Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial.

RATIONALE: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.

Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Evaluation of Proximal Femoral Bone Mineral Density in Cementless Total Hip Arthroplasty: A 3-Arm Prospective Randomized Controlled Trial.

BACKGROUND: Femoral stem design affects periprosthetic bone mineral density (BMD), which may impact long-term survival of cementless implants in total hip arthroplasty (THA). The aim of this study was to examine proximal femoral BMD in 3 morphologically different uncemented femoral stem designs to investigate whether any particular design resulted in better preservation of BMD. METHODS: A total of 119 patients were randomized to receive a proximally coated collarless dual-taper wedge stem, a proximally coated collarless anatomic stem, or a fully coated collarless triple-taper stem. All surgeries were performed via the posterior approach, with mobilization on the day of surgery. Dual x-ray absorptiometry scans (Lunar iDXA, GE Healthcare) assessed BMD across the 7 Gruen zones preoperatively and at 6 weeks and 2 years postoperatively; if available, the native contralateral femur was also assessed as a control. Patient-reported outcomes of pain, function, and health were also assessed at these follow-ups. RESULTS: Averaged across all stems, BMD increased in zones 1 (2.5%), 2 (17.1%), 3 (13.0%), 5 (10%), and 6 (17.9%) at 2 years. Greater preservation of BMD was measured on the lateral cortex (zone 2) for both the dual-taper wedge and anatomic stems (p = 0.019). The dual-taper wedge stem also demonstrated preservation of BMD in the medial calcar (zone 7), while the anatomic and triple-taper stems declined in this region; however, the difference did not reach significance (p = 0.059). Averaged across all stems, BMD decreased in the mid-diaphysis region, distal to the stem tip (zone 4). All stems performed similarly at the time of final follow-up with respect to the patient-reported outcomes. CONCLUSIONS: This study demonstrated maintenance of femoral BMD after use of 3 different cementless femoral stem designs, with all achieving excellent improvements in patient-reported outcomes. The stems designed to load the proximal metaphyseal region resulted in higher BMD in that region. No significant stress-shielding was observed; however, longer follow-up is required to elucidate the impact of this finding on implant survivorship. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Experience of a systematic approach to care and prevention of fragility fractures in New Zealand.

This narrative review describes efforts to improve the care and prevention of fragility fractures in New Zealand from 2012 to 2022. This includes development of clinical standards and registries to benchmark provision of care, and public awareness campaigns to promote a life-course approach to bone health. PURPOSE: This review describes the development and implementation of a systematic approach to care and prevention for New Zealanders with fragility fractures, and those at high risk of first fracture. Progression of existing initiatives and introduction of new initiatives are proposed for the period 2022 to 2030. METHODS: In 2012, Osteoporosis New Zealand developed and published a strategy with objectives relating to people who sustain hip and other fragility fractures, those at high risk of first fragility fracture or falls and all older people. The strategy also advocated formation of a national fragility fracture alliance to expedite change. RESULTS: In 2017, a previously informal national alliance was formalised under the Live Stronger for Longer programme, which includes stakeholder organisations from relevant sectors, including government, healthcare professionals, charities and the health system. Outputs of this alliance include development of Australian and New Zealand clinical guidelines, clinical standards and quality indicators and a bi-national registry that underpins efforts to improve hip fracture care. All 22 hospitals in New Zealand that operate on hip fracture patients currently submit data to the registry. An analogous approach is ongoing to improve secondary fracture prevention for people who sustain fragility fractures at other sites through nationwide access to Fracture Liaison Services. CONCLUSION: Widespread participation in national registries is enabling benchmarking against clinical standards as a means to improve the care of hip and other fragility fractures in New Zealand. An ongoing quality improvement programme is focused on eliminating unwarranted variation in delivery of secondary fracture prevention.

Extending the safety profile of the post-operative administration of an intravenous acetaminophen/ibuprofen fixed dose combination: An open-label, multi-center, single arm, multiple dose study.

PURPOSE: Postoperative pain is typically treated with multimodal analgesia, using systemic acetaminophen and/or nonsteroidal anti-inflammatory drugs in conjunction with opioids as required. The present study aimed to determine the safety and tolerability of repeated doses of an intravenous fixed-dose combination (FDC) of acetaminophen and ibuprofen. METHODS: This multicenter, open-label, single arm, multiple dose study was conducted at 4 centers across New Zealand and the United States between July 2019 and July 2020. Adults (>18 years) requiring multiple doses of parenteral nonopioid analgesics over multiple days following non-laparoscopic general, plastic or orthopedic surgery were eligible. The study drug (acetaminophen 1000 mg+ibuprofen 300 mg) was administered 6-hourly as a 5 min infusion for between 48 h and 5 days. Adverse event data was collected throughout the study, in addition to scheduled vital sign assessments, laboratory tests and electrocardiograms. Participants completed a global evaluation of the FDC at the end of the treatment period. FINDINGS: 232 participants received ≥ 1 dose of the FDC. Most were female (62.1%), White (56.5%) or Black or African American (39.2%), and had undergone orthopedic surgery (85.3%). There was a broad age range (19-87 years), with a mean age of 53.4 years, and 26.3% of participants aged ≥ 65 years. The FDC was safe when used for 48 h to 5 days. Treatment-emergent adverse events (TEAEs) affected 56.0% of participants, the most common were infusion site pain, nausea, infusion site extravasation, constipation, and headache. Minimal changes in vital signs were observed at scheduled timepoints. No clinically significant changes in electrocardiogram assessments occurred. Transient elevations in the hepatic enzymes ALT and AST to < 3 times the upper limit of normal (ULN) affected 10.5% and 9.6% of subjects, elevations to ≥ 3 times the ULN affected 2.6% and 2.2% of subjects, respectively. There were no apparent differences in the safety profile of the FDC in older participants. The FDC was well tolerated; most TEAEs were mild or moderate in severity. Five participants discontinued treatment due to TEAEs, none were considered treatment-related. The FDC was perceived well by study participants; the majority rated their experience as 'excellent' (40.1%) or 'very good' (35.3%). IMPLICATIONS: The safety profile was comparable to previous studies with no novel safety concerns. The FDC was safe, well tolerated, and perceived positively by participants treated for acute pain between 48 h and 5 days following orthopedic or plastic surgery, supporting a favorable risk benefit profile.

Patient characteristics, treatment outcomes and rehabilitation practices for patients admitted with hip fractures using multiple data set analysis.

AIMS: For older patients with hip fracture, we explored patient characteristics, outcomes and osteoporosis treatments for those admitted to rehabilitation compared to those discharged directly from hospital, using data set analysis. METHODS: Retrospective cohort study including all consecutive patients (65 years and over) admitted to Christchurch Hospital over one year. Outcomes were compared for patients in four groups: 1) aged residential care (ARC) residents and 2) not ARC residents discharge from acute orthopaedics, and those discharged from 3) orthogeriatric or 4) general geriatric rehabilitation. Clinical data was extracted from hospital data warehouse using signals from noise. RESULTS: Over 12 months, 415 patients were admitted with hip fracture. Over half (n=282) were transferred for inpatient rehabilitation. Thirty-day mortality was 10%. Mortality at 180 days was 7% in orthogeriatric rehabilitation group and 8% in general rehabilitation group. Length of stay was shorter in orthogeriatric compared with general rehabilitation (median 12.9 vs 20.4 days). Osteoporosis treatment was addressed in 88% of patients in the orthogeriatric group compared with 62% in general rehabilitation group. More patients in orthogeriatric group discharged home compared with general rehabilitation group (70% vs 43%), but functional improvements were similar. For ARC residents discharged following acute admission, length of stay was short (median 6.5 day), but overall 180-day mortality was 7%. The not-ARC resident group discharged directly from hospital was less comorbid than the other groups with lower 180-day mortality (4%). Osteoporosis treatment rates were lower in patients discharged from acute admission (15-42%). CONCLUSION: Mortality was highest in ARC residents discharged from acute orthopaedics. Patients admitted for orthogeriatric rehabilitation had shorter length of stay, lower 30-day mortality, were more likely to return home and most likely to be offered osteoporosis treatment (88%), noting less underlying comorbidity and better baseline functional status in this group. This paper supports further study (eg, randomised trials) to examine the effects of targeted post-surgical rehabilitation for patients with hip fracture and explore measures to increase uptake of osteoporosis treatment.

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension.

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

Enhanced hip fracture management: use of statistical methods and dataset to evaluate a fractured neck of femur fast track pathway-pilot study.

The increasing elderly population and subsequent rise in total hip fracture(s) in this group means more effective management strategies are necessary to improve efficiency. We have changed our patient care strategy from the emergency department (ED), acute orthopaedic wards, operating theatre, post-operation and rehabilitation, and called it Fracture Neck of Femur Fast Track Pathway. All clinical data and actions were captured, integrated and displayed on a weekly basis using 'signalfromnoise' (SFN) software. The initial four months analysis of this project showed significant improvement in patient flow within the hospitals. The overall length of stay was reduced by four days. Time in ED was reduced by 30 minutes, and the wait for rehabilitation reduced by three days. Overall time in rehabilitation reduced by 3-7 days depending on facility. On average, fast track patients spent 95 less hours in hospital, resulting in 631 bed days saved in this period, with projected savings of NZD700,000. No adverse effects were seen in mortality, readmission and functional improvement status. Fractured neck of femur has increasing clinical demand in a busy tertiary hospital. Length of stay, co-morbidities and waiting time for theatres are seen as major barriers to treatment for these conditions. Wait for rehabilitation can significantly lengthen hospital stay; also poor communication between the individual hospital management facets of this condition has been an ongoing issue. Lack of instant and available electronic information on this patient group has also been seen as a major barrier to improvement. This paper demonstrates how integration of service components that are involved in fractured neck of femur can be achieved. It also shows how the use of electronic data capture and analysis can give a very quick and easily interpretable data trend that will enable change in practice. This paper indicates that cooperation between health professionals and practitioners can significantly improve the length of stay and the time in which patients can be returned home. Full interdisciplinary involvement was the key to this approach. The use of electronic data capture and analysis can be used in many other health pathways within the health system.

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial.

BACKGROUND: There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo(®)/ Forsteo(®), recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing. QUESTIONS/PURPOSES: We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety. METHODS: We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 µg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally expected treatment effect but had approximately 80% power to detect a larger difference of 12% between treatment groups for risk of revision surgery. RESULTS: The proportion of patients undergoing revision surgery at 12 months was 14% (11 of 81) in the placebo group versus 17% (13 of 78) in the teriparatide group. Central Adjudication Committee review excluded two of these patients treated with placebo from the primary analysis. After exclusions, the proportion of patients who did not undergo revision surgery at 12 months (primary endpoint) was not different between the study and placebo groups, at 88% in the placebo group (90% CI, 0.79-0.93) versus 84% in the teriparatide group (90% CI, 0.75-0.90; p = 0.743). There also were no differences between groups in the proportion of patients achieving radiographic fracture healing at 12 months (75% [61 of 81] placebo versus 73% [57 of 78] teriparatide; odds ratio, 0.89; 90% CI, 0.46-1.72; p = 0.692) or in measures of pain control (such as pain during ambulation, 92% [55 of 62] placebo versus 91% [52 of 57] teriparatide; odds ratio, 0.91; 90% CI, 0.25-3.37; p = 0.681). The frequency of patients reporting adverse events was 49% [40 of 81] in the placebo group versus 45% [35 of 78] in the teriparatide group (p = 0.634) during the 6-month treatment period. CONCLUSIONS: The small sample size limited this study's power to detect potential differences, and the results are exploratory. With the patients available, teriparatide did not decrease the risk of revision surgery, improve radiographic signs of fracture healing, or decrease pain compared with the placebo. The adverse event data observed were consistent with the teriparatide safety profile. Functional and health outcome data from the studies may help improve our understanding of patients recovering from femoral neck fractures. Further large controlled studies are required to determine the effect of teriparatide on fracture healing. LEVEL OF EVIDENCE: Level II, prospective study.

Measurement of bone density around the Oxford medial compartment knee replacement using iDXA. A precision study.

The goal of this study was to evaluate whether the Lunar iDXA densitometer can accurately measure the bone mineral density (BMD) around the tibial component of the Oxford unicompartment knee replacement (UKR). Both knees in 20 patients were measured 3 times in the supine position with repositioning between each scan. We chose 7 regions of interest to evaluate the bone density around the implant. Small but significant differences between the implant and nonimplanted knee were noticed with the nonimplanted knee having slightly higher BMD and bone mineral content (BMC) in areas 1-3 (p≤0.001) and area 6 (p=0.002). There was higher BMD in area 4 (p=0.028). The precision for BMD in the 7 areas of interest in the implanted knee varied between 0.55% and 4.04% and BMC between 1.8% and 5.3%. There was no significant difference in the precision between the nonimplanted and implanted knees. Prospective serial measurements around the Oxford UKR using iDXA will be able to assess specific areas of stress shielding and potential implant stability, which is likely to help predict the survival of the implant.

Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial.

Osteoporosis is a chronic disease and requires long-term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off-treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off-treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During treatment, more placebo-treated subjects as compared with denosumab-treated subjects sustained a fracture and had significant decreases in BMD. During the off-treatment period (median 0.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49-1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off-treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months.

Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial.

BACKGROUND: Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. METHODS: Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. RESULTS: Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). CONCLUSIONS: Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.

Recruitment strategies for an osteoporosis clinical trial: analysis of effectiveness.

AIM: To examine the effectiveness of a planned rapid recruitment strategy in an osteoporosis clinical trial. METHODS: Multiple recruitment methods were explored, including media advertising, searching bone density scan and X-ray results in specialist and primary practice databases, community initiatives, and generation of research centre and study-specific pamphlets. RESULTS: Of 246 women screened, 41 consenting to the study, only 14 were randomised. Thus, 232 (94%) volunteers were screen failures, ineligible or declined to participate. With regard to the cost-effectiveness of all recruitment strategies, searching the research centre database was the most successful, with four women randomised at a cost of approximately NZ$302 per volunteer. Other strategies were less cost-effective. CONCLUSION: Obtaining a specific study cohort can be achieved by a comprehensive, targeted, rapid recruitment program. A research centre database search was the most successful and cost-effective recruitment modality in this small study.

Atypical subtrochanteric fractures, bisphosphonates, blinded radiological review.

BACKGROUND: Recent reports have suggested that a certain type of subtrochanteric and diaphyseal femoral fractures maybe associated with bisphosphonate (BP) therapy. We assessed the association between BP use in atypical and typical femoral fractures in a retrospective study and also looked at the rate of coding errors. METHODS: All cases between July 2003 and June 2008 with International Classification of Disease, 10th revision discharge codes for femoral fractures (S72.2 subtrochanteric and S72.3 fracture of shaft of femur) were reviewed. Cases were excluded if there was significant trauma, underlying bone disease or coding error. The remaining cases' films were assessed by an independent, blinded, single radiologist to assess for atypical features (thickened cortices, transverse fractures, medial cortical spike) with additional exclusion criteria of periprosthetic fractures and bone pathology. Odds ratios were calculated comparing BP use in atypical and typical fractures. RESULTS: Six atypical fractures were found in the study period. Compared with the 65 typical fractures, there was an association between BP use and atypical fractures (odds ratio 5.5) but it did not reach statistical significance (0.97-31). Atypical femoral fractures accounted for <0.1% of total fracture admissions during this period. There was a 20% rate of miscoding. CONCLUSION: This study shows a nonsignificant trend towards alendronate/BP use and atypical femoral fractures compared with typical femoral fractures. These fractures were rare <0.1% and the benefit and treatment of osteoporosis with BPs currently seems likely to outweigh the perceived risks. Individual case and radiology review is important as coding errors were frequent.

Production, composition and toxicology studies of Enzogenol® Pinus radiata bark extract.

Enzogenol® pine bark extract is a dietary supplement and food ingredient produced by water extraction of Pinus radiata. We present production method, composition, and safety data from rat and dog toxicological and human clinical studies. The dry powder contains proanthocyanidins (>80%), taxifolin (1-2%), other flavonoids and phenolic acids (up to 8%), and carbohydrates (5-10%). Reverse mutation assays showed lack of mutagenic activity. Single and 14-day repeat dosing in rats and dogs had no influence on body weight, feed consumption, blood chemistry, and haematology at any dose level. There were no treatment related findings on gross and detailed necroscopy, organ weights, organ weight ratios and histology. The only adverse events were emesis and diarrhoea in dogs occurring mainly in un-fed condition and at the highest dose level in a total of 18% of applications. The MTD and NOAEL in the present rat and dog studies were 2500 and 750 mg/kg/day, respectively. Consumption of 480 mg/day for 6 months and 960 mg/day for 5 weeks in two human studies showed Enzogenol® had no adverse influence on liver and kidney function, haematology, and did not cause any adverse events. Our studies indicate lack of toxicity of Enzogenol® and support safe use as a food ingredient.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study.

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores -2.0 to -3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D(3) and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10-50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus -0.4% (-3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10-50 mg, n = 26-29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and cross-linked C-telopeptide (CTX) were approximately -55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10-50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated.

Memantine and functional communication in Alzheimer's disease: results of a 12-week, international, randomized clinical trial.

Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimer's disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10-19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement on the FLCI (placebo: -0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: -5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers.