Medical management of patients after atypical femur fractures: a systematic review and recommendations from the European Calcified Tissue Society

Context Atypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing. Evidence acquisition We performed a systematic review to evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF. Evidence synthesis We retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient. Conclusions There is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion

Pain, quality of life and safety outcomes of kyphoplasty for vertebral compression fractures: report of a task force of the American Society for Bone and Mineral Research.

The relative efficacy and harms of balloon kyphoplasty (BK) for treating vertebral compression fractures (VCF) are uncertain. We searched multiple electronic databases to March 2016 for randomised and quasi-randomised controlled trials comparing BK with control treatment (non-surgical management [NSM], percutaneous vertebroplasty [PV], KIVA®, vertebral body stenting, or other) in adults with VCF. Outcomes included back pain, back disability, quality of life (QoL), new VCF and adverse events (AE). One reviewer extracted data, a second checked accuracy, and two rated risk of bias (ROB). Mean differences and 95% confidence intervals were calculated using inverse-variance models. Risk ratios of new VCF and AE were calculated using Mantel-Haenszel models. Ten unique trials enrolled 1,837 participants (age range: 61-76 years, 74% female), all rated as having high or uncertain ROB. Versus NSM, BK was associated with greater reductions in pain, back-related disability, and better QoL (k = 1 trial) that appeared to lessen over time, but were less than minimally clinically important differences. Risk of new VCF at 3 and 12 months was not significantly different (k = 2 trials). Risk of any AE was increased at 1 month (RR = 1.73 [1.36, 2.21]). There were no significant differences between BK and PV in back pain, back disability, QoL, risk of new VCF or any AE (k = 1 to 3 trials). Limitations included lack of a BK versus sham comparison, availability of only one RCT of BK versus NSM, and lack of study blinding. Individuals with painful VCF experienced symptomatic improvement compared with baseline with all interventions. The clinical importance of the greater improvements with BK versus NSM is unclear, may be due to placebo effect, and may not counterbalance short-term AE risks. Outcomes appeared similar between BK and other surgical interventions. Well-conducted randomized trials comparing BK with sham would help resolve remaining uncertainty about the relative benefits and harms of BK. This article is protected by copyright. All rights reserved

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients

A multicenter study to evaluate harmonization of assays for C-terminal telopeptides of type I collagen (ß-CTX): A report from the IFCC-IOF Committee for Bone Metabolism (C-BM)

Background Biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies. Methods We describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield UK) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers’ instructions. Passing-Bablok regressions, Bland–Altman plots, V-shape evaluation method, and Concordance correlation coefficient for ß-CTX values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods. Results We identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum. Conclusion Our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed

Zoledronate in the prevention of Paget's (ZiPP) : protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

Introduction Paget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. Methods and analysis People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events

Factores relacionados con la respuesta inadecuada al tratamiento osteoformador (teriparatida/PTH 1–84) en pacientes con osteoporosis severa. Resultados preliminares

El objetivo de este estudio ha sido analizar la evolución de la masa ósea a largo plazo tras tratamiento osteoformador (teriparatida o PTH 1-84) en pacientes con osteoporosis severa, y determinar la frecuencia y los factores relacionados con una respuesta inadecuada (RI) al tratamiento. Métodos: Se incluyeron 49 pacientes (46 mujeres:3 hombres) con una edad media de 69,5±11,1 años, tratados con teriparatida (41) o PTH1-84 (8) durante 18/24 meses (84% tenían fracturas vertebrales y 84% habían recibido tratamiento previamente). Se analizaron: factores de riesgo y causa de osteoporosis, fracturas y tratamiento antiosteoporótico previo. Se valoraron los marcadores de recambio óseo (MRO), los niveles de 25-OH vitamina D (25OHD) basal y a los 3, 6, 12 y 18/24 meses, radiografías de columna dorso-lumbar y densitometría ósea (DMO) previa, a los 12 y 18/24 meses. Se definió RI cuando el cambio de DMO lumbar era <3% a los 18/24 meses. Resultados: 29% de los pacientes presentaron RI al tratamiento. No se observaron diferencias en la edad, DMO basal, valores de 25OHD y/o MRO entre los pacientes con y sin RI. El 92% de pacientes con RI había seguido tratamiento previo con bisfosfonatos (vs. el 79% de los pacientes sin RI, p=0,34) durante 7±4,8 años (vs. 4,9±4,2 años, p=0,19). No se observaron diferencias significativas en la evolución de los MRO tras iniciar el tratamiento entre ambos grupos de pacientes. Conclusión: El 29% de los pacientes con osteoporosis grave presenta una RI al tratamiento osteoformador. Aunque no se han identificado factores predictores de este tipo de respuesta, es posible que el tratamiento prolongado previo con bisfosfonatos pueda estar relacionado con este hallazgo

Esclerostina y Dkk-1 séricos en pacientes que inician tratamiento con glucocorticoides. Resultados preliminares

Fundamento y objetivos: La vía Wnt y sus inhibidores (esclerostina y Dkk-1) tienen un papel primordial en la regulación de la masa ósea y la osteoblastogénesis. El objetivo de este estudio fue analizar el efecto del tratamiento con glucocorticoides (GCC) sobre los inhibidores de la vía Wnt y su relación con la masa ósea y los parámetros de recambio óseo. Métodos: Estudio transversal que incluyó 15 pacientes (9 mujeres y 6 hombres) con una edad media de 51±21 años al inicio del tratamiento con GCC (≥7,5 mg/día, ≤6 meses). En todos ellos se determinó: esclerostina, Dkk-1 séricos y marcadores séricos del recambio óseo (propéptido N-terminal del procolágeno I [PINP], osteocalcina [OC] y telopéptido carboxiterminal del colágeno tipo I [CTX]), y se les realizó una densitometría ósea en columna lumbar y fémur (DXA). Los resultados se compararon con un grupo control. Resultados: La dosis media de glucocorticoides fue de 58±21 mg/día, en la mayoría de los pacientes indicado por una púrpura trombocitopénica idiopática (73%). Los pacientes tratados con glucocorticoides tenían una disminución de los parámetros de formación ósea comparado con el grupo control (OC: 7,4±2,8 vs. 24,4±6,2 ng/ml, p<0,01) y una disminución del Dkk-1 sérico (29,6±23,6 vs. 48,3±15,6 pmol/L, p=0,02). No se observaron diferencias significativas en los valores esclerostina sérica, aunque ésta se correlacionó positivamente con la dosis de GCC recibida y la densidad mineral ósea lumbar. Conclusión: Contrariamente a lo que sucede en estudios experimentales, el inicio del tratamiento con glucocorticoides se asocia a una disminución de los valores séricos de Dkk-1. Estos resultados indican la necesidad de analizar estos inhibidores y su relación con el remodelado y la masa ósea en este proceso a largo plazo

Letter to the Editor: The Endocrine Society Clinical Practice Guidelines on Paget's Disease: Many Recommendations Are Not Evidence Based

Dear Sir, We write with regard to the Endocrine Society Clinical Guideline on Paget's disease (1). Preparing guidelines that balance the available evidence with the need to give clinicians practical advice is a difficult task, especially in conditions like Paget's disease of bone (PDB) where high-quality evidence on patient-centered outcomes is lacking. Notwithstanding the challenge the authors faced, we have concerns that many recommendations seem to have been based on personal opinion rather than evidence and that some relevant evidence has been overlooked. In the background, the authors state that bone pain is only present in a minority of patients with PDB. Although it is true that many patients with PDB never come to medical attention (2), the guideline focused on the management of those that do present clinically. In this population, bone pain occurs in about 50% of cases (3). In view of this, we were surprised that treatment of bone pain did not figure more prominently in the guideline because the evidence base in support of this is strong (4). Recommendation 2.1 (moderate quality evidence) advises that most patients with active PDB who are at risk of complications should be treated with a bisphosphonate. This recommendation is impossible to implement because there is no validated method of identifying PDB patients who are at risk of complications. Recommendation 2.5 (low quality evidence) suggests that bisphosphonate treatment should be given with the aim of reducing the chosen biochemical marker to below the midpoint of the reference range. The implication from both of these recommendations is that bisphosphonate treatment in general and normalizing bone turnover in particular are beneficial in PDB in helping to prevent complications. However, the supporting evidence is that “it seems reasonable to suppose despite the lack of objective evidence that long-term complications might be reduced by normalization of bone turnover.” With all due respect to the authors, this is an opinion and not evidence. A randomized trial has been performed to investigate whether it is beneficial to try and normalize bone turnover in PDB, but no difference was found in the rate of complications between groups of patients treated with the aim of normalizing alkaline phosphatase concentrations, as opposed to those who were treated symptomatically (5). Recommendation 2.6 (moderate quality evidence) similarly suggests that biochemical markers of bone turnover should be used as a more objective indication of relapse than symptoms. Implicit in this recommendation is that “biochemical relapse” predicts clinical relapse. We are aware of no evidence to suggest that this is the case. Recommendation 3.1 (low quality evidence) suggests that a potent bisphosphonate should be given to prevent worsening of a hearing deficit, with supporting evidence from an observational study with calcitonin (6). The effects of bisphosphonates on hearing loss in PDB have been studied, and no benefit has been observed (5, 7). Recommendation 3.2b (low quality evidence) suggests that bisphosphonates should be given to prevent cartilage degeneration in patients with osteoarthritis adjacent to an affected bone. The supporting evidence is that “it is conceivable that drug treatment of Paget's disease may slow the arthritis process.” This recommendation is based on the authors' opinion, rather than evidence. We have great respect for the authors of the guideline, many of whom have extensive personal experience in the treatment of PDB. It is crucially important, however, that clinical guidelines accurately portray the level of supporting evidence, and if no evidence exists, this should be highlighted as a gap in knowledge. These guidelines have not done that adequately