Antiresorptive Medication Effects on Dental Implant Survival and Implant-Related Jaw Osteonecrosis

Dental implants to replace missing teeth are a predictable treatment option with survival rates ranging as high as 98 to 99%.^1-6 Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a serious dental surgical post-operative risk for patients on antiresorptive medications, and may also interfere with dental implant osteointegration. The data on antiresorptive medication-associated implant failure and implant failure associated with ARONJ have been conflicting and limited.

Antiresorptive medications

Antiresorptive medications were prescribed for malignancies like metastatic bone tumors, cancers, and multiple myeloma; for bone diseases like osteoporosis, osteopenia, Paget’s disease; and for medication-associated bone resorption from antineoplastic agents, thyroid supplements, Lupron therapy for prostate cancer, glucocorticoids, and antacids.⁷ Antiresorptive medications including bisphosphonates (BPs) and denosumab increase bone density by decreasing osteoclastic activity.

On a cellular level, BPs reduce osteoclastic activity while osteoblasts continue bone deposition, resulting in net cortical bone gain. BPs disrupt the normal osteoclastic action, causing retraction of the normal ruffled border from the bone surface, the ensuing osteoclast death results in no new osteoid formation.⁸ In addition, BPs can also inhibit angiogenesis.^9-13 The reduced angiogenesis may have an adverse effect on the dental implant osseointegration. Furthermore, the BP induced avascular and acellular bone may be less able to resist microbial invasion, increasing the risk for peri-implant bone loss or osteonecrosis.

Oral BPs have been used for treating osteoporosis and osteopenia.¹⁴ Intravenous (IV) BPs have been used for treating hypercalcemia-associated bone diseases.^15-17 The effect of BPs on the osteoclasts depends on the chemical structure, non-nitrogen, or nitrogen-containing BP. Nonnitrogen BP include tiludronic acid, etidronate disodium, and clodronate disodium. Osteoclasts metabolize non-nitrogen BP producing cytotoxic analogs of adenosine triphosphosphates, causing apoptosis of osteoclast and impairing resorption. As for osteoclasts metabolism of nitrogen-containing BP, the mevalonate pathway disruption interferes with bone resorption by inhibiting posttranslational protein and osteoclast’s ruffled border formation.^18,19 Nitrogen-containing BPs show stronger antiresorptive activities than non-nitrogen containing BPs.²⁰ BPs have high affinity for hydroxyapatite and accumulate in the bone matrix for an extended period.

Denosumab, a human monoclonal antibody, has been used for treating osteoporosis and bone metastasis.^21,22 Denosumab increases bone density by inhibiting osteoclastic activity and reducing bone resorption.²¹ This highly specific action inhibits receptor activator of nuclear factor-kappa B ligand (RANKL).²³ RANKL regulates osteoclasts survival, differentiation and function. Denosumab, a RANKL neutralizing antibody, has been shown to reduce skeletalrelated pathological fractures, spinal cord compression, or hypercalcemia in cases of metastatic bone cancer.²⁴ Denosumab also suppresses osteoclasts differentiation from osteoclast precursors expressing RANK.²⁴

BPs are most commonly reported in conjunction with dental implant placement (Table 1). The most common indication for BPs use in these studies was osteoporosis. More females than males were taking BPs for osteoporosis. This is because BPs have been effective in increasing bone mineral density and reducing fractures.⁷

Table 1: Antiresorptive Medications and Implant Success (Clinical studies)

Study	No. of BP patients (Male/ Females)	Indications (Medication: no. of patients)	Duration of medication before implants (no. of patients)	ARONJ due to implant surgery	Success rate of implants in medication group	Success rate of implants incontrol group	Manage- ment of implant failure	Bone grafting	Antibiotic therapy	Mouth rinse
Al-Sabbagh et al. 201546	20 (1/19) 46 implants	Osteoporosis (Oral BP)	> 3 yrs	None	Implant level: 100% Patient level: 100%	Implant level: 100% Patient level: 100%	No implant failure	NR	NR	NR
Bell and Bell 200842	42 (2/40) 100 implants	Osteoporosis (Alendronate: 34, Risedronate: 6, Ibandronate: 2)	6 mos – 11 yrs	None	Implant level: 95%	Implant level: 96.5%	All 5 implant failure had subsequent implant replaced successfully	30 patients Grafting materials: autogenous bone from intraoral sites, xenograft 68 bone graft procedures: 41 socket graft, 6 sinus lifts, 4 closed lifts, 14 GTR, 1 tunnel graft, 3 buccal contour graft 1 case of bone graft failure	NR	NR
Famili et al. 201145	22 (0/22) 75 implants	Osteoporosis (Oral BP: Fosamax: 15, Boniva: 1, Fosamax to Boniva:1, Boniva to fosamax:1, Actonel: 4)	6 mos – 1 yr : (6) > 1 yr : (9) > 5 yrs : (5) NR: (1)	None	Implant level: 98.7%	No control	Successful replacement of implant 1 year later	NR	NR	NR
Fugazzotto et al. 200740	61 (0/61) 169 implants	Indication not reported (Oral BP Aldendronate 35 mg: 33, Aldendronate 70 mg: 18, Risedronate 35 mg: 7, Risedronate 70 mg: 3)	1-5 yrs Mean: 3.3 yrs	None	Implant level: 100% Patient level: 100%	NR	No implant failure	Particulate bone graft: 1 patient had exposed bone on torus after immediate implant, which resolved after debridement	Amoxicillin 500 mg TID for 10 days or erythromycin 333mg TID for 10 days if allergic Etodolac 400 mg TID for 5 days, as needed	Post-op CHX rinse BID for 21 days
Grant et al. 200844	89(0/89) 468 implants	Indication not reported (Oral BP)	Mean: 38 mos >3 yrs: (33) <3 yrs: (56)	None	Implant level: 99.6%	None	2 implant failure, 1 redone successfully, 1 was not replaced	1 of the 2 Failed implants case had left maxillary sinus lift 32 of 115 patients had sinus augmentation	NR	NR
Jeffcoat 200638	25 (0/25) 102 implants	Indication not reported (Oral BP: Alendronate Risendronate)	1-4 yrs (mean: 3 yrs)	None	Implant level: 100% Patient level: 100% Compared to control: no statistical significance	Implant level: 99.1% Patient level: 96%	No implant failure	NR	NR	NR
Kasai et al. 200941	11 (0/11) 35 implants	Osteoporosis (Oral BP: Alendronate, Fosamax )	None	None	Implant level: 85.7%	Implant level: 95.7% Patient level: NR	Failed implants removed, no report of replacement	NR	NR
Koka et al. 201035	55 (0/55) 121 implants	Osteoporosis or osteopenia (BP NR)	<3 yrs: (16) 3-5 yr: (20) >5 yr: (19)	None	Implant level: 99.2% Patient level: 98.2%	Implant level: 98.2% Patient level: 97.6%	NR	NR	NR	NR
Memon et al. 201243	100 (0/100) 153 implants	Indication not reported (Oral BP: Alendronate: 72, Risdronate: 23, Ibandronate: 5, IV BP: excluded)	< 1 yr : (2) 1-3 yrs : (19) > 3 yr : (15) NR: (46)	None	Implant level: 93.5%	Implant level: 95.5%	NR	44 patients had bone grafting	44 patients had bone grafting	NR
Mozzati et al. 201536	235 (0/235) 1267 implants	Osteoporosis (Oral BP) Exclusion: Current or past history of IV BP	NR for all subjects	None	Implant level: 98.7% Patient level: 93.2 %	NR	Failed implants were successfully replaced	54 patients needed sinus lifts Strong association of sinus lift and implant failures	54 patients needed sinus lifts Strong association of sinus lift and implant failures	NR
Siebert et al. 201526	12 (0/12) 60 implants	Osteoporosis (IV Zoledronic acid, annual infusions 5 mg)	2-3 yrs	None	Implant level: 100% Patient level: 100% No statistical difference between experimental group and control	Implant level: 100% Patient level: 100%	No implant failure	1g amoxicillin/ clavulanic acid BID for 6 days, starting 24 hours prior to surgery	1g amoxicillin/ clavulanic acid BID for 6 days, starting 24 hours prior to surgery
Tallarico et al. 201539	32 (0/32) 98 implants	Indication not reported (Oral BP: Aldendronate 70 mg)	> 3 yrs	None	Implant level: 98.98%	NR	3 patients had peri- implant mucosal inflammation after 6 mos Improved oral hygiene reduced peri-implant inflammation	NR	NR	CHX 0.2%: 7 day before surgery, day of surgery, and 7 days after surgery
Yajima et al. 201748	11 (0/ 11) 25 implants	Osteoporosis (BP not specified)	1-3 yrs: (5) > 3 yrs: (6)	None	Implant level: 88.9% Patient level: 72.7%	Implant level: 100% Patient level: 100%	NR	NR	NR	NR
Zahid et al. 201118	26 (1/25) 51 implants	Osteoporosis (BP not specified)	Incomplete data set	None	Implant level: 94.1% Patient level: 88.5%	Implant level: 97.1%	3 failed implants, 2 implants replaced successfully, 1 was not replaced	NR	NR	0.5 oz of 0.12% CHX 4 times a day for 2 wks post-

ARONJ

Nitrogen-containing BPs have commonly been associated with implant failure and ARONJ.¹⁸ IV administration of BPs has also been associated with an increased risk of ARONJ.25 ARONJ (Fig.1 & Fig.2) associated with BPs manifest as painful exposed bone, necrotic bone, and intraoral or extraoral fistulas that do not heal within 8 weeks.^26,27 Patients taking BPs needing dental extractions have reported higher risks of ARONJ.^28-33 The ARONJ risk of patients taking BPs needing dental implants has been unpredictable.^29,33,34 Thus, BP use may be a contraindication to elective surgical procedures, including dental implant placement.^29,35 Due to limited data, the American Association of Oral and Maxillofacial Surgeons stated that the risk of ARONJ after dental implant placement may be similar to the risk after dental extractions.²⁷ However, there are conflicting reports of dental implant success without the occurrence of ARONJ.^35-37

Fig. 1

Fig. 2

Dental implant survival in patients on BPs

Table 1 included clinical studies on patients on BPs requiring dental implant surgery, 3 were prospective studies ^26,38,39 and the other 11 were retrospective studies. The use of antibiotics pre-operative, intra-operative, or post-operative may influence ARONJ and dental implant infections. Six studies^{18,26,36,39-41} reported prophylactic antibiotics before and 5-10 days after dental implant surgery, the remaining studies did not report antibiotic use. Antibiotics reporting could have been overlooked if antibiotics were used routinely. Only 1 study⁴⁰ reported the use of chlorohexidine mouthwash postimplant surgery, the rest of the studies did not report the use of postoperative mouthwash.

Bone grafting for site development before dental implant surgery was performed in the 5 studies,^36,40,42-44 one study⁴² reported bone grafting failure, 2 studies reported implant failure associated with sinus lifts,^36,44 and remaining 2 studies did not report on the data.^40,43 Since osteoclasts are integral for graft turnover during healing, BP-related osteoclast apoptosis may decrease bone grafting success.¹³ However, this was not apparent as only 2 out of the 5 studies reported grafting failure. The two studies^36,44 with bone graft failure reported that the graft failure did not progress to osteonecrosis. These implant site development procedures performed included sinus lifts, guided bone regeneration, ridge preservation, and ridge augmentation. The bone graft materials used included combinations of autografts and allografts together or alone.

Six studies^{36,39,40,42,44,45} reported complications like periimplant inflammation, mobility, implant failure, or exposed bone. However, no studies reported ARONJ as an outcome of dental implant surgery. Only one study³⁸ reported no adverse reactions. Implant survival was 85.7-100%. Four studies^26,38,40,46 did not have any implant failures in the BP group. However, patients taking BPs may have a greater risk of peri-implantitis and peri-implant bone loss.¹⁸ Dental implant-related wound healing requires alveolar metabolic and physiologic changes around the implant for successful integration of the dental implant to the alveolar bone. Antiresorptive medication alters the bone physiology (Fig.3). It decreases osteoclastogenesis, increases osteoclasts apoptosis, decreases bone resorption, decreases osteoblastogenesis, and decreases bone formation.¹⁹

Fig. 3

Implant failure has been reported as osteointegration failure.⁴⁷ BPs may affect initial implant integration at the osteoconduction phase which forms new bone at the boneimplant interphase.⁴⁷ BPs can persist for years in the bone matrix, and can affect every aspect of bone remodeling. BPs may be released during bone remodeling, and embedded into new bone.⁷ BP-related bone turnover suppression is associated with cumulative of bone microdamage and excessive occlusal forces, leading to increased bone resorption.¹³

Risks of implant failure in patients on BPs

Eight^{18,26,35,38,41-43,48} studies in Table 1 reported implantlevel data, only one study reported statistically significant difference in implant failure between the antiresorptive medication group and the control.⁴¹ In the antiresorptive medication group, 4.2% (27 of 647) of implants failed compared to 3.0% of implants (62 of 2056) in the control group.

Five^{26,35,38,46,48} studies in Table 1 reported patient-level data, none of the studies reported any statistically significant difference in implant failure between the antiresorptive medication group and control. In the antiresorptive medication group, 3.3% (4 of 123) of patients reported failed implants compared to 2.1% (3 of 142) of patients in the control group.

Other risk factors or medical comorbidities can increase implant failure and ARONJ risks. Besides taking BPs, smoking and radiotherapy were already significantly associated with implant failure. Other health conditions like osteoporosis and diabetes may have some reported effects on implant failure, which may not be statistically significant.⁴⁹ Other factors for implant failure may be related to the alveolar position of the implant, there is increased implant failure in the maxilla⁵⁰ especially the posterior maxilla.⁴²

Osteoporosis and being female may also be co-factors contributing to the antiresorptive medication-associated risk for implant failure. There is a large majority of females with osteoporosis taking antiresorptive medication reported in most studies. The lack of male subjects in the studies could be a rarity of males with osteoporosis requiring antiresorptive medication or a research bias for females. Prevalence studies reporting osteoporosis in > 50 years old was approximately 5-23% females and 1-4% males.^7,46,51 Thus, it may be expected that a larger number of females may be available for study recruitment. Furthermore, osteoporosis may diminish osteointegration around implants,⁵² and increase the risk for implant failure.⁵³

Dental implant failure and ARONJ

ARONJ may not be the etiology of implant failures in all cases. It was reported that implant failures did not result in ARONJ and the failed implants may be replaced successfully. Ten studies^{18,35,36,39,41-45,48} who reported implant failure (Table 1), 5 reported implant replacement ^{18,36,42,44,45} resulting in successful osteointegration. There were no reports of ARONJ as an outcome of dental implant surgery nor was it a consequence of implant failure. The failed implants were subsequently replaced with successfully osseointegrated implants, in the patients who did not refuse replacement.^{18,36, 42,44,45} There were also no healing complications for failed implant removal in patients who refuse implant replacement.^18,41,44

The studies (Table 1) that reported implant failure, none encountered ARONJ. The absence of ARONJ in the studies may relate to the route of BP administration and the dosage. The studies in Table 1 were mainly on oral BP. The oral route of BP administration may contribute to a lower risk of ARONJ.

The risk of ARONJ with patients taking IV forms of BPs may be higher. Patients over 70 years old on IV BPs may have a higher risk of osteonecrosis of the jaw.⁵⁴ This increased risk may be related to patients on IV BPs frequently having accompanying comorbidities, severe osteoporosis, and advanced age. In general, these patients may have an increased risk of ARONJ after any type of oral surgical procedure due to the severity of existing comorbidities. Therefore, implant clinicians need to fully understand the higher risk of ARONJ to these patients, and proceed with caution, or avoid implant surgeries in these IV BP patients.

Effects of BPs on pre-existing dental implants

Patients commencing BPs may be at risk for osseointegration failure of pre-existing dental implants (Table 2). BPs causing failure of pre-existing dental implants may be less common as it has only been reported in some case reports.^55-60 These dental implant failures were reported as early as 11 months after starting BP treatment to 4 yrs after. These failed dental implants have been reported to be in function from 2 years to 11 years before disintegration. Patients in these case reports were older than 54 years and the majority were on IV BPs for cancers, while others were on oral BPs for osteoporosis. It is also possible that the reported peri-implantitis in some of these patients could be a precipitating factor for the development of ARONJ.

Table 2: ARONJ in previous implants after initiation of BP treatment (case reports)

Study	Age (Sex)	Indications	Medications	Time from BP initiation to ARONJ	Duration of implant function	Periodontal condition	Management
Favia et al. 201555	66 yrs (F)	Breast cancer with metastasis	IV Zoledronate	4 yrs	5yrs	NR	Antibiotics Partial mandibular resection
Junquera et al. 201156	59 yrs (M)	Multiple myeloma	IV Zoledronate	11 mos	2 yrs	Healthy	Antibiotics CHX rinse Implant removed
Marín-Fernández 62 yrs (F) Breast cancer IV Zoledronate 1 yr 6 yrs et al. 201560	62 yrs (F)	Breast cancer with metastasis	IV Zoledronate	1 yr	6 yrs	Peri-implantitis	Antibiotics CHX rinse Subtotal maxillectomy
Seki et al. 202158	73 yrs (F)	Osteoporosis Hypercalcemia	Oral Alendronate	4 yrs	10 yrs	Peri-implantitis	Antibiotics Mechanical debridement CHX rinse Maxillary sinus lavage Implant removed
Shirota et al. 200959	54 yrs (F)	Breast cancer with liver and bone metastasis	IV Pamidronate (current) IV Zoledronate (2005-2006)	2 yrs	6 yrs	NR	Antibiotics Hyperbaric oxygen Sequestrectomy
Yuan et al. 201260	69 yrs (M)	Osteoporosis	Oral Risedronate (2005-2007) Oral Alendronate (2007)	3 yrs	11 yrs	Peri-implantitis	Antibiotics Mechanical debridement CHX rinse Implant removed

Management of implant-related ARONJ

ARONJ may have permanent and severe repercussions for patients such as loss of the maxilla or mandible. ARONJ in previously placed dental implants after starting BP treatment can be treated conservatively with antibiotics, antiseptic mouthrinses, mechanical debridement, and removal of the failed dental implant (Table 2). In more severe cases of ARONJ, subtotal maxillectomy, partial mandibular rection, or sequestrectomy may be needed.

Prevention of ARONJ

ARONJ has been associated with severe infections involving Actinomycetes.⁶¹ Thus, it is crucial to lower oral bacterial load with proper oral hygiene in patients on BP needing dental implant surgery. Thus, patients needing dental implants that are periodontally healthy or periodontally stable after periodontal therapy, may contribute to the lower implant failure rates and no ARONJ (Table 1).

Conclusion

Oral or IV antiresorptive medications may impair the integration of dental implants and reduce implant survival. Implant failures in patients on antiresorptive medication do not always lead to osteonecrosis, and failed implants may be replaced with some success. In addition, the commencement of antiresorptive medication may increase the risk of failure in pre-existing and successfully integrated dental implants. Thus, dental implants in patients on antiresorptive medications or commencing antiresorptive medications need to be more meticulously maintained to increase dental implant longevity. Due to the limitations of the available data, larger sample sizes and longer patient follow-ups may be required for more definitive conclusions.

Oral Health welcomes this original article.

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About the Authors

Dr. Miriam Ting, DMD (Temple University, magna cum laude), BDS (Singapore), Cert. Advanced Periodontology and MS (Craniofacial Biology) at USC. Diplomate, American Board of Periodontology and ICOI. Dr. Ting is founder and director, Think Dental Learning Institute and Magnifico Oral Health Foundation and practises at Think Oral Implants and Periodontics in Paoli, PA.

Dr. Jon B. Suzuki, Clinical Professor, University of Maryland, Baltimore, MD, USA. Clinical Professor, University of , Seattle, WA, USA. Clinical Professor, Nova-Southeastern University, Ft. Lauderdale, FL USA. Professor Emeritus, Temple University, Philadelphia, PA, USA.