Bisphosphonates and other anti-resorptives have been used in various bone diseases for many years. All bisphosphonates have a common feature of significantly slowing down or reducing bone remodeling. In this way they aid in stabilizing the bone structure and thus prevention of fractures such as in osteoporosis. They are also used in controlling the symptomatology of skeletal metastases in tumor disease, and also recently in breast cancer, prostate cancer and preventively, even before the occurrence of metastases in multiple myeloma. Anyone who treats patients with these diseases has to systematically query patients about antiresorptives prior to surgical interventions. Bisphosphonates cumulate in bone, and the number of side eff ects increases as the duration of action increases. This also applies to some more recent active substances which are currently on the market or being tested. A selection is listed in Fig. 1. These effects must be taken into account when planning therapy.
Osteonecroses of the jaw do not hurt initially
Bishosphonates took on relevancy in medicine some 15 years ago when the first reports emerged linking these medicines to bone necroses. As multimorbidity was frequently involved, such as in tumor patients, at first it was not clear whether the bone necrosis was triggered by the bisphosphonate or the chemotherapy. There is now a consensus that bisphosphonates, in particular following lengthy administration, can cause bone necroses in patients of a certain disposition. It is typical and diagnostically critical that when these necroses occur they are initially painless and do not become visible until bone is exposed. Only secondary complications, such as an infection, then give rise to pain symptoms. The absence of symptoms initially results in the rate of bone necroses being underestimated. The underlying symptomatology has resulted in the globally recognized definition of the three stages of osteonecrosis of the jaw by the American Association of Oral and Maxillofacial Surgeons (AAOMS).19 The varying degree of prevalence of osteonecroses of the jaw in osteoporosis patients and oncological patients is illustrated in Fig. 2.
Fig. 2: Low vs. high necrosis prevalence
More infections in marginal periodontitis
The last few years have generated a sophisticated discussion about the genesis of these necroses. Although dental extraction was initially considered to be the cause, today we now assume that bony changes are already extant prior to extraction, and extraction of teeth only contributes to the clinical symptomatology (Figs. 3 and 4). In this regard it is particularly interesting that marginal periodontitis, in particular, seems to be accompanied by an increased rate of infection or necrosis.1 This observation is confirmed by a number of epidemiological studies. In simpler terms it could be said that the absent marginal remodeling in periodontological infections brings about the necrosis and sequestration.2,3 It is, however, surprising that apical inflammations relatively rarely seem to trigger an endodontically provoked necrosis. Some authors suspect a change in the pH value from the release of bisphosphonates from bone to be responsible for the necroses.4 Specific infections, such as actinomycetes, have also been implicated.5 but in the final instance the cause of the necroses is unresolved – in particular the fact that they almost only occur in the jaw bone.
Implantation and augmentation
When planning treatment it is important to differentiate between patients with high and low risks of osteonecrosis of the jaw, as shown in Fig. 2. A series of controlled and cohort studies shows that early stage implant healing in patients on bisphosphonate therapy and with low risk profiles seems to proceed smoothly.6 Augmentation procedures also seem to be feasible for low risk patients. Conversely, in high risk patients one needs to be very cautious about implant procedures because of the necrosis risk. The literature describes cases in which an implantation triggered a bone necrosis.7Figs. 5 and 6 strikingly illustrate the situation following implant loss with bone necrosis. These case reports primarily relate to high risk patients. In addition, there is also the interesting question of how to rate implants in relation to the risk of necrosis in the long term. There is relatively little study data on this. However, if marginal periodontitis affecting a tooth can result in bone necroses, so peri-implant inflammation might be equally problematic.
Assessing the risk
For a long time the search for a simple laboratory parameter for assessing the risk of necrosis was the prime focus. The collagen type I telopeptide CTX was discussed as a candidate by some authors.8 Its prognostic significance for the formation of a bone necrosis, however, is deemed to be limited, and in practice the measurement is now hardly ever performed.9 In the final analysis clinical and radiological healing following the extraction of a tooth can, of course, provide insight into bone physiology. Radiologically persisting alveoli with retained lamina dura is considered to be a sign of reduced bone remodeling and, therefore, a sign of a high risk of necrosis.
“Drug holiday” – yes or no?
A further hotly debated topic is the issue of interrupting bisphosphonate therapy (“drug holiday”). If you consider the above-mentioned directly inhibiting effects of bisphosphonates on fibroblasts and vascularization and correlate it with the individual recovery of the CrossLaps level (CTX level)8, a limited bisphosphonate break would really make sense for osteoporosis patients. In oncology this option is usually ruled out. As far as the duration of the break is concerned, most authors assume three months prior to surgery. So far, however, there is no evidence of success from interrupting bisphosphonates. Here, therefore, “clinical feeling” must be substituted for missing “scientific evidence.”10
Future developments: Implants instead of a prosthesis?
If it is assumed that injuries to the mucosa from tegumentally supported prostheses can also give rise to necroses and exposed bone, it would be quite conceivable to use implants for preventing bone necrosis (Fig. 7). As is the case in patients receiving radiotherapy, it would make sense to monitor patients long-term.
Bisphosphonates on implants?
Bisphosphonates, usually as a local coating for surfaces, have been used in the development of bone replacement materials for many years. Due to the slower remodeling, the coating results in more bone apposition.11 Therefore the question of whether bisphosphonates are harmful or beneficial seems to be subject to the dose. Bisphosphonates have tended to be seen in a negative light, but they might now receive an objective re-assessment.
Active prophylaxis prior to treatment with antiresorptives is useful in preventing subsequent osteonecroses. If surgical work is planned on patients receiving anti-absorptive therapy, surgical success (implant healing) and potential of necroses must be weighed against one another. Surgery should be performed along with antibiotic therapy and be adapted according to risk. Systematic reviews6 show that there is no reason to contraindicate implants with bisphosphonate therapy for lower risk patients. High-risk patients should receive relatively cautious therapy.
Guidelines on the topic “Implantology and antiabsorptive therapy”