Despite numerous retrospective studies, however, the use of these biomarkers remains controversial because of the sample size limitations due to the rare prevalence of BRONJ, as well as problems in study design in establishing controls and other study criteria (Table 3) , , , , ,  and . Certain studies ,  and  have set the reference ranges of the manufacturer as a benchmark comparison; however, reference ranges have not yet been established except in premenopausal women, and even this varied among studies .
Other studies  and  used healthy patients or patients taking BPs as the control group; however, this method is flawed because the true control group would be patients who have undergone dentoalveolar surgery without developing BRONJ. Despite having a carefully matched control group, this study could not find a relation between biomarkers and BRONJ development, with the exception of PTH. Epacadostat Tacrolimus price CTX, NTX, and DPD are the representative markers that can quantify the amount of bone absorbed by osteoclastic activity, and they have received large interest as risk predictors. However, such collagen degradation
markers have a high degree of analytical and biological variability . More important, even though these markers quantify the amount of degradation molecules which are produced by osteoclastic activity at the time of sampling, they do not necessarily reflect the overall decrease in bone remodeling activity caused by BPs  and . Thus,
it is likely that these markers will not be highly meaningful for predicting the degree of dentoalveolar trauma and restorative capacities of bone that shows suppression of osteoclastic activity and subsequent abnormal remodeling, the major pharmacologic Teicoplanin effect of BPs. In the present study, the only biomarker that showed a statistical significance for BRONJ development was serum PTH. Ardine et al.  suggested the involvement of hypocalcemia and secondary hyperparathyroidism in the period preceding BRONJ development. Although conflicting study results do exist,  and  this inspiration may serve as an important lead for the investigation of the mechanism behind BRONJ, and additional research is needed. Although novel biomarker candidates related to bone remodeling such as serum VEGF  and TRACP 5b  have been proposed as risk predictors, these have not yielded continuous research. Several reports in the dental literature still recommend that the serum CTX level should be > 150 pg/mL before dental surgery , ,  and . However, it is not unusual for patients taking BPs to have serum CTX levels of < 150 pg/mL according to the large-scale FLEX (Fracture Intervention Trial Long-term Extension)  and HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly)  studies. Moreover, even among persons with levels of < 150 pg/mL, patients that developed BRONJ are very rare  and .