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Bisphosphonates are commonly used in the treatment of osteoporosis. Atypical femoral fracture (AFF) is a well-known adverse effect of bisphosphonate use. The importance of genetic factors has been demonstrated in bone quality, bone turnover, and in the response to osteoporosis treatment. Herein, we present two cases of bilateral AFFs after bisphosphonate use for a short period of time in members of the same family (mother and her daughter) and discuss genetic predisposition to bisphosphonate-induced AFFs in the light of literature data. © 2021 Turkish Society of Physical Medicine and Rehabilitation. All rights reserved.

An AFF is a form of stress fracture induced by excessive physiologic repetitive stress over the bone remodeling capacity. Although glucocorticoid administration is a known risk factor for AFF, no case of AFF with glucocorticoid administration as the only risk factor has been previously reported. In this report, we aimed to highlight the risk of AFF associated with long-term administration of glucocorticoids, and the importance of surveillance and correction of risk factors in patients undergoing long-term glucocorticoid therapy. A 58-year-old male patient was diagnosed with subtrochanteric AFF. He had no medical history of any condition that might disrupt bone metabolism and no known risk factors for AFF, except for long-term administration of glucocorticoid. After fixation of the fracture, the glucocorticoid was replaced with an alternative medication. Although AFF is notorious for delayed union or nonunion, complete union of the fracture was obtained at 14 months postoperatively. This case brought to our attention the possibility that glucocorticoids alone may be responsible for inducing AFF and highlighted the importance of regular assessments in case of necessity of glucocorticoid administration. Additionally, correction of risk factors might expedite the union of AFF.

Objective: We report two cases of atypical femoral fracture (AFF) in patients with cancer. Patients: Two patients, a 53-year-old woman with breast cancer and a 77-year-old man with prostate cancer, could not walk after being injured in a fall. They used bone-modifying agents (BMA) for the prevention of bone metastasis for three and four years, respectively. Results: Intramedullary nails were placed to fix the femoral fractures in each patient. Neither of them had pathological metastatic femoral fractures based on fracture site specimens; however, severe suppression of bone turnover at the fracture site was suspected. Both patients could ambulate with a T-cane and were free of hip pain after surgery. Radiographs showed no callus formation at the fracture site. Conclusion: Based on the two cases of AFF in patients with cancer related to BMA use, we should consider that the incidence of AFF may be associated with long-term BMA use.

Bisphosphonates have been the first drug of choice for osteoporosis in the recent years because of their known ability to suppress osteoclast activity. The adverse effect of long-term bisphosphonate administration in the fracture-healing process is controversial. The aim of our study was to observe not only morphology but also morphometry of the fracture site of atypical femoral fracture with and without long-term bisphosphonate administration, in a case study of two difficult-to-obtain human samples. The patients with insufficient healing of atypical femoral fracture were treated with valgus wedge osteotomy. Histomorphometrical analysis was performed in bone samples of fracture sites harvested during osteotomy. The thickness of the femoral cortex was measured in the fracture site and the adjacent, non-fracture site. A comparative analysis of the content of hypertrophic osteoclasts in fracture sites, shape and size of osteons, mass, and ratio of the woven bone to the total bone mass was performed, comparing bisphosphonate-treated and untreated samples. In bisphosphonate-treated samples, we observed femoral cortex thickening at the fracture site; the appearance of hypertrophic osteoclasts; decreased bone resorption surface, decreased osteoclast numbers on the bone resorption surface, and increased ratio of multinuclear osteoclasts; osteons were misshapen and thin; and the mass and ratio of the woven bone to the total bone mass were higher. This study demonstrated that long-term bisphosphonate administration can alter the morphological features of the fracture site compared to its physiological state.

BACKGROUND Atypical femoral fracture (AFF) is associated with high prevalence rates of prodromal symptoms, bilateral involvement, complications, and the need for prophylactic fixation due to a risk of an impending fracture. Although most complete AFF cases have an asymptomatic contralateral femur at the initial presentation, there is lack of clarity on its progression. We evaluated the radiographic progression of asymptomatic contralateral femora in patients with a complete AFF and investigated the characteristics of these patients. METHODS The medical records of 80 consecutive patients who had been treated for a complete AFF were retrospectively evaluated. We excluded 14 patients who had been lost to follow-up, 10 whose contralateral femur initially had been symptomatic and had been treated simultaneously, and 3 whose contralateral femur had previously been treated surgically. The remaining 53 patients were all women with an average age of 71.8 years. The average duration of bisphosphonate (BP) use was 63.6 months, and the mean follow-up duration was 48.9 months. All of the contralateral femora were asymptomatic and were divided into 2 grades according to the initial radiographic findings. We evaluated the prevalence of radiographic progression according to the grades and compared patient characteristics between the progression and non-progression groups. RESULTS Radiographic progression was noted in 18 patients (34%) during the follow-up: 3 (12%) of 25 in grade 1 and 15 (53.6%) of 28 in grade 2 (p < 0.001). The mean time to progression for these 18 patients was 25.6 months, which also differed significantly depending on the grade (p = 0.02). Eleven and 9 (61.1% and 25.7%) of the patients received BP postoperatively in the progression and non-progression groups, respectively (p = 0.01). CONCLUSIONS The prevalence of radiographic progression was relatively high, even though the contralateral femur was initially asymptomatic, and differed significantly according to the initial radiographic grade. The frequency of postoperative BP use was significantly higher in the progression group. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

We conducted an updated review of the evidence of teriparatide (TPTD) for fracture healing for the following questions. (1) Does it decrease fracture healing time?; (2) Can it be an alternative treatment for nonunion?; (3) Does it aid the union of atypical femoral fracture (AFF)? We searched PubMed, EMBASE, and Cochrane Library including “Fracture” AND “nonunion” AND “Teriparatide”. In total, 57 publications met our inclusion criteria were summarized. This systemic review of the available literature revealed that TPTD works positively with regard to enhancing fracture healing time and union of AFF. There are also many case studies on the use of TPTD could be a potential new safe treatment for nonunion with no side effects. However, level 1 studies on the evidence of TPTD are still lacking so far. Over the last decade, a growing body of evidence has accumulated suggesting that TPTD can be an adjunct to enhance fracture healing or a therapeutic option to treat nonunion, but greater evidences from large volume prospective trials are needed.

McCune-Albright Syndrome (MAS) is characterized by endocrinopathies, café-au-lait spots, and fibrous dysplasia. Bisphosphonates are the most prescribed treatment for reducing the pain but their long-term use has been associated with atypical fractures of cortical bones like femur in patients. We present a 23-year-old girl diagnosed with MAS. She had an atypical mid-shaft left femoral fracture that happened during simple walking. She also had a history of long-term use of alendronate. Because of the narrow medullary canal, we used 14 holes hybrid locking plate for the lateral aspect of the thigh to fix the fracture and 5 holes dynamic compression plate (instead of the intramedullary nail) in the anterior surface to double fix it, reducing the probability of device failure. With double plate fixation and discontinuation of alendronate, the complete union was achieved five months after surgery

Thigh pain after hip arthroplasty is multifactorial; uncovering its etiology is paramount for optimal treatment. This is the first case where 18F‐sodium fluoride positron emission tomography substantially helped in diagnosing the post‐hip arthroplasty persistent thigh pain and appropriate treatment selection. This imaging modality warrants further study and more widespread application.

While bone-modifying agents such as bisphosphonates and denosumab are crucial to preventing skeletal-related events in patients with bone metastases, the optimal duration remains undefined. Extended duration may be associated with adverse effects such as osteonecrosis of the jaw and atypical femoral fracture. Although uncommon, atypical femoral fracture represents a serious consequence of prolonged bone-modifying agent use and are characterized by a prodrome and distinct radiographic findings. The oncology setting encompasses a unique set of atypical femoral fracture risk factors and considerations, with hormonal therapy in early stage disease, bone metastases in the advanced setting, and new targeted agents that may affect bone homeostasis. As outcomes in cancer treatment continue to improve, the questions of risks versus benefits of long-term bone-modifying agents and how to mitigate atypical femoral fracture risk become increasingly pertinent.

Atypical femoral fractures are burdened with a high rate of reoperation. In our nationwide analysis, the increased rate of reoperation was related to patient background characteristics, such as age and health status, rather than fracture type. Introduction Patients with atypical fractures are complex to treat and burdened with a high risk of reoperation. We hypothesized that patients with surgically treated, complete atypical fractures have a higher risk of any reoperation and reoperation related to healing complications than patients with common femoral shaft fractures but that this increase would become insignificant when adjusted for predefined characteristics. Methods A cohort of 163 patients with atypical fractures and 862 patients with common femoral shaft or subtrochanteric fractures treated from 2008 to 2010 and who had follow-up radiographs and register data available until 31 December 2014 was included. Reoperations were identified by a complementary review of radiographs and register data and were used to calculate risks for any reoperation and reoperations related to healing complications. Results Patients with atypical fractures were more likely to be reoperated for any reason, age-adjusted OR 1.76 (95% CI, 1.08 to 2.86). However, patients with common fractures had a shorter follow-up due to a threefold higher death rate. Accordingly, in a multivariable-adjusted time-to-event model, the increased risk lost statistical significance for any reoperations, cause-specific HR 1.34 (95% CI, 0.85 to 2.13), and for reoperations related to healing complications, HR 1.32 (95% CI, 0.58 to 3.0). Continued use of bisphosphonate in the first year after the fracture did not affect the reoperation rate. Conclusions Our findings suggest that the increased risk of reoperation after an atypical femur fracture is largely explained by patient characteristics and not fracture type. Funding Agencies|RegionGavleborgRegion Auvergne-Rhone-AlpesRegion Bourgogne-Franche-ComteRegion Hauts-de-FranceRegion Nouvelle-Aquitaine [CFUG-651191]; ALF Grant, Ostergotland County Council (SE) [LIO-698411]

High-dose bisphosphonate for multiple myeloma patients might elevate risks of skeletal complications earlier than general expectations. This study aims to find incidences of atypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ), elucidate their risk factors, and suggest cut-off values for the safer dosing of high-dose bisphosphonate treatment. By using the clinical data warehouse of a single institute, retrospective cohort data of multiple myeloma-diagnosed patients with high-dose bisphosphonate (pamidronate or zoledronate) treatment from 2009 to 2019 was extracted. Among 644 patients, the incidence of prominent AFF requiring surgery was 0.93% (6/644) and MRONJ was diagnosed in 11.8% (76/644) of the study population. For both AFF and MRONJ, the total potency-weighted sum of total dose per body weight (OR = 1.010, p = 0.005) were significant on logistic regression. Cutoffs of the potency-weighted total dose (mg) per body weight (kg) for AFF and MRONJ were 77.00 and 57.70 mg/kg, respectively. After roughly one year of treatment with high-dose zoledronate (about four years for pamidronate), an earlier thorough re-evaluation of skeletal complications should be taken. Body weight adjustments for accumulative dose calculation in terms of permissible dosing should be taken into consideration.

Aims The incidence of atypical femoral fractures (AFFs) continues to increase. However, there are currently few long-term studies on the complications of AFFs and factors affecting them. Therefore, we attempted to investigate the outcomes, complications, and risk factors for complication through mid-term follow-up of more than three years. Methods From January 2003 to January 2016, 305 patients who underwent surgery for AFFs at six hospitals were enrolled. After exclusion, a total of 147 patients were included with a mean age of 71.6 years (48 to 89) and 146 of whom were female. We retrospectively evaluated medical records, and reviewed radiographs to investigate the fracture site, femur bowing angle, presence of delayed union or nonunion, contralateral AFFs, and peri-implant fracture. A statistical analysis was performed to identify the significance of associated factors. Results The mean follow-up period was 70.2 months (36 to 191). There were 146 AFFs (99.3%) in female patients and the mean age was 71.6 years (48 to 89). The AFFs were located in the subtrochanter and shaft in 52 cases (35.4%) and 95 (64.6%), respectively. The preoperative mean anterior/lateral femoral bowing angles were 10.5° (SD 5.7°)/6.1° (SD 6.2°). The postoperative mean anterior/lateral bowing values were changed by 8.7° (SD 5.4°)/4.6° (SD 5.9°). Bisphosphonates had been used contemporarily in 115 AFFs (78.2%) for a mean of 52.4 months (1 to 204; SD 45.5) preoperatively. Nailing was performed in 133 AFFs (90.5%), and union was obtained at a mean of 23.6 weeks (7 to 85). Delayed union occurred in 41 (27.9%), and nonunion occurred in 13 (8.8%). Contralateral AFF occurred in 79 patients (53.7%), and the use of a bisphosphonate significantly influenced the occurrence of contralateral AFFs (p = 0.019). Peri-implant fractures occurred in a total of 13 patients (8.8%), and a significant increase was observed in cases with plating (p = 0.021) and high grade of postoperative anterolateral bowing (p = 0.044). Conclusion The use of a bisphosphonate was found to be a risk factor for contralateral AFF, and high-grade postoperative anterolateral bowing and plate fixation significantly increased the occurrence of peri-implant fractures. Long-term follow-up studies on the bilaterality of AFFs and peri-implant fractures are warranted. Cite this article: Bone Joint J 2021;103-B(11):1648–1655.

The long-term, continuous use of bisphosphonates (beyond 5 years) is not wholly without risk. Atypical femoral fracture is an uncommon but potentially very serious adverse event associated with the long-term use of bisphosphonates. Here we consider the complexities of long-term bisphosphonate prescribing, particularly in those that are low risk of osteoporotic fracture, wherein the duration of therapy should be reviewed regularly with individualised risk assessment to ensure the duration of treatment is appropriate.

Bisphosphonates are common treatment for osteoporosis. Among patients admitted with hip fracture, atypical femoral fractures (AFF) were more prevalent in those who were treated with Bisphosphonates for five or more years. Five years of Bisphosphonates treatment may signify an increased risk for AFF, though the absolute risk remains very low. Atypical femoral fractures (AFF) are a rare complication of bisphosphonate (BP) treatment. We evaluated the correlation between BP exposure and AFF risk among hip fracture patients. This retrospective nested case–control study included patients over age 50 years, operated for osteoporotic hip fracture between July 2014 and November 2018, who attended our Fracture Liaison Service. We classified fracture radiographs and compared demographic, clinical, biochemical, and drug purchase data between patients with AFF and those with typical osteoporotic hip fracture (controls). To correct for the younger age of patients with AFF, we matched each case (AFF) with three controls according to age ( $$\pm$$ 1 year) and sex and performed a conditional logistic regression model. Of 989 patients, 31 (3%) had AFF. Patients with AFF were younger than those with inter-trochanteric fractures (mean ± SD: 72.3 ± 10.3 vs. 80.2 ± 9.6 years, p

Stress fractures are encountered commonly in clinical practice. Many features of stress fractures are in common, but the differences depend on the condition of the underlying bone. The clinician should approach according to the type of stress fracture. We report a 71-year-old female patient with osteoporosis, who had been taking prolonged bisphosphonate therapy and a single dose denosumab, sustained bilateral atypical femoral fractures (AFF) eight months apart., Stres kırıklarına klinik pratikte sıkça rastlanılmaktadır. Stres kırıklarının birçok özelliği ortaktır, ancak altta yatan kemiğin durumuna bağlı olarak farklılıklar vardır. Klinisyen stres kırığı tipine göre yaklaşımda bulunmalıdır. Bu makalede uzun süreli bifosfonat tedavisi ve tek doz denosumab alan, sekiz ay arayla bilateral atipik femoral kırığı gelişmiş 71 yaşında osteoporozlu bir kadın hastayı sunuyoruz.

Aims Currently, periprosthetic fractures are excluded from the American Society for Bone and Mineral Research (ASBMR) definition of atypical femoral fracture (AFFs). This study aims to report on a series of periprosthetic femoral fractures (PFFs) that otherwise meet the criteria for AFFs. Secondary aims were to identify predictors of periprosthetic atypical femoral fractures (PAFFs) and quantify the complications of treatment. Patients and Methods This was a retrospective case control study of consecutive patients with periprosthetic femoral fractures between 2007 and 2017. Two observers identified 16 PAFF cases (mean age 73.9 years (44 to 88), 14 female patients) and 17 typical periprosthetic fractures in patients on bisphosphonate therapy as controls (mean age 80.7 years (60 to 86, 13 female patients). Univariate and multivariate analysis was performed to identify predictors of PAFF. Management and complications were recorded. Results Interobserver agreement for the PAFF classification was excellent (kappa = 0.944; p < 0.001). On univariate analysis compared with controls, patients with PAFFs had higher mean body mass indices (28.6 kg/m2 (sd 8.9) vs 21.5 kg/m2 (sd 3.3); p = 0.009), longer durations of bisphosphonate therapy (median 5.5 years (IQR 3.2 to 10.6) vs 2.4 years (IQR 1.0 to 6.4); p = 0.04), and were less likely to be on alendronate (50% vs 94%; p = 0.02) with an indication of secondary osteoporosis (19% vs 0%; p = 0.049). Duration of bisphosphonate therapy was an independent predictor of PAFF on multivariate analysis (R2 = 0.733; p = 0.05). Following primary fracture management, complication rates were higher in PAFFs (9/16, 56%) than controls (5/17, 29%; p = 0.178) with a relative risk of any complication following PAFF of 1.71 (95% confidence interval (CI) 0.77 to 3.8) and of reoperation 2.56 (95% CI 1.3 to 5.2). Conclusion AFFs do occur in association with prostheses. Longer duration of bisphosphonate therapy is an independent predictor of PAFF. Complication rates are higher following PAFFs compared with typical PFFs, particularly of reoperation and infection. Cite this article: Bone Joint J 2019;101-B:1285–1291

Bisphosphonates (BPs) are first-line drugs for the treatment of osteoporotic fractures, but long-term use of BP reduces bone turnover and is associated with atypical femur fractures (AFFs). Additionally, BP treatment may cause delayed fracture healing or nonunion, which makes AFF treatment difficult. The incidence of AFF is generally low. In fact, there are only a few clinical reports of AFF and there is no controlled study on AFF treatment. Herein, we report a case of multiple osteoporotic fractures. After 5 years of BP treatment, left and right AFFs occurred within 2 years. The fracture types and surgical operations were the same, but the level of bone metabolism and drug treatment were different. The right AFF healed well following teriparatide initiation compared with non-healed left AFF with BP continuation; thus, our case can be considered a self-controlled study. Furthermore, we have reviewed the diagnosis and treatment of this case in detail and analyzed and investigated the potential causes of the different outcomes of AFFs between the two sides to inform the clinical treatment of atypical fractures. Mini Abstract We report a case of bilateral AFFs. The surgical treatments were the same, but the final treatment outcomes were different with or without teriparatide treatment. We investigated the potential causes of the different outcomes of AFFs between the two sides to inform the clinical treatment of AFFs.

An atypical femoral fracture (AFF) is a rare complication associated with excessive inhibition of osteoclast expression during treatment of osteoporosis. We herein describe a patient who had been treated with alendronate for more than 10 years and subsequently developed an AFF that healed after treatment with vitamin K2 (VK2). We also discuss the potential beneficial effects of VK2 on the healing of AFFs. A 48-year-old Asian man with secondary osteoporosis was treated with alendronate for more than 10 years. The patient underwent surgical treatment for a complete AFF of the right femur. Six months postoperatively, he complained of pain in his left thigh. X-ray examination revealed an incomplete AFF of the left femoral shaft. He was then treated with VK2. After 4 months of VK2 treatment, the patient reported that the pain in his left thigh had decreased, and follow-up X-ray examination demonstrated healing of the left AFF line. This case report indicates that VK2 may be a potential direction for pharmacological treatment of AFFs in future research.

Purpose of reviewThis review describes the rational for bisphosphonate holidays, summaries key evidence to support the concept, and provides a roadmap to help clinicians initiate, monitor, and discontinue a bisphosphonate drug holiday.Recent findingsRandomized trials and data from large observational studies are available to determine the short and long-term bisphosphonate benefits (prevention of fracture) and harms (principally atypical femoral fractures and osteonecrosis of the jaw). Mounting evidence points towards a causal relationship between bisphosphonate use and AFF and ONJ, particularly with > 5years of use. Multiple studies now confirm the risk of AFF falls rapidly after BPs are discontinued. Osteoporosis patients without previous hip, vertebral, or multiple non-spine fractures who are successfully treated with oral bisphosphonates for 5years (3years if intravenous), should be offered a 3-5year drug holiday, particularly if hip BMD T-score is > - 2.5. Bisphosphonates should only be continued beyond 10years (6years if parenteral) in patients at very high risk of fracture.

Bisphosphonates are a class of drugs used as the mainstay of treatment for osteoporosis. Bisphosphonates function by binding to hydroxyapatite, and subsequently targeting osteoclasts by altering their ability to resorb and remodel bone. Whilst aiming to reduce the risk of fragility fractures, bisphosphonates have been associated with atypical insufficiency fractures, specifically in the femur. Atypical femoral fractures occur distal to the lesser trochanter, until the supracondylar flare. There are a number of the differing clinical and radiological features between atypical femoral fractures and osteoporotic femoral fractures, indicating that there is a distinct difference in the respective underlying pathophysiology. At the point of presentation of an atypical femoral fracture, bisphosphonate should be discontinued. This is due to the proposed inhibition of osteoclasts and apoptosis, resulting in impaired callus healing. Conservative management consists primarily of cessation of bisphosphonate therapy and partial weightbearing activity. Nutritional deficiencies should be investigated and appropriately corrected, most notably dietary calcium and vitamin D. Currently there is no established treatment guidelines for either complete or incomplete fractures. There is agreement in the literature that nonoperative management of bisphosphonate-associated femoral fractures conveys poor outcomes. Currently, the favoured methods of surgical fixation are cephalomedullary nailing and plate fixation. Newer techniques advocate the use of both modalities as it gives the plate advantage of best reducing the fracture and compressing the lateral cortex, with the support of the intramedullary nail to stabilise an atypical fracture with increased ability to load-share, and a reduced bending moment across the fracture site. The evidence suggests that cephalomedullary nailing of the fracture has lower revision rates. However, it is important to appreciate that the anatomical location and patient factors may not always allow for this. Although causation between bisphosphonates and atypical fractures is yet to be demonstrated, there is a growing evidence base to suggest a higher incidence to atypical femoral fractures in patients who take bisphosphonates. As we encounter a growing co-morbid elderly population, the prevalence of this fracture-type will likely increase. Therefore, it is imperative clinicians continue to be attentive of atypical femoral fractures and treat them effectively.

Purpose: To introduce the principles and procedure of percutaneous elastic intramedullary nailing (PEIN) as a treatment for symptomatic incomplete atypical femoral fracture (SIAFF). Methods: From October 2014 to April 2019, 6 cases of SIAFF were treated with PEIN. Two pre-bent 4-mm stainless-steel nails were used to apply compressive force to the fracture site. The antegrade method was used for proximal fractures and the retrograde method for middle and distal femoral fractures. The femoral bowing angle in the coronal and sagittal planes, and the time required for callus formation and union, were evaluated on plain radiographs in both planes. Thigh pain, tenderness, and complications were also assessed. Results: The mean operating time was 65.00 ± 22.64 min. No case progressed to complete atypical fracture. In one case, fracture occurred around the point of nail entry after the patient fell from a chair on postoperative day 7. The incomplete fracture lines were united in 5 cases, after excluding one case with a complication. The time taken to confirm endocortical callus formation, fracture line disappearance, and clinical union was 2.11 ± 0.53, 6.45 ± 4.10, and 6.45 ± 3.65 months, respectively. Conclusions: PEIN is a quick, simple but effective treatment for SIAFF that considers the fracture mechanism and is applicable to cases with severe femoral bowing. Level of evidence: Level IV, case series.

Introduction Long-term use of bisphosphonates (BPs) is associated with Atypical Femoral Fracture (AFF). Theoretically, periprosthetic femoral fractures (PFF) should be excluded from the diagnosis of AFF. However, recently several studies reported the occurrence of PPFs around a hip arthroplasty presenting features of an AFF. The present study describes the characteristics of Atypical Periprosthetic Femoral Fracture (APFF) and evaluates the effectiveness of their management through a PRISMA compliant systematic review of the published case reports and series. Materials and methods A literature search was performed using “periprosthetic fracture” and “atypical femoral fracture” as keywords. Patients demographics, drug use, clinical and imaging characteristics, stem fixation and classification, management strategies for APFF and patients’ outcomes, were also collected. Results The present review included and analysed 17 patients from 12 studies. All APFFs occurred in females with a mean age of 75.9 years of age (range 43–87). In 11 patients, APFFs occurred around an uncemented stem, and in 6 around a cemented stem. Ten fractures were incomplete, and 7 complete. Conservative management was effective in 4 of 10 patients with incomplete fracture, while all patients with complete fractures underwent open reduction and internal fixation. A fracture non-union was observed in 5 patients and further surgery was required. Discussions APFFs share several clinical and imaging characteristics with AFF. An appropriate and early diagnosis may allow to improve the outcome of these fractures, the management of which should be based on the same principles of that of AFFs. Conclusions Considering the low quality of published articles and the heterogeneity of the treatment used, a clear recommendation of the most appropriate treatment cannot be formulated.

Atypical femoral fractures are often attributed to the use of anti-resorptive medications such as bisphosphonates (BP). Whilst they have proven effects on fragility fracture prevention, clinical and laboratory evidence is evolving linking BP-related suppression of bone remodelling to the development of atypical stress-related sub-trochanteric fractures (Shane et al. in JBMR 29:1-23, 2014; Odvina et al. in JCEM 90:1294-301, 2005; Durchschlag et al. in JBMR 21(10):1581-1590, 2006; Donnelly et al. in JBMR 27:672-678, 2012; Mashiba et al. in Bone 28(5):524-531, 2001; Dell et al. in JBMR 27(12):2544-2550, 2012; Black et al. in Lancet 348:1535-1541, 1996; Black et al. in NEJM 356:1809-1822, 2007; Black et al. in JAMA 296:2927-2938, 2006; Schwartz et al. in JBMR 25:976-82, 2010). Injuries may present asymptomatically or with prodromal thigh pain and most can be successfully managed with cephalomedullary nailing and discontinuation of BP therapy. Such injuries exhibit a prolonged time to fracture union with high rates of non-union and metal-work failure when compared to typical subtrochanteric osteoporotic femoral fractures. Despite emerging literature on AFFs, their management continues to pose a challenge to the orthopaedic and extended multi-disciplinary team. The purpose of this review includes evaluation of the current evidence supporting the management of AFFs, clinical and radiological features associated with their presentation and a review of reported surgical strategies to treat and prevent these devastating injures.

A female patient with systemic lupus erythematosus developed an atypical femoral fracture of the left femur after 5 years of glucocorticoid and alendronate therapy. We performed intramedullary nailing. However, 1 week later, we performed a revision surgery using a locking plate and an iliac bone graft because of displacement at the fracture site. At this stage, alendronate was discontinued and daily teriparatide was introduced and continued for 24 months. Twenty months after the revision surgery, a re-revision surgery was performed with an iliac bone graft because of breakage of the locking plate and fracture non-union. Fracture healing was eventually obtained 15 months after the re-revision surgery. Biopsies of the ilium before the treatment and 20 months after daily teriparatide treatment were evaluated. The histology revealed that proliferating osteoid and cuboidal osteoblasts were detected around the osteoid tissue after teriparatide treatment. Bone histomorphometry findings showed that bone volume parameters and osteoid parameters prominently increased with the teriparatide treatment, but not bone resorption parameters. Laboratory findings revealed the elevation of bone-specific alkaline phosphatase (24 U/L at 7 months) compared to its pre-teriparatide level (8.1 U/L) and increased bone mineral density of the hip (from -0.2 to 0.0 in

Medication-related osteonecrosis of the jaw (MRONJ) is associated with many drugs, including bisphosphonates (BPs). BPs are associated with atypical femoral fractures and osteonecrosis of the external auditory canal. Thus, many drugs are reported to cause adverse effects on bone. This study aimed to investigate the effects of drugs and patient backgrounds regarding osteonecrosis-related side effects, including MRONJ. This study used a large voluntary reporting database, namely, the Japanese Adverse Drug Event Report database. First, we searched for risk factors related to MRONJ using volcano plots and logistic regression analysis. Next, we searched for bone-necrosis-related side effects using principal component and cluster analysis. Factors that were significantly associated with MRONJ included eight types of BPs and denosumab, prednisolone, sunitinib, eldecalcitol, raloxifene, letrozole, doxifluridine, exemestane, radium chloride, medroxyprogesterone, female, elderly, and short stature. Furthermore, antiresorptive agents (i.e., BPs and denosumab) tended to induce MRONJ and atypical femoral fractures by affecting osteoclasts. We believe these findings will help medical personnel manage the side effects of many medications.

Case Three women with unique subtrochanteric femoral fracture occurring at the medial cortex of the femur are presented. One patient had been on drug holiday for the past 2 years after 3 years of risedronate use; the other patients had been taking alendronate for osteoporosis for 4 years and 20 years without drug holiday. Conclusion The fractures met all major criteria for the revised case definition of atypical femoral fracture (AFF) provided by the American Society of Bone and Mineral Research task force except for the location. Hence, we report 3 cases of AFFs developing in the subtrochanteric medial femoral cortex.

Multiple myeloma (MM) is a plasma cell disorder with related organ dysfunction, including hypercalcemia, renal insufficiency, anemia, and bone disease. Osteolytic bone lesions that result in pain and pathologic fractures are a major source of morbidity and the use of bisphosphonates is generally safe and effective treatment in reducing myeloma-related skeletal fractures and associated morbidity. We present a 73-year-old African American woman with MM in remission and on intravenous (IV) bisphosphonate therapy in the past five years who reported gradually worsening bilateral thigh pain of six months duration. A bone survey showed no neoplastic focus, and bilateral hip X-rays showed incomplete insufficiency stress fractures with characteristic features suspicious for bisphosphonate-related atypical femoral fracture (AFF). Increasingly reported in the literature, bilateral AFF is a unique and serious adverse effect for patients on bisphosphonates. Our case illustrates the distinct challenges in managing a patient with MM on long-term bisphosphonate therapy who suffered bilateral atypical femoral fractures, an uncommon presentation of a relatively rare phenomenon. It is important to balance the established benefits of bisphosphonate therapy with potential fracture risk and be particularly vigilant about adverse effect monitoring and timely intervention.

Highlights • Oncologic use of bone-modifying agents (BMAs) has been dramatically increasing. • Long-term BMA use is a risk factor for atypical femoral fracture (AFF). • We reviewed 721 patients with bone metastasis in a Japanese university hospital. • The incidence of critical AFF (n = 5) was 0.9% among 529 BMA-exposed patients. • The incidence was 6.6% when limited to breast cancer patients alone., Background As the life expectancy of cancer-bearing patients has increased, more patients with bone metastasis are receiving long-term treatment with bone-modifying agents (BMAs; e.g., zoledronate and denosumab), which are a risk factor for developing atypical femoral fracture (AFF). In this study, we surveyed the risk of iatrogenic AFF using a clinical database on treatment of bone metastasis in the past 10 years. Methods From April 2011 through October 2019, 721 patients with bone metastasis (436 men, 285 women; mean age, 65.7 ± 12.4 years) were registered under the bone metastasis consultation system, which has been run by orthopaedic surgeons since 2011, at a university hospital in Japan. We retrospectively reviewed the database to identify patients who had received BMAs for treatment of bone metastasis, and we investigated the incidence of critical skeletal-related events (including AFF) which required surgical interventions by orthopaedic surgeons. Results BMAs were administered to 529 patients (73.4%). Orthopaedic surgery for the treatment of skeletal-related events was performed in 36 patients (5.0%): femur, 13 (1.8%); others, 23 (3.2%). Eight AFFs in 5 patients (breast cancer, n = 4; prostate cancer, n = 1), who all had prior exposure to zoledronate or denosumab before onset of AFF, were treated with internal fixation using intramedullary nailing. In 192 patients with no BMA exposure, critical (surgically treated) AFF was not detected. In summary, the incidence of critical AFF was 0.9% among 529 patients who received BMAs for treatment of bone metastasis, and the incidence was 6.6% when limited to breast cancer patients (4 of 61). Conclusion In treatment of bone metastasis using BMAs, especially for breast cancer patients, attention should be paid to the risk of developing AFFs. Routine radiographic screening for AFF might be necessary in patients with prolonged BMA use for bone metastasis, even if asymptomatic. This report alerts all physicians and surgeons involved in the management of cancer patients, especially those with bone metastasis, regarding the risk of AFF following BMA use.

Atypical Femoral Fractures (AFF) are low energy femoral fractures associated with long-term bisphosphonate therapy. Our aim was to evaluate the cortical bone parameters and biomechanical proprieties by high-resolution peripheral quantitative computed tomography (HR-pQCT) at distal tibia and radius and by iliac crest histomorphometry, 6-12 months after AFF. Twelve patients with AFF were evaluated. Cortical volumetric bone mineral density (Ct.vBMD), cortical thickness (Ct.Th), cortical porosity (Ct.Po), Stiffness (S) and failure load (F.Load) were assessed by HR-pQCT. Histomorphometry of transiliac bone biopsy evaluated Ct.Th, Ct.Po and bone remodeling.

There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre-existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

Introduction:Long-term use of bisphosphonates (BPs) has been associated with a specific type of tensile side femoral stress fracture known as Atypical Femoral Fracture (AFF). Theoretically periprosthetic femoral fractures (PFF) should be excluded from the diagnosis of AFF. However, emerging evidence correlates prolonged BPs use with the occurrence of a type of PFF with an atypical pattern (atypical PFF, APFF). The aim of the present study is to report 3 cases of APFF treated at a single centre.Methods:Clinical and radiographic records of PFF that occurred between January 2016 and August 2018 were retrospectively reviewed. All patients meeting the American Society for Bone and Mineral Research (ASBMR) criteria for definition of PFF were included. Management strategies for APFF and patient outcomes, including fracture healing and hip function (assessed by the Oxford Hip Score [OHS]) were collected.Results:3 patients in the study period were identified as APFF (1 incomplete, 2 complete). All patients were females with a mean age of 83.3 years. All patients were treated with lateral plating. The application of a contralateral strut allograft resulted in fracture healing in cases of complete fractures. Mean OHS at final follow-up was 34.3.Conclusions:Despite occurring around a hip stem like PFF, APFF had peculiar clinical and radiographic features, making them more similar to AFF. Therefore, the orthopaedic surgeon should also consider the natural history and healing problems associated with AFF prior in order to choose the most appropriate management for APFF.

Objective: Increasing numbers of reports have described atypical femoral fracture (AFF) in patients being treated with oral bone resorption inhibitors, such as bisphosphonates. Most AFF patients undergo surgical treatment. However, there is little information about post-operative rehabilitation and patient activity levels after surgery for such fractures. Here we report the outcome of surgical treatment and postoperative rehabilitation for AFF at a single center in Japan. Methods: We retrospectively reviewed 13 patients (14 AFFs) who underwent surgery at Nagano Matsushiro General Hospital between January 2013 and December 2016. The clinical backgrounds of the patients were evaluated. Results: The patients comprised 1 man (1 AFF) and 12 women (13 AFFs). The mean age at surgery was 77.7±7.1 years (mean±SD). Before AFF occurred, 12 of the 13 patients had used bisphosphonates for osteoporosis. An intramedullary nail was inserted in all patients. Partial weight bearing was started on average 2 weeks after surgery, and full weight-bearing gait was permitted on average 3 weeks after surgery. The average time to bone union was 9.9±6.1 months, ranging from 3 to 23 months. None of the patients required additional surgical procedures, including revision surgery for pseudoarthrosis (nonunion) or delayed union. Before AFF, 12 patients walked independently, and 1 patient walked with a single cane. At the final follow-up (mean duration: 34.5±15.7 months), 8 patients could walk independently and 5 patients walked with a single cane. Conclusions: We recognized that rigid fixation for AFF supported early weight-bearing gait after surgery.

Atypical femoral fractures (AFF) are more difficult to treat than typical femoral fractures; they require strong fixation and good reduction. Intramedullary (IM) nailing is the first option for the treatment of complete AFF; however, there are few reports comparing IM nailing and extramedullary fixation. Moreover, there are no reports on the outcomes of bilateral atypical subtrochanteric femoral fractures treated with an IM nail on one side and a compression hip screw (CHS) on the other. We report the case of a 69-year-old woman who had been on risedronate sodium once a month since she was 58 years old. She reportedly felt pain in both her thighs due to an undiagnosed cause. Six months later, she fell and was diagnosed with bilateral complete atypical femoral subtrochanteric fractures (right side: Seinsheimer type IIC; left side: Seinsheimer type IIA). Four days later, she underwent CHS on the right side and IM nailing after open reduction surgery on the left. The reduction was successful. The left side healed 6 months after surgery, but the right side healed only after 14 months, despite assistance with low-intensity pulsed ultrasound. In atypical femoral subtrochanteric fractures, good reduction is important for healing, but, in this case, the CHS side healed slowly despite achievement of good reduction because of the difference in the fixation force between IM nailing and CHS, in addition to a probable occurrence of severely suppressed bone turnover (SSBT). Furthermore, reaming was not done on the CHS side, which may have contributed to the delay in bony union. IM nailing is the first option for atypical femoral subtrochanteric fractures because of faster union and lower reoperation rate than extramedullary fixation. Based on our findings, we recommend IM nailing as the first option for atypical femoral subtrochanteric fractures when good reduction can be achieved.

Bisphosphonates are widely used for treatment of osteoporosis and its use is increasing in geriatric population. Atypical femoral fractures are associated with bisphosphonate therapy. We report an unusual case of femoral shaft fracture following bisphosphonate therapy where the femoral canal of the proximal and distal fracture fragments was blocked and its management.

Objective: Excessive curvature of the femur has been considered to be one of the factors associated with atypical femoral fracture (AFF). Although we clarified that femoral curvature was markedly influenced by a low vitamin D level, very few studies have been conducted on the direct relationship between AFF and a serum low level of vitamin D. Therefore, we compared the serum vitamin D level between AFF and osteoporosis patients. Methods: A total of 48 consecutive AFFs in 36 Japanese patients were retrospectively reviewed using the medical records, and 12 consecutive AFFs in 9 patients (AFF group) whose 25-hydroxyvitamin D (25(OH)D) levels were examined were included in this study. As a non-AFF control group, 45 consecutive age-matched female patients with osteoporosis (Osteoporosis group) were enrolled. We compared some laboratory examination items, the bone mineral density, and curvature of the femur. Results: When univariate logistic regression analysis was performed to compare the 2 groups, Ca levels and lateral and anterior curvatures in the AFF group were significantly greater than in the Osteoporosis group (P < 0.05, P < 0.01, and P < 0.01, respectively), and the 25(OH)D level in the AFF group was significantly lower than in the Osteoporosis group (P < 0.01). We used discriminant analysis of these extracted items to exclude the mutual influence of factors and identify factors closely associated with AFF, and 25(OH)D, Ca and anterior curvature were identified as significant items to differentiate these diseases (P < 0.05, P < 0.01, and P < 0.01, respectively). Conclusion: AFF patients showed low vitamin D levels and marked femoral curvatures.

Antiresorptives such as bisphosphonates (BP) and denosumab are commonly used osteoporosis treatments that are effective in preventing osteoporotic fractures by suppressing bone turnover. Although these treatments reduce fracture risk, their long-term use has been associated with atypical femoral fracture (AFF), a rare potential side effect. Despite its rare occurrence, AFF has had a disproportionately significant adverse impact on society due to its severe outcomes such as loss of function and delayed healing. These severe outcomes have led to the decrease in the use and prescription of osteoporosis treatment drugs due to patient anxiety and clinician reluctance. This creates the risk for increasing osteoporotic fracture rates in the population. The existing information on the pathogenesis of AFF primarily relies on retrospective observational studies. However, these studies do not explain the underlying mechanisms that contribute to AFF, and therefore the mechanistic origins of AFF are still poorly understood. The purpose of this review is to outline the current state of knowledge of the mechanical mechanisms of AFF. The review focuses on three major potential mechanical mechanisms of AFF based on the current literature which are (1) macroscale femoral geometry which influences the stress/strain distribution in the femur under loading; (2) bone matrix composition, potentially altered by long-term remodeling suppression by BPs, which directly influences the material properties of bone and its mechanical behavior; and (3) microstructure, potentially altered by long-term remodeling suppression by BPs, which impacts fracture resistance through interaction with crack propagation. In addition, this review presents the critical knowledge gaps in understanding AFF and also discusses approaches to closing the knowledge gap in understanding the underlying mechanisms of AFF.

Although atypical femoral fracture (AFF) occurs more frequently in patients taking bisphosphonates and longer treatment is associated with higher risk, the causal relationship between AFF and bisphosphonates has not been established. Most patients with AFF have osteoporosis that is being treated with bisphosphonates, but we are not aware of any reports regarding the areal bone mineral density (aBMD) and discordance between the T-scores of the femur and spine in such patients. We investigated the prevalence of aBMD discordance and the characteristics of patients with AFF.Medical records for 63 consecutive patients treated for AFF were retrospectively evaluated, and 48 patients, all female, were eligible for the study. The average age at the time of fracture was 73.0 years, the average duration of bisphosphonate use was 68.5 months, and the average presumed age at bisphosphonate initiation was 67.2 years. We evaluated the prevalence of discordance, defined as a difference between the T-score categories of the femur and spine in the same individual as well as demographic differences between the discordance and concordance groups. We also compared the prevalence of discordance in patients with AFF with that in 114 female patients with intertrochanteric femoral fracture (ITFF).T-score concordance, minor discordance, and major discordance were seen in 14 (29%), 32 (67%), and 2 (4%) of the patients with AFF, respectively. The prevalence of discordance was significantly higher in those with AFF (71%) than in those with ITFF (23%) (p0.001). The average age at bisphosphonate initiation in the AFF group was lower in the discordance group (65.7 years) than in the concordance group (70.7 years) (p = 0.04).The prevalence of T-score discordance between the hip and lumbar spine was relatively high in patients with AFF, and the presumed age at the initiation of bisphosphonate therapy was younger in patients with discordant T-scores in this study.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Atypical femoral fracture (AFF) has emerged as one of the most concerning issues in the management of osteoporosis. However, the surgical and other treatment methods for AFF have not been f...

WOS: 000410750200011 Although the overall safety profile of bisphosphonates (BP) is favorable, adverse effects associated with long-term use have came up during recent years. In this report, a case of bilateral incomplete atypical femoral fracture (AFF) due to prolonged BP use was presented. A 69-year-old patient, who has been in surgical menopause for 20 years and was started on BP following vertebral fracture almost 10 years ago, was admitted with thigh pain, which was increased two weeks ago. On physical examination, she had antalgic gait, increased thoracic kyphosis and tenderness to percussion over the thoracolumbar region. Lateral cortical thickness in the subtrochanteric region of both femurs and cortical radiolucency on the left femur were observed on plain radiography. Loss of height in L3 and L4 vertebrae was detected on vertebral radiography. Serum 25-hydroxy vitamin D [25(OH) D], parathyroid hormone, alkaline phosphatase and calcium levels, along with osteoporosis markers were all within the normal ranges. As the patient was diagnosed with AFF, BP therapy was terminated and vitamin D-calcium supplementation was continued. Since she did not have severe pain, conservative management (limited weight bearing, using a walking stick) was recommended for 3 months. Teriparatide therapy was started and she was discharged with recommendations. AFF, which is a rare disorder, should be kept in mind in patients on long-term BP treatment who are admitted with thigh pain and, necessary interventions should be tailored before the occurrence of complete fracture.

Altres ajuts: The present study was supported by the Allgemeine Unfallversicherungsanstalt (AUVA), research funds of the Austrian workers compensation board, and the Wiener Gebietskrankenkasse (WGKK), Viennese sickness insurance funds. Long-term antiresorptives use has been linked to atypical subtrochanteric and diaphyseal femoral fractures (AFF), the pathogenesis of which is still unknown. In the present case report we present the results of analysis of bone chips from a 74-year old female patient that had been on alendronate, ibandronate and denosumab treatment, and who sustained an atypical femoral fracture, by histology, quantitative backscattered electron imaging, and Raman spectroscopic analysis. The results indicate ongoing osteoclastic resorption, but also several abnormalities: 1) an altered arrangement of osteons; 2) impaired mineralization; 3) the presence of pyrophosphate, which might contribute to the impaired mineralization evident in the present case. Taken together, these changes may contribute to the focally reduced bone strength of this patient.

BACKGROUND Intramedullary nailing is the treatment of choice for atypical femoral fractures. However, several problems, such as iatrogenic fracture and medial gap opening, can occur during intramedullary nailing when atypical femoral fractures are associated with excessive anterolateral bowing. To overcome these problems, we have developed a new grading system for anterolateral femoral bowing and a new technique for intramedullary nailing. The core of this new technique is matching the anterior curvature of the femoral nail with the anterolateral bowing of the femur when the nail passes the apex of the curvature, by rotating the nail externally. METHODS From January 2005 through March 2016, 24 female patients (30 cases) who underwent a surgical procedure for atypical femoral fracture with anterolateral bowing at 2 institutes were evaluated. The postoperative outcomes (anterolateral bowing grade, anterior and lateral bowing angles, medial gap and posterior gap of the fracture site, iatrogenic fracture, and time to initial medial callus formation and osseous union) were compared between the new technique (18 cases) and the conventional technique (12 cases). RESULTS With regard to the reliability of the new grading system, the interobserver and intraobserver reliability of the new grading system demonstrated an almost perfect agreement (kappainter = 0.893, kappaintra = 0.883). For patients with complete fractures, the differences between the preoperative and postoperative anterior and lateral bowing angles were significantly less (p = 0.013 for both) in the new technique group. The medial and posterior gaps at the fracture site were also significantly less in the new technique group (p = 0.013 for the medial gaps and p = 0.022 for the posterior gaps). Iatrogenic fracture occurred only in the conventional technique group, affecting 2 cases. The time to initial medial callus formation was significantly shorter (p = 0.033) in the new technique group compared with the conventional technique group. CONCLUSIONS Our new grading system for anterolateral femoral bowing is convenient and reliable. Furthermore, the new intramedullary nailing technique with the current intramedullary nail system is appropriate for the repair of atypical femoral fractures with excessive anterolateral bowing. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.