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Advancements in dental implant therapy have transformed oral rehabilitation, offering predictable solutions for functional and esthetic tooth replacement in individuals with partial or complete edentulism. Dental implants heal through a biologic process known as osseointegration, which is defined as "a direct structural and functional connection between ordered, living bone and the surface of a load-carrying implant on the light microscopic level."1 Tooth loss affects approximately 52% of US adults, and approximately 23% of patients with partial or complete edentulism are projected to have dental implants by 2026.2 Generally, implant survival has been defined as an implant that is present at the follow-up examination, regardless of condition, and implant success has been defined as an implant that is free of complications at the follow-up.3 The 2017 American Academy of Periodontology/European Federation of Periodontology World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions defined peri-implant health as the absence of inflammation (ie, erythema, swelling, bleeding on probing, suppuration) and the absence of additional bone loss after the initial healing period.4 Regarding the timing of assessment, it has been suggested that implant success should be assessed at a minimum of 12 months after prosthetic loading and that long-term success should be assessed after implants are in function for 7 or more years.5
Although it has been estimated that the 10-year survival rate of dental implants is 96.4%,6 the rates of biologic and prosthetic complications are significant.7-10 Biologic implant complications include both peri-implant mucositis and peri-implantitis, and prosthetic implant complications include fracture of the restorative material, screw loosening, fracture of the screw, and fracture of the implant fixture. Implant survival and success rates are impacted by environmental and local factors. Systemic conditions such as diabetes mellitus, rheumatoid arthritis, smoking, and other chronic diseases result in a hyperinflammatory state, which can affect osseointegration early in healing and increase the risk of peri-implant disease. Furthermore, certain medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), proton pump inhibitors (PPIs), antiresorptive medications, and antihypertensive medications, can impact wound healing and/or bone metabolism and may influence implant success and survival (Table 1).11
Medications That Affect Dental Implant Success
Many common systemic medications have both intended effects and side effects with wide-ranging implications for wound healing, cell activity, and immune system modulation. Some of these medications can affect the initial healing of dental implants and/or long-term bone levels and stability, including the following:
NSAIDs
NSAIDs are widely recognized for their anti-inflammatory and analgesic properties. They are commonly used for short durations to manage acute pain, including pain from dental treatment, and over extended periods to manage chronic pain and/or inflammatory conditions. NSAIDs reduce pain and inflammation by inhibiting cyclooxygenase enzymes (eg, COX-1, COX-2) and blocking prostaglandin production. Prostaglandins play a crucial role in bone turnover by promoting the recruitment and activation of osteoblasts. By blocking prostaglandin production, NSAIDs may impede osteoblast differentiation, potentially leading to reduced bone formation.12
In one study involving an animal model, minimal bone formation was observed in COX-2 knockout mice, which demonstrates the role of COX-2 in bone healing.13 In vivo human investigations have demonstrated equivocal evidence that the short-term use of NSAIDs impacts dental implant osseointegration.14 Although the results of individual studies have been equivocal, one retrospective study reported higher rates of implant failure and peri-implant bone loss in patients who used NSAIDs after implant placement.15 The results indicated that perioperative NSAID use was associated with a 44% implant failure rate, whereas patients who did not use NSAIDs experienced a 38% failure rate.15 Moreover, when compared with individuals who did not take NSAIDs, those taking NSAIDs demonstrated a 3.2-fold higher rate of significant bone loss and a 2-fold increase in loss of multiple implants.15
Given these findings, it has been hypothesized that systemic NSAID administration during the healing period following implant placement may impair bone healing.14 This may be particularly true for COX-2 specific inhibitors and more potent NSAIDs because they have been shown to have a greater effect on bone metabolism in animal and human models.14 Testing of the use of high-potency NSAIDs, such as meloxicam, in animal models has shown reduced bone density, bone formation, and implant-to-bone contact.14 Celecoxib, another COX-2 inhibitor, has also been associated with higher bone loss and potential osseointegration failure in vulnerable patients, according to retrospective studies.14 Conversely, in a randomized controlled study, ibuprofen showed no significant effect on marginal bone levels post-implant placement.14
Given the current evidence, it may be advisable to avoid the use of COX-2 inhibitors and more potent NSAIDs in the perioperative implant placement period. This precaution is particularly important for patients with systemic conditions associated with delayed healing and/or bone metabolism, such as osteoporosis/osteopenia, diabetes mellitus, and immunosuppression.16 However, for healthy individuals, the clinical impact of perioperative NSAID use may be minimal.
Antidepressant Medications
SSRIs are antidepressant medications commonly prescribed for treating depression and anxiety disorders. These medications function by inhibiting the reuptake of serotonin, thus increasing serotonin availability in synaptic clefts. Due to their efficacy and minimal adverse effects, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line antidepressants. In a recent systematic review and meta-analysis, antidepressant users were found to have higher rates of implant failure when compared with nonusers [risk ratio, 3.73 [95% CI, 1.85 to 7.52].17 SSRIs were used by between 36.3% and 57.5% of the individuals as monotherapy or part of a combination treatment.17 Less common medications prescribed among the patients included SNRIs (2.9% to 6.6%), tricyclic antidepressants (TCAs) (1.6% to 2.5%), and monoamine oxidase inhibitors (MAOIs) (0% to 0.1%).17
SSRIs impact bone metabolism by disrupting the balance of osteoblasts and osteoclasts, potentially reducing bone mineral density and impairing bone regeneration. SSRIs decrease osteoblast differentiation and mineralization. The influence of SSRIs on bone healing and turnover could negatively affect osseointegration and result in an increased risk of implant failure in users. In one study, dental implants placed in patients taking SSRIs demonstrated higher failure rates when compared with those placed in patients who were not taking SSRIs (hazard ratio, 6.28; [95% CI, 1.25-31.61]).18 Other antidepressant medications, including SNRIs and TCAs, have also been associated with increased implant failure rates and may place patients at greater risk than SSRIs. In fact, one study found that the frequency of implant failure was 33.3% in TCA users and 31.3% in SNRI users when compared with 6.3% in SSRI users and 3.9% in nonusers.19
Given these findings, SSRIs, SNRIs, and TCAs may negatively impact dental implant success. Patients using these medications may face higher risks of implant failure due to their effects on bone metabolism. However, the exact mechanisms by which these drugs affect osseointegration remain unclear, and further research is needed to better understand these relationships.
When evaluating the impact of antidepressant medications on dental implant outcomes, one confounding factor is that underlying psychological conditions, such as depression and anxiety, may also contribute to the higher risk of implant failure. Chronic stress can lead to suppression of both the cellular and innate immune responses, which can result in increased susceptibility to infection, delayed wound healing, and increased peri-implant tissue destruction. Consultation with treating healthcare providers to fully assess the impact of both underlying psychological conditions and antidepressant medications is advisable when considering implant treatment for patients with a medical history significant for these conditions and/or medications.
PPIs
PPIs are over-the-counter or prescribed medications used to treat gastroesophageal reflux disease, peptic ulcers, dyspepsia, Helicobacter pylori infection, and stress gastritis. PPIs competitively bind to and block hydrogen-potassium ATPase pumps in parietal cells, reducing intragastric acidity. PPIs can negatively impact bone metabolism through various mechanisms, including decreased calcium absorption due to reduced gastric acidity, which impairs intestinal absorption of dietary calcium. Calcium balance is important for the maintenance of bone health, and an imbalance may affect osseointegration.20 PPIs may also reduce osteoclastic and osteoblastic cell density and lead to an eventual decrease in bone turnover.21 Long-term PPI use may lead to reduced bone density, volume, cortical thickness, mineral content, and biomechanical properties.21 For long-term PPI users, it has been recommended that dietary calcium and vitamin D intake be monitored to optimize gastrointestinal absorption and reduce the risk of osteoporosis or osteopenia.21,22
These bone changes associated with PPIs have also been found to have an impact on implant success and survival. Chrcanovic and colleagues found that the implant failure rate among PPI users was 12% compared with 4.5% in nonusers.23 They concluded that PPI use may increase the risk of dental implant failure.20 Similarly, PPI use was associated with a statistically significant increase in implant failure rate (OR 2.02) in a systematic analysis of two retrospective cohort studies.21
Antiresorptive Medications
Osteoporosis and osteopenia are metabolic bone diseases that may be considered a relative contraindication for implant therapy because the decrease in bone density may affect bone-to-implant contact.24 Osteoporosis and osteopenia are characterized by decreased bone mass and increased trabecular space, which increase the risk of fractures. Antiresorptive medications, which are commonly used to treat osteoporosis and osteopenia, reduce osteoclast activity and bone resorption. Common drugs used to treat osteoporosis and osteopenia include calcitonin, bisphosphonates, selective estrogen receptor modulators (SERMs), monoclonal antibodies, and teriparatide.
Bisphosphonates help preserve bone density and strength by reducing osteoclastic activity, and they have been studied for their impact on implant osseointegration.12 Use of low-dose bisphosphonate medications for osteoporosis treatment has not been found to negatively impact implant outcomes and may actually have a protective effect on marginal bone levels.25 Patients on low-dose bisphosphonates do not show a higher incidence of implant failure or an increased risk of dental implant complications, such as graft failure, peri-implant bone loss, or peri-implantitis, when compared with those who do not take bisphosphonate medications.23 A report presenting data from two controlled studies suggested that low-dose oral bisphosphonates are not associated with implant failure.25 In addition, the investigators found no evidence of osteonecrosis of the jaw and no evidence of bone loss greater than 2 mm around the dental implants over a 3-year period.25
There is limited information on the impact of high-dose bisphosphonates or other antiresorptive drugs (eg, monoclonal antibodies) on implant therapy.26 Patients on long-term oral bisphosphonates or high-dose antiresorptive drugs for malignancies, or those with comorbidities (eg diabetes, corticosteroid intake), should be considered at increased risk for medication-related osteonecrosis of the jaw (MRONJ).26 A recent systematic review and meta-analysis found that the use of denosumab was associated with a higher risk of developing MRONJ when compared with a common bisphosphonate medication, zoledronic acid. Therefore, clinicians should use caution when planning surgical procedures during active antiresorptive therapy.27
In osteoporotic patients who are unresponsive to or intolerant to first-line antiresorptive medications, anabolic agents, such as teriparatide, have been shown to increase osseointegration of implants and may improve bone density and the success of implant outcomes.28 In an animal model, pre-implantation teriparatide delivery was shown to improve primary implant stability and accelerate the process of osseointegration. Furthermore, post-implantation administration of teriparatide enhanced peri-implant bone formation, and this effect became stronger if the medicine was taken for a longer period.29The substitution of other antiresorptive medications with teriparatide or other anabolic medications may be considered by treating physicians for individuals with osteoporosis and/or osteopenia who are undergoing implant therapy.
Antihypertensive Medications
Hypertension is a major risk factor for cardiovascular mortality, and an estimated 1.56 billion adults will be affected by it by 2025.30,31 Antihypertensive medications, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, and thiazide diuretics, are commonly prescribed to manage hypertension. ACE inhibitors and ARBs support bone formation by inhibiting the renin-angiotensin system.32 Beta blockers suppress the bone resorbing activity of osteoclasts by inhibiting their beta-2 adrenergic receptors, and thiazide diuretics promote bone formation by enhancing calcium absorption in the distal convoluted tubule. Some studies suggest that beta blockers may be associated with higher bone mineral density and a lower risk of fracture when compared with other antihypertensive medications.33 Patients taking renin-angiotensin system inhibitors, such as ACE inhibitors or ARB medications, to control hypertension have shown implant success rates comparable to patients who are not taking hypertension medications.33 However, peri-implantitis and bone loss have been found to be more frequent in hypertensive patients who take calcium channel blockers.33 Because calcium channel blockers have been noted to cause medication-influenced, dental plaque-induced gingival overgrowth, increased probing depths associated with gingival enlargement could affect the maintenance of oral hygiene in these patients.34
Clinical Implications for Dental Treatment
Adequate assessment of the risks and benefits associated with implant therapy in individual patients, including a systematic evaluation of medical conditions and current and past medication use is critical to enable clinicians to acquire informed consent from patients. Multiple analyses have associated the use of SSRIs and PPIs with increased rates of initial osseointegration failure. Other commonly prescribed medications, including NSAIDs, antiresorptive medications, and antihypertensive medications, may influence both early and late implant outcomes. It is imperative that dental healthcare providers understand the role that these and other systemic medications may play in implant survival and success. Additional research to further elucidate the effect of these and other medications, as well as the influence of polypharmacy, on dental implant survival and success rates is needed to better understand these interactions. Dental healthcare providers should be empowered to interact within interdisciplinary and interprofessional teams to better assess patients' current conditions and their potential impact on dental implant therapy.
Conclusion
A comprehensive assessment of patients' medical histories and risks associated with systemic conditions and medications should be conducted prior to implant surgery and restoration. Understanding the risks associated with systemic medical conditions and medications can help to facilitate appropriate peri-implant supportive therapy and monitoring. Dental healthcare professionals should stay abreast of any emerging data relating systemic medication use to implant survival and success to continue to enhance the patient-centeredness of implant therapy.
Queries regarding this course may be submitted to authorqueries@conexiant.com
About the Authors
Deepali Rasila, BDS, MDS
PGY3 Periodontics Resident
Department of Periodontology
University of Alabama at Birmingham
School of Dentistry
Birmingham, Alabama
Maria L. Geisinger, DDS, MS
Diplomate
American Board of Periodontology
Professor
Department of Periodontology
University of Alabama at Birmingham
School of Dentistry
Birmingham, Alabama
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