Indian Journal of Dental Research

: 2012  |  Volume : 23  |  Issue : 1  |  Page : 107--111

Bisphosphonate-associated osteonecrosis of the jaws

Pankaj Agarwal, Nirmala N Rao 
 Department of Oral Pathology, KD dental college and Hospital,NH-2, Mathura,Uttar Pradesh, India

Correspondence Address:
Pankaj Agarwal
Department of Oral Pathology, KD dental college and Hospital,NH-2, Mathura,Uttar Pradesh


Bisphosphonates constitute a group of drugs capable of modulating bone turnover and reduce its remodeling when an excessive resorption occurs. This is why they are indicated in a large group of bone diseases like postmenopausal osteoporosis or osteolysis associated with breast cancer or multiple myeloma. Over the last few years and due to their extensive use, many cases of complications associated with their use have been published. Among the most important possible adverse effects are the oral ones, with the appearance of ulcerations and, especially, osteonecrosis of the jaws associated with this therapy. In this paper, we have analyzed the general characteristics of these drugs and their mechanisms of action as well as the described adverse effects, especially oral and maxillofacial, have been made special reference, regarding the prevention of osteonecrosis of the jaws, heightened by cases described in the medical and odontological literature. The preventive protocol backs up the fundamental role of the odontologist in the effective prevention of this process before, during and after the treatment.

How to cite this article:
Agarwal P, Rao NN. Bisphosphonate-associated osteonecrosis of the jaws.Indian J Dent Res 2012;23:107-111

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Agarwal P, Rao NN. Bisphosphonate-associated osteonecrosis of the jaws. Indian J Dent Res [serial online] 2012 [cited 2022 Jun 28 ];23:107-111
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Bisphosphonates (BPP) are non-metabolized analogues of pyrophosphate, capable of binding to the bone and inhibiting the osteoclast function, reducing bone turnover and active remodeling in places where excessive bone reabsorption occurs. [1] They have been used in toothpaste as antiplaque and in diagnostic tests as a conveyor of Tc 99.[2]

The first BPP introduced was etidronate, with a low power and with a tendency to produce osteomalacia. [3] Searching for more powerful compounds and without adverse effects, second- (alendronate, pamidronate, ibandronate, tiludronate) and third-generation BPP (risedronate, zoledronic acid, minodronate) have been developed. Few changes in the structure of BPP modify their physicochemical, biological, therapeutic and toxicological properties. [4]

The structure of BPP shows two phosphate groups binding to a carbon atom (P-C-P), which, to a certain extent, is responsible for their low bioavailability. Like pyrophosphates, BPP strongly bind to hydroxyapatite, explaining their pharmacological actions in the bone. [5] R1 radicals influence their affinity and, therefore, OH groups increase the fixation while Cl groups decrease it. This would explain why BPP with OH groups (alendronate, pamidronate) bind more than clodronate. [6]

BPP are released when there is bone reabsorption, which would explain their long half-life. [7] This release is multiphasic and, in the case of alendronate, is 10.5 years. This fact would explain their persistent long-term effect in the bone. [8]

 Mechanism of Action

BPP inhibit bone reabsorption by reducing the osteoclast reabsorptive activity, [9] promoting their apoptosis, [10] avoiding their formation from hematopoyetic precursors [11] or affecting osteoblasts. [12]

Once inside the osteoclast, the R2 chain determines the power and efficacy of the drug. In the case of clodronate (Cl in R2) and etidronate (CH3 in R2), they act through metabolism of toxic analogues of ATP that induce osteoclastic apoptosis. [13] Different studies, [14],[15] have proved the role of FPP-synthases like molecular targets of nitrogen-containing BPP.

These drugs induce osteoclast apoptosis by the inhibition of cholesterol biosynthesis and the mevalonate pathway due to the inhibition of the synthesis of farnesilpirophosphate. [16],[17],[18],[19] These disturbances affect the organization of the cytoskeleton, vesicle traffic and the formation of the osteoclast brush border. BPP also have some effect on the osteoblasts, which is still not totally clear, reducing apoptosis and stimulating the secretion of inhibitors in the recruitment of osteoclasts. [20] These are also said to have an antiangiogenic effect on BPP by the inhibition of endothelial cells, reducing their proliferation and inducing apoptosis. [21]

 Therapeutic Indications

The indications of BPP have undergone a large evolution since they were introduced in the treatment of some bone and calcium metabolic disorders. [22],[23] Now-a-days, the main indications of BPP are:

In postmenopausal and corticosteroid-induced osteoporosis. In these cases, the most used BPP is alendronate, which precludes the appearance of pathological fractures. [24]

In Paget's disease, it is used to improve bone morphology and reduce pain. [25]In hypercalcaemia of malignancy, its role is in trying to check hypercalcaemia, reducing pain and preventing the development of osteolitic lesions and fractures. [26]In patients with breast and prostate cancer with bone metastasis, it is used to relieve pain, reduce fractures and hypercalcaemia. [27],[28]In multiple myeloma, it is indicated in reducing associated bone pathologies such as vertebral collapse, fractures and pain. [29],[30]

 General Adverse Effects

Various adverse effects and complications associated with the use of BPP have been described. In the case of oral BPP, the digestive effects are the most frequently described: gastric ulcerations, oesophagitis and oesophagostenosis. Isolated cases of uveitis in patients treated with alendronate, [31],[32] pamidronate [33],[34] and, recently, with zoledronic acid [35] have been described. The continuous administration of etidronate can produce a picture of osteomalacia that regresses after discontinuation of therapy. [36],[37] Nevertheless, the most modern BPP do not present this adverse effect. Some experimental models have contemplated the possibility that the inhibition of bone remodeling may lead to a reduction of bone resistance, although there is no clinical evidence, at least concerning the administration of oral BPP. In fact, even with the most powerful BPP, the remodeling process is completely annulled. [38] The general adverse effects of intravenous BPP are similar to the oral ones, and some cases of flebitis (18%) have been described. There are also accounts of transitory febricula, shivers (10-41%) and a pseudogrippal syndrome (20%) in the first 2 days. [39] There are references of hypocalcaemia, usually asymptomatic, after high doses of BPP. [40],[41] Nevertheless, most of the patients are unaffected thanks to the compensatory increase of parathyroid hormone. [42] One has to be careful when high doses of intravenous BPP are administrated because its rapid administration can cause renal failure due to the formation of a solid phase in the blood, which is retained in the kidney.

 Oral Adverse Effects

There are some cases of chronic ulcerations in the oral mucosa associated with the administration of aldosterone in osteoporotic patients. [44] These cases belong to postmenopausal osteoporotic women on treatment with alendronate. They presented oral ulcerations in the mucosa secondary to an inappropriate administration, which disappeared with topic corticoids. There are other cases of oral ulcerations generally associated with an inappropriate administration. [45],[46] In the past 4 years, there have been publications describing numerous cases of a special form of osteonecrosis of the jaws (ONJ) in patients affected with myeloma or breast cancer and in treatment with high-effectiveness BPP, especially pamidronate and zoledronic acid, and, more rarely, with alendronate. [47],[48],[49],[50] Two theories have been proposed to explain the appearance of ONJ. One related to the action of the BPP in bone turnover and the other to their antiangiogenic action. [51] The main theory suggests that ONJ is caused by the cessation of bone remodeling and the osteoclast-inhibiting effect. BPP is highly concentrated in the jaws because there is a greater blood supply than in other bones and a faster bone turnover, related to their high activity and the presence of the teeth. This circumstance, together with the frequent appearance of dental pathologies, odontological treatment and the thin mucosa over the maxilary bone, explains why osteonecrosis is especially prevalent in these bones. Bone turnover maintenance is crucial to maintain bone viability. If osteoclast function decreases severely, osteocytes are not replaced and the bone capillary network is not maintained, permitting the appearance of avascular bone necrosis. [52] The breakdown of the oral mucosa, caused by a traumatic ulceration or surgery, causes local bone necrosis, which progresses when healing fails. The risk of ONJ increases with dental manipulation and poor hygiene because the bone is exposed to the oral microbiota, later causing infection with pain, tumefaction, suppuration and progressive bone necrosis, which is difficult to control. [53] The other etiopathogenic theory is based on experimental evidence showing that most potent BPP also inhibit capillary neoangiogenesis, decreasing capillary formation and inhibiting endothelial growth factors, [21] leading to avascular necrosis. However, this is not the only cause as it is not associated with the administration of more potent antiangiogenic drugs. [54],[55] There are accounts of ONJ cases associated with BPP in patients who have been on medication for years and even in those who have been on medication for a few weeks. [53] However, a study of multiple myeloma patients showed that ONJ risk is time-dependent and is significant only after 12 or 36 months. [56]

 Prevention of BPP-Associated ONJ

As in any prophylactic approach, the preventive measures of ONJ are introduced before initiating BPP therapy.

Measures before initiating BPP therapy

As soon as the oncologist or other specialists consider that administration of BPP is necessary, the patient should be referred to a dentist for an urgent oral examination, [57] consisting of a complete clinical and radiographic exploration.

Oral treatment is aimed at eliminating infections and the need for invasive dental procedures in the near future. Thus, preventive therapy should be aggressive and should include tooth removal, periodontal surgery, root canal treatment, tooth decay control, dental restorations and prothesis, if needed. These patients are not candidates for dental implants because of the risk elements involved. [51] A month before initiating BPP therapy, removal of the large mandibular tori or palatal tori with thin overlying mucosa is recommended to avoid the risk of ulcerations.

Patients with no cardiac disease do not require prophylactic antibiotic coverage for non-invasive procedures, but there is a need for an invasive procedure. In this case, the chosen drug is penicillin and its derivatives. For individuals with penicillin allergy, a combination therapy using quinolones and metronidazole has proven to be efficient. Clindamycin alone is not recommended because it is ineffective against actinomycetes, Eikenella corrodens, and similar species that frequently colonize the exposed bone in the oral cavity. [51]

If the patient requires only non-invasive dental care, BPP therapy is not delayed. But, if the patient requires invasive procedures, BPP therapy should be deferred for a month to allow bone recovery and good healing. A surveillance schedule every 4 months with plaque control and strict hygienic measures is recommended.

Measures during BPP therapy

The dentist should carefully examine the oral cavity for the presence of bone expositions in the most commonly affected areas, such as the posterior and the lingual areas of the mandible. A complete radiographic examination should be carried out to look for signs of osteolysis, osteosclerosis, widened periodontal spaces and furcation affection.

A careful dental cleaning and preventive use of fluor and clorhexidine should be considered as well as strict hygienic measures should be practiced. [51]

All the needed procedures to conserve the teeth and avoid the appearance of infections should be carried out as soon as possible. If the tooth is not restorable, root canal treatment and amputation of the crown are preferable to extraction. Root canal treatment should be carried out with minimum trauma to the marginal and apical periodontal tissues. [58]

In relation to periodontal disease, teeth will only be removed when they have three or more mobility grade or an associated periodontal abscess. In these situations, adequate antibiotic treatment is imperative, as indicated previously. [51]

Surgery procedures are contraindicated. Nevertheless, in patients needing surgery, BPP withdrawal is recommended in the case of a bad recovery. However, it is not certain that BPP withdrawal will prevent the appearance of ONJ due to their half-life. [59]

When an oral surgery procedure is needed in a patient with BPP therapy, some special precautions should be taken, as, for instance, absolutely aseptic procedures, atraumatic surgery and achieving a first-intention closing if possible. [60]

If prosthesis is needed, it should be preferably fixed and well carried out to avoid, if possible, the appearance of secondary traumatic ulcerations.

In patients on treatment with BPP, it is recommended to engage in a continuous surveillance schedule every 3 or 4 months with plaque control and strict hygienic measures.


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