## 4 Discussion  
Our study confirms that in OI-I adolescents treated with BPs, the extraction of the third molar is safe, and socket healing after surgery occurs properly. Indeed, all OI-I patients included in this study failed to show a delayed healing of the surgical wound and clinical and imaging features consistent with BRONJ. At the time of extraction, they were all into a \"drug holiday\" of BPs consistent with that (i.e., 4 months) suggested in different guidelines [4; 38]. The absence of features of BRONJ was observed before and also after the third molar extraction indicating that BP treatment and teeth extraction are not associated with its development. These findings are overall consistent with previous studies. For example, in the study of [PERSON] and colleagues [8], no case of BRONJ was observed among 278 pediatric patients treated with cyclical intravenous pamidronate over a median period of 4.6 years during childhood or adolescence. Notably, 221 of the patients included in this study were affected by OI, and 113 underwent dental extraction either during or after treatment. In addition, in two systematic reviews estimating the risk of MRONJ among children with OI treated for 4.5 to 6.8 years [9] and subjects under the age of 24 treated with BPs for different conditions [10], no cases of MRONJ were identified. In our study, we also evaluated BMD focusing on different ROIs. Our analysis failed to detect significant differences for all ROIs between OI-I patients and age-matched healthy subjects before third molar extraction. In contrast, after the extraction, the OI-I patients showed a statistically significant increase for ROI-1/-2 (\(p\) = 0.0464), ROI-3/-4 (\(p\) = 0.0037) and ROI-7/-8 (\(p\) = 0.0079) compared to age-matched HSs. This result is consistent with the positive and persistent effect of BPs on BMD in osteogenic patients including OI-I ones [39; 40; 41]. Indeed, as synthetic analogues of pyrophosphate, BPs absorb to mineral surfaces, have antiresorptive and antiangiogenic effects and have a cumulative inhibitory effect on pathological bone loss [42; 43]. As in bone remodeling, bone resorption and formation are coupled and BPs suppress bone turnover [39; 40], and the increase in BMD could reflect the increased secondary mineralization related to the BP-dependent reduction in bone turnover [44; 45; 46]. Relevant limitations are associated with this study. The strongest limitation is the small sample size for both OI-I adolescents (five patients, nine sites) and age-matched HSs (four subjects, eight sites). Even though OI-I is a rare disease and its prevalence, even though not unequivocally proven in any population, has been estimated to be 5.16/100,000 [47], this small sample size limits the ability to make reliable inferences or generalize findings. A second important limitation of this study is the wide range of \"drug holidays\" of BPs as, at least in one patient (OI-I-1 in Table 1), the use of different BPs that, inevitably, introduce significant heterogeneity among the subjects make it difficult, if not impossible, to draw valid comparisons or conclusions. A third limitation is that our study is a descriptive study,