Mohammad Kharazmi

Oral ulcer associated with alendronate: a case report

Irritation of the mucosa of the aerodigestive tract is a well-known adverse effect of alendronate, whereas oral ulceration has been reported in only 14 articles in both the English and non-English literature. All of these have been associated with misuse of the drug. We here present the first case of severe oral ulceration attributable to use of alendronate without inappropriate therapeutic administration of the medication.

Oral Ulcers, a Little Known Adverse Effect of Alendronate: Review of the Literature

PURPOSE To review the published data on a hitherto not widely known adverse effect of alendronate manifesting as mucosal ulcers in the oral cavity. MATERIALS AND METHODS The electronic database PubMed was searched for reports of this adverse effect. Publications published up to August 2010 were included. This electronic search was combined with a manual search of the reference lists of the selected publications. RESULTS A total of 47 publications were retrieved from the electronic and manual searches. Of these, 12 were selected for the review. Mostly, the ulcers were preceded by misuse of alendronate, but they also appeared after correct administration. The appearance of the ulcers varied from a few days to several months after the start of alendronate use. Effective treatment was withdrawal of the drug or revision of the dosing and administration instructions. CONCLUSIONS Alendronate can cause mucosal ulcerations in the oral cavity, affecting patients with intense pain and causing severe morbidity. Successful treatment of this oral pathosis is achieved by aborting the use of alendronate. This adverse effect of alendronate is a rare entity in published reports but careful monitoring of patients at risk is recommended.

Pharmacovigilance of oral bisphosphonates : adverse effects manifesting in the soft tissue of the oral cavity

PURPOSE It is well known that oral bisphosphonates can induce necrosis of the osseous structures of the jaws. However, there seems to be a limited awareness that oral bisphosphonates can also induce adverse effects in the soft tissues of the oral cavity, as indicated by the paucity of reported cases in the literature. Because oral bisphosphonates are widely used drugs for several skeletal conditions, it is reasonable to assume that mucosal adverse effects are more common than the small number of published cases indicates. The purpose of this study was to investigate whether this adverse effect of bisphosphonates is represented as reports from health practitioners in an adverse drug reaction database, as well as to gain knowledge about which substances are being associated with adverse drug reactions affecting the oral mucosa. MATERIALS AND METHODS The database of the Medical Products Agency-Sweden was searched for adverse effects from oral bisphosphonates manifesting in the oral and maxillofacial region. Reports of reactions limited to the soft tissues of the oral cavity were selected and further analyzed. Only those reports showing recovery or improvement after the cessation of bisphosphonate use were included in the study. RESULTS A total of 83 cases of adverse reactions to oral bisphosphonates were retrieved from the search. Of these, 12 were included in the study. They were associated with the use of alendronate, etidronate and risedronate, in descending order. Sixteen percent of the reports comprising the oral and maxillofacial region were limited to the oral mucosa and reported recovery or improvement after discontinuation of the drug. CONCLUSIONS Adverse effects of oral bisphosphonates with manifestations in the soft tissue of the oral cavity seem to be more common than the small number of published cases indicates. However, considering that oral bisphosphonates are widely used drugs, the incidence is still low. These adverse drug reactions are not limited to alendronate and may also be induced by etidronate and risedronate. Still, a significant proportion of the cases are associated with alendronate. Regardless of the substance used, discontinuing the drug is an effective treatment for the mucosal lesions.

Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw

Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw

Mortality After Atypical Femoral Fractures: A Cohort Study

Although osteoporotic fracture rates can be reduced by bisphosphonates, prolonged therapy is associated with higher risk of atypical femoral fractures. Ordinary fragility fractures are linked to high mortality rates. We aimed to determine whether atypical femoral fractures also confer excess mortality. Radiographs were reviewed for all patients aged ≥55 years who had experienced a subtrochanteric or femoral shaft fracture in Sweden in 2008 to 2010. The fractures were classified as either atypical or ordinary. Data on medication use, coexisting conditions, and date of death were obtained from national registers. We estimated multivariable-adjusted relative risks of death after atypical femoral fractures compared with ordinary subtrochanteric or femoral shaft fractures and calculated age- and sex-standardized mortality ratios (SMRs) for atypical and ordinary fractures compared with the population average. During a mean of 4 years of follow-up, 39 of 172 (23%) patients with an atypical fracture had died compared with 588 of 952 (62%) with an ordinary fracture, corresponding to a relative risk of 0.51 (95% confidence interval [CI] 0.38-0.68). The lower risk was evident in both users and nonusers of bisphosphonates. No patient with atypical fracture died in the first year after fracture. Individuals with an ordinary fracture had a higher mortality risk than the general population (SMR = 1.82; 95% CI 1.69-1.99), but no excess risk was found in patients with atypical fracture (SMR = 0.92; 95% CI 0.65-1.26). We conclude that in contrast to ordinary subtrochanteric and femoral shaft fractures, atypical femoral fractures are not associated with excess mortality.

Risk of atypical femoral fractures and osteonecrosis of the jaw associated with alendronate use compared with other oral bisphosphonates

Risk of atypical femoral fractures and osteonecrosis of the jaw associated with alendronate use compared with other oral bisphosphonates

Mandibular bone exposure and osteonecrosis as a complication of general anaesthesia

Trauma to the oral structures sometimes occurs as a complication to general anaesthesia. We here report two cases of an unusual type, mandibular osteonecrosis. To our knowledge, there has been only one previous publication of this condition (1). The first case was a 69-year-old man who underwent oral examination 3 months prior to planned cardiac surgery. His medical history included hypertension, diabetes mellitus, and mitral insufficiency, and he was on treatment only with enalapril. Three molars in his lower jaw were extracted due to periodontitis, and healing was uneventful at follow-up. At cardiac surgery, he was intubated with a standard endotracheal tube (number 8) and was placed on a cardio-pulmonary bypass (CPP) machine. Two weeks later, he complained of pain in the right side of his mandible, which had started directly after recovery from surgery and successively increased. Examination revealed a 4 × 8 mm area of exposed non-vital bone at the right mylohyoid ridge. There was no sign of infection, and radiography was unremarkable. He was treated with 2 mg/mL chlorhexidine mouth rinse twice daily and amoxicillin 500 mg three times daily. Three weeks later there was spontaneous exfoliation of a sequestrum, and there was complete healing 2 months after his cardiac surgery. The other case was an 86-year-old man with progressive aorta stenosis and a history of myocardial infarction. Medication included enalapril, isosorbide mononitrate, simvastatin, acetylsalicylic acid, and glyceryl trinitrate. He was planned for cardiac surgery and underwent oral examination 2 months before. Two upper and three lower molars were extracted due to apical periodontitis, and healing was uneventful at follow-up. At cardiac surgery, the patient was intubated with a standard endotracheal tube (number 8) and placed on a CPP machine. Two weeks later, he complained about right-sided mandibular pain, which had started directly after recovery from surgery. Examination revealed an 8 × 5 mm area of non-vital exposed bone at the right mylohyoid ridge. There was no sign of infection, and radiography was unremarkable. He was treated with 2 mg/mL chlorhexidine mouth rinse twice daily and phenoxymethylpenicillin 1 g three times daily, and there was complete healing 2 months after surgery preceded by exfoliation of a small sequestrum. The incidence of osteonecrosis as here described is unknown. It is probably low, but the location at the medial aspect of the mandible could make it easily mistaken for discomfort after intubation (2). The pathogenesis is unclear, but the prominence of the mandibular shelf, covered by only a thin layer of oral mucosa, is probably vulnerable to trauma, which may affect the blood supply to the periosteum leading to local ischemia and osteonecrosis. Another possibility could be soft tissue necrosis caused by several hours of pressure from the endotracheal tube or the transesophageal echocardiograph with its bite blocks. Although the anaesthesiologists reported no procedural complications, reduced blood pressure could have aggravated the condition through diminished blood flow in the soft tissue. In a previously published case series (Table I), it appears that the affected area was at the right side of the posterior part of the mandible in all cases, indicating that trauma from the laryngoscope blade was a possible cause (1). Table 1. Summary of cases in the literature and the present report. Although the exact mechanism involved in this type of osteonecrosis remains unknown (2), we believe that an association with general anaesthesia in our cases is very likely. There was no history of bisphosphonate use or radiation treatment, and follow-up oral examination prior to surgery showed no sign of osteonecrosis. Also, the onset of mandibular pain was right after recovery from anaesthesia in both cases. Factors that may predispose to this type of osteonecrosis include prominent mandibular shelves, limited mouth opening, and extensive oral manipulation while managing the airway during anaesthesia. Previous or ongoing treatment with bisphosphonates or radiation might also lead to more severe complications in affected patients. We hope that our reported cases will increase the awareness of this type of complication to general anaesthesia.

Bisphosphonate-associated osteonecrosis of the auditory canal

Only rare cases of osteonecrosis of the auditory canal associated with bisphosphonates, have been published. Our results confirm that similar reports can also be encountered in databases of adverse drug reactions.

Lateral fixation: an alternative surgical approach in the prevention of complete atypical femoral fractures

Little evidence is available on how to treat incomplete atypical fractures of the femur. When surgery is chosen, intramedullary nailing is the most common invasive technique. However, this approach is adopted from the treatment of other types of ordinary femoral fracture and does not aim to prevent the impending complete fracture by interrupting the mechanism underlying the pathology. We suggest a different surgical approach that intends to counteract the underlying biomechanical conditions leading to a complete atypical fracture and thus could be better suited in selected cases. Here, we share an alternative surgical approach and present two cases treated accordingly.

Bisphosphonate-associated atypical femoral fractures and one-year mortality.

Dear Editor, It is well known that osteoporotic fractures (OF) of the hip are associated with increased mortality, in particular immediately after the fracture (1). Although several theories have been proposed, the cause of the increase is not fully understood. In the past few years there have been an increasing number of reports of femoral fractures associated with bisphosphonate use (2). The pattern of these fractures differs from the typical OFs, and hence they are referred to as atypical fractures (AF). One of the differences between the two is the fact that OFs are secondary to a disease, while AFs is the result of an adverse drug reaction (ADR). However, both affect patients with osteoporosis, and the end result is fracture of the same bone (femur). Whether or not AFs are associated with a similar increase in mortality as OFs is unknown. We aimed to investigate this question. The Medical Products Agency (MPA) is the Swedish regulatory authority registering spontaneous reports of ADRs from health care professionals. We reviewed all reports of AF received by the MPA, from January 2006 through September 2013, associated with use of oral bisphosphonates or once-yearly intravenous zoledronic acid, prescribed with osteoporosis as the indication. Reports not fulfilling diagnostic criteria for AF were excluded (3). Diagnostic accuracy (3) was confirmed in all patients consenting to have their medical records and radiographs reviewed. The one-year mortality rate was determined by using data from the national population register of the Swedish tax authority. For all cases, survival or mortality was determined at least one year after the fracture. A total of 48 reports had been received from January 2006 through September 2013. Forty-four reports (2 men, 42 women) fulfilled the diagnostic criteria for AF (3). Twenty-seven patients consented to complete a structured interview about their medical history and drug therapies, and to have their medical records and radiographs reviewed. Diagnostic accuracy (3) could be confirmed in each case. Data on co-morbidities were collected based on either interviews and medical records, or on information from case narratives. The mean age of the 44 patients at the time of the AF was 73 years. During the mean follow-up time (from fracture to determination of mortality) of four years, five (all women) of the included 44 patients had died (11.4%), of which one (2.3%) had done so within one year after the fracture. Like patients who experience OFs, the great majority of the patients in the current study were women. Based on the results of a previously published Swedish nation-wide study, the one-year mortality rate among women aged 70–75 years who experience a hip fracture has been estimated to be 9.6% (4). In comparison, based on the results of the present study, the one-year mortality rate following AF of the hip appears significantly lower (2.4% for the 42 women). As frequencies of co-morbidities were similar (cardiovascular disease 21.4% versus 28.6%; obstructive lung disease/pneumonia 14.3% versus 5.0%; diabetes 4.8% versus 5.0%; cancer 7.1% versus 8.3%; psychiatric disease 4.8% versus 12.5%), the difference in mortality rate is unlikely to be explained by differences in patient characteristics. In conclusion, although AF is often associated with delayed healing (3), our results reveal no evidence of a high mortality rate. In this respect, AF appears less hazardous compared to OF, which should be of importance when assessing the benefit risk ratio of bisphosphonate therapy. Since both AF and OF affect the same category of patients and the same bone, it is reasonable to assume that the higher mortality rate associated with OF is not entirely due to the fracture (5), but rather the overall systemic effects of the disease, and possibly genetic factors.