It is known that stronger the potency of BP, higher the risk of developing MRONJ. In general, the incidence of MRONJ with IV medication is significantly higher than that with oral medication. Oral BP had a relatively smaller effect on the osteoclast function because oral BP has a lower absorption rate (10%) in the gastrointestinal tract and is excreted largely unchanged by the kidneys [4, 20, 21]. It had been reported that the MRONJ incidence with a high dose of IV BP is significantly higher than oral BP . AAOMS position paper on MRONJ also noted that patients with cancer treated with IV BP had a high incidence of ONJ, whereas the risk of developing ONJ in osteoporotic patients exposed to oral or IV BP remained very low . Thomas et al.  reported that among patients with cancer who were exposed to IV BP, the ONJ risk ranged from 0 to 6.7%, and the chances of developing ONJ in patients with cancer exposed to an oral BP was 0.7%. Systematic review on the treatment and outcome of MRONJ concluded that IV BP is more frequently associated with ONJ than oral BP . AAOMS position paper suggested that the incidence of ONJ in oral BP users is very low . However, long-term administration of oral BP also can significantly suppress bone turnover and ONJ is one of the major concern for the osteoporosis patients with oral BP . Recent national survey in Japan (2018)  showed that proportion of ONJ related with oral BP was increased compared to 2014 data , which is nearly similar to IV BP-related ONJ. Taiwanese population showed higher incidence of 82 per 100,000 person who had been received alendronate . A report from Sweden suggested that 67 cases per 100,000 patient-years . According to the Korean data, ONJ incidence was suggested as 21 per 100,000 person in osteoporosis patients , which is comparable to 28 per 100,000 person-years of oral BP treatment in data from the USA . The previously reported incidence was much higher than number of reported ONJ cases after alendronate treatment for osteoporosis of approximately 0.7 cases per 100,000-year exposure from Merck in 2006 . In our institute, the ONJ caused by oral BP administration was predominatly higher (90.3%) than IV BP group (9.7%). It is also reported at the nationwide survey on clinical department in Korea (2013) and showed that 78.7% of reported BRONJ cases were related with oral BP and much higher than IV BP (21.3%) . Although the incidence of ONJ is low in Korea , a long-term administration and increased cumulative dose of BP might be attributed to increased proportion of the ONJ cases in oral BP group in our study.
The important finding of this study was the difference in the clinical features and treatment prognosis of MRONJ related with oral versus IV BP. In this study, the oral BP group was likely to develop at older age (73.2 years) than the IV BP group (64.1 years). Our results confirm previous reports by Shintani et al.  who reported similar pattern of mean age; oral BP 76.6 years versus IV BP 67.3 years. Similarly, Hallmer et al.  reported that osteoporosis with oral BP were older than those with cancer treated with IV BP. The duration of medication in the IV BP group was significantly shorter than that in the oral BP group. In general, IV BP has a considerably higher absorption rate and potency in the body than oral BP; therefore, MRONJ is more likely to occur even if the duration of IV medication is shorter than that for oral BP.
The development of MRONJ with oral BP requires a long period of exposure (53.1 months) than IV BP (31.4 months). Lo et al. reported a higher prevalence of MRONJ (0.21%) in patients treated with oral BP for > 4 years as compared to that in those who were treated for < 2.5 years . As reported in a previous literature, the longer duration of BP therapy is one of risk factor of MRONJ, and the risk appears to be higher after 3 years of treatment .
The number of involved sites was also higher in the IV BP group than in the oral BP group (1.63 ± 0.84 vs. 1.21 ± 0.48). This result implies the stronger effect of IV BP than oral BP in developing ONJ. MRONJ appears to be more likely to affect the mandible and maxilla than the other parts of the skeleton. The jaws are the only bones that are in contact with the outside frequently and are subject to repeated micro-trauma through the presence of teeth and the forces associated with mastication. Moreover, the turnover of the alveolar bone is 10 times as much as that of the long bones [28, 32]. The mandible was affected by MRONJ more commonly than the maxilla. This could be attributed to the decreased vascularity of the mandible, and the existing local conditions could contribute to MRONJ. This distribution is similar to that reported previously. Aljohani et al.  also showed that the mandible was the most common MRONJ site, followed by the maxilla and both. Haller et al.  also reported that most lesions were located in the mandible (75%). In a similar manner, in our study, the incidence of MRONJ in the mandible was higher in both the groups. However, the tendency to occur more in both jaws was greater in the IV BP group.
In the present study, the evaluation of treatment prognosis was based on the number of surgeries. Reoperation was performed if there was no improvement or recurrence after conservative and surgical treatment. Therefore, the number of operations could be used as a measure for evaluating patient prognosis. The average number of surgeries in patients treated with IV BP (1.65 ± 095) was higher than that in those given oral BP (0.98 ± 0.73). In our experience, most of the patients with oral BP underwent surgery with sequestrectomy and surgical curettage rather than radical surgical resection. However, definitive sequestra formation had not been existed in IV BP-related ONJ and there was difficulty in establishing the margin of the lesion.
It had been proposed that ONJ after oral BP is a rare and real entity that is less frequent, less severe, more predictable, and more responsive to treatment than IV BP-induced osteonecrosis . Other report showed that > 90% of the patients treated with oral BP could be cured. However, only 50% of those treated with IV BP showed no improvement . IV BP treatment generally causes more advanced and extensive BRONJ and is less sensitive to conservative treatment than oral BP . Similar to the previously reported results, the treatment prognosis of MRONJ for patients with oral BP was better than that for patients with IV BP in our study.
Reich et al.  categorized the postoperative results into 4 groups. Similarly, in this study, we divided the treatment outcomes into 3 groups, as “good”, “moderate”, and “poor” to evaluate the postoperative prognosis. In the oral BP group, “good” outcome was the most common (81.7%, n = 205) after initial surgery; thus, the treatment outcomes were relatively favorable. However, in the IV BP group, the proportions of patients with “moderate” or “poor” outcomes (55.5%, n = 15) were higher, indicating that reoperation was required more frequently.
Serum CTX refers to the examination of C-terminal cross-linking telopeptide of type I collagen. Type I collagen is a structural organic compound that accounts for 98% of the total protein in the bone. Telopeptide fragment is a derivative from which the main cross-linking chain proceeds with bone resorption by osteoclasts. The serum level of the telopeptide fragment is proportional to the level of osteoclast activity at the time of blood collection. Therefore, serum CTX is considered most relevant for bone replacement. The normal level of serum CTX is usually > 300 pg/mL, and in most patients, it ranges from 400 pg/mL to 550 pg/mL. An imbalance in bone remodeling resulting from the suppression of osteoclastic activity is a major factor related to MRONJ onset. The progression of MRONJ represents reduced level of bone turnover markers; therefore, some reports state that the CTX value can be used to assess the MRONJ risk or severity [11, 19]. In contrast, several reports have revealed that no biological marker can predict the development and reflect the severity of MRONJ . Marx et al.  suggested that the relative risk could be evaluated as follows: CTX values < 100 pg/mL represent high risk, CTX values of 100–150 pg/mL represent moderate risk, and CTX values > 150 pg/mL represent minimal risk. In this study, the average CTX value (219 pg/mL) was higher in the oral BP group than in the IV BP group (134 pg/mL). This suggests that the osteoclast activity and turnover rate of the bone were lower in the IV BP group as compared to that in the oral BP group, indicating that poor prognosis.
ESR is a type of blood test that measures how quickly erythrocytes settle at the bottom of a test tube. Generally, red blood cells settle down relatively slowly. A faster-than-normal rate, and thus elevated ESR, may indicate inflammation in the body. The CRP level rises when there is inflammation throughout the body. It is a group of proteins called acute phase reactants that rise in response to inflammation. Choi et al.  reported that the inflammatory markers, ESR and CRP, were significantly higher in MRONJ patients than in the controls and were closely related to MRONJ severity at the time of the diagnosis. MRONJ could cause chronic inflammation; thus, the ESR was elevated in both, the oral and IV administration groups. In the IV group, the CRP level was higher; thus, acute inflammation was more severe than that in the oral BP group.
One of the limitations of this study is the lack of data on other drugs taken with BP, such as corticosteroids, and close examination of the patients’ medical history. Further research is required to determine the difference in the doses for oral and IV BP medication that can cause MRONJ.
In conclusion, IV administration of BP causes more severe inhibition of bone remodeling and could result in a higher degree of inflammation. Therefore, even if the duration of IV medication of BP is shorter than that of oral BP, the extent of lesion could be more extensive. Furthermore, IV BP is administered for MRONJ is associated with poorer prognosis.