Long-term Bisphosphonate Use Research Articles

Intérêt de l’avivement des extrémités osseuses à ciel ouvert associé à un enclouage dans les fractures secondaires à l’utilisation des biphosphonates au long cours

BackgroundDelayed unions are quite common in the treatment of atypical femur fractures, which are thought to result from the long-term use of bisphosphonates. The effects of interventions for sclerotic tissue on the fracture line in atypical femoral fractures are not fully known. For this reason, we compared the results of patients with atypical femoral fractures treated by closed intramedullary nailing to patients treated by open surgery accompanied with interventions for their sclerotic bone ends, aiming to answer: In the treatment of atypical femoral fractures, do bone-end interventions have a positive effect on the radiological union rate and radiological union time? Do bone-end interventions influence complication rates in the treatment of atypical femoral fractures? HypothesisBone-end interventions provide a faster and higher rate of union compared to closed intramedullary nailing and result in fewer complications in atypical femoral fractures. Patients and methodsA total of 32 patients who met the inclusion criteria and had atypical femoral fractures treated by intramedullary nailing between 01/01/2012 and 12/31/2016 were reviewed. Of these, 15 fractures were treated with intramedullary nailing (Group 1), and 17 were treated with open surgery and drilling of the bone ends followed by intramedullary nailing (Group 2). Demographic data, laboratory values, radiological union times, and complications were compared between the groups. Nonunion was defined as fractures with a persistent fracture line 12 months after surgery without any sign of union. ResultsA similar rate of primary union was obtained in both groups (Group 1, 13/15 [87%]; Group 2, 16/17 [94%]; p=0.471). The mean radiological consolidation period was shorter in Group 2 (Group 1, 6.8±1.8 months; Group 2, 5.1±1.3 months; p=0.004). Nonunion rates were similar between the groups (Group 1, 1/15 [7%]; Group 2, 1/17 [6%]; p=0.927). For 1 patient in Group 1, a femoral neck fracture occurred 10 months after surgery, and a revision was performed with a long femoral stem. DiscussionIn the treatment of atypical femoral fractures with intramedullary nailing, we found that the patients who were treated with open intervention of the bone ends had similar union and complication rates to those treated with closed methods, but radiological union time was found to be shorter in the open-intervention group. Level of evidenceIII, retrospective case-control study.

Assessment the effect of the use of bisphosphonates on dental implant rehabilitation and peri-implant tissues

Background: Long-term use of bisphosphonates (BP) has been associated with the risk of BP-related osteonecrosis of the jaw (BRONJ). The number of post-menopausal women receiving BP therapy for osteoporosis continues to increase as the life expectancy increases. Dental implant rehabilitations have progressed over the years. The purpose of the present study was to evaluate the peri-implant conditions of patients taking oral or intravenous (IV) BPs. Methods: This was a retrospective study using an ORACLE database search by means of a Procedural Language/Structured Query engine. Fifty female patients with dental implant rehabilitations and taking bisphosphonates, and fifty female patients with dental implants but not taking BP were evaluated. Peri-implant health and rehabilitation conditions were collected and statistics analyzed. Results: Data analysis revealed a strong indication (p<0.01; 82.81%) of the use of bisphosphonates and absence of abscesses. Relative risk indicated 25 times more chance of a person that does not use bisphosphonates to develop abscess when compared with people using bisphosphonates. This shows that the use of bisphosphonates may play a protecting role in the patients with dental implants. Alternatively, there was a strong indication (p<0.01) of existence of association between the occurrence of mucositis and the use of bisphosphonates. Most of the cases of mucositis (94.44%) occurred in patients that used bisphosphonates while the majority of the cases where mucositis did not occur (59.76%) referred to the group being treated with bisphosphonates. Conclusion: This study revealed that there was absence of indications of significant associations between doses of bisphosphonates and the occurrence of peri-implant diseases.

Atypical stress femoral shaft fracture secondary to alendronate therapy

Bisphosphonate (BP) therapy is widely used as it remains the first-line of treatment for osteoporosis. These antiresorptive drugs inhibit osteoclast function and promote apoptosis. However, atypical stress femoral fractures occurring in the diaphysis and subtrochanteric region are linked to prolonged BP use. The risk of fracture is directly proportional to the time exposed to the treatment. Ongoing BP exposure prevents bone resorption and replacement in areas with accumulated microdamage through targeted remodeling. Therefore, long-term BP use (more than 5 years) is an important risk factor. Atypical femoral fractures remain very rare, and the benefits of BP therapy for osteoporotic fracture prevention and treatment outweigh the risk. The present report consists of a rare case of a patient with an atypical diaphyseal femoral stress fracture secondary to prolonged alendronate use.

Efficacy of bone-end intervention on fracture healing in bisphosphonate-related atypical femoral fractures

BackgroundDelayed unions are quite common in the treatment of atypical femur fractures, which are thought to result from the long-term use of bisphosphonates. The effects of interventions for sclerotic tissue on the fracture line in atypical femoral fractures are not fully known. For this reason, we compared the results of patients with atypical femoral fractures treated by closed intramedullary nailing to patients treated by open surgery accompanied with interventions for their sclerotic bone ends, aiming to answer: (1) In the treatment of atypical femoral fractures, do bone-end interventions have a positive effect on the radiological union rate and radiological union time? (2) Do bone-end interventions influence complication rates in the treatment of atypical femoral fractures? HypothesisBone-end interventions provide a faster and higher rate of union compared to closed intramedullary nailing and result in fewer complications in atypical femoral fractures. Patients and methodsA total of 32 patients who met the inclusion criteria and had atypical femoral fractures treated by intramedullary nailing between 01/01/2012 and 12/31/2016 were reviewed. Of these, 15 fractures were treated with intramedullary nailing (Group 1), and 17 were treated with open surgery and drilling of the bone ends followed by intramedullary nailing (Group 2). Demographic data, laboratory values, radiological union times, and complications were compared between the groups. Nonunion was defined as fractures with a persistent fracture line 12 months after surgery without any sign of union. ResultsA similar rate of primary union was obtained in both groups (Group 1, 13/15 [87%]; Group 2, 16/17 [94%]; p=0.471). The mean radiological consolidation period was shorter in Group 2 (Group 1, 6.8±1.8 months; Group 2, 5.1±1.3 months; p=0.004). Nonunion rates were similar between the groups (Group 1, 1/15 [7%]; Group 2, 1/17 [6%]; p=0.927). For 1 patient in Group 1, a femoral neck fracture occurred 10 months after surgery, and a revision was performed with a long femoral stem. DiscussionIn the treatment of atypical femoral fractures with intramedullary nailing, we found that the patients who were treated with open intervention of the bone ends had similar union and complication rates to those treated with closed methods, but radiological union time was found to be shorter in the open-intervention group. Level of evidenceIII, retrospective case-control study.

Temporal Trends and Factors Associated with Bisphosphonate Discontinuation and Restart.

Adverse events related to long-term use of bisphosphonates have raised interest in temporary drug discontinuation. Trends in bisphosphonate discontinuation and restart, as well factors associated with these decisions, are not fully understood at a population level. We investigated temporal trends of bisphosphonate discontinuation from 2010 to 2015 and identified factors associated with discontinuation and restart of osteoporosis therapy. Our cohort consisted of long-term bisphosphonate users identified from 2010 to 2015 Medicare data. We defined discontinuation as ≥12 months without bisphosphonate prescription claims. We used conditional logistic regression to compare factors associated with alendronate discontinuation or osteoporosis therapy restart in the 120-day period preceding discontinuation or restart referent to the 120-day preceding control periods. Among 73,800 long-term bisphosphonate users, 59,251 (80.3%) used alendronate, 6806 (9.2%) risedronate, and 7743 (10.5%) zoledronic acid, exclusively. Overall, 26,281 (35.6%) discontinued bisphosphonates for at least 12 months. Discontinuation of bisphosphonates increased from 1.7% in 2010, reaching a peak of 14% in 2012 with levels plateauing through 2015. The factors most strongly associated with discontinuation of alendronate were: benzodiazepine prescription (adjusted odds ratio [aOR] = 2.5; 95% confidence interval [CI] 2.1, 3.0), having a dual-energy X-ray absorptiometry (DXA) scan (aOR = 1.8; 95% CI 1.7, 2.0), and skilled nursing facility care utilization (aOR = 1.8; 95% CI 1.6, 2.1). The factors most strongly associated with restart of osteoporosis therapy were: having a DXA scan (aOR = 9.9; 95% CI 7.7, 12.6), sustaining a fragility fracture (aOR = 2.8; 95% CI 1.8, 4.5), and an osteoporosis or osteopenia diagnosis (aOR = 2.5; 95% CI 2.0, 3.1). Our national evaluation of bisphosphonate discontinuation showed that an increasing proportion of patients on long-term bisphosphonate therapy discontinue medications. The factors associated with discontinuation of alendronate were primarily related to worsening of overall health status, whereas traditional factors associated with worsening bone health were associated with restarting osteoporosis medication. © 2019 American Society for Bone and Mineral Research.

Potential risks of rare serious adverse effects related to long-term use of bisphosphonates: An overview of systematic reviews.

There have been concerns about a potential link between long-term use of bisphosphonates (BPs) for the treatment of osteoporosis and rare serious adverse effects, such as atypical femoral fractures. However, many reviews exist with conflicting conclusions about this issue. The aim of this overview of reviews was to systematically evaluate the risk of rare serious adverse effects of long-term use of BPs for the treatment of osteoporosis. We identified systematic reviews with meta-analyses of randomized controlled trials (RCTs) and (or) observational studies published in English or Chinese that evaluated the safety of BPs through to December 2018. The Cochrane library, PubMed, Web of Science and hand-searching of reference lists and clinical practice guidelines were electronically searched for data sources. Carcinogenicity, atypical fracture, osteonecrosis of jaw (ONJ) and fracture union time were specified as the primary outcomes. The methodological quality of each systematic review was assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) tool, and the quality of evidence for key outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. In total, 1376 potentially relevant citations were identified, of which only 8 systematic reviews with meta-analyses met the eligibility criteria. All the included reviews were published between 2012 and 2015 and documented the pooled estimates of effect size (relative risk [RR], odds ratio [OR] or hazard ratio [HR] and their 95% confidence intervals [95% CI]) for the incidence of adverse events. All included systematic reviews were of moderate or high quality. The median AMSTAR score was 7.5 (interquartile range, 5-10). However, evidence of the key outcomes was mainly of very low or moderate quality. BP treatment only increased the risk of atypical fracture and ONJ, and prolonged union time compared with placebo or other anti-osteoporosis drugs (P＜.05). This study indicated that long-term use of BPs could increase the risk of rare serious adverse effects, but the relationship between long-term use of BPs and carcinogenicity was often uncertain. Therefore, high-quality research and more complete inclusion criteria are needed.

Letter to the Editor: “Comparison of Teriparatide and Denosumab in Patients Switching from Long-Term Bisphosphonate Use”

Letter to the Editor: “Comparison of Teriparatide and Denosumab in Patients Switching from Long-Term Bisphosphonate Use”

High bisphosphonate treatment rates and the prevalence of atypical femoral fractures in patients with systematic lupus erythematosus: a single-center retrospective study performed in Japan

Treatment of systemic lupus erythematosus (SLE) often continues with moderate-to-low doses of glucocorticoids for the long term. Bisphosphonates aid in the prevention and management of glucocorticoid-induced osteoporosis (GIOP). However, long-term use of bisphosphonates increases the relative risk of atypical femoral fracture (AFF) and the incidence is typically 16 or 113 per 100,000 person-years in patients treated with bisphosphonates for 5 or 10years, respectively. Here, we explored bisphosphonate prescription rate and prevalence of AFF in patients with SLE. In total, 270 patients with SLE were enrolled. The Japanese Society for Bone and Mineral Research Guideline 2014 for GIOP management and treatment was used. We also explored AFF history through medical records. Most (n = 251) patients were recommended to treat by the GIOP guideline (scores ≥ 3); bisphosphonates, denosumab, teriparatide, or active vitamin D was prescribed for 85.7%. Bisphosphonates were currently used by 66.1% of the patients, and 65% had used them for ≥ 5years. Of all patients, 76.7% had a history of bisphosphonate use, 5 of 270 (1.9%) had histories of AFF. Four of five patients with AFF had taken bisphosphonates for ≥ 3.5years, in addition to moderate doses (≥ 10mg/day) of glucocorticoids. For the SLE patients with a history of bisphosphonate use, the incidence of AFF was calculated to be 278 per 100,000 person-years. Our single-center study found that bisphosphonates were commonly used long term by Japanese patients with SLE. As AFF is not rare, AFF should be cared in patients with SLE.

Bisphosphonates and primary breast cancer risk: an updated systematic review and meta-analysis involving 963,995 women.

ImportancePrevention of primary breast cancer (BCa) in women is of great public health importance. The existing results from observational epidemiologic studies focused on the association between bisphosphonates and primary BCa risk have been inconsistent.ObjectiveTo update this systematic review and meta-analysis to assess the effect of bisphosphonates on primary BCa risk.Data sourcesWe comprehensively searched MEDLINE, EMBASE, Cochrane libraries, ProQuest, and Web of Science through June 25, 2018 for relevant studies.Study selectionEpidemiological studies that assessed the effect of bisphosphonates on the risk of primary BCa in women.Data extraction and synthesisWe reported this meta-analysis according to the PRISMA guidelines. Available multivariable-adjusted effect estimates and corresponding 95% CIs were pooled with a random-effects model.Main outcomes and measuresThe prespecified main outcome was the risk of primary BCa.ResultsIn total, five cohort studies involving 657,558 women and 12,991 primary BCa patients, three population-based case-control studies involving 54,701 primary BCa cases and 237,962 healthy controls and two randomized controlled trials (RCTs) involving 13,774 women and 165 primary BCa patients were included in this meta-analysis. Bisphosphonates were associated with a 12% decreased risk of primary BCa (RR, 0.88; 95% CI, 0.83–0.94). However, when we analyzed study designs separately, the pooled results from observational studies were inconsistent with that from RCTs. The observed association of primary BCa risk with long-term use (≥1 year) of bisphosphonates seemed to be more robust and stronger than that of short-term use (<1 year) (RR, 0.75; 95% CI, 0.66–0.84; and 0.90; 95% CI, 0.84–0.97; respectively).ConclusionThis meta-analysis adds to the body of evidence for an association between bisphosphonates and a significantly decreased risk of primary BCa. However, future large-scale RCTs are required to validate this concern.

Characteristics of Chronic Maxillary Sinusitis in Patients With a History of Long-term Bisphosphonate Use.

Background Bisphosphonates are widely used as bone stabilizers, which can cause major side effects including bisphosphonate-related osteonecrosis of the jaw (BRONJ) that occurs more frequently in the mandible. Consequently, there is a need for a detailed investigation of BRONJ of the maxilla and, in particular, of involvement of the maxillary sinus. Objective Our aim was to evaluate the characteristic radiologic and clinical manifestations in patients with maxillary sinusitis and a history of long-term bisphosphonate use. Methods Between January 2015 and July 2018, 55 patients with symptoms consistent with chronic rhinosinusitis who underwent a paranasal sinus computed tomography (CT) and had a history of &gt;12 months of bisphosphonate therapy were included in the analysis. Results Radiologically and clinically evident chronic rhinosinusitis was noted in 24 of the 55 patients, of whom more than half (14/24, 58.3%) had BRONJ. The CT studies demonstrated that the maxillary sinus was involved in all 24 patients, characterized by unilateral involvement (70.8%) and bony remodeling in the posterior maxillary region (90.5%). The evidence of osteitis on CT and/or single-photon emission CT was observed in the majority of cases (19/21, 90.5%) and 12 patients (50.0%) had oroantral fistula. However, there were no differences in the clinical appearance of the diseases with respect to the radiologic aspects. Conclusions Besides its well-known effects on the mandible, long-term bisphosphonate use can also affect the maxillary sinus, with typical clinical and radiological manifestations.

The Effects of Long-term Use of Nitrogen-containing Bisphosphonates on Fracture Healing.

Nitrogen-containing bisphosphonates (N-BPs) are pharmaceutical agents that have been used for many years to treat osteoporosis, multiple myeloma, Paget's disease, metastatic bone disease, and a variety of other diseases in which bone mineral density is reduced. Given that N-BPs inhibit bone resorption, an important stage in the fracture healing process, they have been extensively studied in preclinical models for their activity. In animal models, treatment with N-BPs is associated with a larger callus formation in fracture area and delay in remodeling from primary woven bone to lamellar bone, but there is no delay in formation of the fracture callus. In humans, all existing evidence suggest that initiating treatment with N-BPs, after upper and lower limb fractures, does not appear to have a significant effect on fracture healing. Rarely, patients with long-term use of N-BPs may develop “atypical fractures” and delay in their healing. Therefore, this clinical condition is not fully understood and many questions remain unanswered. Similarly, there are few studies about the benefits of stopping a long-term treatment with them, if a fracture occurs. Although most studies support that chronic N-BP therapy may lead to fracture healing delay, this is not fully documented. On the other hand, there are studies that are in complete disagreement with them. All of the above suggest that there is a need for more detailed future research into larger patient populations and different types of fractures, with sufficient data on the type, dosage, route and duration of administration of N-BPs, and the control methods of fracture healing, in order to have a safe final conclusion on the effect of their long-term administration in this highly complex process.

Atypical diaphyseal femoral fractures: Considerations on surgical technique

In the last two decades bisphosphonates (BP) has become the mainstream therapy for osteoporosis and the benefit in reducing the incidence of fractures has been well demonstrated in several studies, together with the drug long term (5–10 years) efficacy and safety.A complication of the long-term use of bisphosphonates is a low-energy stress fractures located in the sub-trochanteric region and the femoral shaft called atypical femur fracture (AFF).These stress fractures can be seen on plain radiographs as simple transverse patterns, with unicortical beaking and hypertrophy of the diaphyseal lateral cortex. Usually a localized thigh pain in the prodromal phase may precede the fracture by months. The current surgical treatment of choice for AFFs is intramedullary nailing (IMN). However, the treatment of AFFs is associated with a higher rate of intra-operative and post-surgical complications. This is related to anatomical e biomechanical reasons. Iatrogenic fractures, deformities, medial gap opening, eccentric position of the distal nail tip with anterior cortex perforation, delayed or non-union are frequent complications of this procedure and healing rate of AFFs. The average healing time of almost 8 months for AFFs appeared to be longer than that for typical femoral fractures, which heal at an average of 3–6 months.The purpose of this study is to analyze the different surgical devices and techniques and to advance some considerations that can be useful to diminish the rate of failure and/or complications in the treatment of AFFs in both oncologic and osteoporotic patients.

Current situation and future issues of antiresorptive agent-related osteonecrosis of the jaw

Bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is characterized by refractory bone exposure, has recently emerged as a serious side effect of bisphosphonate (BP) treatment. BRONJ was first thought to be due to administration of high doses of intravenous BP to treat metastatic bone lesions or multiple myeloma. However, more recent studies have indicated that BRONJ also frequently occurs in patients receiving low doses of BP for the treatment of osteoporosis. In addition, patients treated with denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL) whose antiresorptive effects differ from those of BP, may develop osteonecrosis of the jaw. Since both BP and denosumab are associated with osteonecrosis of the jaw (ONJ), antiresorptive agent-related ONJ (ARONJ) has been suggested as a comprehensive term. Although the pathophysiology of BRONJ remains unclear and the number of affected patients is increasing in Japan, significant improvements have been made with respect to risk reduction strategies and treatment. Despite the publication of the first position paper on BRONJ in Japan in 2010, an increase of the number of patients of BRONJ is hypothesized to result from an increase in the long-term use of BP. Previous findings have suggested that inadequate preventive measures including restriction of tooth extraction may be responsible for increases in BRONJ incidence.

Surgical Management of Atypical Femur Fractures Associated With Bisphosphonate Therapy.

Atypical femur fractures associated with long-term bisphosphonate use can be challenging injuries to manage. Not only do they have a prolonged healing time and increased rate of nonunion as compared to typical femur fractures, intraoperative complications are not infrequent and can be catastrophic. Given the pathologic nature of these fractures, a multidisciplinary approach to the patient's care is necessary. Treatment begins with medical optimization and careful surgical planning. Radiographic characteristics of the fracture and femoral osteology dictate reduction strategy, adjunctive surgical techniques, and implant choice. Intraoperative complications including malreduction, iatrogenic fracture, and fracture propagation can be avoided with thoughtful planning. The purpose of this article is to discuss the technical aspects of surgical management of atypical femur fractures. We also discuss management of intraoperative complications and treatment failure. Finally, we provide an update on recommendations for postoperative medical treatment and management of the contralateral femur.

Research advances on atypical femoral fractures related to Bisphosphonates

Bisphosphonates have become the first-line drugs for the treatment of osteoporosis, which can reduce the risk of brittle fracture by inhibiting osteoclast activity and increasing bone density. Bisphosphonates bring benefits to osteoporosis patients, while some side effects can occur. In recent years, bisphosphonate related femoral atypical fractures (AFF) have been gradually recognized and become the focus of researches. AFF has typical clinical features and X-ray findings: Patients with long-term usage of bisphosphonate drug. AFF were defined as atraumatic or low-trauma fractures located in the subtrochanteric region or femoral shaft. X-ray showed transverse or short oblique fracture of the medial cortex which shaped like a spike, and the bone cortex at the fracture area becomes thicker because of localized or diffuse periosteal reaction. AFF pathological mechanism is not clear, mainly with long-term use of bisphosphonates which seriously inhibit bone turnover, other theories including the theory of syndrome like collagen abnormal theory, mineral abnormal theory, hypophosphatasia, precise pathological mechanism still needs further study. Although the absolute incidence of AFF is very low, the number of AFF will inevitably increase with the increasing number of aging osteoporosis patients and the widespread application of bisphosphonates, which should be paid more attention to. AFF risk factors included long-term usage history of bisphosphonate, glucocorticoid treatment history, female patients, fracture prodromal symptoms including pain, discomfort or weakness in the thighs or groin and the bowing of the femoral shaft was associated with the location of AFF fracture. At present, the point of view of AFF treatment is: complete fracture of femoral length, reamed intramedullary nail fixation. Even for incomplete fractures, preventive intramedullary nailing should also be considered. The healing time of AFF fracture increases obviously. The most common complications are delayed union and nonunion. The rate of delayed union can be as high as 26%. How to improve the curative effect of this kind of fracture needs further study. In this paper, the latest literature on the clinical features, diagnostic criteria, morbidity, risk factors, pathological mechanisms, treatment and complications of atypical fractures of the femur were reviewed.

Persistence with brand versus generic oral bisphosphonates among newly treated osteoporosis patients: a retrospective cohort study in the French claims database

Introduction The first line of osteoporosis (OP) treatment is oral bisphosphonate (BP) and aims to reduce the risk of osteoporotic fracture. Although BP demonstrated his efficacy in preventing fractures, persistence with BP was estimated very low in previous studies in France and other countries. It has been proposed that persistence with generic BP formulations may be lower compared to brand formulations, due to changes of excipients reported to result in differences in disintegration time increasing the risk of upper gastrointestinal irritation. We aimed to compare the persistence with brand versus generic oral BPs. Methods We conducted a retrospective, comparative cohort study in the EGB (“Echantillon Generaliste des Beneficiaires”), a representative sample of the French Health Insurance claims database. We included all patients aged 50 and older, newly treated with oral BP (alendronic acid, ibandronic acid, risedronic acid or etidronic acid, without association with vitamin D) for primary osteoporosis between 01/01/2009 and 31/12/2015. Patients were followed from the initiation date until: switch (change from generic to brand drug and conversely, or change of BP molecule); discontinuation of BP (no new dispensation during a period greater than twice the expected duration of supply if taken as prescribed); or 12 months. Persistence was evaluated as time to discontinuation and as proportion of patients still on treatment at 6 and 12 months. Time to discontinuation and 6- and 12-month persistence were compared between patients who initiated treatment with generic and patients who initiated with brand BP, excluding patients who switched. Results In total, 3903 patients initiated an oral BP treatment for primary OP during the 7-year inclusion period, 1710 (44.0%) with generic BP and 2193 (56.0%) with brand BP. Mean age was comparable between the 2 groups: 70.8 (± 10.6) in “generic BP” group and 70.0 (± 10.4) in “brand BP” group. There were fewer women in the “generic BP” group than in “brand BP” group (respectively 87.8% and 90.3%; P = 0.01. 236 (13.8%) patients in “generic BP” group and 306 (14.0%) patients in “brand BP” group switched to the other BP group during the 12 months after initiation; 56 (3.3%) patients in the “generic BP” group and 175 (8.0%) patients in “brand BP” group have changed to another BP molecule, respectively. After exclusion of patients who switched, 6- and 12-month persistence were not statistically different between the 2 groups: respectively 43.9% and 33.8% in “generic BP” group and 41.7% and 31.3% in “brand BP” group (P = 0.22 and 0.14 respectively for 6- and 12-month persistence). Mean time to discontinuation was 185.6 days (± 138.3) in “generic BP” group and 183.1 days (± 138.1) in “brand BP” group. Conclusions There were no differences in persistence with brand or generic BP in this population. Low persistence rates in our analysis are consistent with results of other studies, and confirm that discontinuation of BP treatment is currently a public health concern. The reasons for discontinuation require further investigation, to inform shared decision-making in treatment choice and strategies to support long-term BP use.

Material heterogeneity, microstructure, and microcracks demonstrate differential influence on crack initiation and propagation in cortical bone.

The recent studies have shown that long-term bisphosphonate use may result in a number of mechanical alterations in the bone tissue including a reduction in compositional heterogeneity and an increase in microcrack density. There are limited number of experimental and computational studies in the literature that evaluated how these modifications affect crack initiation and propagation in cortical bone. Therefore, in this study, the entire crack growth process including initiation and propagation was simulated at the microscale by using the cohesive extended finite element method. Models with homogeneous and heterogeneous material properties (represented at the microscale capturing the variability in material property values and their distribution) as well as different microcrack density and microstructure were compared. The results showed that initiation fracture resistance was higher in models with homogeneous material properties compared to heterogeneous ones, whereas an opposite trend was observed in propagation fracture resistance. The increase in material heterogeneity level up to 10 different material property sets increased the propagation fracture resistance beyond which a decrease was observed while still remaining higher than the homogeneous material distribution. The simulation results also showed that the total osteonal area influenced crack propagation and the local osteonal area near the initial crack affected the crack initiation behavior. In addition, the initiation fracture resistance was higher in models representing bisphosphonate treated bone (low material heterogeneity, high microcrack density) compared to untreated bone models (high material heterogeneity, low microcrack density), whereas an opposite trend was observed at later stages of crack growth. In summary, the results demonstrated that tissue material heterogeneity, microstructure, and microcrack density influenced crack initiation and propagation differently. The findings also elucidate how possible modifications in material heterogeneity and microcrack density due to bisphosphonate treatment may influence the initiation and propagation fracture resistance of cortical bone.

Interaction of Microcracks and Tissue Compositional Heterogeneity in Determining Fracture Resistance of Human Cortical Bone.

Recent studies demonstrated an association between atypical femoral fracture (AFF) and long-term bisphosphonate (BP) use for osteoporosis treatment. Due to BP treatment, bone undergoes alterations including increased microcrack density and reduced tissue compositional heterogeneity. However, the effect of these changes on the fracture response of bone is not well understood. As a result, the goal of the current study is to evaluate the individual and combined effects of microcracks and tissue compositional heterogeneity on fracture resistance of cortical bone using finite element modeling (FEM) of compact tension (CT) specimen tests with varying microcrack density, location, and clustering, and material heterogeneity in three different bone samples. The simulation results showed that an increase in microcrack density improved the fracture resistance irrespective of the local material property heterogeneity and microcrack distribution. A reduction in material property heterogeneity adversely affected the fracture resistance in models both with and without microcracks. When the combined changes in microcrack density and tissue material property heterogeneity representing BP treatment were evaluated, the models corresponding to BP-treated bone demonstrated reduced fracture resistance. The simulation results also showed that although microcrack location and clustering, and microstructure significantly influenced fracture resistance, the trends observed on the effect of microcrack density and tissue material property heterogeneity did not change. In summary, these results provide new information on the interaction of microcracks, tissue material property heterogeneity, and fracture resistance and may improve the understanding of the influence of mechanical changes due to prolonged BP use on the fracture behavior of cortical bone.

Atypical femoral fracture-a possible complication in long term use of bisphosphonates (case report)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Treatment of systemic diseases and oral focal infection

AbstractOral lesions are highly correlated with the occurrence and development of many diseases. In addition, the treatment of systemic diseases may aggravate oral focal infections, affect the life quality of patients, interfere with the treatment of systemic diseases, and even cause systemic infection in serious cases. Treatment strategies for systemic diseases may induce or aggravate oral local lesion infections. In specific, administration of oral antiepileptic drugs and immunosuppressive drugs may induce gingivitis, radiotherapy or chemotherapy for malignant tumors may cause oral mucositis, long-term use of bisphosphonates for inhibition of tumor bone metastasis or prevention of osteoporosis may cause osteonecrosis of the jaw, and allogeneic hematopoietic stem cell transplantation may cause oral rejection reactions.