Bisphosphonates and Dental Implants

ABSTRACT

Bisphosphonates are the important group of drugs in the management of osteoporosis, Paget’s disease, osteolytic lesions of multiple myeloma, hypercalcemia of malignancy, and bone metastasis associated with breast, prostate lung and some other soft tissue tumors. However, many patients represent with presence of necrosis of the jaw as a complication of taking oral and intravenous bisphosphonate treatment. So prevention is important. The main aim is to discuss the implications of bisphosphonate therapy on dental implants and to determine whether the bisphosphonates affected the overall success of dental implants.

Keywords: Bisphosphonates, Dental implants, Pathophysiology, Bisphosphonate-associated osteonecrosis of jaw (BONJ), Oral epithelium.

INTRODUCTION

In the last three decades, implant dentistry has emerged as a fully accepted discipline in dentistry1. Several studies have shown that dental implants are a predictable way to replace a missing tooth /teeth. A review by Simonis et al found the long-term implant cumulative survival rate till16 yrs to be 83%2. But some of the systemic disorders are found to be a contraindication for dental implant placement which includes patients on bisphosphonate therapy. Bisphosphonates are group of drugs used to treat a number of ailments affecting the bone metabolism, so research has centred to know the benefits as well as their adverse effects in implant therapy.

Bisphosphonate is the first choice of drug taken prescribed for the prevention of osteoporosis, as it slows down the deteriorating process of thinning of bone to a substantial extent. This drug can be prescribed to both men and women, but to a larger extent it is consumed by post-menopausal women. These drugs are also used for the treatment of Paget’s disease, osteolytic lesions of multiple myeloma and hypercalcemia, and metastasis associated with breast, prostate, lung and other soft tissue tumors3.FleischH et al stated that bisphosphonates can be administered in two ways, which is oral and intravenous. Intravenous bisphosphonates are most potent than the oral bisphosphonates. The bisphosphonates have a profound effect on bone metabolism. It reduces the osteoclastic activity and subsequently suppresses the remodeling of bone. Most of the bisphosphonates are classified as nitrogen -containing (BP) and non- nitrogen containing (BP)4. Recently various other studies have emphasized the action of bisphosphonates on the oral mucosa, particularly the oral epithelium which comprises of fibroblasts, keratinocytes, and macrophages which lead to impaired oral wound healing5. This has lead to the occurrence of GIT and oesophageal ulceration with oral bisphosphonate therapy. Bisphosphonate related osteonecrosis of jaw (BRONJ) which occurs because of ill-fitting dentures without any surgical trauma leads to inhibition of angiogenesis eventually leading to avascular necrosis6.

Many studies report about the adverse effects of long-term use of bisphosphonates because it is believed that these drugs can be retained in the bone more than 10 yrs.

Bisphosphonates are the structural analogues of pyrophosphates with a core p-c-p structure. Bisphosphonates are classified according to their mode of action, chemical structure, potency, delivery, bioavailability, dosage, and half-life7.

Bisphosphonates are classified as:

a. Non–nitrogen containing bisphosphonates are Clodronate, Tiludronate, Etidronate.These are known as first generation bisphosphonates.

b.Nitrogen-containing bisphosphonates are Zoledronate, Ibandronate, Alendronate, Risedronate, Pamidronate. These are second and third generation bisphosphonates8,9.

PATHOPHYSIOLOGY OF BISPHOSPHONATES

Bisphosphonates have a strong affinity for calcium phosphate. They have a selective action on calcified tissue. They bind to the osteoclasts and interfere with bone remodelling.

According to Gutta and Louis, there are seven proposed mechanism of action of bisphosphonates

1.The first generation bisphosphonates, such as clodronate and etidronate, do not contain an amino group. They are metabolized to form cytotoxic adenosine triphosphate (ATP) analogues that accumulate intracellularly in osteoclasts and induce apoptosis10.

2. The potent amino bisphosphonates are inhibitors of the mevalonate pathway, a biosynthetic pathway for isoprenoid proteins such as farnesyl diphosphate and geranylgeranyl diphosphate. The isoprenoid proteins are required for post-translational prenylation of the small GTPases such as RAS, Rho, and Rac11.

The Rho and Rac groups of proteins are responsible for cytoskeletal organisation and cell membrane ruffling and are activated through geranylgeranylation. The cytoskeleton is essential to maintain the “ruffled border”, the area with which the osteoclast makes contact with bone and breaks down bone tissues12. When the ruffled border is compromised, the osteoclast initiates apoptosis, resulting in a decrease in bone turnover.

3. Bisphosphonates also inhibit various matrix metalloproteinases involved in cancer growth and metastasis.

4. Although BPs are also known to have antiangiogenic effects, there has been some controversy based on histological reports of osteonecrotic samples.

5. There are some reports that bisphosphonates may inhibit bone resorption by stimulating osteoblasts to produce an osteoclast-inhibitory factor13.

6. Bisphosphonates are also powerful inhibitors of macrophage proliferation, cells that are of the same category as osteoclasts.

7. Other mechanisms include inhibition of osteoclast proton ATPase, phosphatases, and other lysosomal enzymes.

Bisphosphonates also have antiangiogenic properties .The overall effect is the decrease in bone turn over and inhibition of the bones reparative activity14. Injury to the bone in these patients via tooth extraction, dental surgery, , implant therapy , mechanical trauma is thought to initiate the Bisphosphonate related osteonecrosis of the jaw (BRONJ)15.

Current terminologies used are “Bisphosphonate-associated osteonecrosis”(BON).Other acronyms are “osteonecrosis of the jaw”(ONJ), “Bisphosphonate-related osteonecrosis of the jaw”(BRONJ, Naser & Suzuki 2006),Bisphosphonate-induced osteonecrosis of the jaw (BIONJ),Bisphosphonate –associated osteonecrosis of the jaw (BONJ)16.

DEFINITION OF BRONJ

Bisphosphonate- related Osteonecrosis of the Jaws (BRONJ) has been defined as an area of bone exposure in the maxilla-facial region that does not heal within 8 weeks after diagnosis by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate without a history of radiation therapy to the head and neck 17.

IMPLANT PLACEMENT AND BISPHOSPHONATES:

In recent years implant therapy for rehabilitation of edentulous areas or for whom tooth prognosis was considered hopeless has been successful. Limited data is available regarding dental implant placement and bisphosphonate therapy. So treatment plans for patients under bisphosphonate therapy should be considered carefully because implant therapy requires osteotomy site preparation for implant placement18. Creating trauma has a greater risk for development of BON when extensive implant placement or guided bone regeneration to augment the deficient alveolar ridge before implant placement is necessary.

Studies have concluded that dental implants placed in patients who are taking bisphosphonates either oral or IV therapy tend to have a worse prognosis compared to those who are not taking the medication. This is due to the constant renewal of bone known as “bone turnover&rdquo19.This takes place with the help of osteoclasts and osteoblast cell types. Bisphosphonates may interfere with the function of osteoclasts. It may increase the bone density, but the placement of implants requires both cell activity and bone healing at the implant placement site. Bisphosphonate drugs alter the drug activity and the area may not heal well20.

The incidence of BON is higher with long-term IV use of bisphosphonates compared to the oral administration . The rate of incidence of BON with IV route is approximately 20%(Boonyyatakorn et al.2008; Cummings et al.,2002). BON incidence with oral administration is between 0-0.34% (Mavrokokki et al.,Gerbic et al ., 2008).

Osteonecrosis of the jaw is a condition characterized by the failing of bone tissues to heal after any minor trauma such as tooth extraction , or dental implant placement and cause the bone to become exposed, which leads to infection and fracture .At times this requires long-term antibiotic therapy or even surgery in order to remove the necrotic bone tissue and finally this leads to implant failures at the implant site.21,22

Co- risk factors for BON are patients with periodontitis, extractions , on steroid treatment, Diabetes mellitus, and smoking and it clinically presents with pain , neuropathy, erythema, swelling, suppuration, tooth/implant mobility, halitosis, sinus tract formation, sequestration and possible pathological fracture of the jaw23. Osteonecrosis of the jaws always starts in the alveolar bone and extends to the basal bone or ramus in the mandible.

Bisphosphonates are metabolically active in all bones of the body, the pathological condition of bisphosphonate is related to the osteonecrosis of the jaw (BRONJ), which has been only been described in the maxilla and mandible ,because of thin maxillary and mandibular ridge mucosa (<5mm).This is in comparsion less favourable with other bones that are covered with thicker, more durable tissues such as muscle and skin24.

Dixon et al. 26 documented the remodelling rates of bone at various sites, finding that the alveolar crest remodels at a rate 10 times faster than the tibia, 5 times quicker than the inferior border of the mandible and 3 -5 times the rate of the mandible at the level of the ID canal. Marx et al. postulated from this that the jaws accumulate higher concentrations of bisphosphonates because of the alveolar ridges rapid rate of remodelling.

A study by Dixon et al. was also deemed to have demonstrated the importance of osteoclastic resorption/remodelling and renewal in the jaws compared with any other bone in the adult skeleton. Allen et al.27confirmed Dixon’s findings however, he further demonstrated that the remodelling rates were even more specific within different regions of the jaw.

Laboratory parameter to identify the risk levels for developing BRONJ in patients taking oral bisphosphonates is by determining the serum CTX29 (telomere C-terminal of collagen 1), it is a biological index to measure bone remodeling and bone resorption , for those patients who had taken oral BPs for more than 3 yrs and who had CTX below 150 pg/ml would be at greater risk of developing BRONJ during dental surgery25.

CTX LEVELS AND INTERPRETATION/RECOMMENDATIONS FOR PATIENTS TAKING ORAL BISPHOSPHONATE

ADI GUIDELINES FOR PATIENTS UNDER BISPHOSPHONATE THERAPY:

1.Patients on IV bisphosphonates treatment are at a higher risk of developing bisphosphonate-associated osteonecrosis (BON), particularly if they have been receiving IV treatment for more than six months. Elective dental implant treatment cannot be recommended for these patients26. If treatment is necessary ,it should be carried out in a hospital environment with intravenous antibiotic therapy and full aseptic techniques should be done appropriately.

2.Patients on IV bisphosphonates for less than six months should be at low risk of

developing problems in relation to non-surgical periodontal and restorative care.

3.However, surgical treatment, e.g. extractions, should only be done only if it is mandatory and should be meticulously treated in a conservative and cautious technique. If possible, a single intervention should be undertaken and at an interval period of two months should be considered to verify acceptable healing before considering further surgical intervention27.

4.Patients on oral bisphosphonates treatment for a time span of three years or lesser have

only a slight increased risk of developing BON and as such, elective dental

therapies including extractions and dental implants are not contraindicated. The

patient should , however be informed of the risk and appropriate consent obtained.

5.Patients on oral bisphosphonates treatment for more than three years are at an

increased risk of developing BON and this risk may increase with the duration of

bisphosphonates therapy and other co-factors such as smoking. Therefore, surgical

treatment, e.g. extractions, should be approached extremely cautiously and

conservatively. If possible, a single intervention should be undertaken and an interval period

of two months should be given to verify acceptable healing before considering further surgical

intervention28.

6.All patients on bisphosphonates treatment should rinse for one minute using a

chlorhexidine aqueous solution 0.2% prior to dental treatment and to continue

rinsing twice daily for 14 days after treatment.

7.All patients on bisphosphonates treatment should be administered systemic antibiotics

one day to two days prior to any dental procedures, which involve trauma to bone , e.g. extractions, implant placement and periodontal surgery.

8.All patients on bisphosphonates treatment should be encouraged to attend

regular dental assessment and maintenance. The importance of ensuring high

standards of oral hygiene and a good diet should be emphasized to reduce the need

for possible future dental surgical intervention29.

9.Patients who smoke should also be encouraged to cease smoking .

CONCLUSION:

Bisphophonate therapy poses risks for patients undergoing Implant surgery, because of excessive reduction of bone around the surgical site, infection, impaired angiogenesis and toxicity to soft tissues. There is a risk of developing BRONJ and implant failures is greater in patients under long-term (3-5yrs) I.V.bis-phosphonate therapy compared to oral bisphosphonates. A complete medical history is most important in patients with bisphosphonates .Route of administration, and the duration of treatment also should be taken into consideration American Dental Association Expert panel recommends that patients taking bisphosphonates should be informed about the risks and benefits. Before going to the dental implant placement, make the treatment based on the AAOMS recommendations, and do further periodic longer period follow-ups, because it is still remains controversial about the intensity of exposure to these medications which have a direct impact on dental implant treatment.

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