A 5-year retrospective cohort research of denosumab induced treatment associated osteonecrosis of the jaw in osteoporosis sufferers

Baseline traits The baseline traits of the 98 individuals surveyed on this research, together with

Baseline traits

The baseline traits of the 98 individuals surveyed on this research, together with the typical age, intercourse, and the comorbidities of the sufferers earlier than tooth extraction are introduced in Desk 1. The individuals’ age ranged from 36 to 91 years, with a median age of 70.5 ± 10.3 years. There have been 87 ladies (88.8%). Of 98 sufferers recognized with osteoporosis, 59 (60.2%) had hypertension, 31 (31.6%) had diabetes, 13 (13.3%) had most cancers, and three (3.1%) had underlying rheumatoid arthritis.

Desk 1 Demographics and medical traits.

Incidence of MRONJ in Dmab solely and BP + Dmab handled sufferers

The individuals have been divided into two teams, one receiving solely denosumab (Dmab, n = 52 [53.0%]) and one other that acquired bisphosphonate as the primary therapy and denosumab because the second therapy (BP + Dmab, n = 46 [46.0%]) (Desk 2).

Desk 2 Traits of sufferers handled with denosumab and bisphosphonate with extraction.

Within the Dmab solely group, the imply age was 69.08 ± 11.82 years. Denosumab was administered on common 2.37 ± 1.67 instances earlier than tooth extraction. The imply interval from drug cessation to extraction was 6.22 ± 4.85 months. Thirty-seven (71.2%) of the 52 sufferers acquired denosumab after tooth extraction, 2 (3.8%) acquired bisphosphonate, 2 (3.8%) acquired selective estrogen receptor modulator (SERM), and 11 (21.2%) didn’t obtain any drug. The imply interval from tooth extraction to drug initiation or resumption was 7.7 ± 9.1 months. Residual roots, dental caries and different endodontic lesions have been the primary causes for tooth extraction, the extraction website was maxillary in 26 sufferers (50.0%), mandibular in 18 (34.6%), and each in 8 (15.4%).

In BP + Dmab group, the imply age was 72.04 ± 8.13 years which was increased than that within the Dmab group. Bisphosphonate was administered for a median of 43.85 ± 47.80 months earlier than denosumab administration. Denosumab was administered on common 2.50 ± 1.61 instances earlier than tooth extraction. The imply interval from drug cessation to extraction was 6.28 ± 3.86 months. Sixteen (34.8%) of the 46 sufferers acquired denosumab after tooth extraction, 2 (4.3%) acquired bisphosphonate, 6 (13.0%) acquired an SERM, 3 (6.5%) acquired teriparatide, and 19 (41.3%) didn’t obtain any drug. The imply interval from tooth extraction to drug initiation or resumption was 2.56 ± 2.03 months. The principle purpose of tooth extraction was residual root, dental caries, and different endodontic lesions in 23 (50.0%) sufferers, adopted by periodontitis in 20 (43.5%) sufferers. The extraction website was maxillary in 24 sufferers (52.2%), mandibular in 18 (39.1%), and each in 4 (8.7%).

4 of the 98 (4.1%) sufferers developed MRONJ on this research. Two sufferers belonged to the Dmab group and a pair of sufferers belonged to the BP + Dmab group. Two of 4 sufferers developed MRONJ earlier than tooth extraction, and a pair of sufferers developed MRONJ after tooth extraction.

Elements affecting MRONJ growth

The elements affecting MRONJ growth are introduced in Desk 3. Amongst all sufferers, 43 (43.9%) have been of their 70 s, as have been 3 (75.0%) sufferers who developed MRONJ.

Desk 3 The prevalence of MRONJ in line with drug administration and timing.

Amongst 4 sufferers with MRONJ, 2 had hypertension, 2 had diabetes, and 1 had rheumatoid arthritis (i.e., one had hypertension and rheumatoid arthritis, one had diabetes, and the opposite had hypertension and diabetes). Two of 46 sufferers with a historical past of bisphosphonate administration developed MRONJ, and a pair of of 52 sufferers and not using a historical past of bisphosphonate administration developed MRONJ. Amongst 98 sufferers, 73 (74.5%) sufferers administered denosumab earlier than tooth extraction and 53 (54.1%) sufferers administered denosumab after tooth extraction. Certainly one of 3 sufferers who developed MRONJ had tooth extraction inside 1 month after denosumab administration, 1 affected person had tooth extraction 6 months later, and 1 affected person had tooth extraction after > 6 months. Among the many sufferers who acquired denosumab after tooth extraction, one developed MRONJ > 6 months after tooth extraction. There was no important distinction between the prevalence of MRONJ and elements affecting MRONJ.

A a number of logistic regression confirmed no affiliation between the comorbidities of most cancers, hypertension, and diabetes and the prevalence of MRONJ (Desk 4). Nonetheless, sufferers with comorbidities of arthritis have been roughly 35 instances extra more likely to prevalence of MRONJ than these with out arthritis (P = 0.033).

Desk 4 Significance of comorbidities by a number of logistic regression.

Case description of MRONJ sufferers

4 sufferers have been recognized with osteoporosis on this research inhabitants. Following bisphosphonate and denosumab remedy, MRONJ developed earlier than extraction in Instances 1 and a pair of. In Case 3, after tooth extraction following solely denosumab remedy, MRONJ had occurred. In Case 4, the affected person had no historical past of osteoporosis therapy on the time of extraction, and developed MRONJ afterwards, following denosumab administration 1 12 months after extraction (Fig. 1). Desk 5 summarizes the MRONJ medical traits for circumstances 1–4.

Determine 1
figure 1

Circulate of MRONJ prevalence. Drug administration and MRONJ route earlier than and after tooth extraction in 98 sufferers recognized with osteoporosis. 4 sufferers developed MRONJ. In two of those sufferers, MRONJ occurred after administration of bisphosphonate and denosumab and earlier than extraction. One affected person acquired denosumab solely and developed MRONJ after tooth extraction. The remaining one affected person had undergone extraction with out prior osteoporosis therapy, after which MRONJ developed after administration of denosumab. BP bisphosphonate, Dmab denosumab, EXT extraction, MRONJ medication-related osteonecrosis of the jaw. The dotted line represents the MRONJ stream.

Desk 5 Case description of MRONJ of osteoporosis affected person handled with denosumab.

Case 1

A 74-year-old lady had rheumatoid arthritis, hypercholesterolemia, and hypertension and a historical past of zoledronic acid (5 mg/100 mg) remedy from March 2015 to March 2016 attributable to osteoporosis. From October 2017 to October 2018, she acquired a complete of three denosumab doses. In December 2018, there was extreme tooth mobility attributable to localized persistent superior periodontitis, and extraction was deliberate to be carried out after ≥ 3 to six months. Non‐surgical periodontal remedy (i.e., dental scaling and a pair of% minocycline ointment software [Periocline] into the gingival sulcus) was carried out earlier than extraction; nonetheless, MRONJ was recognized in the appropriate mandibular area 6 months after the final denosumab administration. The drug was modified to Calcitriol [0.25 mcg/Soft Cap], and extraction and sequestrectomy have been carried out after lesion localization (see Supplementary Fig. S1 on-line).

Case 2

A 76-year-old lady had secure angina pectoris and coronary artery illness, aside from osteoporosis, was handled with endodontics and prosthesis for a crown and root fracture that had occurred roughly 10 years prior. From January 2007 to Could 2017, she was administered alendronate and ibandronate, and in August 2017, she was administered zoledronic acid (5 mg/100 mg). One 12 months later, denosumab was administered as soon as. Six months thereafter, MRONJ occurred within the left maxillary area within the presence of localized persistent superior periodontitis, and bone necrosis was noticed as much as the mesial root website from the primary premolar to the second molar within the radiographic picture. Roughly 4 weeks later, tooth extraction and sequestrectomy of the affected space have been carried out, adopted by prosthetic rehabilitation of the lacking enamel (see Supplementary Fig. S2 on-line).

Case 3

A 54-year-old lady had diabetes mellitus, osteoporosis. In April 2019, denosumab was administered as soon as. Inside a month, the mandibular proper second molar had a hopeless prognosis attributable to a fracture within the tooth, and the tooth was extracted. Three months after extraction, necrotic bone publicity (MRONJ) was discovered on the lingual facet of the extraction website. With denosumab clearing up round October 2019, the world was noticed throughout follow-up and handled conservatively (see Supplementary Fig. S3 on-line).

Case 4

A 79-year-old lady with underlying illnesses akin to hypertension, diabetes mellitus, and acute myocardial infarction, aside from osteoporosis, didn’t bear any osteoporosis therapy earlier than tooth extraction. With the removing of partial dentures used > 10 years, the mandibular anterior enamel had extreme mobility and periodontic-endodontic lesions. The enamel have been extracted in July 2018. Denosumab was administered twice 11 months after the extraction, and bone loss and elevated sclerosis have been noticed within the anterior mandible in April 2020, 10 months after denosumab administration. Conservative therapy was carried out by altering denosumab by raloxifene (60 mg/T) in June 2020 (see Supplementary Fig. S4 on-line).