Simplifying the dental/periodontal management of patients with metabolic bone fragility receiving treatment with denosumab

Denosumab (DNB) is a bone-targeted medication used to preserve structural integrity and minimise the risk of fragility fractures in metastatic cancer and metabolic bone disorders. DNB targets and binds RANK Ligand, inhibiting osteoclast maturation, function, and survival. In contrast with nitrogen-containing bisphosphonates (N-BPs), DNB does not bind to hydroxyapatite and incorporate into bone; thus, bone cellular remodelling recovers rapidly after drug suspension. Qeios, CC-BY 4.0 · Article, June 16, 2020 Qeios ID: D95OWG · https://doi.org/10.32388/D95OWG 1/10 Denosumab has benn linked to the occurrence of osteonecrosis of the jaw (MRONJ), a uncommon but severe oral side effect with a higher prevalence in metastatic cancer patients than in patients with metabolic bone fragility. Although several oral triggers can initiate MRONJ, invasive oral treatments and tooth extraction still remain the most common precipitating event. In general, tooth extraction and oral surgery should be avoided in patients at increased risk of MRONJ, while extraction of unsalvageable teeth should be performed based on specific risk reduction protocols to eliminate dental/periodontal infections, still protectig from MRONJ onset. Based on the different pharmacological properties of DNB and N-BPs, it is likely that the MRONJ risk profile of patients with metabolic bone fragility receiving receiving different ARs could somewhat vary. We hypothesize the chance to maximize the pharmacokinetic of Prolia® and identify a time interval in which invasive oral treatments can ideally take place without restrictions in patients with metabolic bone fragility, provided that careful case selection, adequate communication among specialists, planning of a delayed dosing window and rigorous postoperative follow-up are granted.

Denosumab has benn linked to the occurrence of osteonecrosis of the jaw (MRONJ), a uncommon but severe oral side effect with a higher prevalence in metastatic cancer patients than in patients with metabolic bone fragility. Although several oral triggers can initiate MRONJ, invasive oral treatments and tooth extraction still remain the most common precipitating event. In general, tooth extraction and oral surgery should be avoided in patients at increased risk of MRONJ, while extraction of unsalvageable teeth should be performed based on specific risk reduction protocols to eliminate dental/periodontal infections, still protectig from MRONJ onset. Based on the different pharmacological properties of DNB and N-BPs, it is likely that the MRONJ risk profile of patients with metabolic bone fragility receiving receiving different ARs could somewhat vary. We hypothesize the chance to maximize the pharmacokinetic of Prolia® and identify a time interval in which invasive oral treatments can ideally take place without restrictions in patients with metabolic bone fragility, provided that careful case In recent years, a new antiresorptive drug (AR) called denosumab (DNB) has been approved worldwide for use in patients with cancer or metabolic bone disorders . DNB targets and binds RANK Ligand, inhibiting osteoclast maturation, function, and survival.
[1] [2] In contrast with nitrogen-containing bisphosphonates (N-BPs), DNB does not bind to hydroxyapatite and incorporate into bone; thus, bone cellular remodelling recovers rapidly after drug suspension, with a rebound of bone turnover. [3] Denosumab proved to perform better than zoledronic acid and other N-BPs in terms of prevention of skeletal related event (SRE) in patients with bone metastases [4] and is a valid alternative to bisphosphonates for the reduction of fracture risk in osteoporosis. [5] Different formulations and dosages of DNB are recommended for prevention of SREs in metastatic cancer patients and myeloma patients (Xgeva®, 20 mg SC q4 weeks) and for prevention of fragility fractures in high risk patients (Prolia®, 60 mg SC q6 months).
At present, Prolia® is indicated for several osteometabolic disorders including: 1) treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures, 2) cancer treatment induced bone loss (CT IBL) associated with hormone ablation in men and women with non-metastatic prostate and breast cancer respectively, who are at increased risk of fragility fractures and, 3) treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture [6] .
Based on the reported advantages of the use of DNB over N-BPs, [5]  MRONJ is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible and maxilla of patients exposed to the treatment with medications known to increase the risk of disease, in the absence of a previous radiation treatment. [11] N-BPs and DNB have been associated to MRONJ onset [12] [13] , alone or in combination with antiangiogenic (AA) drugs . [14] T he prevalence of MRONJ in patients with osteometabolic disorders ranges between 0% and 0.4%, and it is definitely much less than observed in metastatic cancer patients (between 0.2% and 6.7% ). [12] In addition, MRONJ clinical course in patients with metabolic bone disorders is seemingly less severe than usually seen in cancer and myeloma patients receiving high-dose ARs.
[13] [15] M R O N J r i s k f a c t o r s a n d "t r i g g e r s " M R O N J r i s k f a c t o r s a n d "t r i g g e r s " Despite MRONJ occurrence has been linked to several risk factors , including 1) the given AR medication (i.e. type and dosage schedule), 2) the patient disease profile (bone metastases and metabolic bone fragility), 3) the ongoing cancer therapy, 4) the chronic use of immunosuppressant drugs and steroids and 5) the associated comorbidities, [12] [ 16] it is still unknown what factor is most likely to impact on disease course and prognosis.
Several oral triggers apparently can initiate MRONJ , including dental and periodontal infection, ill-fitting dentures and dental extraction. Despite a growing body of evidence suggests that dental infection might represent the main local risk factor for MRONJ, [17] tooth extraction still remains the most common precipitating event, accounting for up to 2/3 of the reported MRONJ cases. [12] [17] [13] In contrast, several studies has proved that surgical tooth extraction, including alveoloplasty and primary wound closure is very successful and protects high-risk patients from MRONJ development. [18] [19] Since then, several risk reduction strategies implemented the routine use of simple and surgical extraction of unsalvageable teeth to eliminate dental/periodontal infections and minimize the risk of MRONJ onset in patients undergoing AR treatment (secondary prevention ). [20] Assessment of individual MRONJ risk profile (high risk vs low risk) becomes critical to select the appropriate dental treatment and protect patients from unnecessary (overtreatment) or insufficient (undertreatment) interventions.
T he cumulative risk of MRONJ in patients receiving ARs for bone metastasis and metabolic bone fragility increases with the time and varies based on the rate of bone turnover suppression that largely depends on the dosage regimen and the duration of treatment; that risk is at least comparable for N-BPs and DNB. [21] Cumulative dosage (i.e. dose x number of given doses) plays a key role in the individual risk assessment of MRONJ due to N-BPs, irrespective of the route of administration, but not necessarily for patients receiving DNB, as it does not incorporate into bone. [17] Based on the different pharmacological properties of DNB and N-BPs, it is likely that the MRONJ risk profile of patients at increased risk of fragility fractures receiving different ARs could somewhat vary. As a consequence, it is rational to stratify the individual risk of MRONJ in patients with metabolic bone fragility also based on the type of drug received as described in Figure 1. After a single dose of Prolia®, bone resorption markers (serum CT X levels) reach nadir within 3-7 days and decreasing by up to 80% from baseline levels . Bone turnover remains suppressed for at least 150 days after last administration [24] [25] and gradually Qeios, CC-BY 4.0 · Article, June 16, 2020 Qeios ID: D95OWG · https://doi.org/10.32388/D95OWG 5/10 regains the pre-dose values within 7-8 months (1-2 month off-therapy). [23] [24] [26] T reatment interruption leads to reversal of the Prolia® effect on bone mineral density (BMD) to pretherapy levels within 1 year. [3] In addition, stopping Prolia® in patients at increased risk of fragility fractures has been associated with a rebound vertebral fracture risk. [1] [27] For this reason, a drug-holiday prior to surgical dental treatment is not advisable at present.  T he chance to adopt a "delayed dosing window" to perform unrestricted elective oral and dentoalveolar surgery depends on the ability of the dental practitioner to: 1. identify the dental/periodontal conditions whom treatment can be reasonably postponed to the 5th month from the last denosumab injection (i.e elective dentoalveolar and periodontal surgery, nonurgent tooth extraction), from those who require urgent management; these latter should not be delayed in any case and finalized according to well-suited risk reduction strategies that represent an effective means of reducing the incidence of MRONJ associated with ARs; [20] 2. directly interact with the bone specialist (drug prescriber), communicate the treatment plan and profile the appropriate "delayed dosing window". T hen, truly provide patients with exhaustive information about the possible risk and benefit of the planned procedure; 3. treat the patient according to routine dental protocols and strictly follow-up the healing process; 4. promptly communicate the progress of healing to the bone specialist, who will jointly evaluate the opportunity to restart DNB.

In conclusion
In conclusion, we hypothesize that invasive oral treatment of non emergent dental/periodontal conditions can be performed without restrictions in patients with metabolic bone fragility receiving Prolia®, provided that careful case selection, adequate communication among specialists, planning of a delayed dosing window and rigorous postoperative follow-up are granted. Longitudinal clinical studies are needed to endorse its adoption in the dental practice.