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.

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.

Fracture rates lower in rural than urban communities : the Geelong Osteoporosis Study

Background: Urban and rural communities differ in the incidence of several diseases including coronary heart disease and some cancers. Lower hip fracture rates among rural than urban populations have been reported but few studies have compared rural and urban fractures at sites other than the hip.

Objective: To compare total and site specific fracture rates among adult residents of rural and urban communities within the same population.

Design and setting: This is a population based study on osteoporosis in Australia. All fractures occurring in adult residents over a two year period were ascertained using radiological reports. The rural and urban areas are in close proximity, with the same medical, hospital, and radiological facilities permitting uniform fracture ascertainment.

Main outcome measures: All fracture rates were age adjusted and sex adjusted to the Australian population according to the 1996 census of the Australian Bureau of Statistics and described as the rate per 10 000 person years. The p values refer to the adjusted rate difference.

Results: The hip fracture rate (incidence per 10 000 person years) was 32% lower (39 v 57, p<0.001), and the total fracture rate 15% lower (160 v 188, p=0.004) among rural than urban residents, respectively. The lower fracture rates in the rural population were also apparent for pelvic fractures.

Conclusion: In the older rural population, lower fracture rates at sites typically associated with osteoporosis suggest environmental factors may have a different impact on bone health in this community. If the national rate of hip fracture could be reduced to that of the rural population, the projected increase in hip fracture number attributable to aging of the population could be prevented.

Age- and gender-specific rate of fractures in Australia : a population-based study

There is little population-based data concerning fracture rates in Australia. We ascertained all fractures occurring during 2 years in adults aged 35 years and over residing within a defined region (population 218 000), representative of the Australian population. The major strength of this study is the comprehensive ascertainment of fractures, which was ensured by regular searches of the only two radiologic providers in the Geelong Osteoporosis Study region. Nevertheless, vertebral fractures are likely to be underestimated since our ascertainment relied on a clinical indication for a medical imaging procedure. Among those aged 35 – 55 years, the fracture rate (persons per 10 000/year) in men was about double the rate in women (65 vs 35). The fracture rate was almost 7 times higher in women over 60 years versus women less than 55 years of age. In contrast, the fracture rate in men over 60 years was only 50% higher than in men less than 55 years of age (72 vs 104). Fracture rates in women and men were highest at the hip (28 and 10 respectively), spine (21 and 7), distal forearm (Colles’) (18 and 4) and humerus (11 and 3), and were 3–4 times higher in women than men. These fractures accounted for 63% of all fractures in women and 32% in men. By contrast, the rate of lower leg and ankle fractures was less than 10 per 10 000 in both women and men and did not increase to the same extent with age. Hip fracture rates appear high, particularly among the older age strata, compared with retrospective ascertainment in other populations. In Australia, as in many other countries, there is an increasing longevity of the population. The number of women aged 90 years and over increased by 32% and the number of men of this age increased by 48% in the 5 years between the Australian national census of 1991 and 1996. Given stable fracture rates, the substantial health burden imposed by age-related fractures, particularly hip fractures, will continue to escalate in both women and men.

A Multifaceted Strategy for Implementation of the Ottawa Ankle Rules in Two Emergency Departments

Problem Despite widespread acceptance of the Ottawa ankle rules for assessment of acute ankle injuries, their application varies considerably. Design Before and after study. Background and setting Emergency departments of a tertiary teaching hospital and a community hospital in Australia. Key measures for improvement Documentation of the Ottawa ankle rules, proportion of patients referred for radiography, proportion of radiographs showing a fracture. Strategies for change Education, a problem specific radiography request form, reminders, audit and feedback, and using radiographers as “gatekeepers.” Effects of change Documentation of the Ottawa ankle rules improved from 57.5% to 94.7% at the tertiary hospital, and 51.6% to 80.8% at the community hospital (P<0.001 for both). The proportion of patients undergoing radiography fell from 95.8% to 87.2% at the tertiary hospital, and from 91.4% to 78.9% at the community hospital (P<0.001 for both). The proportion of radiographs showing a fracture increased from 20.4% to 27.1% at the tertiary hospital (P=0.069), and 15.2% to 27.2% (P=0.002) at the community hospital. The missed fracture rate increased from 0% to 2.9% at the tertiary hospital and from 0% to 1.6% at the community hospital compared with baseline (P=0.783 and P=0.747). Lessons learnt Assessment of case note documentation has limitations. Clinician groups seem to differ in their capacity and willingness to change their practice. A multifaceted change strategy including a problem specific radiography request form can improve the selection of patients for radiography.

A cluster randomised controlled trial to evaluate a policy of making hip protectors available to residents of nursing homes

Objectives: to evaluate the effectiveness of a policy of making hip protectors available to residents of nursing homes. Design: a cluster randomised controlled trial of the policy in nursing and residential homes, with the home as the unit of randomisation. Setting: 127 nursing and residential homes in the greater Belfast area of Northern Ireland. Participants: 40 homes in the intervention group (representing 1,366 occupied beds) and 87 homes in the control group (representing 2,751 occupied beds). Interventions: a policy of making hip protectors available free of charge to residents of nursing homes and supporting the implementation process by employing a nurse facilitator to encourage staff in the homes to promote their use, over a 72-week period. Main outcome measures: the rate of hip fractures in intervention and control homes, and the level of adherence to use of hip protectors. Results: there were 85 hip fractures in the intervention homes and 163 in the control homes. The mean fracture rate per 100 residents was 6.22 in the intervention homes and 5.92 in the control homes, giving an adjusted rate ratio for the intervention group compared to the control group of 1.05 (95% CI 0.77, 1.43, P = 0.76). Initial acceptance of the hip protectors was 37.2% (508/1,366) with adherence falling to 19.9% (272/1,366) at 72 weeks. Conclusions: making hip protectors available to residents of nursing and residential homes did not reduce the rate of hip fracture.

Skeletal morbidity among survivors of critical illness

Objectives: To describe the incident fracture rate in survivors of critical illness and to compare fracture risk with populationmatched control subjects.

Design: Retrospective longitudinal case– cohort study.

Setting: A tertiary adult intensive care unit in Australia. Patients: All patients ventilated admitted to intensive care and requiring mechanical ventilation for >48 hrs between January 1998 and December 2005.

Interventions: None.

Measurements and Main Results: New fractures were identified in the study population for the postintensive care unit period (intensive care unit discharge to January 2008). The incident fracture rate and age-adjusted fracture risk of the female intensive care unit population were compared with the general population adult females derived from the Geelong Osteoporosis Study. Over the 8-yr period, a total of 739 patients (258 women, 481 men) were identified. After a median follow-up of 3.7 yrs (interquartile range, 2.0–5.9 yrs) for women and 4.0 yrs (interquartile range, 2.1–6.1 yrs) for men, incident fracture rates (95% confidence interval) per 100 patient years were 3.84 (2.58 –5.09) for females 2.41 (1.73–3.09) for males. Compared with an age-matched random population-based sample of women, elderly women were at increased risk for sustaining an osteoporosisrelated fracture after critical illness (hazard ratio, 1.65; 95% confidence interval, 1.08 –2.52; p .02).

Conclusions: The increase in fracture risk observed in postintensive care unit older females suggests an association between critical illness and subsequent skeletal morbidity. The explanation for this association is not explored in this study and includes the effects of pre-existing patient factors and/or direct effects of critical illness. Prospective research evaluating risk factors, the relationship between critical illness and bone turnover, the extent and duration of bone loss, and the associated morbidity in this population is warranted.

Adjacent vertebral failure after vertebroplasty: a biomechanical study of low-modulus PMMA cement

PMMA is the most common bone substitute used for vertebroplasty. An increased fracture rate of the adjacent vertebrae has been observed after vertebroplasty. Decreased failure strength has been noted in a laboratory study of augmented functional spine units (FSUs), where the adjacent, non-augmented vertebral body always failed. This may provide evidence that rigid cement augmentation may facilitate the subsequent collapse of the adjacent vertebrae. The purpose of this study was to evaluate whether the decrease in failure strength of augmented FSUs can be avoided using low-modulus PMMA bone cement. In cadaveric FSUs, overall stiffness, failure strength and stiffness of the two vertebral bodies were determined under compression for both the treated and untreated specimens. Augmentation was performed on the caudal vertebrae with either regular or low-modulus PMMA. Endplate and wedge-shaped fractures occurred in the cranial and caudal vertebrae in the ratios endplate:wedge (cranial:caudal): 3:8 (5:6), 4:7 (7:4) and 10:1 (10:1) for control, low-modulus and regular cement group, respectively. The mean failure strength was 3.3 +/- 1 MPa with low-modulus cement, 2.9 +/- 1.2 MPa with regular cement and 3.6 +/- 1.3 MPa for the control group. Differences between the groups were not significant (p = 0.754 and p = 0.375, respectively, for low-modulus cement vs. control and regular cement vs. control). Overall FSU stiffness was not significantly affected by augmentation. Significant differences were observed for the stiffness differences of the cranial to the caudal vertebral body for the regular PMMA group to the other groups (p < 0.003). The individual vertebral stiffness values clearly showed the stiffening effect of the regular cement and the lesser alteration of the stiffness of the augmented vertebrae using the low-modulus PMMA compared to the control group (p = 0.999). In vitro biomechanical study and biomechanical evaluation of the hypothesis state that the failure strength of augmented functional spine units could be better preserved using low-modulus PMMA in comparison to regular PMMA cement.

Variation of the mechanical properties of PMMA to suit osteoporotic cancellous bone

Poly(methyl methacrylate) (PMMA) is by far the most frequently used bone substitute material for vertebroplasty. However, there are serious complications, such as cement leakage and an increased fracture rate of the adjacent vertebral bodies. The latter may be related to the mechanical properties of the augmented segment within the osteoporotic spine. A possible counter-measure is prophylactic augmentation at additional levels, but this aggravates the risk for the patient. Introduction of pores is a possible method to reduce the inherent high stiffness of PMMA. This study investigates the effect of porosity on the mechanical properties of PMMA bone cement. Different fractions of a highly viscous liquid were mixed into the PMMA during preparation. An open-porous material with adjustable mechanical properties resulted after removal of the aqueous phase. Different radiopacifiers were admixed to investigate their suitability for vertebroplasty. The final material was characterized mechanically by compressive testing, microscopically and radiologically. In addition, the monomer release subsequent to hardening was measured by means of gas chromatography. The Young's modulus in compression could be varied between 2800 +/- 70 MPa and 120 +/- 150 MPa, and the compression ultimate strength between 170 +/- 5 MPa and 8 +/- 9 MPa for aqueous fractions ranging between 0 and 50% of volume. Only a slight decrease of the Young's modulus and small changes of ultimate strength were found when the mixing time was increased. An organic hydrophilic and lipophilic radiopacifier led to a higher Young's modulus of the porous material; however, the ultimate strength was not significantly affected by adding different radiopacifiers to the porous cement. The radiopacity was lost after washing the aqueous phase out of the pores. No separation occurred between the aqueous and the PMMA phase during injection into an open porous ceramic material. The monomer released was found to increase for increasing aqueous fractions, but remained comparable in magnitude to standard PMMA. This study demonstrates that a conventional PMMA can be modified to obtain a range of mechanical properties, including those of osteoporotic bone.

Incidence and clinical implications of stent fractures of the Xpert self-expanding nitinol stent in infrainguinal arteries

BACKGROUND: Different stents in infrainguinal arteries have recently been associated with stent fractures and unfavorable clinical outcome, although data is limited regarding fractures of the Xpert selfexpanding nitinol stent. Thus, purpose of the present investigation was to evaluate its incidence and clinical implications in lower limb arteries. PATIENTS AND METHODS: Fifty-three consecutive patients (53 limbs) with peripheral arterial disease underwent secondary Xpert stent implantation due to suboptimal primary balloon angioplasty (PTA). Median age was 76 years. Stent fractures were evaluated by plain X-ray at median follow-up of 16 months. Stent patency was assessed by duplex ultrasound and sustained clinical improvement was defined as improvement of the ABI of > or = 0.10 together with improvement of at least one Rutherford class above the baseline finding throughout follow-up. RESULTS: Median length of femoropopliteal and infrapopliteal lesion was 3.0 and 2.3 cm, respectively. Sixtyfive stents were implanted in 43 limbs with femoropopliteal and 10 stents in 10 limbs with infrapopliteal lesion, respectively. Stent fractures occurred in 3 of 43 limbs (7.0%) of patients with femoropopliteal lesion with stent-based fracture rate of 4.6%. All fractured stents showed multiple struts fractures and occurred in the distal and middle superficial femoral artery. No stent fracture was observed in infrapopliteal lesions. The fractured stents were not associated with any clinical deterioration. Sustained clinical improvement was 71.0% and 54.6% for femoropopliteal and infrapopliteal lesions, respectively. Stent patency assessed by duplex was 65.2 and 63.9% for femoropopliteal and infrapopliteal lesions, respectively. CONCLUSIONS: Fractures of the Xpert stent were seldom and not associated with unfavorable clinical outcome at midterm follow-up.

Complications with computer-aided designed/computer-assisted manufactured titanium and soldered gold bars for mandibular implant-overdentures: short-term observations

BACKGROUND Implant-overdentures supported by rigid bars provide stability in the edentulous atrophic mandible. However, fractures of solder joints and matrices, and loosening of screws and matrices were observed with soldered gold bars (G-bars). Computer-aided designed/computer-assisted manufactured (CAD/CAM) titanium bars (Ti-bars) may reduce technical complications due to enhanced material quality. PURPOSE To compare prosthetic-technical maintenance service of mandibular implant-overdentures supported by CAD/CAM Ti-bar and soldered G-bar. MATERIALS AND METHODS Edentulous patients were consecutively admitted for implant-prosthodontic treatment with a maxillary complete denture and a mandibular implant-overdenture connected to a rigid G-bar or Ti-bar. Maintenance service and problems with the implant-retention device complex and the prosthesis were recorded during minimally 3-4 years. Annual peri-implant crestal bone level changes (ΔBIC) were radiographically assessed. RESULTS Data of 213 edentulous patients (mean age 68 ± 10 years), who had received a total of 477 tapered implants, were available. Ti-bar and G-bar comprised 101 and 112 patients with 231 and 246 implants, respectively. Ti-bar mostly exhibited distal bar extensions (96%) compared to 34% of G-bar (p < .001). Fracture rate of bars extensions (4.7% vs 14.8%, p < .001) and matrices (1% vs 13%, p < .001) was lower for Ti-bar. Matrices activation was required 2.4× less often in Ti-bar. ΔBIC remained stable for both groups. CONCLUSIONS Implant overdentures supported by soldered gold bars or milled CAD/CAM Ti-bars are a successful treatment modality but require regular maintenance service. These short-term observations support the hypothesis that CAD/CAM Ti-bars reduce technical complications. Fracture location indicated that the titanium thickness around the screw-access hole should be increased.

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.

Temperature and strain-rate dependent fracture strength of graphynes

Graphyne is an allotrope of graphene. The mechanical properties of graphynes (α-, β-, γ- and 6,6,12-graphynes) under uniaxial tension deformation at different temperatures and strain rates are studied using molecular dynamics simulations. It is found that graphynes are more sensitive to temperature changes than graphene in terms of fracture strength and Young's modulus. The temperature sensitivity of the different graphynes is proportionally related to the percentage of acetylenic linkages in their structures, with the α-graphyne (having 100% of acetylenic linkages) being most sensitive to temperature. For the same graphyne, temperature exerts a more pronounced effect on the Young's modulus than fracture strength, which is different from that of graphene. The mechanical properties of graphynes are also sensitive to strain rate, in particular at higher temperatures.

Size independent fracture energy from fracture energy release rate in plain concrete beams

Size independent fracture energy and size effect on fracture energy are the key concerns for characterization of concrete fracture. Although there have been inconsistencies in results, a consensual fact is that the fracture energy from a large specimen is size independent. The fracture energy is proportional to the size of the fracture process zone (FPZ). FPZ size increases with size of the specimen, but the rate of increase of FPZ size decreases with increase in specimen size 1] implying that rate of increase of fracture energy decreases with increase in specimen size, more appropriately with increase in un-cracked ligament length. The ratio of fracture energy to the un-cracked ligament length almost becomes a constant at larger un-cracked ligament lengths. In the present study an attempt is made to obtain size independent fracture energy from fracture energy release rate. (C) 2012 Elsevier Ltd. All rights reserved.

An experimental study on loading rate effect on acoustic emission based b-values related to reinforced concrete fracture

This article reports on analysis of fracture processes in reinforced concrete (RC) beams with acoustic emission (AE) technique. An emphasis was given to study the effect of loading rate on variation in AE based b-values with the development of cracks in RC structures. RC beams of length 3.2 m were tested under load control at a rate of 4 kN/s, 5 kN/s and 6 kN/s and the b-value analysis available in seismology was used to study the fracture process in RC structures. Moreover, the b-value is related to the strain in steel to assess the damage state. It is observed that when the loading rate is higher, quick cracking development lead to rapid fluctuations and drops in the b-values. Also it is observed that concrete behaves relatively more brittle at higher loading rates (or at higher strain rates). The average b-values are lower as a few but larger amplitudes of AE events occur in contrast to more number of low amplitude AE events occur at low loading rates (or at low strain rates). (C) 2014 Elsevier Ltd. All rights reserved.