Awareness and education of patients receiving bisphosphonates
Introduction
Bisphosphonates (BPs) are analogues of inorganic pyrophosphates that are widely used in the treatment of osseous diseases. Most bisphosphonates inhibit the precipitation of calcium phosphate, even at very low concentrations, and also slow down the dissolution of these crystals (Fleisch et al., 1969, Fleisch, 2002, Francis et al., 1969). BPs suppress bone resorption through prolonged inhibitory effects on osteoclast function and maturation. The mechanisms that lead to the inhibition of bone resorption are complex. BPs target mevalonate metabolism at the cellular level. They have been shown to block GTPases, which led to programmed cell death (apoptosis). Osteoclastic adhesion to the bone was reduced by the incorporation of BPs in the resorption lacunae (Coxon et al., 2008, Fleisch, 2002).
BPs are administered orally, as tablets, or intravenously, via infusion or injection. Intravenous administration ensures that 50–70% of the BPs reach the bone. BPs are bound to albumin in plasma. From the plasma, BPs are bound actively to the bone in resorption lacunae. The half-life of BPs in bone may be several years.
Highly effective BPs are typically administered intravenously in patients with metastatic bone lesions following treatment for breast, prostate, and lung cancers, or primary osteolytic pathologies of the bone (multiple myeloma and Paget’s disease) (Coleman, 2006, Rosen et al., 2001, Terpos et al., 2009). Administration of BPs in postmenopausal osteoporosis reduces the risk of bone fractures, because they can inhibit osteoclastic bone destruction. In oncology, BPs are used for the treatment of tumour-induced osteoporosis and to control osseous metastases. BPs can diminish both the hypercalcaemia induced by a tumour and the development of metastases. The control of osseous metastases can be explained by the reduced bone destruction, which results in a limited area for tumoural expansion.
The adverse reactions of BPs are described as low-grade, and they are almost never severe. In 2–10% of cases, gastrointestinal side effects occur after oral administration. After infusion of aminobisphosphonates, 20–40% of cases showed an acute-phase immune response caused by osteoclast secretion of tumour necrosis factor-alpha (TNFα and interferon-gamma (INFγ)). This, in turn, triggers the proliferation of interleukin-6 (IL-6). This results in flu-like symptoms with fever and bone pain. Side effects also occur in the kidneys, because BPs are largely excreted there. In the past, large quantities of Etidronate® (Jenapharm GmbH & Co. KG) and Clodronate® (Bonefos; Bayer AG, Switzerland) led to acute renal failure. Nevertheless, an existing renal insufficiency is not a general contraindication for BPs.
Osteonecrosis of the jaws is a severe side effect. In 2003, Marx et al. reported the first clinical occurrence of BP-related osteonecrosis of the jaw (BRONJ) (Marx, 2003). Most of the patients with BRONJ were treated with highly potent injectable BPs, such as Pamidronate® (Aredia; Novartis Pharmaceuticals Corp, Basel, Switzerland) and Zoledronate® (Zometa; Novartis Pharmaceuticals Corp) (Estefania et al., 2006, Leite et al., 2006, Migliorati, 2003, Ruggiero et al., 2004). The incidence of BRONJ was low among patients treated with oral BPs compared to those treated with intravenous BPs (Pazianas et al., 2007).
The pathogenesis of BRONJ and the mechanism that specifically affects the jaws are currently not well understood. Frequently, dental or surgical treatment had been undertaken prior to the appearance of osteonecrosis. In addition, BPs have shown an inhibitory effect on angiogenesis. This leads to reduced vascularization, and thus, reduced blood circulation. The increased incidence of osteonecrosis of the mandible might be explained by the generally low blood supply to the very dense, compact bone of this area (Abu-Id et al., 2006, Dannemann et al., 2007, Dannemann et al., 2008, Fehm et al., 2009). Furthermore, BPs inhibit the function of osteoclasts and osteoblasts, thus, they reduce physiological bone remodelling. Osteonecrosis mostly occurs during treatment with aminobisphosphonates (Pamidronate®, Zoledronate®); this may be due to the long tissue half-life. Thus, the data appear to point to a multifactorial cause of BRONJ. Factors thought to influence the development of BRONJ include endosseous infection (e.g. dental trauma, extraction), soft tissue-bone wounds (pressure sores, micro trauma, etc.), radiotherapy in the head and neck areas, chemotherapy, immunosuppression, and long-term therapy with cortisone (Abu-Id et al., 2006, Dannemann et al., 2008, Fehm et al., 2009).
The majority of cases of have BRONJ developed following the intravenous administration of Pamdronate and Zoledronat. Other BPs such as orally administrated Alendronate and Risedronate play a minor role.
The different bisphosphonates have a variable risk-potential. According to Abu-Id et al. patients with malignant disease receiving intravenous BP therapy (Zoledronate or Pamidronate) and/or with a history of chemotherapy, radiotherapy or current exogenous steroid use are high-risk patients (Abu-Id et al., 2008).
Patients taking oral BPs without a history of chemotherapy, radiation therapy or current exogenous steroid use (mainly patients with non-steroid-induced osteoporosis) have a low-risk for developing BRONJ (Abu-Id et al., 2008).
It seems prudent to limit the use of Pamidronate and Zoledronate to treatment of documented hypercalcemic states and multiple bone metastases with close monitoring to prevent avascular necrosis of bone (Marx, 2003).
The treatment of BRONJ is difficult. It includes conservative therapy, such as treating exposed necrotic bone with antibiotics and mouthwash, hyperbaric oxygen treatment, and jaw resection and reconstruction (Alons et al., 2009, Freiberger et al., 2007, Marx et al., 2005).
The primary goal should be prevention of BRONJ. To avoid the serious complications of BPs, it is necessary for clinicians and patients to note and attend to any side effects. It is also mandatory for doctors to explain the potential difficulties and clarify the possible risks and side effects to patients. Endodontic treatment, periodontal therapy, and tooth extraction should be performed prior to BP initiation (Estefania et al., 2006, Hewitt and Farah, 2007, Leite et al., 2006).
Montefusco et al. concluded in their investigation that antibiotic prophylaxis for dental procedures has a protective effect on BRONJ occurrence. It may reduce the incidence of ONJ in bisphosphonate treated patients with multiple myeloma submitted to dental procedures (Montefusco et al., 2008).
For the dentist it is very important to know that tooth extractions may increase the risk of BRONJ development. Root canal treatment of teeth should be an alternative to dental extractions (Kyrgidis and Vahtsevanos, 2010).
To avoid infection of the alveolar socket after tooth extraction the oral bacterial load has to be minimized by professional oral hygiene and chlorhexidine mouthwash. Antibiotic treatment, soft tissue primary closure and chlorhexidine gel may avoid local infection (Lodi et al., 2010).
Additional dental and medical attention should be paid to BP patients using removable dentures to avoid mucosal breaches caused by dentures (Kyrgidis and Triaridis, 2009).
Dental preventive measures can significantly reduce the incidence of BRONJ in cancer patients receiving BPs therapy. Dental exams combined to the identification of patients at risk in cooperation with the Dental Team can improve outcomes and increase the number of BRONJ-free patients (Ripamonti et al., 2009).
Many patients lack sufficient knowledge about drugs they are taking due to the complexity of some clinical environments. For example, treating and informing the patient may be performed by different specialists. Without close interdisciplinary cooperation, communication gaps may occur between the BP-prescribing physicians, the dentists, and the patients; this lack of communication might increase the risk of BRONJ. The aim of this study was to determine the extent of patient knowledge regarding the potencies and side effects of BPs.
Section snippets
Methods
This study involved patients with osteoporosis or advanced cancer of the breast or prostate that were taking BPs. A questionnaire was used to survey two patient groups. One group included patients that were attending self-help groups, either for osteoporosis or for cancer of breast or prostate in Bavaria; the other group included patients in BP-consultation at the Clinic of oral- and maxillofacial surgery at the University hospital of Erlangen. Prior to the study, approval from the ethics
Patients
Fifty-five of the 142 questionnaires distributed were evaluated in the study. Of the 130 questionnaires given to patients participating in a self-help group, 43 were returned; of the 12 questionnaires given to patients in the BP-consultation group, all 12 were returned to the investigator. This resulted in a participation rate of 38%. The patients comprised 47 females and 8 males, with an average age of 61.9 years (range 45–84 years). The average age of patients with osteoporosis was slightly
Discussion
In this study, we evaluated patient awareness of the risks and side effects associated with BPs. This is the first study that specifically examined the patients’ knowledge of information regarding BP treatment. We gave questionnaires to patients attending self-help groups, either for cancer or osteoporosis, because these patients are most often treated with BPs.
BPs are typically well tolerated. Side effects are minimal and rarely serious. Nevertheless, patients should receive precise
Conclusion
The study shows that the level of information amongst patients about possible side effects regarding their medication with bisphosphonates is poor. This is especially true for the severe complications concerning an osteonecrosis of the jaw.
Opportunities should be created for the users of bisphosphonates to be informed about the risks involved in taking these drugs at several points. These include: the revision of the package inserts, the creation of information brochures, the motivation of
Conflict of interest
All authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence or bias our work. The authors did not have any writing assistance for this paper.
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