2. Monoclonal Antibodies

Denosumab (Prolia^®, Xgeva^®)

These medications are human monoclonal antibodies that function as RANK (receptor activator of nuclear kappa B) ligand inhibitor, which results in decreased osteoclast function and slows the progression of bone disease. Denosumab recognizes the specific protein that normally activates osteoclasts, inhibiting their activation and preventing them from resorbing bone.

Prolia is a semiannual subcutaneous injection for the treatment of osteoporosis. It has a short half-life (26 days) and does not accumulate in the bone like bisphosphonates. Xgeva, which is prescribed at a much higher dose than Prolia, has been used to treatmetastatic bone disease.

Dental Implant Treatment Considerations

There is some debate on how implant dentists should treat patients on denosumab. Although not as common as bisphosphonates, denosumab has been linked to MRONJ. There are several oral triggers to developing MRONJ, such as invasive surgical procedures (e.g., extractions, implant placement, bone grafting).

Studies have shown that the treatment interruption of denosumab leads to the reversal of its bone-mineral-density effect, resulting in pre-therapy levels within one year of discontinuation. In addition, it has been reported that these patients are at an increased risk of fragility fractures, and drug cessation has been associated with a high risk of rebound vertebral fractures.Therefore, many physicians are reluctant to approve a discontinuation of Prolia because of increased susceptibility to bone fractures.² Recently, a new protocol has been reported that minimizes the possibility of bone fragility (Table 3).³

Patients on Xgeva (higher doses of denosumab) are usually on a monthly regimen for metastatic bone disease. Because of the potential for MRONJ, any type of elective dental treatment is absolutely contraindicated.

1. Biologics

Varies (Table 4)

Biologics are a newer class of therapeutic drugs that are utilized in the treatment of autoimmune diseases and cancers. Biologic medications are tumor necrosis factor (TNF) inhibiting drugs, which are involved in inhibiting chronic inflammatory conditions and the resulting immune response (Table 4).

Dental Implant Treatment Considerations

Although case reports with dental implants and biologics are minimal, caution must be exercised, as patients are susceptible to increased infectious episodes, intraoperative bleeding and compromised bone healing.

For patients who have used biologic medication in the past, medical consultation is recommended to determine the level of immune suppression and the current status of the patient’s disease process. A detailed oral and written informed consent is recommended. For patients concurrently taking biologic medications, medical consultation/clearance is highly recommended. Physicians will evaluate the specific medication in question, medication dosage, treatment duration, comorbidities, possibility of disease rebound and type of surgical procedure to be performed. In most cases, physicians will recommend the modification of the medication in the perioperative period, which most likely will include a discontinuation via a drug holiday of four to five times the half-life of the medication.^4,5

For example, the most common biologics — etanercept (two weeks), adalimumab (six to eight weeks), and infliximab (four to six weeks) — would be discontinued prior to surgery. The dental clinician should recommend that the physician instruct the patient of the specific instructions of the drug holiday. In no situation should a dental clinician modify a patient’s biologic medication that is prescribed by the patient’s physician. In addition, a detailed verbal and written informed consent should be presented. Biologic medications are most commonly restarted postoperatively provided that wound healing is satisfactory with no evidence of infection or prolonged bleeding.

Dental Implant Implications

Past biologic therapy: Relative contraindication after medical consultation

Concurrent biologic therapy with implant therapy: Medical consult and relative or absolute contraindication

2. Chemotherapy Agents

Methotrexate: Otrexup^® (PF), Xatmep^® , Trexall^® and Rasuvo^®

Cyclosporin: Sandimmune^® , Neoral^® , Gengraf^® and Restasis^®

Chemotherapeutic agents (cytotoxins) are common medications in the treatment of malignant disease. Unfortunately, these drugs cannot discriminate between malignant and normal tissues and become cytotoxic to normal tissue. Most chemotherapeutic agents are known to have detrimental effects on bone, especially on grafted bone in which the blood supply is compromised.

Many of these cytotoxic medications have been shown to predispose patients to infection and delayed bone healing. In addition, studies have shown that these medications may negatively influence the bone-implant interface of previously placed dental implants.⁶

Dental Implant Treatment Considerations

The effect of cytotoxic medications on the healing or maintenance phases of dental implants is variable and is dependent on many factors, including the patient’s immune status. Therefore, a medical consultation is highly recommended for any patient who has had or will have therapy. The physician and implant clinician should take into consideration the current immunosuppressive level, medication toxic effects and the patient’s ability to tolerate the implant surgery.

In most cases, concurrent chemotherapy is an absolute contraindication to dental implant therapy, as there is a high infection and failure rate. However, it is not uncommon for some of the cytotoxic medications to be used in lower doses for various other diseases. For example, methotrexate, originally an aggressive cancer therapy, is now a first-line treatment (in low doses) of psoriasis and rheumatoid arthritis. At the low doses, the cytotoxic medication is considered a relative contraindication.

3. Antihypertensive Medications

Oral Antihypertensives: Amlodipine (Norvasc^®), irbesartan (Avapro^®), lisinopril (Prinivil^®), losartan (Cozaar^®), metoprolol (Lopressor^®), valsartan (Diovan^®) and enalapril (Vasotec^®)

Hypertension is a chronic medical condition that affects approximately half of adults in the United States, and only about 24% of patients with hypertension have the condition under control. Hypertension is most commonly treated with oral medications, such as beta-blockers, thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Interestingly, antihypertensive drugs can affect bone metabolism in different ways (Table 5).⁷

Dental Implant Treatment Considerations

The use of antihypertensive medications may directly affect dental implant treatment in the following ways:

1. Surgical Risk: Patients who are hypertensive pose a risk to the implant clinician with respect to perioperative cardiovascular emergency events.
2. Positive Effect: Antihypertensive medications have been shown to positively affect the integration of implants with higher survival rates.⁸
3. Negative Effect: A higher incidence of bruxism has been shown with hypertensive patients. Bruxism is a risk factor for prosthetic failure and dental implant loss.⁹

Care must be exercised when treating patients on antihypertensive medications, as they pose a possible surgical and prosthetic risk. In cases of suspected poor hypertension compliance, clinicians should obtain medical clearance and verify the patients have a stable cardiovascular status.