Improved Oral Health in Adults With X-Linked Hypophosphatemia Treated With Burosumab

Abstract

Context

X-linked hypophosphatemia (XLH) is a rare genetic bone disease affecting both children and adults, with oral manifestations such as spontaneous dental infections. The main treatments for XLH are conventional treatment (CT) with oral phosphate salts and active vitamin D supplementation and burosumab, an antibody targeting fibroblast growth factor 23. While the beneficial effect of CT on oral manifestations is established, the effect of burosumab on oral health is unknown, especially in adults.

Objective

We aimed to compare the oral health (number of missing or endodontically treated teeth and presence of periodontal disease) and incidence of endodontic infections of adult patients with XLH according to their treatment's modalities (no treatment, CT, or burosumab).

Methods

This was achieved through a single-center, retrospective analysis of oral health data from 44 patients who had undergone dental monitoring for at least 6 months.

Results

Oral health varied according to the proportion of their adult life spent under treatment for XLH, and the incidence of dental infections during follow-up was influenced by the type of treatment received. There was a 55.9% reduction of infections during CT and an 86.4% reduction during burosumab treatment compared to periods with no treatment (P < .0001). Comparing treatment and nontreatment periods within the same patient showed a strong association between burosumab treatment and decreased infection incidence (.006 vs .09 infection per month, P < .01).

Conclusion

We observed that adults with XLH treated with burosumab developed fewer endodontic infections during dental follow-up than patients who were untreated or received CT.

X-linked hypophosphatemia (XLH) is a rare genetic disease that affects the mineralization of the skeleton and teeth. The main clinical manifestations in children are rickets, disproportionate growth retardation, craniosynostosis, and spontaneous dental infections, while in adults these include osteomalacia associated with pseudofractures, osteoarthritis, enthesopathy, hearing loss, chronic pain, spontaneous dental infections, and periodontitis (1-3). Abnormal mineralization is caused by inactivating mutations in the PHEX gene, responsible for an excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23), an impaired activation of vitamin D metabolism, and the accumulation of peptides that inhibit mineralization locally (1). Dental infections are thought to be caused by defective dentin formation and mineralization, resulting in odontomalacia, abnormally large pulp chambers, prominent horns extending to the dentino-enamel junction, and micro-cracks in enamel, which allow oral bacteria to reach the dental pulp and cause necrosis (4-6).

There are several treatment options for children and adults with XLH (7). The first is daily supplementation with active vitamin D and oral phosphate salts. This treatment, known as conventional treatment (CT), is indicated in children during growth and can be continued in adults with or without symptoms. A second, more recent, treatment is burosumab, a monoclonal antibody directed against FGF23. Its efficacy on several key clinical parameters (rickets activity and severity, growth velocity) is superior to that of CT in children (8-10). In adults, burosumab has also shown convincing results in the consolidation of pseudofractures, the correction of osteomalacia, and the improvement of stiffness, mobility, fatigue, and musculoskeletal pain (11-15). For these reasons, an increasing number of XLH children and adults are now being treated with burosumab.

Like skeletal bone, defects in tooth mineralization and periodontium can be improved or even corrected by general (ie, systemic) XLH treatment. A major difference, however, is the remodeling potential of dental and periodontal tissues, which is absent (enamel) or very limited (dentin, cementum), unlike bone tissue. For this reason, it is crucial to correct the mineralization defects through systemic treatment as early as possible, during tooth formation, to prevent future dental infections. This has been shown for CT and burosumab (16, 17). The superiority of 1 treatment over the other in preventing dental infections in children is questionable. In children treated first with CT and then with burosumab, fewer abscesses were observed during treatment with burosumab (18).

Limited remodeling of dental tissues also explains why oral manifestations of XLH such as spontaneous infections may persist in patients on treatments with improved musculoskeletal health and why the dental benefit of treatments in adults has long remained uncertain. Two studies have shown a dental benefit to continuing or resuming CT in adults with XLH. Connor et al (19) found that the proportion of time spent under treatment in adult life was negatively associated with the risk of having severe dental manifestations (5 or more dental abscesses). In a previous study (20), we reported that adults who continued CT after the end of growth had on average fewer endodontically treated teeth (reflecting the history of dental infections) and less periodontitis. Only 1 study to date reports on the effects of burosumab on dental infections in adults and unexpectedly found more abscesses in the burosumab group compared to the placebo group during 24 weeks of follow-up (11).

In this study, our main goal was to evaluate the influence of burosumab on the incidence of dental infections in adults with XLH. This was achieved through a retrospective analysis of oral health data from 44 adults with XLH who received no treatment, CT, or burosumab and were followed up at our dental center. Additionally, a secondary objective was to examine the oral health of adults with XLH based on the duration of treatment they received during their adult life.

Methods

Study Population

This study was retrospective and monocentric and followed STROBE guidelines. We included all individuals older than 18 years diagnosed with XLH, referred to and followed up in our center for oral health care from 2015 to 2023. The dental follow-up period had to be at least 6 months in our center while taking the same treatment for XLH. Patients were excluded from the study if another general disease that may affect oral health was present, if they were edentulous, or if information on the general treatment of XLH was missing.

Diagnosis and general treatment of XLH were carried out in expert centers following international recommendations (7). Patients on CT or burosumab were either adults who had not stopped treatment after the end of growth or symptomatic adults who had resumed treatment. The choice of burosumab over conventional treatment was based on the decision of a multidisciplinary consultation meeting (verifying that the indication corresponded to those authorized for the marketing in France, that is patients with severe disease despite conventional treatment or with intolerance to conventional treatment: presence of fractures or pseudofractures, significant bone deformities, pain associated with osteomalacia, significant functional impact and impairment of quality of life associated with osteomalacia, need for corrective orthopaedic surgery). The dose of burosumab was started at 1 mg/kg and adjusted (increased or decreased as appropriate). Individual adjustments were based on both serum phosphate concentration to target the lower limit of the age-reference range, clinical improvement, and, if appropriate, radiological monitoring. The injections of burosumab were performed every month. Patients received CT with vitamin D analogues and phosphate supplements, according to international guidelines (7). Compliance with conventional treatment was assessed based on clinical and radiological improvement as well as 24-hour calciuria and PTH level. Compliance with burosumab was assessed based on phosphate levels after injection, 1 week, and 15 days and clinical and radiological improvement.

In the patients' medical files, we collected and collated the following data: sex, age at XLH diagnosis (year), clinical and biological features of XLH, comorbidities (nephrolithiasis and/or nephrocalcinosis, osteoarthritis, enthesophytes and/or osteophytes, pseudofractures and/or fractures, musculoskeletal pain, fatigue, overweight or obesity, diabetes mellitus, hyperparathyroidism, and hearing loss), age at start and end of dental follow-up (year), smoking status, type of XLH treatment (conventional or burosumab), if any, duration of the XLH treatment (month), duration of the dental follow-up (month), number of dental abscesses during the dental follow-up period, number of cellulites of odontogenic origin during the follow-up period, presence of caries, periodontal status (21), and presence and severity of alveolar bone loss at the initial dental exam. Dental abscesses, cellulites of odontogenic origin, and periodontal diseases were diagnosed based on clinical and radiological manifestations by dentists with experiences of the oral complications of XLH.

For each patient, we calculated the time spent during adult life (percentage) without treatment, with CT, and with burosumab, as well as the number of dental abscesses per month of dental follow-up under the same XLH treatment during the dental follow-up. Only dental abscesses and cellulitis diagnosed during the dental follow-up period in our center were considered and counted.

Statistics

Descriptive statistical analysis of the population and results were summarized as mean and SD for continuous normally distributed data, as median and interquartile ranges for continuous nonnormally distributed data and as n (%) for categorical data. The characteristics of participants according to their treatment status (absence, CT, or burosumab) were assessed by one-way ANOVA for continuous variable and Chi-test for categorical variable. The primary endpoint was the number of dental abscesses per month of dental follow-up.

The subgroup comparison of the number of abscesses in patients according to the treatment sequence (no treatment then burosumab, CT then burosumab, or no treatment then CT) was performed using a bivariate analysis for matched data.

The association between the dental disease and the proportion of time spent under treatment (conventional or burosumab) in adult life was assessed by 1-way ANOVA for continuous variable and Chi-test for categorical variable.

The association between the number of endodontically treated teeth, missing teeth, and the proportion of time spent under treatment (conventional or burosumab) in adult life was assessed using a linear regression model. Variables significantly associated with the variable exposure in univariate analysis were then included in the multivariate linear regression model.

For all the analyses, a P-value < .05 was considered significant. All analyses were performed on the statistical software R, version 3.5.2.

Regulatory Approval

This study was designed, conducted, recorded, and reported in accordance with the principles established by the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. All participants were verbally informed about the potential use of their anonymized medical data for research purposes, and the participants' nonobjection was collected. All participants had the right to withdraw their consent by completing the form available from a link at http://recherche.aphp.fr/eds/droit-opposition. According to French law (loi Jardé), anonymous monocentric retrospective studies do not require institutional review board approval. However, we submitted the study protocol, and the study was approved by the ethical committee of our institution (AP-HP, approval provided on request). It was also approved by the French National Data Processing and Liberties Commission.

Results

The medical records of 62 adults with XLH followed at our center were analyzed, and 44 patients were included. Reasons for noninclusion were either a dental follow-up shorter than 6 months (n = 16); missing data on XLH management, including the type of treatment during adult life (n = 1); or being edentulous (n = 1). The characteristics of the patients included are detailed in Table 1.

The general management of XLH was highly variable (Fig. 1). Some patients had never been treated during adulthood (n = 6, 13.6%), while others had always been treated (n = 6, 13.6%). The remaining 32 patients (72.7%) alternated between periods with and without treatment. Thirty-four patients (77.3%) had been treated with CT during their adult life and 15 (34.1%) with burosumab. Of the latter, 11 (25%) had been previously treated with CT.

The duration of dental follow-up (44.6 months ± 36.0) was also variable but relatively long, allowing 103 dental infections and 2 cellulitis to be diagnosed in 32 patients (72.7%) during follow-up. The mean number of endodontic infections per month of dental follow-up was .035 ± .046 (mean, SD), ie, approximately 1 infection every 29 months. The frequent occurrence of dental infections resulted in high numbers of endodontically treated or missing teeth (7.25 ± 5.04 and 3.39 ± 3.65, respectively). Thirty-six patients (81.8%) had stage II or III periodontitis and alveolar bone loss.

Focusing on oral health parameters at the time of inclusion (number of endodontically treated, number of missing teeth, and presence of caries), we were unable to demonstrate any association between these parameters and the rate of dental infection during follow-up (P = .19, P = .87, and P = .83, respectively). We did not find any association between the number of dental infections during follow-up and the presence or absence of XLH features such as nephrolithiasis and/or nephrocalcinosis (P = .79), osteoarthritis (P = .69), enthesophytes and/or osteophytes (P = .23), pseudofractures and/or fractures (P = .89), musculoskeletal pain (P = .073), fatigue (.59), overweight or obesity (P = .46), diabetes mellitus (P = .41), hyperparathyroidism (.85), and hearing loss (.44).

We first analyzed the influence of the duration of general management of XLH on oral health, regardless of the type of treatment. To do this, we separated the patients into 3 groups according to the proportion of time spent under treatment: less than 20%, between 20% and 80%, and over 80% (Table 2). While the individuals in the first 2 groups were approximately the same age, the third group was younger and mainly comprised young adults who had not interrupted their treatment at the end of growth. In terms of clinical or biological manifestations of XLH (nephrolithiasis and/or nephrocalcinosis, osteoarthritis, enthesophytes and/or osteophytes, pseudofractures and/or fractures, musculoskeletal pain, fatigue, overweight or obesity, diabetes mellitus, hyperparathyroidism, and hearing loss), we observed no statistically significant differences between the 3 groups. On average, the over 80% group had fewer endodontically treated or missing teeth than the first 2 groups, in which these numbers were quite similar. According to the regression model, a greater proportion of adult life on treatment was significantly associated with a reduction in the number of endodontically treated teeth. However, when adjusted for age, the association was not significant (Supplementary Table 1) (22).

Periodontal health was markedly different between the 3 groups, with more frequent and more severe periodontitis as the proportion of time spent under treatment in adult life decreased (Table 2). Thus, almost a third of the patients who had been treated for XLH for less than 20% of their adult life had rapidly progressing, severe, generalized periodontitis (stage III, grade C), compared with 6% and 0% in the 20% to 80% and >80% groups, respectively.

Because most adults followed at our center had successive periods with and without treatment, several had dental follow-up of over 6 months under different treatment modalities (no treatment, CT, and burosumab) and were included in several groups at once for unpaired analysis (Table 3). We then compared the occurrence of infections specifically in these patients in a pairwise analysis (Tables 4 and 5). The sex ratio, mean age, mean age of diagnosis, smoking status, and mean duration of dental follow-up of patients in the different groups of treatment modalities (no treatment, CT, and burosumab) were very similar (Table 3); the number of dental infections observed during the dental follow-up varied according to the type of treatment received during this period of time, with a 55.9% and 86.4% reduction in the occurrence of infections under the conventional and burosumab treatment, respectively, compared with no treatment (.059 ± .062 vs .026 ± .030 and .008 ± .014, P < .0001). Age-adjusted odds ratios for the risk of infection per year of dental follow-up were the following: burosumab treatment vs no treatment odds ratio (OR) = .69 [95% confidence interval (CI) .55-.87; P = .003]; burosumab treatment vs CT OR = .62 (95% CI .40-.96; P = .04); CT vs no treatment OR = .73 (95% CI .59-.92; P = .009).

We next compared for the same patient the occurrence of infections between periods without treatment and periods with burosumab. Eight patients had a follow-up greater than 6 months in our center with both treatment modalities (Table 4). For all participants, the untreated period preceded the burosumab period. The time spent under burosumab in adult life was shorter than the time without treatment, as was the mean duration of dental follow-up. We observed that the mean number of dental infections per month of follow-up was reduced during burosumab treatment, compared with periods without treatment (.006 vs .09, P < .01).

We performed the same type of paired analysis, this time including patients who were followed in our center while on CT and later during treatment with burosumab (n = 8, Table 5). For all patients, the period on CT preceded the burosumab period. The percentage of adult life on burosumab was lower than on CT, as was the mean duration of dental follow-up. We observed that the mean number of dental infections per month of follow-up was reduced during burosumab treatment, compared with CT periods (.008 vs .025, P < .01).

The paired analysis was also performed with patients included for periods without treatment and on CT (n = 8, Supplementary Table 2) (22). The time spent under CT was shorter than the time spent without treatment, as was the mean duration of dental follow-up. We observed that the mean number of dental infections per month of follow-up was reduced during CT, compared with periods without treatment (.020 vs .096, P < .01).

Discussion

Since 2018, burosumab, a fully humanized antibody targeting FG23, has become available for the treatment of XLH, and it is increasingly being favored as the treatment choice for adults. Treatment with burosumab results in a dose-dependent improvement of serum phosphate levels and improves the clinical manifestations associated with hypophosphatemia. Notably, the advantages of burosumab over no treatment in adults with XLH are established in terms of improvement of musculoskeletal pain, stiffness, and signs of osteomalacia including radiological lesions (eg, pseudofractures) (11-15).

Very little information is available on the efficacy of burosumab in reducing the occurrence of dental infections in adults. This is a major gap for 2 primary reasons. First, dental infections have a substantial impact on the quality of life for individuals with XLH (23, 24). Among adults, the deterioration of quality of life is most notably associated with dental manifestations (25). Second, the prevalence of dental infections is notably high among adults with XLH. In a survey on the burden of disease, 82% of adults with XLH reported dental abscesses (26), while an observational study showed that more than 60% of adults with XLH had experienced 5 or more dental infections (19). Here we included 44 adults with XLH followed in our dental center and confirmed that infections are very common in adults, occurring in more than 70% of patients during dental follow-up. These infections led to endodontic treatment and sometimes tooth extraction. Few studies describing the epidemiology of oral health in adults have been carried out in France (27), but it appears that the population included in our study had more missing teeth and more endodontically treated teeth than the general population.

So far, the only information we have on the effect of burosumab on dental complications in adults comes from a randomized control trial comparing burosumab vs placebo, which did not report a beneficial effect of burosumab on the occurrence of dental abscesses (11). During the 24-week follow-up period, more abscesses were observed in the burosumab group than in the placebo group (13.2% vs 7.6% patients). It is possible that the duration of the trial was too short to see the effects of treatment. A second study looked at the oral health of adults with XLH treated with burosumab (28) but did not separately analyze adults treated with CT and those treated with burosumab. Thus, the impact of burosumab on dental manifestations in adults have not been assessed so far.

Here, for the first time, we observed a beneficial effect of burosumab on the incidence of dental infections in adults, with a significant reduction in infections during burosumab treatment periods compared with those without treatment or with CT.

A notable strength of our study was how dental infections were recorded since the infections were diagnosed during follow-up by dentists and not self-reported by the patient during a visit to his or her doctor. This reduced the risk of undetected infections with few or no symptoms. Additionally, our study offered the advantage of comparing infections within the same individual across different treatment modalities, even if this was only possible for a small number of adults. It is valuable given the variability in the severity of XLH and oral manifestations among patients (19, 28, 29). This intraindividual analysis also showed a benefit of burosumab compared to no treatment or CT. However, this paired analysis may have led to a bias, since it is possible that dental infections prompted the extraction of causal teeth, artificially diminishing the risk of subsequent infections. Furthermore, since access to burosumab was granted in 2018, the mean percentage of adult life spent on burosumab was shorter compared to other treatment modalities. Future studies should aim to include patients with longer treatment periods to provide a more comprehensive understanding of the effects of burosumab on dental infections in patients with XLH.

The biological mechanisms that might explain an effect of burosumab on adult dental infections are unknown and intriguing. Evidence suggests that for XLH treatment (whether conventional or with burosumab) to have the greatest effect on oral manifestations, it should be started as early as possible, ie, during tooth formation and mineralization (16, 17, 28). For this reason, systemic treatments may have limited impact once the tooth is fully formed, and the benefit of burosumab treatment in adults with pre-existing dental abnormalities is considered uncertain (30). In contrast, our results suggest that normalizing phosphatemia could reduce the occurrence of infections in adults with established XLH-related dental disease. It is known that dentin mineralization progresses throughout life during secondary dentinogenesis, even if this mineralization slows down once the tooth has formed (31). It is therefore possible that burosumab improves dentin mineralization, as previously reported in Hyp mice and adult XLH patients (32). Burosumab may also have the potential to improve osteomalacia in the alveolar bone surrounding the tooth and its response to endodontic infection (32, 33). Finally, as FGF23 is involved in the immune response to infection by modulating leukocytes' function and recruitment (34, 35), it is possible that targeting excess FGF23 may improve the host's response to infection.

Our study confirms that, irrespective of the type (conventional or burosumab), general treatment is associated with better oral health in adults with XLH and that the proportion of time spent under treatment in adult life is inversely correlated with the number of dental infections (19, 20).

We also observed, as previously reported, that adults with XLH have on average more frequent and more severe periodontitis than the general population (20, 36). Periodontal health seemed particularly related to the proportion of time spent on treatment in adult life, as periodontitis frequency and severity differed markedly depending on treatment history. We did not measure the presence of dental plaque, and it is possible that a difference exists between the 3 groups and contributes to periodontal health status. However, in a previous study we observed no difference in the mean plaque index between untreated patients and those treated with CT (20).

The increased periodontal attachment loss in XLH appears to be related to defective mineralization of cementum and alveolar bone that constitute the periodontium (20, 33). Systemic treatments could improve the homeostasis of both tissues, as observed in Hyp mice (32), translating into less periodontal attachment loss over time. As periodontitis are chronic diseases with a slow course, it was not possible in our study to assess the specific benefit of burosumab treatment.

A limitation of our study is its monocentric nature. All dental data analyzed here came from the same XLH expert center, which regularly sees adults with XLH from all over France. In addition, there may be an overrepresentation of patients with the most severe oral manifestations since patients with no or mild manifestations may prefer to be followed up by their local dentist.

In conclusion, we observed that adults with XLH treated with burosumab developed fewer endodontic infections during dental follow-up than patients not treated or treated with CT. These data, if confirmed by prospective and controlled studies with sufficient follow-up to detect any impact on dental and periodontal tissues, are reassuring about the oral impact of burosumab and could provide an additional argument for starting treatment in symptomatic untreated adults or for replacing CT with burosumab.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions

A.H. contributed directly to the management of the patients reported in the manuscript, collected and analyzed the data; M.G. contributed directly to the management of the patients reported in the manuscript, collected and analyzed the data; J.H. performed the statistical analysis and contributed directly to the management of the patients reported in the manuscript and data acquisition; M.I. contributed directly to the management of the patients reported in the manuscript and collected the data; A.L. contributed directly to the management of the patients reported in the manuscript and data acquisition; M.C.S contributed directly to the management of the patients reported in the manuscript and data acquisition; A.L.L. contributed directly to the management of the patients reported in the manuscript and data acquisition; P.K. contributed directly to the management of the patients reported in the manuscript and data acquisition; KB contributed directly to the management of the patients reported in the manuscript and data acquisition; C.C. contributed directly to the management of the patients reported in the manuscript, data acquisition and study design; M.B.D. contributed directly to the management of the patients reported in the manuscript, designed the study, analyzed the data, and wrote the first draft of the manuscript.

All authors commented on successive versions of the manuscript, read, and gave their final approval. They agreed to be accountable for all aspects of the work.

Disclosures

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.H., A.L., M.C.S., A.L.L., P.K., K.B., C.C., and M.B.D. have received honoraria and/or grant for research in other projects independent of this study from Kyowa Kirin Pharma. A.H., M.G., and M.I. have no relevant financial or nonfinancial interests to disclose.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Ethical Approval

The study and protocols conformed to the Declaration of Helsinki and local legislation and ethics guidelines.

Consent to Participate

All patients gave their approval to participate.

Consent to Publish

All patients gave their approval to publish.

References

Author notes