## 4 Discussion  
Two previous systematic reviews have been performed on the use of serum or baseline BTMs for monitoring the early response to osteoporosis treatment, especially in fracture prediction and patients' persistence/adherence to therapy [34; 35]. The correlations between the BTMs and the BMD changes were also investigated, but the analyses on the correlations between the BTMs and the BMD changes were not incomplete [34; 35]. It should also be noted that even though the correlations between BTMs and BMD changes have been studied in the last 20 years, the quantitative relation between are still not clearly established. In this review, we made a systematic analysis of the correlation between the BTMs and BMD changes based on all available data with the intention to evaluate the value of the BTMs in predicting long-term BMD changes and identify several promising biomarkers for further study on their clinical application. We revealed the correlation between the BTMs and BMD changes in terms of bone sites, intervention, time duration of the BTMs measurements, and time duration of the BMD measurements. According to the results of the systematic review, the correlation of the baseline BTMs with BMD changes from baseline after drug intervention were all positively correlated, and the intensity of the correlation presented a big disparity as the bone sites, intervention, time duration of BTMs, and BMD measurements varied. For the BTMs after intervention, the changes in BTMs and BMD from baseline were positively correlated under antiresorptive therapy; under the anabolic therapy (i.e., teriparatide), the correlation between the changes in BTMs and BMD were not consistent in the direction; however, from the results of the systematic review, the correlation under anabolic therapy were all weak. Based on the results of the systematic review, further subgroup analyses were performed to evaluate the promising BTMs that presented a meaningful correlation with the BMD changes. According to the results of the systematic review, several BTMs presented moderately strong correlation with the BMD changes under specific conditions, such as bone ALP, osteoclastin, PINP, urine NTX, and urine/serum CTX. The further subgroup analyses on their correlation with the BMD changes in terms of bone sites, intervention, time duration of BTMs measurements, and time duration of BMD measurements indicated that the correlation of the biomarkers of osteoclastin, PINP, and urine NTX with BMD changes under specific conditions were moderately strong and negative. Therefore, the three promising BTMs may play a role in evaluating the long-term BMD changes and therefore could be valuable in the prediction of the future fracture risk after drug intervention; however, they still need to be further studied for the clinical application. As for the other BTMs, they were not specific according to the subgroup analyses and therefore were excluded from the promising candidates. Osteocalcin, the product of the osteoblasts, was thought to reflect the activity of the bone formation [36]. PINP, the product during the process of the collagen formation, was also the biomarker for the process of the bone formation [37]. Urine NTX, the product during the process of the collagen degradation, was thought to be the marker for the bone resorption process [38]. According to this study, the moderate correlations between the BMD changes and the three identified BTMs (i.e., osteoclastin, PINP, and urine NTX) suggest that the three biomarkers are valuable in predicting the future BMD changes. Furthermore, if the BMD changes could be quantitatively calculated by the identified biomarkers, the fracture risk could be better predicted with the early changes of the biomarkers, therefore providing the physicians with better references in evaluating the efficacy of the treatment.