development of ROMO leading to its first approval for the treatment of osteoporosis in individuals at high risk of fracture.
Lewiecki et al[@177272]	2019	12 months of ROMO led to persistent fracture reduction and ongoing BMD gains	NA	Results of the FRAME (FRActure study in postmenopausal woMen with osteoporosis) Extension Study showed that in postmenopausal women with osteoporosis, 12 months of ROMO led to persistent fracture reduction and ongoing BMD gains when followed by 24 months of DENO.
Geusens et al[@177276]	2019	ROMO was efficacious	NA	Results of the FRAME Study showed that ROMO treatment for 12 months was associated with rapid and large reductions in clinical vertebral fracture risk versus placebo.
Hernandez et al[@177277]	2019	ROMO was efficacious	NA	A systematic review and network meta-analysis of ranzomized controlled trials (RCTs) showed that abaloparatide, ROMO, and teriparatide were the best treatments, respectively, to diminish vertebral/non-vertebral fractures, augment BMD, and increase bone formation
Kendler et al[@177278]	2019	After 12 months off-treatment, a second ROMO course again led to rapid and large BMD gains.		In this phase 2, dose-finding study it was found that following DENO, BMD gains with ROMO were smaller than with initial treatment
Bovijn et al[@177279]	2020	NA	ROMO could elevate cardiovascular risk	Evidence from meta-analysis of clinical trials and human genetics advised a rigorous evaluation of the cardiovascular safety of ROMO.
Fuggle et al[@177280]	2020	NA	ROMO had been demonstrated to have a possible cardiovascular signal	In this narrative review of the literature it was stated that post-market surveillance of this drug will be vital
Paik and Scott[@177281]	2020	ROMO was efficacious	NA	This review article stated that ROMO could extend the treatment alternatives in postmenopausal women with osteoporosis who have a high risk of fracture and in those who have failed or are intolerant to other available osteoporosis treatment.
Simpson et al[@177275]	2020	This systematic review and network meta-analysis analyzed the clinical effectiveness of DENO, raloxifene, ROMO, and teriparatide for the prevention of osteoporotic fragility fractures. The four non-bisphosphonate interventions studied were all statistically significantly clinically effective for reducing vertebral fractures when compared to placebo, and were beneficial for change in femoral neck BMD compared to placebo.	NA	The four non-bisphosphonate interventions reduced hip fractures, and this was statistically significant for teriparatide, ROMO followed by alendronate, and DENO.
Rauner et al[@177267]	2021	NA	In this narrative review ROMO appeared to be a safe and well-tolerated medication.	ROMO should not be utilized in individuals with a myocardial infarction or stroke in the year previous to therapy or while on therapy, and the benefits and risks should be carefully outweighed in individuals at high risk of cardiovascular events.
Tanaka and Matsumoto[@177269]	2021	ROMO was effective	NA	This review summarized clinical studies that demonstrated the efficacy of ROMO to increase BMD and reduce osteoporotic fractures.
Aditya and Rattan[@177270]	2021	The efficacy of ROMO has been established in trials.	The safety of ROMO has been established in trials	These authors screened all the journal articles published from 2015 to 2020 that discussed the relevant clinical studies of ROMO.
Brown et al[@177274]	2021	ROMO improved lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women.	NA	The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial demonstrated the efficacy of ROMO.
Migliorini et al[@177282]	2021	DENO was associated with the lowest rate of non-vertebral fractures; ROMO with the lowest rate of vertebral fractures; and ibandronate with the lowest rate of hip fractures. DENO was more effective in reducing the occurrence of non-vertebral fractures. ROMO and ibandronate were the best to prevent vertebral fractures and hip fractures, respectively.	Adverse events leading to study discontinuation were less frequent in the ROMO and deno groups, while raloxifene and alendronate showed a lower incidence of serious adverse events overall.	This level I evidence-based-expert opinion concluded that ROMO and ibandronate were the best options for the prevention of vertebral fractures and hip fractures, respectively.
Fixen and Tunoa[@177283]	2021	Incidence of new vertebral fracture was dramatically reduced with 12 months of ROMO use compared with the placebo and active bisphosphonate control groups in patients with postmenopausal osteoporosis. Significant non-vertebral anti-fracture benefit was also demonstrated in patients with more severe osteoporosis. ROMO had impressive anti-fracture effects in postmenopausal women with high risk of fragility fracture.	Numerical increases in cardiovascular events call into question the safety of ROMO use, particularly in patients with cardiovascular history or at high cardiovascular risk. Despite no significant differences in baseline cardiovascular risk factors between groups, a numerical increase in serious cardiovascular adverse events was demonstrated with ROMO in randomized trials, with no discernable etiology.	This review article concluded that until more real-world evidence is available, ROMO should not be used in patients with a recent cardiovascular event and should be used cautiously in patients with high cardiovascular risk. ROMO’s place in therapy appears to be in patients with severe postmenopausal osteoporosis and low cardiovascular risk.
Vestergaard Kvist et al[@177284]	2021	NA	This pharmacovigilance analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) identified a potential signal for elevated major cardiovascular events, particularly in Japan.	The results of this study supported the safety warnings from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to avoid use in high-risk individuals.
Tominaga et al[@177285]	2021	This 6-month study showed that ROMO is effective in preventing fractures and useful for increasing the spine BMD.	ROMO was relatively safe to use.	ROMO was especially effective in individuals with low baseline spine BMD, high 5b (TRACP-5b), and high iP1NP).
Baek et al[@177286]	2021	This phase 3 study evaluated the efficacy and safety of 6-month treatment with ROMO in postmenopausal women with osteoporosis. After treatment with ROMO, the percent change from baseline in procollagen type 1 N-terminal propeptide transiently increased at months 1 and 3, whereas that in the C-terminal telopeptide of type 1 collagen showed a sustained decrease. At month 9, 17.6% and 2.9% of patients in the ROMO group developed binding and neutralizing antibodies, respectively.	No events of cancer, hypocalcemia, injection site reaction, positively adjudicated atypical femoral fracture or osteonecrosis of the jaw, or positively adjudicated serious cardiovascular adverse events were observed.	This randomized, double blind, placebo-controlled efficacy and safety study (phase 3) found that treatment with ROMO for 6 months was well tolerated and significantly increased lumbar spine, total hip, and femoral neck BMD compared with placebo in postmenopausal women with osteoporosis.
Nealy and Harris[@177287]	2021	ROMO increased BMD at the lumbar spine, femoral neck, and total hip in patients with osteoporosis. After 12 months, ROMO provided greater BMD gains at the lumbar spine and hip than teriparatide. However, teriparatide was likely to further increase BMD if continued for up to 24 months. In postmenopausal women with a high fracture risk, 1 year of ROMO followed by 1 year of alendronate resulted in lower vertebral, nonvertebral, clinical, and hip fractures than alendronate alone for 2 years.	Although absolute event rates were low, serious cardiovascular and cerebrovascular events were numerically higher in 2 clinical trials compared with alendronate (2.5% vs 1.9%, respectively) and placebo (4.9% vs 2.5%, respectively).	In this study, PubMed, MEDLINE, and ClinicalTrials.gov searches (1966 to July 2020) were conducted using the keywords romosozumab and osteoporosis. It was concluded that ROMO offered an alternative for patients with a high risk of osteoporotic fractures. Clinicians should avoid ROMO in patients with a history of myocardial infarction or stroke in the past 12 months.
Langdahl et al[@177288]	2021	NA	ROMO should be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.	Regarding the cardiovascular risk of ROMO, this review article stated that the evidence from the large clinical trials in postmenopausal women is conflicting.
Takeuchi[@177289]	2021	NA	There remains a concern for increased adverse cardiovascular events. Further relevant investigations are essential to understand whether ROMO is actually involved in the development of cardiovascular events.	This article briefly reviewed concerns about cardiovascular safety in ROMO obtained from prospective RCTs and presented real-world clinical data for its safety, especially in Japan. The conclusion was that more robust evidence to establish an appropriate and reasonable guide to prescribe ROMO in clinical practice is required.
McCloskey et al[@177290]	2021	Compared with placebo, ROMO reduced the incidence of all fracture outcomes in the first year (range: 32% reduction in major osteoporotic fracture [MOF] to 80% reduction in clinical vertebral fractures). Significant interactions were observed between efficacy and the baseline Fracture Risk Assessment Tool (FRAX) probability for composite outcomes of clinical fractures, osteoporotic fractures, and MOF, but not vertebral fractures. For example, ROMO decreased all clinical fractures by 22% at the 25th percentile of FRAX probability, but the reduction was 41% at the 75th percentile. Exclusion of vertebral fractures from each composite fracture outcome (i.e., only nonvertebral fractures) showed even stronger interactions with baseline FRAX probability.	NA	A post hoc analysis of the first year of the FRAME study showed that the efficacy of ROMO on clinical fracture, osteoporotic fracture, and MOF was significantly greater in patients at high baseline fracture risk compared with placebo.
Tominaga et al[@177291]	2021	Percent changes from baseline in the spine and total hip BMD after 12 months of ROMO treatment were 10.67% and 2.04%, respectively. ROMO had better effects in cases of severe osteoporosis with low spine BMD, high TRACP-5b, and high iP1NP at the start of ROMO treatment. The percent change in the spine BMD at 12 months was significantly lower in the group transitioning from bisphosphonate than in the group not previously treated with other anti-osteoporosis medications.	There were 5 cases of new fractures during 1-year ROMO treatment. There were no fatal adverse events.	This study was an observational study designed as a pre-post study in 262 patients. It was concluded that ROMO was an effective treatment for spine osteoporosis because it significantly increased the percentage of change in the spine BMD at 12 months. This change was higher in patients not previously treated with other anti-osteoporosis medications.
Singh et al[@177292]	2022	ROMO significantly reduced the incidence of vertebral fractures, nonvertebral fractures, and clinical fractures (all high quality of evidence) at 24 months. Significant reduction in incidence risk of falls (high quality) was observed with ROMO. BMD was significantly increased in the ROMO-treated groups in the lumbar spine (high quality), total hip (moderate quality), and femoral neck (moderate quality) at 12 months.	The total adverse events (moderate quality) and serious adverse events (moderate quality) with ROMO were comparable to the control group.	This systematic review and meta-analysis of efficacy and safety of ROMO in postmenopausal osteoporosis advised ROMO treatment for postmenopausal osteoporosis.
Shen et al[@177293]	2022	ROMO (92.1%) was the most effective in reducing the risk for all fractures, with the best therapeutic effects on vertebral fracture (97.2%) and non-vertebral fracture (88%). ROMO (92.5%) provided better therapeutic effects for the reduction of hip fracture. The best treatment agents for improving whole-body BMD (100%), spine BMD (95.7%), hip BMD (92.4%), femoral neck BMD (86.7%), and trochanter BMD (95.5%) were alendronate, strontium ranelate, ibandronate, risedronate, and ibandronate, respectively.	The use of bazedoxifene was associated with the highest incidence of any upper-gastrointestinal event, nasopharyngitis, and back pain, whereas risedronate was associated with higher incidence of abdominal pain and dyspepsia.	This Bayesian Network Meta-analysis found that ROMO yielded the best effects for reducing fracture risk, while abaloparatide was the most effective in reducing the risk of vertebral fracture and non-vertebral fracture.
Poutoglidou et al[@177294]	2022	ROMO significantly increased lumbar spine, total hip, and femoral neck BMD compared with placebo, alendronate, and teriparatide at both 6 and 12 months.	Adverse events were comparable between ROMO and other treatments, except for the incidence of injection-site reactions, which were higher in the anti-sclerostin antibody groups.	This meta-analysis and systematic review stated that ROMO represents a valid therapeutic option for osteoporosis treatment.
Miller et al[@177295]	2022	ROMO reduced the relative risk of new vertebral fractures at month 12 among patients with estimated glomerular filtration rates of 30-59, 60-89, and ≥90 mL/min by 72%, 70%, and 84%, respectively, versus placebo, in the Fracture Study in Postmenopausal Women with Osteoporosis; and by 51%, 19%, and 57%, respectively, versus alendronate, in the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk.	Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups.	This post hoc analysis of two randomized, multicenter, phase 3 clinical trials-FRAME and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of ROMO in postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease. It was concluded that ROMO was an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across various levels of kidney function.
Miyauchi et al[@177296]	2022	Compared with placebo, ROMO increased lumbar spine BMD by 14.8% and 15.2% in the estimated glomerular filtration rate <90 and ≥90 mL/min/1.73 m2 subgroups, total hip BMD by 4.6% and 5.5%, and femoral neck BMD by 4% and 5.5% at 12 months, respectively.	The incidence of adverse events was similar between subgroups. New vertebral fracture incidence was numerically lower with ROMO than placebo at 12 months in both estimated glomerular filtration rate subgroups.	This post hoc analysis of the placebo-controlled phase 3 FRAME study assessed the efficacy and safety of ROMO in a subpopulation of Japanese postmenopausal women with osteoporosis and chronic kidney disease. It was shown that ROMO for 12 months was an effective and well-tolerated treatment option for Japanese patients with osteoporosis and mild-to-moderate chronic kidney disease.