Bisphosphonates For Osteoporosis Research Articles

Tip-apex distance as a risk factor for cut-out in cephalic double-screw nailing of intertrochanteric femur fractures.

Proximal femur fractures treatment can involve anterograde nailing with a single or double cephalic screw. An undesirable failure for this fixation is screw cut-out. In a single-screw nail, a tip-apex distance (TAD) greater than 25 mm has been associated with an increased risk of cut-out. The aim of the study was to examine the role of TAD as a risk factor in a cephalic double-screw nail. A retrospective study was conducted on 112 patients treated for intertrochanteric femur fracture with a double proximal screw nail (Endovis BA2; EBA2) from January to September 2021. The analyzed variables were age, sex, BMI, comorbidities, fracture type, side, time of surgery, quality of reduction, pre-existing therapy with bisphosphonate for osteoporosis, screw placement in two different views, and TAD. The last follow-up was at 12 months. Logistic regression was used to study the potential factors of screw cut-out, and receiver operating characteristic curve to identify the threshold value. A total of 98 of the 112 patients met the inclusion criteria. Overall, 65 patients were female (66.3%), the mean age was 83.23 years (SD 7.07), and the mean follow-up was 378 days (SD 36). Cut-out was observed in five patients (5.10%). The variables identified by univariate analysis with p < 0.05 were included in the multivariate logistic regression model were screw placement and TAD. The TAD was significant with an odds ratio (OR) 5.03 (p = 0.012) as the screw placement with an OR 4.35 (p = 0.043) in the anteroposterior view, and OR 10.61 (p = 0.037) in the lateral view. The TAD threshold value identified was 29.50 mm. Our study confirmed the risk factors for cut-out in the double-screw nail are comparable to those in the single screw. We found a TAD value of 29.50 mm to be associated with a risk of cut-out in double-screw nails, when good fracture reduction is granted. This value is higher than the one reported with single-screw nails. Therefore, we suggest the role of TAD should be reconsidered in well-reduced fractures treated with double-screw intramedullary nail.

Bisphosphonates for osteoporosis: from bench to clinic.

Bisphosphonates for osteoporosis: from bench to clinic.

Clinical characteristics, densitometric parameters and outcomes of patients with atypical femoral fractures related to bisphosphonate treatment for osteoporosis.

We described the clinical and densitometric characteristics and treatment outcomes of patients who developed atypical femoral fractures (AFF) while on bisphosphonate for osteoporosis. We performed a retrospective cohort study including all adults aged ≥50 years who developed AFF while on bisphosphonates between 1 January 2008 and 31 December 2020, and subsequently managed in the Osteoporosis Centre at Queen Mary Hospital in Hong Kong. A control group of patients who developed fragility hip fractures while on bisphosphonates in the same period was included for comparison. We compared the clinical and densitometric characteristics between the two groups, and described the clinical outcomes for the AFF group. In total, 75 patients were included (AFF: n = 35; fragility hip fracture: n = 40). All were related to oral bisphosphonates. The AFF group was characterised by a longer duration of bisphosphonate use (median of 5 years), higher bone mineral density (BMD) and more acute neck-shaft angle (all p < 0.05). Following AFF, 8 patients (22.9%) did not receive any subsequent bone-active agents: due to refusal to use an injectable, or BMD out of osteoporotic range. Most of those who received bone-active agents were given teriparatide, followed by raloxifene, and achieved stable BMD. However, subsequent fragility risk remained high. Nonetheless, AFF did not confer excess morbidity and mortality. AFF was characterised by usually long duration of bisphosphonate use, higher BMD and more acute neck-shaft angle. AFF did not confer significant impairment in mobility or mortality. Nonetheless, further research work is necessary to optimise bone health among patients who develop AFF.

Zoledronate and osteonecrosis of the jaw in osteoporosis: incidence and risk factors. Analysis of the French Pharmacovigilance Database

IntroductionBisphosphonate-related osteonecrosis of the jaw (BRONJ) have been characterized with the use of oral bisphosphonates in osteoporosis and zoledronate in oncology. Uncertainties remain, though, with the occurrence of BRONJ related to the use of zoledronate in osteoporosis. ObjectivesWe aimed to estimate the incidence and characterize the risk factors of zoledronate-associated BRONJ in osteoporosis as compared with oral bisphosphonates in real life setting. MethodsCases of BRONJ associated with zoledronate, alendronate or risedronate were extracted from the French pharmacovigilance database up to 2020. The incidence of BRONJ was estimated as their respective numbers related to cases of BRONJ in patients treated with bisphosphonates for osteoporosis, over the same period, according to the Medic’AM database. ResultsBetween 2011 and 2020, BRONJ incidence with zoledronate was 9.6/100,000 patient-year (PY), significantly higher than with alendronate (5.1/100,000 PY, P<0.001), and risedronate (2.0/100,000 PY, P<0.001). The number of patients treated with bisphosphonates has steadily decreased by 44.5% over 10 years. Meanwhile, the incidence of BRONJ decreased (5.8/100,000 PY in 2011; 1.5/100,000 in 2020), although a rebound was observed in 2018, including 47.6% of BRONJ following denosumab. Apart from classical risk factors, recent dental cares stood out in more than 40% of BRONJ, and zoledronate had a shorter exposure time than oral bisphosphonates. ConclusionsIn a real-life setting, our data confirm that zoledronate-associated BRONJ in osteoporosis is scarce, seeming slightly more common compared with oral bisphosphonates. We also raise awareness of dental care guidelines and greater vigilance when using bisphosphonates in patients with previous exposure to denosumab.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

Anti-osteoporotic medication and scleroderma

Scleroderma (systemic sclerosis) represents a challenging condition, usually requiring a multi-disciplinary team due to multi-organ involvement; it is mostly considered an autoimmune disease; the signature of the malady is the extensive fibrosis at the level of skin and multiple organs, associating endothelial/vessel damage and anomalies of immune response. We point out a few aspects concerning scleroderma-related osteoporosis. This is a literature review. Patients might associate low bone mineral density (the underling mechanisms are not entirely understood), thus an increased risk of fractures; so early recognition and treatment is mandatory for a better outcome. Some data showed that particularly vertebral fractures are prone to the condition. Almost half of individuals with the malady have osteoporosis (female prevalence, especially post-menopausal) and one third of them have an osteoporotic fracture. Older age and associated vitamin D deficiency increases the risk of fracture. Vitamin D has pleomorphic distribution, also targeting the immune modulation, cytokines puzzle, and the muscle-bone crosstalk in scleroderma. Hypovitaminosis D might be expected in these patients, while general D-supplementation has controversial benefits effects. Chronic inflammatory rheumatic conditions might benefit from the TBS use as fracture risk indicator through micro-architecture evaluation. It seems that patients with systemic sclerosis and malnutrition have lower TBS; high Dkk-1 serum levels (Dickkopf-1) is correlated with reduced TBS and advanced disease; TBS is correlated to the extent of microvascular complications; exposure to glucocorticoids (certain high-dose regimes) supplementary lowers TBS. Gastrointestinal complications are presented in 90% of patients with systemic sclerosis, involving fibrosis at any level which is a poor prognostic factor; malabsorption of nutrients and weight loss correlates with reduced bone formation while esophageal and gastric anomalies contraindicate the use of oral bisphosphonates for osteoporosis. Other abnormal elements of skeleton frame include: premature ovarian failure, serotonin system anomalies, chronic inflammation, potential side effects of immunosuppressant drugs. In patients with systemic sclerosis, the choices of medication targeting osteoporosis are limited; the use of intravenous bisphosphonates remains first line option (if renal function is adequate); the consideration of skin and esophageal anomalies is mandatory in the management of osteoporosis. Overall, the landscape of bone domain in systemic sclerosis is multi-leveled and some areas are still waiting for clear answers.

The treatment gap: The missed opportunities for osteoporosis therapy.

Despite substantial advances in delineation of the epidemiology, pathophysiology, risk assessment and treatment of osteoporosis over the last three decades, a substantial proportion of men and women at high risk of fracture remain untreated - the so-called "treatment gap". This review summarises the important patient-, physician- and policyrelated causes of this treatment gap, before discussing in greater detail: (a) the evidence base for the efficacy of bisphosphonates in osteoporosis; (b) recent evidence relating to the adverse effects of this widely used therapeutic class, most notably atypical femoral fracture and osteonecrosis of the jaw; (c) available strategies to improve both secondary and primary prevention pathways for the management of this disorder.

Adherence with brand versus generic bisphosphonates among osteoporosis patients: a new-user cohort study in the French National Healthcare Insurance database

Several studies documented declines in treatment adherence with generic forms of oral bisphosphonates in osteoporosis compared to branded forms, while others did not support this relation. Our aim was to compare medication adherence with brand versus generic forms of oral bisphosphonates. A new-user cohort study was conducted using routinely collected administrative and healthcare data linked at the individual level extracted from a nationwide representative sample of the French National Healthcare Insurance database. We included all patients aged 50 and older, new users of oral bisphosphonates for primary osteoporosis between 01/01/2009 and 31/12/2015. Two components of adherence were measured: implementation (continuous multiple-interval measure of medication availability version 7; CMA7) and persistence (time to discontinuation). The sample was composed of 1,834 in the “brand bisphosphonate” group and 1,495 patients in the “generic bisphosphonate” group. Initiating oral bisphosphonate treatment with brand was associated with a higher risk of discontinuation within 12 months (Hazard Ratio = 1.08; 95%CI = [1.02;1.14]). The risk of good implementation (CMA7 ≥ 0.90) was significantly lower in “brand bisphosphonate” group (Risk Ratio = 0.90; 95%CI = [0.85; 0.95]). We did not find any evidence to support the hypothesis of a lower adherence to generic bisphosphonates. In fact, prescribing of generic bisphosphonates led to a higher persistence rate and to better implementation at 1 year.

Practical guidance for the use of bisphosphonates in osteoporosis.

Bisphosphonates are widely used in the treatment of osteoporosis in postmenopausal women and older men. In clinical trials they have been shown to reduce fractures in women with osteoporosis and there is increasing evidence that they are also effective in women with osteopenia, in whom the majority of fractures occur. In addition to their role as initial therapy in individuals at increased risk of fracture, bisphosphonates are used as sequential therapy after treatment with anabolic drugs. There are no head-to head studies to compare the anti-fracture efficacy of different bisphosphonates, but there is limited evidence that zoledronate treatment results in greater increases in BMD than risedronate or alendronate. This, together with the need for less frequent administration of zoledronate, supports its wider use in clinical practice, particularly if longer dosing intervals than those currently recommended are shown to be effective.

Medication-related osteonecrosis of the jaw

Medication-related osteonecrosis of the jaw (MRONJ) is a rare, but well-documented, complication following the administration of anti-resorptive and anti-angiogenic drugs. MRONJ has a negative effect on quality of life, and can result in reduced social contact, pain and masticatory difficulties. Prescription of implicated medication is within the remit of GPs, and thus National Institute for Health and Care Excellence (NICE) guidelines have been published to inform prescribing. Careful consideration of the potential deleterious oral side-effects of these drugs is needed. NICE guidelines on the prescribing of bisphosphonates for osteoporosis acknowledge that osteonecrosis of the jaw was not included in the adverse events when the economic model was assessed. This article provides an overview of MRONJ, highlighting key areas for possible GP intervention when caring for patients at risk of developing MRONJ, and what to do if MRONJ is suspected.

Post-operative Rehabilitation of Atypical Femoral Fracture in a Single Center.

ABSTRACTObjective: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.

Prevalence and risk factors of medication-related osteonecrosis of the jaw in osteoporotic and breast cancer patients: a cross-sectional study.

Medication-related osteonecrosis of the jaw (MRONJ) has been reported as a side effect of bisphosphonate (BP). The aim of this study was to identify the prevalence of MRONJ in women taking BP for osteoporosis and for metastatic breast cancer and correlate it with risk factors and biochemical markers of bone metabolism. Patients taking oral or intravenous BP with osteoporosis (G1; n = 153; median 72.8years) and with metastatic breast cancer (G2; n = 134; median 58.2years) had their hospital charts reviewed, were submitted to dental inspection, and answered a health questionnaire. Fasting blood samples were randomly collected from both groups to measure osteocalcin, carboxy-terminal cross-linking telopeptide of type I collagen, intact parathyroid hormone and procollagen type 1 amino-terminal propeptide (P1NP), 25 hydroxyvitamin D (25OHD), creatinine, and total calcium. G1 was older (p = 0.001) and had more cases of diabetes (p = 0.043). P1NP was higher (p = 0.022) and 25OHD lower (p = 0.004) in G2 compared with G1. MRONJ was not found in the G1, whereas 4 cases (3%) were detected in G2. Positive risk factors for MRONJ were number of BP doses and number of visits to the dentist and dental extractions. The biochemical parameters, however, could not identify those who developed MRONJ. The prevalence of MRONJ was 3% in women with metastatic breast cancer receiving BP. No cases were identified in women receiving oral BP chronically for osteoporosis. P1NP was higher in women with metastatic breast cancer, even during treatment with antiresorptives, but could not differentiate those with MRONJ.

Natural history of incomplete atypical femoral fractures in patients after a prolonged and variable course of bisphosphonate therapy-a long-term radiological follow-up.

Retrospective study evaluating the natural history of lateral femoral stress fractures (FSF) by serial radiography over a variable period of time in a cohort of patients treated for some time with bisphosphonates for osteoporosis, whilst also identifying the fracture response in cases where bisphosphonates were discontinued. The radiographs of 76 consecutive patients (92 femurs) with 161 FSF were reviewed to document their change over time. Femurs were classified into the following: A-normal, B-focal cortical thickening, C-dreaded black line and D-displaced fracture. Bisphosphonate history was recorded. 66.5% FSF showed group stability between the first and last radiographs: group B (79.1%), group C (45.7%). 28.6% progressed, mostly following an ordered sequence starting from group A, progressing to B, then C, before culminating in D. Progression rate was as follows: A-100% (11/11), B-18.3% (21/115), C-40% (14/35). Regression in FSF was uncommon-5.6% (8/161). 34.8% (32/92) sustained displaced fractures. Kaplan-Meier analysis showed statistically significant difference between the groups; median survival (95% CI): A-4189 (-), B-3383.0 (-), C-1807 (0.0-3788.6) and progression to displaced fracture when bisphosphonate had been stopped for at least 6months. The group without recent bisphosphonates had a lower group progression rate (17.1%, 12/70). Nevertheless, 10.9% (5/46) progressed to displaced fracture. This group also had the highest proportion of stable (77.1%, 54/70) and regressive lesions (5.7%, 4/70). In FSF, there is natural progression from normal bone, to focal cortical thickening, to dreaded black line and eventually to displaced fracture. Most lesions persist, remaining static or progressing, especially if a dreaded black line is present and bisphosphonates are continued. Regression is uncommon and more frequent when bisphosphonates are discontinued. Despite stopping bisphosphonates, there remains a 10.9% risk of progression to displaced fracture.

SAT-LB092 Adherence to Weekly Alendronate Predicts Mortality in Male US Military Veterans

Background: The use of oral bisphosphonates in osteoporosis is associated with a lower rate of all-cause mortality, however, data are primarily available on postmenopausal women. It is unknown if poor adherence to bisphosphonates affects mortality in men. This study examines the association between weekly alendronate adherence and mortality in a male Veteran cohort. Methods: A retrospective cohort was generated from VA databases selecting Veterans who were initiated on weekly alendronate and had at least 2 years of follow up. Individuals had an identifiable reason for prevention or treatment of osteoporosis including index bone mineral density T-score ≤ -1 at total hip or lumbar spine, diagnosis of prostate cancer, evidence of a fracture, or diagnosis of osteoporosis or osteopenia. Adherence was measured by Medication Possession Ratio (MPR) calculated as the percentage of days’ supply for all fills divided by the number of days in the observation period. Good adherence was defined as a year one MPR ≥80%. A cox proportional hazard model was constructed to assess the association between adherence and mortality, adjusting for age, history of rheumatoid arthritis, alcohol abuse, tobacco use, use of oral glucocorticoids or acid suppression therapy. Results: The cohort included 706 male veterans between the ages of 50 and 90 years of age. After the initial required two-year follow-up for inclusion, the median follow up was 3.24 (interquartile range 1.14-5.35) years. Out of 706 veterans, 367 had MPR <80% and 339 had MPR ≥80%. Death occurred in 129 vs 105 (35.2% vs 31.0%), for year one MPR <80% vs ≥80%, respectively [HR 0.73; 95% CI 0.56- 0.95, P=0.02]. Other factors such as history of rheumatoid arthritis, alcohol abuse, tobacco use, use of oral glucocorticoids or acid suppression therapy were not associated with higher mortality. Conclusion: Adherence to weekly alendronate in the first year of treatment was associated with lower rate of mortality in male veterans. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Osteoporosis therapy in patients with inflammatory rheumatic diseases and osteonecrosis of the jaw

The aim of the present study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to assess the prevalence of relevant dental, behavioral, and medical risk factors for MRONJ. Atotal of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from atertiary rheumatological/immunological referral center between June 2015 and September 2016. They were assessed using astructured interview. Amaxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. In cases of osteonecrosis, dental records were obtained and evaluated. Preventive measures taken and dental as well as other clinical risk factors were evaluated. Of the 198 patients, three suffered from osteonecrosis of the jaw, none of whom had any history of malignant disease or radiation therapy, resulting in aprevalence of 1.5%. Of these three patients, only one was given bisphosphonates intravenously (i.v.), whereas all three had been treated orally. All three diagnoses of MRONJ had been previously known to the patients and their maxillofacial surgeons. Two of the patients had rheumatoid arthritis, and one patient suffered from large vessel vasculitis. Long anti-osteoporotic treatment duration, low functional status, and low bone density of the femur were significantly associated with MRONJ development. Inflammatory rheumatic diseases constitute arisk factor for MRONJ in patients treated with bisphosphonates for osteoporosis. Patients should be counseled accordingly and should be offered dental screening and regular dental check-ups.

Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate

Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient’s age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient’s derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.

The effect of antiresorptive drugs on implant therapy: Systematic review and meta-analysis.

A considerable portion of the adult population has received and/or is receiving treatment with antiresorptive drugs (ARDs). It is thus relevant to assess possible side effects of ARD intake in connection to various aspects of implant therapy. The aim of this study was to answer the focused question "In patients with systemic intake of ARDs, what is the outcome and complication rate of implant therapy including associated bone grafting procedures comparing to patients without systemic intake of ARDs?" Original studies fulfilled predefined inclusion criteria (e.g., case series, cohort studies, case-control studies, and controlled and/or randomized controlled clinical trials; retro- or prospective design; and ≥10 patients with systemic intake of ARDs). Various patient-, medication-, and intervention-related parameters [i.e., implant loss, grafting procedure complication/failure, peri-implant marginal bone levels/loss, medication-related osteonecrosis of the jaws (MRONJ), and peri-implantitis] were extracted, and meta-analyses and quality assessment were performed. Twenty-four studies with bisphosphonate (BP) intake (mainly low dose for osteoporosis treatment) and seven studies on hormone replacement therapy (HRT), including ≥10 patients, and controls not taking the medication were identified. Furthermore, seven studies on MRONJ associated with implants were included. Meta-analyses based on four studies reporting on patient level and eight studies reporting on implant level showed no significant differences in terms of implant loss between patients on BPs (mainly low dose for osteoporosis treatment) and controls. Furthermore, low-dose BP intake did not compromise peri-implant marginal bone levels. Based on two studies, no negative effect of HRT was observed on the implant level, while HRT appeared to exert a marginally significant negative effect regarding implant survival on the patient level and regarding peri-implant marginal bone levels. Based on six studies reporting single-patient data, MRONJ in patients on BP for osteoporosis appeared in 70% of the cases >36months after start of drug intake, while in patients with cancer, MRONJ appeared in 64% of the cases ≤36months after first BP intake. Low-dose oral BP intake for osteoporosis treatment, in general, does not compromise implant therapy, that is, patients on ARDs do not lose more implants nor get more implant-related complications/failures comparing to implant patients without BP intake. There is almost no information available on the possible effect on implant therapy of high-dose BPs or other widely used ARDs (e.g., denosumab), or on the success or safety of bone grafting procedures. Patients with high-dose ARD intake for management of malignancies, patients on oral BP over a longer period of time, and patients with comorbidities should be considered as high-risk patients for MRONJ.

Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions.

BackgroundThe harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.Objectivesi. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.MethodsData on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson’s Cube was used to conduct the HBA.ResultsThe most common assessment of animal harms by the expert panel was ‘severe’. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson’s Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.ConclusionsThis is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits.

Long-term use of bisphosphonates in osteoporosis.

[No Abstract Available].

Long-term use of bisphosphonates in osteoporosis.

Objectives:To report and describe the management and response to treatment of patients referred to the osteoporosis clinic after prolonged use of bisphosphonate BPs) (4 years and more) with and without new fracture (any site) or any other new skeletal symptoms.Methods:This is a single center observational retrospective cohort study conducted from January 2009 to May 2016 in a tertiary center. We describe cause of referral, X-rays findings, management, and response to treatment.Results:Thirty-four patients, aged 46-89 years, were collected. Reason for referral included review of therapy (11 patients), recent low trauma fracture (21 patients), or chronic severe thigh pain (2 patients) of unknown etiology. All patients with fracture or thigh pain (23/34 patients) were treated with teriparatide 20 mcg daily. Sixteen of them (16/23) completed teriparatide course (18-24 months), 11 patients had complete healing of fracture at the end of the course, and 5 remained with nonunion of fracture, the remaining 5 patients were lost to follow up.Conclusion:Prolonged use of bisphosphonates can lead to atypical femoral fracture that may involve sites other than femoral shaft or rarely chronic thigh pain without fracture. Teriparatide may facilitates fracture healing and improve thigh pain.