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Table of Contents
Year : 2022  |  Volume : 12  |  Issue : 2  |  Page : 78-85

Systemic medications and implant success: Is there a link? Part three: The effects of antiresorptive and anti-angiogenic agents on the outcome of implant therapy

1 Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, England
2 Department of Oral and Maxillofacial Surgery, Hospital Sutanah Nora Ismail, Johor, Malaysia
3 Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University Malaya, Kuala Lumpur, Malaysia
4 Departments of Restorative Dentistrym Faculty of Dentistry, University Malaya, Kuala Lumpur, Malaysia

Date of Submission09-Oct-2022
Date of Decision10-Oct-2022
Date of Acceptance15-Nov-2022
Date of Web Publication10-Jan-2023

Correspondence Address:
Dr. Prema Sukumaran
Centre for Oral, Clinical and Translational Sciences, King's College London
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdi.jdi_24_21

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Dental implants require healthy bone for successful osseointegration. However, bone health can become compromised by aging and/or the presence of underlying medical conditions. The severity and complications associated with these medical conditions usually indicate that they require medication for successful management. Some of these medications may undoubtedly exert effects on bone through direct or indirect mechanisms and, therefore, may also affect osseointegration. These include antihypertensive drugs, oral hypoglycemic agents/insulin, hormones (corticosteroid, thyroxin, and tamoxifen), and antiresorptive agents, including bisphosphonates and anti-angiogenic agents. Part three of this paper reviews the current knowledge regarding the effects of antiresorptive agents on the outcome of implant therapy.

Keywords: Bone-to-implant interface, medical conditions, medications, osseointegration, review, success rate, systemic conditions

How to cite this article:
Sukumaran P, Dionysius DD, Ngeow WC, Tan CC, Hussin MZ. Systemic medications and implant success: Is there a link? Part three: The effects of antiresorptive and anti-angiogenic agents on the outcome of implant therapy. J Dent Implant 2022;12:78-85

How to cite this URL:
Sukumaran P, Dionysius DD, Ngeow WC, Tan CC, Hussin MZ. Systemic medications and implant success: Is there a link? Part three: The effects of antiresorptive and anti-angiogenic agents on the outcome of implant therapy. J Dent Implant [serial online] 2022 [cited 2023 Jun 8];12:78-85. Available from:

   Introduction Top

Bone remodeling is a continuous process that is tightly regulated to ensure the repair of microdamage and replacement of old bone with new bone through sequential osteoclastic resorption and osteoblastic bone formation. The rate of remodeling is regulated by a wide variety of calcitropic hormones (parathyroid hormone, calcitriol, growth hormone, glucocorticoids, thyroid hormone, and sex steroids), some of which have been discussed in paper one and two of this series.[1] Calcitropic hormones modulate the receptor activator of nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) system as well as regulate osteoclast recruitment and many other different factors (e.g., runt-related transcription factor, Osterix) that are involved in osteoblast differentiation.[2] Bone undergoes constant remodeling throughout life, enabling it to perform the anatomical function of providing structural support to the body and its physiological function as reservoir for mineral homeostasis. In adults, remodeling occurs at a rate of about 2%-5% each year.[1] There are three consecutive phases of normal bone remodeling, namely resorption, reversal, and formation.[1] In general, remodeling in cancellous bone is faster than in cortical bone and jawbones remodel faster than the other skeletal bones.[1],[3] As a person ages, the remodeling process becomes less efficient, and more bone mass is lost than formed. This essentially is the cause of osteoporosis that usually affects the elderly, especially post menopause. And to counter this effect, we prescribe bisphosphonates or novel antiresorptive agents.

As more and more countries edge toward aging populations, we expect to see an increased number of older patients seeking dental implants. This cohort of patients will very likely be suffering from a myriad of diseases associated with aging, including osteoporosis. Hence, it is important to include antiresorptive agents in the discussion of systemic medications that can potentially affect the outcome of implant therapy. The article aims to review the available literature on the effects of anti-resorptive medication on the outcome of implant therapy so help clinicians in their decision-making process when encountering these patients.

   Bisphosphonates Top

Bisphosphonates, introduced in 1995, have become one of the most commonly prescribed medications to treat osteoporosis worldwide. They are a group of antiresorptive drugs that have a phosphate-carbon-phosphate bond in the formulation. They include alendronate, risedronate, etidronate, pamidronate, and zolendronate. There is also a nonbisphosphonate group of antiresorptive agents that includes denosumab and strontium ranelate (see the subsequent subtopic: Anti-angiogenic agents); and selective estrogen receptor modulators such as tamoxifen, raloxifene, and tibolone (see the preceding subtopic) that are used to treat osteoporosis.[4],[5] However, pharmacologic management of osteoporotic bone can result in adverse reactions, which include necrosis of bone, which can also occur spontaneously.[6],[7] Histologically, osteonecrosis is characterized by the degeneration of osteocytes which can be visualized as empty lacunae within the bony trabeculae. This results in the inability of necrotic bone to remodel. The mechanism of osteonecrosis is believed to be linked to osteocyte apoptosis.[8] Besides bisphosphonates, other causes of osteonecrosis are treatment with glucocorticoids (See Part Two), radiation therapy, alcohol abuse, and sickle cell anemia disease.[8]

The success and survival of dental implants in patients undergoing treatment with bisphosphonates or other antiresorptive is a topic of immense interest, with various research findings documented worldwide.[9] Although bisphosphonate therapy increases the quality of life, placement of dental implants in this group of patients poses a considerable risk for the development of medication-related osteonecrosis of the jaw (MRONJ).[10] In general, the specific mechanism of action of bisphosphonates in inhibiting bone resorption is complex and may not be fully understood, although the eventuality is apoptosis of osteoclasts. Nonnitrogen-containing bisphosphonates (e.g., tiludronate, clodronate, and etidronate) are taken up by osteoclasts, triggering an intracellular mechanism leading to apoptosis of the osteoclasts[11] The nitrogen-containing bisphosphonates (e.g., alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid) have a more complex pathway of action resulting in interference with osteoclastogenesis, apoptosis of osteoclasts and changes in cytoskeletal dynamics.[12] The effect of bisphosphonates may not be due to the direct action on osteoclasts alone as there are reports suggesting the involvement of osteoblasts,[13],[14] although the mechanism of action may not be fully understood yet. As bisphosphonates interfere with bone remodeling through various mechanisms, primarily with osteoclasts function, it is reasonable to consider that these medications may compromise aspects of dental implant therapy; for example, more implants might fail to integrate, larger peri-implant marginal bone loss might occur during modeling or functional loading, or that these patients may be prone to peri-implant infections

Marx reported the first case of MRONJ that resulted from an oral bisphosphonates (alendronate), prescribed to treat osteoporosis.[15] Subsequent studies reported that osteonecrosis of the jaw affected 4.1% of patients treated for osteoporosis. It was also observed that nearly 60% of those cases developed osteonecrosis following some form of dentoalveolar intervention.[6],[16] Since 2005, publications have started describing the loss of dental implants in patients taking bisphosphonates.[17] According to a study, it takes roughly 63 months for the onset of osteonecrosis following oral bisphosphonates administration.[18] However, this duration is significantly reduced when an invasive procedure like implant surgery is performed on patients who are prescribed with any of these medications.[18]

Oral bisphosphonates (e.g., alendronate and risedronate) are predominantly used in the treatment of osteoporosis and rarely, in some types of cancers, for the prevention of secondary osteoporosis while intravenous bisphosphonates (e.g., pamidronate and zoledronate) are prescribed in the management of malignancies and Paget's disease, and only in rather limited extent for osteoporosis.[19],[20] There are many case reports/case studies in the literature documenting failure of implants in patients on oral bisphosphonates.[21],[22] However, there are also scientific evidence which have reported that oral bisphosphonates have not significantly affected the success of dental implants.[23],[24] Grant et al. reviewed 486 implants placed in 115 patients and reported that all but two of the implants integrated fully and met the criteria for establishing implant success.[23]

Jeffcoat[24] published a controlled study on the alveolar bone taking effect from oral bisphosphonates in 2006. In the test group, 25 postmenopausal women were using intraoral bisphosphonates for the mean duration of 3 years. The control group of 25 age-matching participants were chosen with no history of bisphosphonate therapy. One hundred and two implants were placed in subjects in the bisphosphonate group versus 108 implants in the control group subjects. 3-year follow-up examinations (radiographical and clinical diagnostics) with at least 1 visitation once a year showed a 100% success rate in the medicated group and a 99.2% success rate in the control group, resulting in no significant difference between groups.

A retrospective study in 2008, published by Bell and Bell[25] involved the examination of 100 surgically placed dental implants in 42 patients. Intraoral bisphosphonates were prescribed from 6 months to 11 years and were still successfully being used after the surgery. Thirty participants of the group also received additional procedures such as socket grafts, sinus lifts, guided tissue regenerations, tunnel graft, and buccal contour regenerations. The mean duration of follow-up was 3.1 years to ensure that no bone loss or inflammation occurred. Five implants failed, resulting in a 95% success rate and the authors postulated that oral bisphosphonates did not seem to be the reason for implant failure. For comparison, the same operator had a 96.5% success rate in 734 implants inserted in the same year in patients with no history of bisphosphonate intake.[25]

In a more objective perspective, a systematic review conducted by Chappuis et al.,[26] they reported that oral bisphosphonates did not substantially contribute to implant failures. Mendes et al.[27] suggested that scientific evidence demonstrated patients with a history of oral bisphosphonate use do not present a higher risk of dental implant failure or marginal bone loss compared to patients who have not used bisphosphonates. In addition, Diz et al.[28] also echoed in favor of Chappuis' and Mendes' findings with regard to the placement of dental implant in patients who are on oral bisphosphonate therapy. In another systematic review and meta-analysis, Stavropoulos et al.[20] concluded that low-dose oral bisphosphonate intake for osteoporosis treatment, in general, does not compromise implant therapy; that is, these patients do not lose more implants nor get more implant-related complications/failures (i.e., in regard to grafting procedures, peri-implant marginal bone loss, MRONJ, and peri-implantitis), compared to implant patients without bisphosphonate intake.[20] [Table 1][23],[24],[25],[29],[30],[31],[32],[33],[34] summarizes studies that have reported on survival rates of dental implants in patients prescribed with oral bisphosphonates.
Table 1: Effects of bisphosphonates in dental implant osseointegration

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In contrast, there is evidence to suggest a causal relationship between intravenous bisphosphonates and MRONJ, especially in patients receiving high intravenous doses of the medication to manage cancer.[35],[36] In addition, for patients who have been on oral bisphosphonates over a long period of time and patients with comorbidities (e.g., diabetes mellitus) placement of implants, explantation of implants and the mere presence of implants per se may trigger MRONJ.[20]

There has also been contradicting evidence on the placement of dental implants in patients treated with intravenous bisphosphonates with some suggesting an absolute contraindication,[36] while others suggest that there is no significant difference in implant success rates between intravenously and orally medicated groups of bisphosphonate patients.[10],[26] However, in their extensive systematic review and meta-analysis, Stavropoulos et al. reported that there is almost no relevant information available on the possible effect of high-dose bisphosphonate, although the authors qualified that some of the information was derived from studies with questionable quality in terms of study design, number of cases included and/or controls and manner of reporting.[20]

In summary, we could potentially align ourselves with the guidelines by the American Association of Oral and Maxillofacial Surgeons[36] who have suggested that, for placement of implants in patients who are on oral bisphosphonates, a great deal of caution is needed to enquire about the duration of intake of the medication, dosage, length of bisphosphonate therapy before surgery and time since cessation of medication, if applicable. It is also imperative to obtain informed consent after explaining to patients regarding the risk of implant failure and the development of osteonecrosis. In addition, the general consensus is that there is insufficient data to ensure the success and survival of dental implants in patients receiving intravenous bisphosphonates. More randomized clinical trials with control groups are needed for statistically reliable results. As of now, patients treated with intravenous bisphosphonates stand a higher chance of developing MRONJ.

Denosumab, an anti-RANKL (receptor activator of NFκB ligand) antibody, is a potent antiresorptive drug also used in the treatment of osteoporosis. However, MRONJ occurred at a similar or higher rate compared to bisphosphonates.[37] As there is a paucity of studies investigating the effects of denosumab on dental implants, a similar (if not higher) degree of caution for patients on bisphosphonates must be exercised when evaluating the suitability of patients on denosumab before implant therapy.

   Anti-Angiogenic Agents Top

Besides osteoclastic and osteoblastic activities, another physiological process that occurs in bone is angiogenesis, a process that entails the formation of new blood vessels along with bone remodeling. It is a critical process in growth and development, in wound healing and in the formation of granulation tissue that eventually becomes bone. Among the many identified growth factors that serve to initiate, and control angiogenesis are vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor-2, epidermal growth factor, and angiopoietin-1.[38] Unfortunately, angiogenesis also has a sinister role in the growth and spread (metastasis) of tumor cells.[39] Similar to a healthy cell, tumor cells require oxygen and nutrients to grow and metastasize and these fundamental requirements are supplied by blood vessels that sprout within the tumor.

In order to meet the growing demands of oxygen supply in tumor cells, tumor-derived angiogenic factors are released, and in return, these factors trigger the expression of VEGF. VEGF, released from tumor cells and tumor-associated stromal cells, is responsible to stimulate vascular growth in the hypoxic tumor tissue, thus meeting the oxygen demands of these tissues.[40]

Anti-angiogenic medications interfere with the various stages of new blood vessel formation, and are particularly used in the treatment of cancer and the prevention of its metastasis. One group of anti angiogenic drugs (e.g., bevacizumab and aflibercept) bind to VEGF and block these growth factors from attaching to receptors on endothelial cells that line the blood vessels.[41] The second group of anti-angiogenic drugs stop the VEGF receptors from sending growth signals into the blood vessel cells. This group of drugs are also known as tyrosine kinase inhibitors (e.g., sunitinib, sorafenib pazopanib, and axitinib).[41] Finally, is a group of medications, thalidomide, and lenalidomide, which exhibit their anti-angiogenic properties by acting on chemicals that cells use to signal to one another to proliferate and grow.

The main aim of anti-angiogenic therapy is to supress tumor growth by obstructing the supply of nutrients and oxygen, which causes the regression of tumor tissues. However, these drugs also cause damage to healthy blood vessels and in a large number of patients, result in side effects such as proteinuria, hypertension, leukopenia, and lymphopenia.[42] In reference to the mechanism of action of this group of medications, it is highly likely that bleeding and thromboembolic events are also anticipated adverse effects in addition to gastric perforations.[43]

In particular, when anti-angiogenic medications bind to the surface of endothelial cells (VEGF blockade), it results in loss of integrity of these endothelial lining cells (apoptosis of endothelial cells), and they then trigger a cascade of events that results in bleeding.[43] During the loss of endothelial cell integrity, the underlying prothrombin basement membrane also undergoes destruction and, in return, potentiates thrombotic events with an increased platelet activation.[44]

In implant therapy, the formation of blood vessels is an integral part of the initial phase of osseointegration. The formation of the blood clot, which then transform into vascularized granulation tissue, is essential for the initial phase of osseointegration. Blood vessels are also required in the subsequent bone development and remodeling around the implant.[45] Many studies have underlined the importance of the development of new blood vessels (neovascularization) in osseointegration and documented the impairment of osseointegration in patients who have compromised blood vessels formation, for example, in untreated diabetes mellitus;[46] in smokers[47],[48] and in postradiation patients.[49]

Studies have reported that VEGF improves bone healing by enhancing angiogenesis[50] and stimulating bone turnover through osteoclasts activities.[51],[52],[53],[54],[55] Inhibiting angiogenesis may have a negative effect on bone healing and osseointegration, and, particularly, anti-angiogenic drugs may negatively affect peri-implant bone formation.[56],[57] These anti-angiogenic drugs exhibit their effect by suppressing angiogenesis or osteoclasts. There are studies that have looked at the mechanism of how anti-angiogenic drugs affect osseointegration. In 2015, Al Subaie et al.[58] performed an animal model study and reported that inhibiting VEGF negatively affected osseointegration of dental implants and delayed bone healing around the implant. However, in their study, the authors documented that the compromised bone healing and osseointegration among the anti-VEGF group were likely to be caused only by the downregulation of angiogenesis since the anti-VEGF drug did not affect the osteoclastic number. Mair et al.[45] also looked at the effect of an angiogenesis inhibitor in an animal model and concluded that the inhibition of blood vessel formation negatively affected the process of osseointegration. They further suggested that a prolonged healing time post implant insertion may compensate for the inhibition of blood vessel formation.

The more imperative concern with implant placement in patients on anti-angiogenic therapy would be the risk of bleeding. Bleeding is one of the most severe and potentially life-threatening adversities of anti-angiogenic drugs. Bevacizumab retains the highest frequency of bleeding complications, including epistaxis, hemoptysis, hematemesis, gastrointestinal or vaginal bleeding, and brain hemorrhage.[59] One of the common problems in managing bleeding is trying to achieve the right balance between efficacy and adversity from the affiliated risk of thromboembolic complications.[59] Coincidentally, thrombotic events are also one of the adverse effects of anti-angiogenic drugs. In a review written by Diz et al.,[28] the authors highlighted that bleeding is a common complication of dental implant placement. In the current practice, there is no solid evidence to contraindicate dental implant placement in patients with bleeding disorders. Nevertheless, patients' safety should be prioritized, and a thorough medical assessment should be done for every patient before implant surgery to negate the complication of bleeding and thrombotic events in patients on anti-angiogenic therapy.

   Conclusion Top

It appears that our understanding on the effect of antiresorptive agents, and to a larger extent, systemic diseases and their medications on the success of osseointegration, is still evolving. The providers of dental implants in the past adopted a rather strict patient selection and treatment protocol, but the paradigm is changing over the past five decades with the provision of implants in patients with undiagnosed chronic systemic diseases or patients who are on various medications to manage these systemic medical conditions. This change follows the current trend in population, in which there is an increase in the older population who are living longer and are not only on systemic medications but are also in need of dental rehabilitation.

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