Osteoporosis Management after the Occurrence of Medication-Related Osteonecrosis of the Jaw: A 13-Year Experience at a Tertiary Center
Article information
Abstract
Background
We investigated osteoporosis management strategies and clinical outcomes following the occurrence of medicationrelated osteonecrosis of the jaw (MRONJ).
Methods
We retrospectively studied individuals diagnosed with MRONJ during osteoporosis treatment who were managed in the Osteoporosis Center or the Oral Maxillofacial Surgery & Dental Unit at Queen Mary Hospital in Hong Kong between 2010 and 2022. We examined subsequent osteoporosis management plans, fracture events, and bone mineral density (BMD).
Results
Thirty-six individuals were included (mean age, 78.5 years; 94.4% women). The estimated prevalence of MRONJ was 0.26%. All patients had been exposed to bisphosphonates, and seven had also received denosumab before MRONJ. Following MRONJ, only 14 individuals continued anti-osteoporosis treatment, a decision influenced by a higher fracture probability at MRONJ onset. The most common regimen was a teriparatide-raloxifene sequence (n=8): three patients achieved stable BMD, four achieved improving BMD, and one exhibited a mixed response. The patient with a mixed BMD response had also been treated with denosumab. Six patients sustained incident fractures after MRONJ, and these patients had lower BMD T-scores than their counterparts. Two patients experienced MRONJ recurrence, which was associated with the resumption of bisphosphonate or denosumab therapy after MRONJ. These patients had higher BMD T-scores than those who did not experience MRONJ recurrence.
Conclusion
MRONJ is challenging because high fracture risk necessitates discontinuation of antiresorptive agents. Teriparatide followed by raloxifene may be a reasonable regimen. Individualised decisions in osteoporosis management after MRONJ are required to balance fracture risk reduction with minimising MRONJ recurrence.
INTRODUCTION
Osteoporosis is a global health issue that is becoming increasingly prevalent in ageing societies. It is characterised by low bone mass and microarchitectural deterioration, leading to fragility fractures [1] that are associated with significant morbidity and mortality [2]. A range of anti-osteoporosis therapies with proven efficacy in reducing fractures are available, and these are classified as antiresorptive or osteoanabolic agents [3]. Notably, antiresorptive agents such as bisphosphonates and denosumab specifically inhibit osteoclastic activity, reducing bone resorption and thereby lowering fracture risk [3]. Although antiresorptive agents are the cornerstone of osteoporosis treatment, they are associated with rare but potentially serious side effects, including medication-related osteonecrosis of the jaw (MRONJ), which impairs quality of life and causes significant morbidity [4]. MRONJ refers to the persistence of necrotic bone lesions in the maxillofacial region for at least 8 weeks [5]. The incidence of MRONJ among patients treated with bisphosphonates for osteoporosis has been reported to range from 0.02% to 0.05%, and for denosumab, from 0.04% to 0.3% [5]. There is some suggestion that MRONJ is more prevalent among Asians [6,7]. The risk of MRONJ associated with antiresorptive agents must be balanced against the risk of fragility fractures if left untreated. Given the rarity of MRONJ, it is widely believed that the fear of MRONJ alone should not impede the treatment of osteoporosis [5].
In the unfortunate event of MRONJ, there are few reports regarding subsequent osteoporosis management. Although reducing fracture risk in these patients remains a priority, there is concern regarding the recurrence of MRONJ upon resumption of bisphosphonate or denosumab therapy. Regarding osteoanabolic agents, rare cases of MRONJ have been reported with romosozumab, although these appear to be even rarer than those associated with bisphosphonates and denosumab [8]. This limitation restricts the role of romosozumab in post-MRONJ osteoporosis management. Conversely, the use of teriparatide after MRONJ is not without its challenges. In patients who develop denosumab-related MRONJ, switching from denosumab to teriparatide may lead to progressive reductions in total bone mineral density (BMD), cortical thickness, and overall bone strength [9]. However, discontinuing denosumab without subsequent therapy carries the risk of rebound vertebral fractures [10]. These factors contribute to the complexity of post-MRONJ osteoporosis management, particularly in cases related to denosumab. Here, we present a 13-year case series of patients who developed MRONJ during osteoporosis treatment, with a focus on their subsequent osteoporosis management and skeletal outcomes, to inform our clinical practice.
METHODS
Study design
This retrospective cohort study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 24-348), and the need for informed consent was waived due to its retrospective nature.
Setting
Data were collected from individuals managed in the Osteoporosis Center [11] or the Oral Maxillofacial Surgery & Dental Unit at Queen Mary Hospital in Hong Kong between January 1, 2010 and December 31, 2022. Data collection was concluded on June 11, 2024.
Participants
All individuals diagnosed with MRONJ while receiving treatment for osteoporosis and managed at the Osteoporosis Center [11] or the Oral Maxillofacial Surgery & Dental Unit at Queen Mary Hospital in Hong Kong between January 1, 2010 and December 31, 2022 were included.
Exclusion criteria were: (1) absence of information regarding the anti-osteoporosis treatment regimen before MRONJ; (2) follow-up of less than 1 year after MRONJ; and (3) treatment with antiresorptive agents for malignancy.
Osteoporosis management at the Osteoporosis Center during the inclusion period adhered to the 2013 Osteoporosis Society of Hong Kong Guideline for Clinical Management of Postmenopausal Osteoporosis [12]. Abaloparatide and romosozumab were not available during the inclusion period. The management of MRONJ in the Oral Maxillofacial Surgery & Dental Unit followed the guidelines outlined by the American Association of Oral and Maxillofacial Surgeons (AAOMS) [13].
Variables
Oral surgeons diagnosed MRONJ according to the recommendations of the AAOMS [5]. The criteria included: (1) the presence of exposed bone in the maxillofacial region for at least 8 weeks; (2) current or previous treatment with antiresorptive therapy; and (3) no history of radiation therapy to the jaws or evidence of metastatic disease to the jaws.
We collected demographic and anthropometric data (age, sex, body mass index [BMI]), initial indications for osteoporosis treatment, history of osteoporosis treatment prior to MRONJ, clinical risk factors for osteoporosis for calculating Fracture Risk Assessment Tool (FRAX®), dental extractions before MRONJ, and the MRONJ treatment strategy. The clinical risk factors for osteoporosis were defined according to the original FRAX® definitions. Specifically, smoking was defined as current smoking, and alcohol use was defined as consumption of at least 3 units per day. Diabetes was defined as an HbA1c ≥ 6.5%, a previous physician diagnosis of diabetes, or the use of antidiabetic medications. Prevalent fracture was defined as the presence of major osteoporotic fractures, including those of the spine, forearm, hip, or shoulder. The FRAX® algorithms estimate the 10-year probability of hip fracture and major osteoporotic fractures (clinical spine, forearm, hip, or shoulder fractures). The Charlson comorbidity index was calculated. Following the occurrence of MRONJ, the treatment strategy employed was documented. The outcomes of interest included: (1) the decision regarding anti-osteoporosis management; (2) MRONJ recurrence; and (3) skeletal outcomes (dual-energy X-ray absorptiometry [DXA] measurements and incident fractures).
Statistical analyses
All statistical analyses were performed using SPSS version 27 for Windows (IBM Corp., Armonk, NY, USA). Results were reported as means±standard deviations, medians with interquartile ranges (IQR), or numbers with percentages, as appropriate. Comparisons of characteristics between patients who continued versus discontinued osteoporosis management were performed using the t test or the Mann–Whitney U test for continuous variables and the chi-square or Fisher exact test for categorical variables. A similar approach was used to compare individuals who did and did not sustain fragility fractures after MRONJ, those who did and did not experience MRONJ recurrence, and cases of bisphosphonate- versus denosumab-related MRONJ. In all analyses, two-sided P values <0.05 were considered statistically significant.
To estimate the prevalence of MRONJ among patients treated for osteoporosis with antiresorptive agents, we considered patients who might have received anti-osteoporosis treatments in other hospitals and were subsequently referred to our center for further management following MRONJ. Accordingly, we identified all individuals who received antiresorptive treatment for osteoporosis (excluding those who received bisphosphonates or denosumab for malignancy management) in the referral catchment area between January 1, 2010 and December 31, 2022 using the territory-wide anonymised electronic health database of the Hospital Authority of Hong Kong–the Clinical Data Analysis and Reporting System (CDARS). The Hospital Authority is the sole statutory public healthcare provider in Hong Kong (with a population of over 7.5 million), offering care for the majority of patients with chronic diseases due to high government subsidies. CDARS captures nearly all inpatient and outpatient data, including patient demographics, diagnoses, procedures, laboratory results, medication prescriptions and dosages, clinic attendance, hospital admissions, and mortality. Using CDARS, several high-quality, large population-based studies related to chronic diseases, including diabetes and osteoporosis, have been published [14,15]. The prevalence of MRONJ was calculated by dividing the number of MRONJ cases identified in this series by the number of patients exposed to antiresorptive therapy for osteoporosis during the same period.
RESULTS
Experiences of our osteoporosis center
During the inclusion period, 2,677 individuals (88.6% female) attended clinic visits at our osteoporosis center. Among them, 2,089 individuals (91.3% female) received anti-osteoporosis medication for fracture prevention: 1,556 received oral bisphosphonates (of whom 92.5% received alendronate, 5.4% received risedronate, and 4.7% received ibandronate), 978 received subcutaneous denosumab, and 233 received intravenous zoledronic acid. No patient received combination therapy (i.e., concurrent administration of two types of antiresorptive therapy). However, 656 individuals received more than one type of antiresorptive therapy during the inclusion period (538 received both denosumab and oral bisphosphonates; 62 received denosumab and intravenous zoledronic acid; 100 received oral bisphosphonates and intravenous zoledronic acid; and 22 received denosumab, oral bisphosphonates, and intravenous zoledronic acid).
Estimated prevalence of MRONJ during treatment for osteoporosis
In this study, 36 individuals (all Chinese) who developed MRONJ during osteoporosis treatment were identified and included. During the same inclusion period, 13,651 individuals receiving antiresorptive treatments for osteoporosis were identified in the referral catchment area. Thus, the estimated prevalence of MRONJ among patients treated for osteoporosis was 0.26% (36/13,651).
Characteristics of the 36 patients who developed MRONJ while on-treatment for osteoporosis
Baseline characteristics are summarised in Table 1. The mean age was 78.5±9.0 years, and most (94.4%) were women. The mean BMI was 22.8±4.0 kg/m2, and the median Charlson comorbidity index was 4 (IQR, 4 to 6). Fifty-two percent of the patients had prevalent fragility fractures at the time of osteoporosis diagnosis. Three patients were on steroids (patients no. 4, 16, and 19, receiving 5 mg prednisolone daily at the time of MRONJ). None were on antiangiogenic medications or tyrosine kinase inhibitors. At the time of MRONJ, the mean BMD T-score remained low—within the osteoporotic range for hip BMD—and the mean 10-year probabilities of major osteoporotic and hip fractures, as calculated by FRAX, were greater than 20% and 3%, respectively, indicating a generally high fracture risk in this cohort. The sites of MRONJ were recorded for 23 patients: 16 (69.6%) occurred in the mandibular region, six (26.1%) in the maxillary region, and one (4.3%) in both the mandibular and maxillary regions.
Comparison between Patients Who Continued and Discontinued Anti-Osteoporosis Treatment after Experiencing Osteonecrosis of the Jaw
All patients had been exposed to bisphosphonates before MRONJ. Two cases were associated with intravenous zoledronic acid. Among the 34 individuals exposed to oral bisphosphonates, 28 received alendronate, six received ibandronate, and two received risedronate. Twenty-seven patients (79.4%) had exposure for 4 or more years (a duration associated with higher risks of MRONJ) [16,17], and three were even treated for >10 years (patients no. 31, 32 and 35). Notably, among the seven patients with denosumab exposure before MRONJ, all had prior bisphosphonate exposure. All seven patients who received denosumab, except one, had short-term exposure (≤2 years).
Fifteen patients (41.7%) had dental extraction identified as the trigger of MRONJ. While one patient underwent dental extraction only 1 month after the last dose of denosumab (patient no. 12), some had withdrawal of bisphosphonate 3 months before dental extraction (patients no. 21, 23, and 24) and one even had bisphosphonates off already for 2 years when dental extraction took place (patient no. 25).
Factors associated with continuation of anti-osteoporosis treatment post-MRONJ
Following MRONJ, treating physicians thoroughly discussed the benefits and risks of continuing anti-osteoporosis treatment with the patients, after which a joint decision was made. Among all 36 patients, only 14 (38.9%) chose to continue treatment. Those who chose to continue treatment had a higher 10-year probability of major osteoporotic fracture at the time of MRONJ diagnosis (28.8% [95% confidence interval, 24.2% to 33.3%] vs. 21.3% [95% confidence interval, 16.2% to 26.5%], P=0.035) compared to those who discontinued treatment (Table 1). It is important to note that decisions to discontinue anti-osteoporosis treatment following MRONJ are often individualised, taking into account patients’ age, comorbidities, and personal preferences; however, statistical analyses did not identify age or comorbidities as determinants of treatment continuation in the current cohort. A review of clinical notes suggested that, in some cases, patients who decided against continuing treatment were influenced by a fear of further adverse events from subsequent anti-osteoporosis therapy.
Post-MRONJ outcomes: anti-osteoporosis treatment regime, fragility fractures, and MRONJ recurrence
Among the 14 patients who continued treatment, the most common regimen was teriparatide administered for 1.5 to 2 years (n=8): seven subsequently transitioned to raloxifene, while one switched to denosumab. A less common regimen included strontium (n=3), which was later discontinued when the medication was withdrawn from the market due to its association with cardiovascular risks [18]. Notably, patient no. 15, who was switched to denosumab by a private practitioner after strontium was discontinued, developed MRONJ recurrence when dental extraction was performed 3 months after the last denosumab injection. Similarly, patient no. 4, who resumed oral bisphosphonate therapy following resolution of the initial MRONJ episode, experienced MRONJ recurrence after a further 5 years of treatment.
At a median follow-up of 54 months (IQR, 29.5 to 94.5), six patients (16.7%) sustained incident fragility fractures following the initial MRONJ episode. There was no significant difference in the rate of incident fragility fractures between patients who continued anti-osteoporosis treatment and those who did not (3 [21.4%] vs. 3 [13.6%], respectively; P=0.658). The subsequent changes in BMD after MRONJ are summarised in Table 2 and Fig. 1. Twenty-nine patients had valid BMD measurements of the lumbar spine or hip at the time of MRONJ, and 21 of these underwent reassessment DXA. Unsurprisingly, patients who did not continue anti-osteoporosis treatment experienced a decline in BMD upon reassessment, particularly as the effects of bisphosphonates waned. Notably, one patient (patient no. 14) who received a single dose of denosumab immediately before MRONJ experienced BMD deterioration as early as 6 months after the event, underscoring the need for timely subsequent anti-osteoporosis treatment following denosumab discontinuation (in contrast to bisphosphonate therapy). Among the three patients who continued treatment with strontium, two (patients no. 1 and 15) underwent reassessment and demonstrated stable BMD over subsequent years. Of the eight patients treated with sequential teriparatide-raloxifene therapy (patients no. 12, 17, 23, 25, 26, 28, 30, and 36), three achieved stable BMD, four experienced improved BMD, and one had a mixed response with improved lumbar spine BMD but decreased total hip BMD. Interestingly, the patient with the mixed BMD response had also been treated with denosumab in addition to oral bisphosphonates. Among the remaining three patients who were restarted on bisphosphonate (patient no. 4) or denosumab (patients no. 16 and 29) after MRONJ, notably, one patient (patient no. 4) experienced a recurrence of MRONJ after a further 5 years of oral bisphosphonate treatment.
Characteristics of Patients Who Developed Medication-Related Osteonecrosis of the Jaw
Summary of clinical outcomes of the 36 patients who developed medication-related osteonecrosis of jaw (MRONJ) during treatment for osteoporosis. Among the 36 patients, 14 continued anti-osteoporosis treatment following MRONJ and 22 discontinued anti-osteoporosis treatment following MRONJ. (A) It describes the subsequent anti-osteoporosis treatment regime and changes in bone mineral density (BMD) (if available). Patient no. 4 developed recurrence of MRONJ while on oral bisphosphonates requiring bisphosphonate discontinuation, and subsequently developed incident vertebral fracture. Patient no. 15 developed recurrence of MRONJ related to denosumab started 4 years after strontium was discontinued. Three patients developed fragility fractures (patients no. 3, 4, 7). (B) It describes the clinical course of patients who discontinued anti-osteoporosis treatment following MRONJ. Patients no. 6, 9, 11 developed incident fragility fractures.
We performed several comparisons to identify potential factors associated with various clinical outcomes. First, individuals who did and did not develop incident fractures after MRONJ were compared (Table 3). Those who developed incident fractures tended to have a poorer fracture risk profile, as indicated by FRAX scores and BMD T-scores; however, these comparisons did not reach statistical significance, likely due to the small sample size. Secondly, individuals who did and did not experience MRONJ recurrence were compared (Table 4). Those who developed MRONJ recurrence had significantly higher BMD T-scores within the osteopenic range (–1.2±0.4 vs. –2.6±0.8, P=0.030). There was no association between fragility fractures after MRONJ and MRONJ recurrence (P=0.193). Thirdly, comparisons between individuals who developed bisphosphonaterelated and denosumab-related MRONJ (Table 5) revealed that bisphosphonate-related MRONJ was more likely to be managed surgically (26 [86.7%] vs. 2 [33.3%], P=0.014).
Comparison between Those Who Did and Did Not Sustain Fragility Fractures after MRONJ
Comparison between Those Who Did and Did Not Have MRONJ Recurrence
Comparison between Bisphosphonate- and Denosumab-Related ONJ
DISCUSSION
Our study examined osteoporosis management in a series of Chinese patients who developed MRONJ while receiving antiresorptive agents for osteoporosis—a subject that is less well described in the literature. Continuation of anti-osteoporosis therapy is often necessary in these patients, given their persistently high risk of subsequent fractures. Administration of teriparatide followed by raloxifene appears to be a feasible option after MRONJ related to either bisphosphonates or denosumab, since resuming antiresorptive therapy may precipitate MRONJ recurrence.
The inclusion of only 36 patients over a 13-year period underscores the rarity of MRONJ, with our study estimating its prevalence at 0.26%. We were unable to further delineate the prevalence attributable to bisphosphonates versus denosumab. Our reported prevalence represents the best estimate based on the available data from the territory’s electronic health records. A slight overestimation cannot be entirely excluded, as some patients may have been prescribed antiresorptive therapies in the private sector and thus not captured if they have never attended services under the Hong Kong Hospital Authority. Nonetheless, our estimate is reasonably consistent with the literature, which reports a risk of MRONJ of approximately 0.05% for oral bisphosphonates and 0.04% to 0.3% for denosumab in the context of osteoporosis treatment [5]. A recent study in Taiwan even reported a lower risk of MRONJ with denosumab compared to oral bisphosphonates (1.47 per 1,000 person-years vs. 2.49 per 1,000 person-years, respectively) [19]. In line with these findings, patients in our case series were predominantly exposed to bisphosphonates.
In accordance with existing literature, MRONJ in our series most commonly occurred in the mandibular region, and dental extraction was identified as the triggering event in 41.7% of cases. Previous reports have noted that dental extraction contributes to MRONJ in up to 60% of cases [20]. Organisations including the AAOMS have issued position statements addressing the risks of MRONJ following invasive dental procedures [21], and it cannot be overemphasised that maintaining good oral hygiene is essential for reducing MRONJ risk [21]. Nevertheless, if a patient requires an invasive dental procedure such as extraction, some professional societies in Italy [22], Japan [23], and Korea [16], have adopted the practice of a drug holiday for bisphosphonate users—stopping bisphosphonates approximately 2 months before dental treatment and resuming only after the wound has healed. However, the AAOMS remains inconclusive regarding the efficacy of such drug holidays in reducing MRONJ risk [5]. A 2024 review summarised the various international guidelines and suggested considerable variability among clinicians in the management and prevention of MRONJ [24]. In fact, several patients in our series developed MRONJ despite discontinuing bisphosphonates 3 months prior to dental extraction. Although a drug holiday may not fully mitigate MRONJ risk in bisphosphonate users due to the drug’s long half-life, evidence indicates that temporarily stopping bisphosphonates for at least 1 to 2 weeks before oral surgery can reduce direct toxicity on the keratinocytes of the oral mucosa [17]. In our comparison of bisphosphonate-versus denosumab-related MRONJ, patients with bisphosphonate-related MRONJ were more likely to undergo surgical treatment. However, given the relatively small sample size and the absence of a bisphosphonate-naïve denosumab cohort, further studies are required to validate these findings.
MRONJ poses a significant challenge for subsequent osteoporosis treatment, particularly in cases of denosumab-related MRONJ [25]. As demonstrated in our case series, the resumption of antiresorptive therapy may lead to MRONJ recurrence. Individuals who develop MRONJ may have inherent predispositions, such as genetic factors, that increase the risk of recurrence [4]. Patients with bisphosphonate-related MRONJ may discontinue bisphosphonates while retaining the BMD gains achieved from prior treatment [26], as reflected in our practice of prescribing a ‘bisphosphonate holiday.’ Conversely, patients with denosumab-related MRONJ may lose BMD gains—returning to pre-treatment baseline values after 1 to 2 years off treatment— and face a risk of multiple vertebral fractures upon denosumab discontinuation [10]. Therefore, especially in denosumab- related MRONJ, it is imperative to consider alternative antiosteoporosis therapies to optimise patients’ fragility fracture risk profiles. For atypical femoral fractures, the European Calcified Tissue Society recommends a regimen of teriparatide for 2 years, followed by raloxifene, as one feasible strategy [27]. However, applying this regimen in the context of MRONJ is challenging because denosumab accounts for a significant proportion of MRONJ cases [25]. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study) revealed a transient or progressive loss of BMD when switching from denosumab to teriparatide [28]. Specifically, in the lumbar spine, a transient drop in BMD occurs during the initial 6 months of teriparatide treatment, followed by an increase over the subsequent 18 months to levels exceeding baseline; at the femoral neck and total hip, the BMD decline persists for the first 12 months, with improvement in the following 12 months to return to baseline levels. In contrast, the distal radius exhibits a progressive BMD loss throughout the 2-year course of teriparatide treatment. In our cohort, patient no. 12 demonstrated this phenomenon, with an increase in lumbar spine BMD but a decrease in total hip BMD. The remaining seven patients treated with a teriparatide to raloxifene sequence maintained stable or improved BMD. Conversely, raloxifene alone may be insufficient to maintain BMD after denosumab discontinuation, as suggested by the recent comparison of alendronate and raloxifene after denosumab (CARD) study comparing alendronate and raloxifene following denosumab [29]. Thus, immediate transition to raloxifene after denosumab-related MRONJ may be inferior to teriparatide, particularly for patients who remain at high fracture risk at the time of MRONJ. Rare cases of MRONJ have also been reported in the landmark FRActure study in postmenopausal woMen with ostEoporosis (FRAME) study of romosozumab [8], pending further clarification of the causal relationship between romosozumab and MRONJ [30], romosozumab is unlikely to be the optimal choice for osteoporosis management post-MRONJ. Our cohort showed no significant difference in post-MRONJ anti-osteoporosis treatment patterns between bisphosphonate-related and denosumab-related MRONJ.
Comparisons between patients with and without fragility fractures after MRONJ, as well as between those with and without MRONJ recurrence, support an individualised approach to osteoporosis management post-MRONJ. While patients with high fracture risk, as indicated by low BMD T-scores, should be offered appropriate anti-osteoporosis therapy, overly aggressive treatment—especially when BMD T-scores are in the osteopenic range or higher—should be avoided.
We present our 13-year experience from a tertiary referral center in managing osteoporosis among individuals who developed MRONJ. Our study largely reaffirms existing knowledge regarding the medications and risk factors associated with MRONJ. We also demonstrated the feasibility of using subcutaneous teriparatide followed by oral raloxifene post-MRONJ, and we reported the outcomes in these patients. However, our results should be interpreted in light of several limitations. First, the sample size was relatively small. Second, because our study cohort consisted exclusively of Chinese individuals, the results may not be generalisable to other ethnicities. Given that MRONJ prevalence may vary by ethnicity [6], broader studies in other populations are necessary. Third, detailed information on oral health was unavailable, particularly in cases where dental extraction was not the triggering event for MRONJ; these cases were presumably associated with dental or periodontal infections [17]. Furthermore, we had limited data regarding oral hygiene practices and dental follow-up, although evidence supports the role of preventive dental measures, such as professional cleaning, in potentially mitigating MRONJ risk [24]. Fourth, all included patients had prior bisphosphonate exposure, so it remains unclear whether these results apply to bisphosphonatenaïve patients with denosumab-related MRONJ. Fifth, as inherent in retrospective studies, the varying time points of follow-up BMD measurements after MRONJ make it challenging to draw quantitative comparisons of treatment-specific effects, and residual biases cannot be entirely excluded. Lastly, FRAX was used as a proxy for fracture risk in patients undergoing antiresorptive therapy. We acknowledge that FRAX was originally designed for treatment-naïve patients; nevertheless, studies suggest that on-treatment FRAX can also be used for fracture risk stratification, potentially guiding decisions regarding continued treatment or treatment withdrawal [31].
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: Y.S., D.T.W.L. Acquisition, analysis, or interpretation of data: C.H.W., K.H.T., J.J.P., N.S.J., S.S.Y.C., C.H.N.L., X.Z., C.H.Y.F., D.T.W.L. Drafting the work or revising: C.H.W., K.H.T., J.J.P., E.K.H.L., A.C.H.L., C.H.L., K. C.B.T., Y.C.W., Y.S., D.T.W.L. Final approval of the manuscript: Y.S., D.T.W.L.