Bisphosphonate-associated peri-implant fractures: a new clinical entity?: A series of 10 patients with 11 fractures

Background and purpose

The current definition of atypical femoral fractures (AFFs) associated with bisphosphonate use includes only de novo fractures. However, in recent years reports of bisphosphonate-associated periprosthetic fractures involving stemmed arthroplasty implants have emerged. In a case series of peri-implant fractures in femurs with plate/screw constructs, we aimed to assess similarities with classical AFFs and how their location may have implications for the pathogenesis and management of AFFs.

Patients and methods

We retrospectively identified 10 patients with 11 peri-implant fractures.

Results

The patients were ambulant women, mean age 80 (70–92) years. Mean duration of bisphosphonate use was 5 (1–10) years. The peri-implant fractures were sustained an average of 4 years (6 months to 9 years) from the time of index surgery. They were all associated with low-energy mechanisms. 8 fractures occurred near the tip of a plate, while 3 traversed the penultimate screwhole of a plate. The peri-implant fractures showed clinical and radiological features of atypicality such as lateral cortical thickening, simple fracture pattern, and lack of comminution. The patients underwent revision surgery, with bone grafting used in all but 1 case. Radiological union was evident after 2–4 months.

Interpretation

Atypical peri-implant fractures of the femur associated with bisphosphonate use may be a new entity. Stress lesions and atypical fractures may tend to develop over stress risers along the operated femur. This finding has implications for the pathogenesis and clinical management of AFFs.Bisphosphonates form the cornerstone of antiresorptive therapy in the management of post-menopausal osteoporosis. They are used in the treatment of malignant and osteoclast-mediated metabolic bone disease. Their use in patients who have undergone total joint arthroplasty of the lower limb is associated with higher periprosthetic bone mineral density and longer implant survival (Bhandari et al. 2005). Bisphosphonates exert their therapeutic effect by reducing bone turnover and increasing overall mineralization. This translates to increased bone mineral density and bone strength, corresponding clinically to reduced risk of vertebral and non-vertebral fragility fractures (Black et al. 1996).In recent years, several published reports have described atypical femoral fractures (AFFs) of the proximal femoral diaphysis and subtrochanteric region, in association with bisphosphonate use (Goh et al. 2007, Neviaser et al. 2008, Isaacs et al. 2010). Bisphosphonates are associated with a higher age-adjusted relative risk of AFF in women than in men, which is higher in alendronate users than in risedronate users (Schilcher et al. 2015). Bisphosphonates may cause changes in bone matrix composition and bone mechanical properties, increasing the propensity for accumulation of microdamage. Impaired target remodeling would contribute to the progression of macrocracks. High interfragmentary strain from physiological loads at a thin fracture line may be a mechanical factor in lack of bone healing (Aspenberg et al. 2010).Periprosthetic/peri-implant fractures are currently excluded from the definition of AFFs. We suggest that peri-implant fractures of the femur with features of atypicality may be linked to bisphosphonate use and that they should be recognized as a clinical entity.     

Ministry of Health Clinical Practice Guidelines: Anxiety Disorders

The Ministry of Health (MOH) has developed the clinical practice guidelines on Anxiety Disorders to provide doctors and patients in Singapore with evidence-based treatment for anxiety disorders. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on anxiety disorders, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

1.1 Background information

Anxiety disorders are known to be one of the most prevalent of psychiatric conditions, yet they often remain under-diagnosed and under-treated. Their chronic, disabling symptoms cause considerable burden not only to sufferers but also to their families, and contribute to poorer quality of life and considerable economic burden on society.In many instances, there is a delay in seeking treatment and in some cases such delay may stretch up to nearly ten years. This may result from ignorance of the condition, fear of taking medications, and the stigma of receiving a psychiatric diagnosis, and or having to accept psychiatric treatment.The anxiety disorders include panic disorder with or without agoraphobia, social anxiety disorder, specific phobia, obsessive-compulsive disorder, generalised anxiety disorder, acute stress disorder and post-traumatic stress disorder. In the clinical evaluation of anxiety disorders, it is important to ascertain the type of anxiety disorder present. This would allow treatment to be targeted at the specific type of disorder.These guidelines are developed to provide practical, evidence-based recommendations to primary care physicians and specialists in psychiatry for the diagnosis and management of the anxiety disorders.The first edition of the guidelines was published in 2003. In this edition, we present data from newer research as well as older data not previously reported in the earlier guidelines.For example, we examine the efficacy of combining medications with psychological therapy over medications alone, or psychological therapy alone. In view of the majority of anxiety sufferers being female we have made recommendations for pharmacotherapy during pregnancy and breastfeeding. As these guidelines are intended for use in the Singapore context, we have omitted treatments that are currently not available in Singapore.

1.2 Aim

These guidelines are developed to facilitate the diagnosis and assessment of the anxiety disorders, and to ensure that their management is appropriate and effective.

1.3 Scope

These guidelines will cover the management of anxiety disorders in adults and address the issues of medication use during pregnancy and breastfeeding.

1.4 Target group

The content of the guidelines will be useful for all doctors treating patients with anxiety disorders. Efforts have been made to ensure that the guidelines are particularly useful for primary care physicians and specialists in psychiatry, including all those involved in the assessment and management of patients with anxiety disorders in the community. The doctor treating the patient is ultimately responsible for clinical decisions made after reviewing the individual patient’s history, clinical presentation and treatment options available.

1.5 Development of guidelines

These guidelines have been produced by a committee of psychiatrists, a clinical psychologist, pharmacist, patient representative, and family practitioners appointed by the Ministry of Health. They were developed by revising the existing guidelines, reviewing relevant literature, including overseas clinical practice guidelines, and by expert clinical consensus of professionals with experience in treating patients in the local setting.The following principles underlie the development of these guidelines:

• Treatment recommendations are supported by scientific evidence whenever possible (randomised controlled clinical trials represent the highest level of evidence) and expert clinical consensus is used when such data are lacking.
• Treatment should maximise therapeutic benefits and minimise side effects.

1.6 What’s new in the revised guidelines

This edition of the guidelines contains updated recommendations based on latest evidence, as well as detailed discussions and recommendations on the management of anxiety disorders in adult populations.The following represent changes to the revised guidelines

• An extensive review of the literature, including new evidence. This involved the re-writing and extensive revision of the chapters.
• Length of treatment, which provides answers to a pertinent question.
• Use of medications during pregnancy and breastfeeding. Given that females are more likely to be at risk of being diagnosed with anxiety disorders, this is an important subject.

We are aware that the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) was released in 2013. In DSM-5, post-traumatic stress disorder and obsessive-compulsive disorder have been removed and classified separately from the rest of the anxiety disorders. If we were to adhere strictly to DSM-5, this would entail omitting discussion on post-traumatic stress disorder and obsessive-compulsive disorder. As it is our aim to provide an update on the 2003 guidelines, post-traumatic stress disorder and obsessive-compulsive disorder have been included in this edition of the guidelines.In addition, anxiety conditions in children are included in DSM-5. Since the present guidelines are meant to address only adult anxiety disorders, guidelines on children’s anxiety conditions are not included here.Hence, for purposes of these guidelines, we will continue to use classifications based on the International Classification of Diseases-10 (ICD-10) and DSM-IV-TR criteria.

1.7 Review of guidelines

Evidence-based clinical practice guidelines are only as current as the evidence that supports them. Users must keep in mind that new evidence could supersede recommendations in these guidelines. The workgroup advises that these guidelines be scheduled for review five years after publication, or when new evidence appears that requires substantive changes to the present recommendations.     

Outcome of off-pump coronary artery bypass in renal dialysis patients

BACKGROUND: Renal dialysis patients are a subgroup at major operative risk when undergoing coronary artery bypass grafting (CABG). Even though CABG without cardiopulmonary bypass (CPB) has decreased the surgical risk and provided good short-term results, the long-term survival seems uncertain. We report here on the long-term outcome of CABG without CPB in renal dialysis patients. METHODS: From 1998 to 2002, 44 renal dialysis patients underwent elective CABG without CPB, including 17 minimally invasive direct coronary artery bypass (MIDCAB) and 27 off-pump CABG (OPCAB) procedures. There were 5 one-vessel, 12 two-vessel and 27 multi-vessel coronary artery disease patients, who mainly had left internal thoracic artery (LITA) to left anterior descending coronary artery (LAD) grafting with an additional saphenous vein graft to non-LAD coronaries. RESULTS: All 44 patients were followed up for 44.4 +/- 31.2 months. Three (6.8 %) surgical deaths within 30 days occurred and 25 late mortalities happened over a period of 2 - 79 months. The 5-year cumulative rate of total survival is 38.2 % and the freedom from cardiac death is 70.9 %. Using hazard analysis, old age (> 60 years) and incomplete coronary revascularization was found to significantly affect the total survival. CONCLUSIONS: CABG without CPB provided an acceptable surgical mortality and morbidity. The high incidence of non-cardiac death associated with dialysis complications had an adverse impact on the overall outcome. The LITA bypass operation method combined with intensive care for dialysis complications would hopefully fulfill the goal to improve the short- and long-term results in this subgroup.     

Epinephrine injection therapy versus a combination of epinepnrine injection and endoscopic hemoclip in the treatment of bleeding ulcers

AIM: To assess the efficacy of hemoclip application in combination with epinephrine injection in the treatment of bleeding peptic ulcers and to compare the clinical outcomes between patients treated with such a combination therapy and those treated with epinephrine injection alone. METHODS: A total of 293 patients (211 males, 82 females) underwent endoscopic therapy for bleeding peptic ulcers. Of these, 202 patients (152 males, 50 females) received epinephrine injection therapy while 91 patients (59 males, 32 females) received combination therapy. The choice of endoscopic therapy was made by the endoscopist. Hemostatic rates, rebleeding rates, need for emergency surgery and 30-d mortality were the outcome measures studied. RESULTS: Patients who received combination therapy were significantly older (mean age 66±16 years, range 24-90 years) and more suffered from chronic renal failure compared to those who received epinephrine injection therapy alone (mean age 61±17 years, range 21-89 years). Failure to achieve permanent hemostasis was 4% in the group who received epinephrine injection alone and 11% in the group who received combination therapy. When the differences in age and renal function between the two treatment groups were taken into account by multivariate analysis, the rates of initial hemostasis, rebleeding rates, need for surgery and 30-d mortality for both treatment options were not significantly different. CONCLUSION: Combination therapy of epinephrine injection with endoscopic hemoclip application is an effective method of achieving hemostasis in bleeding peptic ulcer diseases. However, superiority of combination therapy over epinephrine injection alone, could not be demonstrated.     

Impact of Pelvic Radiotherapy on Morbidity and Durability of Sphincter Preservation After Coloanal Anastomosis for Rectal Cancers

Purpose This study was designed to assess the impact of pelvic radiotherapy on the incidence of complications and colostomy-free survival of patients after a coloanal anastomosis for rectal cancer. Methods A total of 192 patients underwent a coloanal anastomosis between 1982 and 2001: 87 patients did not receive pelvic radiotherapy; 105 patients received pelvic radiotherapy (39 preoperative and 66 postoperative). Early and late complications requiring surgical intervention and the colostomy-free survival rate were assessed by retrospective review of patient records. Results After a median follow-up of 62 months, 151 patients were alive. The most frequent complication was development of an anastomotic stricture (5-year rate of a stricture, 16 percent; 95 percent confidence interval, 10–21). Patients receiving pelvic radiotherapy had a higher rate of complications other than anastomotic strictures, including fecal incontinence, fistulas, abscesses, and bowel obstructions compared with patients not receiving pelvic radiotherapy (5-year rate: 20 percent (95 percent confidence interval, 10–29) vs. 5 percent (95 percent confidence interval, 0–10); P = 0.001). Patients receiving pelvic radiotherapy had a lower colostomy-free survival than did patients not receiving pelvic radiotherapy (5-year colostomy-free rate: 72 percent (95 percent confidence interval, 62–84) vs. 92 percent (95 percent confidence interval, 86–98); P < 0.001). There was no significant difference in the colostomy-free survival of patients receiving preoperative and postoperative pelvic radiotherapy. Conclusions After coloanal anastomosis, a significant number of patients will have complications requiring surgical intervention, and some will require a permanent colostomy. Pelvic radiotherapy, whether it is administered preoperatively or postoperatively, significantly increases the need for a permanent colostomy.     

Post-translational transport into intact chloroplasts of a precursor to the small subunit of ribulose-1,5-bisphosphate carboxylase

A precursor to the small subunit of ribulose-1,5-bisphosphate carboxylase [3-phospho-D-glycerate carboxylyase (dimerizing), EC 4.1.1.39] has been identified among the products of cell-free translation of polyadenylated RNA from spinach and pea. In both cases, the precursor is larger than the mature protein by 4000-5000 daltons. Upon incubation of post-ribosomal supernatants of the in vitro protein synthesis mixtures with purified intact chloroplasts, the pea and spinach precursors are transported interchangeably into the chloroplasts and processed to the mature size and charge. Moreover, the newly transported small subunits are found to assemble with endogenous large subunits to form the holoenzyme. In contrast, a precursor to the Chlamydomonas reinhardtii small subunit is not taken up by higher plant chloroplasts, indicating the specificity of the transport events. Together, these results demonstrate that the in vitro reconstruction of the post-translational transport of the higher plant precursors is physiologically significant.     

A rapid procedure for selective enrichment of photosynthetic electron transport mutants.

Metronidazole (2-methyl-5-nitroimidazole-l-ethanol) is shown to be effective for the selective enrichment of mutants of Chlamydomonas reinhardtii that posses impaired photosynthetic electron transport. More than 99.9% of wild-type cells are killed when incubated in the presence of 6-10 mM metronidazole for 24 hr under illumination of 7500 lux. Survival of wild-type cells in darkness and of mutants that are blocked at different steps in photosynthetic electron transport is nearly 100% when incubated in the presence of the drug under identical conditions. The toxicity of metronidazole is demonstrated to depend upon its reduction by photosynthetic electron transport. Light-dependent oxygen uptake mediated by metronidazole is shown to require active photosystem l in vitro and in vivo. Ferredoxin is necessary for metronidazole reduction by thylakoid membrane fractions enriched in photosystem l activity. We propose that the toxicity of metronidazole is due to the formation of lethal derivatives of the drug or to the accumulation of hydrogen peroxide, which could occur upon autooxidation of metronidazole reduced by one electron. The results indicate that mutants of C. reinhardtii, and probably other photosynthetic organisms, with any lesion in photosynthetic electron transport from the oxidizing side of photosystem ll to ferredoxin can be isolated by metronidazole treatment of mutagenized cultures.     

Orbital Fracture in a Professional Diver: Issues and Management

Background

We present a case report of a professional diver who sustained a fracture of the left orbital medial wall as well as floor exceeding 50% with orbital fat herniation blocking the maxillary sinus ostium. This may result in a closed cavity within the maxillary sinus that could potentially result in barotraumas during future diving. The aim of his surgery consists of repairing the orbital fracture and to aerating the sinus at the same sitting.

Method

A transconjunctival approach was used combined with endoscopic sinus surgery approach to the maxillary sinus. The orbital floor fracture was repaired with a titanium plate. A wide middle meatal antrostomy was performed. A size eight Foley’s catheter was inserted into the maxillary sinus and the balloon inflated to elevate and support the displaced inferior orbital floor bone fragment. The balloon was left in situ for 4 weeks to support the mobile inferior orbital fragment till adequate bone healing and stability.

Results

Patient recovered well. At 3 months post-operatively, the maxillary antrostomy remained patent, and a hyperbaric oxygen challenge test was performed with success. A repeat orbital CT scan 1 day after hyperbaric challenge showed no signs of air leakage, and the bony inferior orbital floor fracture has healed completely with the titanium plate in situ.

Conclusion

This is the first case report of repair of orbital floor fracture with simultaneous aeration of the maxillary sinus in a professional diver using a combined approach. The patient was able to resume his occupation as a professional diver following surgery.