Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

In silico methods to evaluate Fracture Risk and Bone Mineral Density changes in patients undergoing Total Hip Replacement

La sostituzione totale d’anca è uno degli interventi chirurgici con le più alte percentuali di successo. Esistono due varianti di protesi d’anca che differiscono in base al metodo di ancoraggio all’osso: cementate (fissaggio tramite cemento osseo) e non cementate (fissaggio tramite forzamento). Ad oggi, i chirurghi non hanno indicazioni quantitative di supporto per la scelta fra le due tipologie di impianto, decidendo solo in base alla loro esperienza. Due delle problematiche che interessano le protesi non cementate sono la possibilità di frattura intra-operatoria durante l’inserimento forzato e il riassorbimento osseo nel periodo di tempo successivo all’intervento. A partire da rilevazioni densitometriche effettuate su immagini da TC di pazienti sottoposti a protesi d’anca non cementata, sono stati sviluppati due metodi: 1) per la valutazione del rischio di frattura intra-operatorio tramite analisi agli elementi finiti; 2) per la valutazione della variazione di densità minerale ossea (tridimensionalmente attorno alla protesi) dopo un anno dall’operazione. Un campione di 5 pazienti è stato selezionato per testare le procedure. Ciascuno dei pazienti è stato scansionato tramite TC in tre momenti differenti: una acquisita prima dell’operazione (pre-op), le altre due acquisite 24 ore (post 24h) e 1 anno dopo l’operazione (post 1y). I risultati ottenuti hanno confermato la fattibilità di entrambi i metodi, riuscendo inoltre a distinguere e a quantificare delle differenze fra i vari pazienti. La fattibilità di entrambe le metodologie suggerisce la loro possibilità di impiego in ambito clinico: 1) conoscere la stima del rischio di frattura intra-operatorio può servire come strumento di guida per il chirurgo nella scelta dell’impianto protesico ottimale; 2) conoscere la variazione di densità minerale ossea dopo un anno dall’operazione può essere utilizzato come strumento di monitoraggio post-operatorio del paziente.

Mitigating surgical risk in patients undergoing hip arthroplasty for fractures of the proximal femur

Recently the National Patient Safety Agency in the United Kingdom published a report entitled "Mitigating surgical risk in patients undergoing hip arthroplasty for fractures of the proximal femur". A total of 26 deaths had been reported to them when cement was used at hemiarthroplasty between October 2003 and October 2008. This paper considers the evidence for using cement fixation of a hemiarthroplasty in the treatment of hip fractures.

Is there a need for routine follow-up after primary total hip arthroplasty?

Background: The objective of routine outpatient assessment of well functioning patients after primary total hip arthroplasty (THA) is to detect asymptomatic failure of prostheses to guide recommendations for early intervention. We have observed that the revision of THAs in asymptomatic patients is highly uncommon. We therefore question the need for routine follow-up of patients after THA. Methods: A prospective analysis of an orthopaedic database identified 158 patients who received 177 revision THAs over a 4 year period. A retrospective chart review was conducted. Patient demographics, primary and revision surgery parameters and follow-up information was recorded and cross referenced with AOA NJRR data. Results: 110 THAs in 104 patients (average age 70.4 (SD 9.8 years). There were 70 (63.6%) total, 13 (11.8%) femoral and 27 (24.5%) acetabular revisions. The indications for revision were aseptic loosening (70%), dislocation (8.2%), peri-prosthetic fracture (7.3%), osteolysis (6.4%) and infection (4.5%). Only 4 (3.6%) were asymptomatic revisions. A mean of 5.3 (SD 5.2 and 1.9 (SD 5.3 follow-up appointments were required before revision in patients with and without symptoms, respectively. The average time from the primary to revision surgery was 11.8 (SD 7.23) years. Conclusions: We conclude that patients with prostheses with excellent long term clinical results as validated by Joint Registries, routine follow-up of asymptomatic THA should be questioned and requires further investigation. Based on the work of this study, the current practice of routine follow-up of asymptomatic THA may be excessively costly and unnecessary and a less resource-intensive review method may be more appropriate.

Re-cementing in revision total hip replacement

Removal of well-fixed cement at revision surgery risks bone loss, cortical perforation and fracture, is time-consuming, technically demanding and carries increased risks for the patient. The cement-in-cement technique avoids these problems and when used appropriately has given favourable results at our centre when used on both the femoral and acetabular sides of the articulation. A modified technique has also been used in selected cases of infection and peri-prosthetic fracture. This chapter highlights the results to date and the operative techniques employed. It is essential to recognise that this technique relies fundamentally on the presence of a well-fixed cement mantle, and it is imperative that the criteria laid out are adhered to in order to achieve success. If there is loosening or lysis on the femoral side extending distal to the lesser trochanter or around more than just the periphery of the acetabular cement mantle, then alternative revision techniques should be employed.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 Duncan et al.

Risedronate in adults with osteogenesis imperfecta type I: Increased bone mineral density and decreased bone turnover, but high fracture rate persists

Summary Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Introduction Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Methods Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Results Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm 2, p=0.007; mean Z-score, -1.93 vs. -1.58, p=0.002), with no significant change at TH. P1NP fell by 37% (p=0.00041), with no significant change in bone ALP (p=0.15). Bone pain did not change significantly (p=0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Conclusions Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Cement mantle fatigue failure in total hip replacement: Experimental and computational testing

One possible loosening mechanism of the femoral component in total hip replacement is fatigue cracking of the cement mantle. A computational method capable of simulating this process may therefore be a useful tool in the preclinical evaluation of prospective implants. In this study, we investigated the ability of a computational method to predict fatigue cracking in experimental models of the implanted femur construct. Experimental specimens were fabricated such that cement mantle visualisation was possible throughout the test. Two different implant surface finishes were considered: grit blasted and polished. Loading was applied to represent level gait for two million cycles. Computational (finite element) models were generated to the same geometry as the experimental specimens, with residual stress and porosity simulated in the cement mantle. Cement fatigue and creep were modelled over a simulated two million cycles. For the polished stem surface finish, the predicted fracture locations in the finite element models closely matched those on the experimental specimens, and the recorded stem displacements were also comparable. For the grit blasted stem surface finish, no cement mantle fractures were predicted by the computational method, which was again in agreement with the experimental results. It was concluded that the computational method was capable of predicting cement mantle fracture and subsequent stem displacement for the structure considered. (C) 2006 Elsevier Ltd. All rights reserved.

Comparison of two osteoporotic fracture management pathways: experience at 1 year

Introduction: Osteoporosis presenting as low-impact fractures to traumatology units is often undiagnosed and under-treated. Results from the Osteocare study in Lausanne (a nurse based intervention, passive pathway) showed that only 19% of patients received management for osteoporosis, and in the literature [1], the rate is between 10-25%. We have evaluated a different management concept, based on the systematic assessment of patients with osteoporotic fractures during and after hospitalization (active pathway). Methods: Inpatients admitted to the Department of Musculoskeletal Medicine for a fragility fracture were identified by a nurse according to a predefined questionnaire and were then clinically evaluated by a doctor. Based on the results, a management plan was proposed to the patients. Patients could choose between follow up either by their GP or by the Centre of Bone Disease of the CHUV. For patients who chose follow-up in our Centre, we assessed their adherence to medical follow-up 1 year inclusion. The results of patients who had been evaluated in our cohort between the 1 November 2008 and the 1 December 2009 were analysed. Results: 573 inpatients received specific management of their osteoporotic fracture over 18 months. The mean age was 77 y (31-99), 81% were women (203 hip fractures, 40 pelvis fractures, 101 arm fractures, 57 vertebral fractures, 63 ankle fractures, and 25 others sites). During the study period, 303 patients received a proposition of a specific treatment. 39 (13%) chose a follow up with the GP, 19 (6%) dead and 245 (81%) preferred a follow up in our Centre. After 1 year, 166 (67%) patients are under follow up in our outpatient clinic. Conclusion: With an active clinical pathway that starts during the hospitalization, consisting on a nursing evaluation followed by a medical consultation by an expert in osteoporosis, the adherence increased from 19% to 67% in terms of follow up. These results lead us to propose a consultation with a doctor experienced in osteoporosis after all osteoporotic fractures.

Bone mineral density measurement and osteoporosis treatment after a fragility fracture in older adults: regional variation and determinants of use in Quebec

Affiliation: Pierre Dagenais : Hôpital Maisonneuve-Rosemont, Faculté de médecine, Université de Montréal

Prevalence and risk factors of radiographic vertebral fracture in Brazilian community-dwelling elderly

The prevalence and risk factors of radiographic vertebral fracture were determined among Brazilian community-dwelling elderly. Vertebral fractures were a common condition in this elderly population, and lower hip bone mineral density was a significant risk factor for vertebral fractures in both genders. The aim of the study was to estimate the prevalence of radiographic vertebral fracture and investigate factors associated with this condition in Brazilian community-dwelling elderly. This cross-sectional study included 943 elderly subjects (561 women and 382 men) living in So Paulo, Brazil. Thoracic and lumbar spine radiographs were obtained, and vertebral fractures were evaluated using Genant`s semiquantitative method. Bone mineral density (BMD) was measured by dual X-ray absorptiometry, and bone biochemical markers were also evaluated. Female and male subjects were analyzed independently, and each gender was divided into two groups based on whether vertebral fractures were present. The prevalence of vertebral fracture was 27.5% (95% CI 23.8-31.1) in women and 31.8% in men (95% CI 27.1-36.5) (P = 0.116). Cox regression analyses using variables that were significant in the univariate analysis showed that age (prevalence ratio = 1.03, 95% CI 1.01-1.06; p = 0.019) and total femur BMD (PR = 0.27, 95% CI 0.08-0.98; p = 0.048) were independent factors in predicting vertebral fracture for the female group. In the male group, Cox regression analyses demonstrated that femoral neck BMD (PR = 0.26, 95% CI 0.07-0.98; p = 0.046) was an independent parameter in predicting vertebral fractures. Our results suggest that radiographic vertebral fractures are common in Brazilian community-dwelling elderly and that a low hip BMD was an important risk factor for this condition in both genders. Age was also significantly correlated with the presence of vertebral fractures in women.

Modular hybrid total hip arthroplasty. Experimental study in dogs

Background: This prospective experimental study evaluated the surgical procedure and results of modular hybrid total hip arthroplasty in dogs.Methods: Ten skeletally mature healthy mongrel dogs with weights varying between 19 and 27 kg were used. Cemented modular femoral stems and uncemented porous-coated acetabular cups were employed. Clinical and radiographic evaluations were performed before surgery and at 30, 60, 90, 120, 180 and 360 days post-operation.Results: Excellent weight bearing was noticed in the operated limb in seven dogs. Dislocation followed by loosening of the prosthesis was noticed in two dogs, which were therefore properly treated with a femoral head osteotomy. Femoral fracture occurred in one dog, which was promptly treated with full implant removal and femoral osteosynthesis.Conclusions: The canine modular hybrid total hip arthroplasty provided excellent functionality of the operated limb.

Tomographic index as auxiliary criteria for surgery indication in fracture dislocation of acetabulum posterior wall

There are situations which the tomographic exam is done on the affected hip or situations where the contralateral hip presents abnormalities that make it impossible to compare. In this study we aimed to evaluate a tomographic index that does not require comparison between the both hips. Twenty two patients with unilateral acetabular fracture dislocation with fracture of posterior wall were studied. We established the relationship between the remaining posterior wall and the femoral head diameter (head/wall index-H/W index). We evaluated 45 two-dimensional computed tomography scan in normal hips and established the H/W index. In 45 normal hips we simulated a posterior wall fracture with involvement of 25% and 30% of the posterior wall and calculated the H/W index. We divided into five groups with five different H/W index (fractured group with non surgical treatment; fractured group; normal group; normal group with simulated fracture of 25% and; 30% of the posterior wall). 2.4 was the lowest limit of confidence interval of the group with 25% of the posterior wall fracture. When we analyzed the confidence interval of the 30% fracture group the upper limit of the confidence interval was 2.7, close to the lower limit of the surgical group that was 2.9. Thus, we suggest the 2.4 the H/W index limit as an auxiliary criteria to indicate whether or not to operate. H/W index is helpful to decide whether or not surgery indication in the fracture dislocation of the posterior wall of the acetabulum. © 2012 Fujiki et al.; licensee BioMed Central Ltd.