Is Romosozumab better than Teriparatide for the treatment of osteoporosis? A meta-analysis through a grade analysis of evidence

Osteoporosis is a common systemic skeletal disease. With an ageing population, the socioeconomic effect of osteoporosis will remarkably improve. Romosozumab (EVENITYTM) is a new osteoanabolic drug, which is a humanised monoclonal antibody against sclerostin, and received its first global approval for the treatment of osteoporosis in patients at high risk of fracture in Japan on January 8, 2019. Teriparatide is the first osteoanabolic drug. However, there is no comprehensive analysis and systematic review about the efficacy and safety of the two treatment.

Based on the available studies, our current results demonstrated that Romosozumab was better than Teriparatide both in terms of efficacy and side effects.

Introduction
Osteoporosis is identified as a systemic skeletal disorder characterized by low BMD and qualitative changes in microarchitecture of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [1]. In elderly patients, Osteoporotic fracture (fragility fracture) is a catastrophic complication, which causes substantial morbidity and mortality [2]. This fracture often occurs in the spine , hip and wrist, but also affects other bones, such as humerus and radius [3].Drugs for osteoporosis fall into two major categories, antiresorptive drugs and osteoanabolic drugs. Antiresorptive drugs for osteoporosis increase bone mineral density and prevent the progression of structural damage but may not restore bone structure [4]. However, osteoanabolic drugs can reverse microarchitectural deterioration of bone tissue and seem to be better. Now for osteoporosis treatment, the classic drug bisphosphonate represents the vast majority of prescriptions, and is conventional drugs. However, either by oral or intravenous administration, bisphosphonate is reported that atypical femoral fractures and osteonecrosis of jaw may be more common [5][6][7][8]. Teriparatide (brand name FOTTEO TM ), an N-terminal (1-34) fragment of human parathyroid hormone, is the first one osteoanabolic drug approved by Food and drug administration in 2003 [9,10]. It can significantly improve BMD. However, patients must inject this drug one time each day in their thigh or abdomen. Besides, After Teriparatide is discontinued, its benefits are quickly lost [11].
What's worse, a study of the Forteo Patient Registry (FPR) anticipated that their on-going study will be able to detect a fourfold increase in the risk of osteosarcoma if one exists in 2024 [12].
Sclerostin, a glycoprotein produced primarily by osteocytes, is encoded by the SOST gene, which can specifically block the canonical Wnt signaling [13,14]. This pathway plays a pivotal role in promoting bone formatiom and regulating bone homeostasis [15] [15].
Sclerostin increases the expression of RANKL and decreases that of OPG, resulting in bone absorption [16,17]. Romosozumab, a humanized monoclonal anti-sclerostin antibody, is a new osteoanabolic drug that inhibits sclerostin with a dual effect on bone, increasing bone formation and decreasing bone resorption [4].
However, the efficacy and safety of this new drug are not well documented. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials of romosozumab and teriparatide to fully evaluate their effects in postmenopausal osteoporosis patients Materials And Methods

Literature search
The way to identify relevant studies was to use "Romosozumab "," Teriparatide" and "postmenopausal osteoporosis" as key words with Boolean operators "AND" or "OR" in electronic databases including PubMed, Embase, the Cochrane Library, Web of Science and the Cochrane Controlled Trials Register up to June 2019 . Only randomized controlled trials (RCTs) performed on human beings were included in our studies. The Flow chart of the trial selection process was presented in the figure of flow chart (Fig. 1 Outcomes: The primary outcomes included the following: the percentage change of lumbar spine and total hip from baseline in bone mineral density at month 6 and month 12 in each group. The secondary outcomes contained the following: the percentage change of femoral neck from baseline in bone mineral density at month 6 and month 12 in each group and the incidence of adverse events at month 12 in each group.
Study design: RCT

Data extraction
A standard data extraction form was used to collect the relevant data from included studies. Two reviewers collected available data from included studies independently, and any disagreement between the two reviewers was judged by a third reviewer. The relevant data included authors, published dates, intervention types, age, sample size, outcomes, duration of follow-up and reference type. Baseline characteristics of included trials were presented in Table 1. Data on BMD were obtained from the data presented in tables or figures if no direct data were available from the article text.

Grading quality of evidence
We used GRADE system to evaluate the level of the evidence and strength of recommendations for included outcomes. GRADE software was used to evaluate the evidence of included outcomes. Initially, RCTs were considered as high confidence in an estimate of effect and cohort studies were considered as low confidence in an estimate of effect. Reasons that might decrease the level of confidence include limitations, inconsistency, indirectness, and imprecision, and publication bias. Reasons that might raise the level of confidence include large effect, plausible confounding, dose-response.
The GRADE evidence was divided into the following categories: (1) High-quality evidence, which indicated that further research was unlikely to change the confidence in an estimate of effect; (2) Moderate-quality evidence, which indicated that further research was likely to have an important impact on confidence in an estimate of effect and may change the estimate; (3) Low-quality evidence, which indicated that further research was likely to have an important impact on confidence in an estimate of effect and was likely to change the estimate; and (4) Very low-equality evidence, which indicated that we were very uncertain about the results. The results of the GRADE analysis were presented in Table 2.

Statistical analysis and data synthesis
Meta-analyses were performed with Review Manager Software for Windows (version 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The mean difference (MD) was used to assess continuous outcomes in month 6 and 12, such as BMD of different parts, with a 95% confidence interval (CI). Relative risks with a 95% CI were used to assess dichotomous outcomes, such as AEs. The inverse variance and Mantel-Haenszel methods were used to combine separate statistics. If P values were <0.05, the results were considered statistically significant.

Investigation of heterogeneity and publication bias
Statistical heterogeneity of the included studies was evaluated using the chi-square test in accordance with the values of P and I 2 . If the values of I 2 < 50%, the heterogeneity might not be important. A fixed-effects model was used to assess these outcomes. If I 2 was between 50% and 100%, it could represent substantial heterogeneity. We used random-effects model to evaluate these outcomes. Thresholds for the interpretation of I 2 can be misleading, since the importance of inconsistency depends on several factors. Therefore, subgroup analysis or sensitivity analysis was performed to interpret the potential source of heterogeneity. Because of only four studies included, publication bias test were not necessary.  Table 1.

Primary outcome
The BMD of lumbar spine and total hip were the primary outcome in our meta-analysis, which were used to evaluate the therapeutic effect of osteoporosis. The treatment period were divided into two subgroups (month 6 and 12).

BMD of lumbar spine
Four studies assessed lumbar spine BMD of 620 patients through month 12 Fig. 6).

Adverse events
There were also two studies[23, 24] evaluating the incidence adverse events. The common points of interest were serious adverse event, death and injection-site reaction. No significant differences were found between the two group in the incidence of serious  Fig. 7).

Summary of evidence
According to our study, Romosozumab can significantly increase the BMD of lumbar spine, total hip and femoral neck, with a lower incidence of injection-site reaction. And those differences all have statistical significance (P 0.05). There is no difference in the incidence of death and other serious adverse events. Fewer adverse events (P 0.05) and longer half-life may improve the compliance of patients and reduce the loss of benifits.

Limitations
Our meta-analysis has several limitations (1) there were only 4 RCTs in our meta-analysis, the sample size of included studies was small(N=1304). (2) In regard to the significant heterogeneity of LS BMD (I 2 =86%) and TH BMD(I 2 =84%), although we used a random effect model, we tried to find the source of heterogeneity. When we excluded the study of

Conclusions
With an ageing population, Osteoporosis, especially the most common postmenopausal osteoporosis has brought great economic burden to the global public health, and also seriously affects the quality of life of patients themselves [25,26]. In America, age-related fractures are projected to increase nationally to over 3 million fractures in 2025 [27]. The process of ageing in women is associated with an increase in the rate of bone remodelling in both cancellous and cortical bone, combined with a negative remodeling balance, resulting in bone loss and disruption of bone microarchitecture [1]. It is generally believed that the key to the treatment of osteoporosis is to restore the dynamic balance of bone metabolism, and the signal pathway between cells has become a key to research [28]. With the emergence of new signaling pathways, new types of avenue s targeting them are also emerging, such as Melatonin [29].
The real-life challenge, however, roots in the long therapeutic procedure for osteoporosis. its registration was denied in Europe on the grounds of concerns about its effectiveness in reducing non vertebral fractures, and increases in heart rate and palpitations [1]. EMA's Committee for Medicinal Products for Human Use (CHMP) thought some data from study sites of Abaloparatide were not reliable and had to be excluded as the study had not been conducted in compliance with 'good clinical practice' (GCP) at those sites [33]. After enough clinical trials in postmenopausal women with osteoporosis [34][35][36][37][38][39], Romosozumab (EVENITY TM ) has been proved to be safe and effect, then approved by FDA in 2019 [40].
There is a new avenue for the treatment of osteoporosis. Dating back to 1979, Frost first proposed the concept of sequential therapy for osteoporosis [41]. However, relevant DATA-Switch studies do not attach enough attention until now and have shown better outcomes than monotherapy [42][43][44][45][46][47]. Similarly, there are few similar researches on Romosozumab.
Compared with monotherapy, the transition from Romosozumab to other antiresorptive drugs may further increase bone mineral density in postmenopausal osteoporotic women.
Through bone-targeting systems to deliver siRNA is also a new method for osteoporosis, and it has already been examined in a preclinical study [48].
In summary, all the current drugs for osteoporosis more or less have some side effects or lack efficacy, and an very ideal osteoporosis therapy has not yet been developed. Other

Ethics approval and consent to participate
This article is not involved in ethical requirements.

Consent for publication
The manuscript is approved for publication by all the authors.

Availability of data and materials
All data generated or analyzed during this study are available from all the included studies from those databases mentioned in the abstract.