The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis.

OBJECTIVE: To evaluate the efficacy of available bisphosphonate therapies regarding the prevention of vertebral, hip, and nonvertebral-nonhip fractures in postmenopausal women with osteoporosis. METHODS: Eight randomized placebo controlled trials investigating the effects of zoledronic acid (1 study), alendronate (3), ibandronate (1), risedronate (2), and etidronate (1) in terms of fractures with a follow-up of 3 years (or 2 years if used for registration purposes) were identified with a systematic literature search. The endpoints of interest were morphometric vertebral fractures, hip fractures, and nonvertebral-nonhip fractures. Results of all trials were analyzed simultaneously with a Bayesian network meta-analysis by which the relative treatment effect of 1 intervention to another can be obtained in the absence of head-to-head evidence. Given the estimated treatment effects and their uncertainty, the Bayesian approach allowed for calculations of the probability of which bisphosphonate is best in terms of overall fracture reductions by weighting the impact of each by type of fracture on costs, quality of life, and incidence. RESULTS: There is a 79% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all bisphophonates compared. Zoledronic acid showed a relative risk (RR) of 0.30 (95% Credible Interval 0.23-0.37) relative to placebo, an RR of 0.55 (0.41-0.76) relative to alendronate, an RR of 0.50 (0.36-0.70) relative to risedronate, and an RR of 0.58 (0.37-0.92) relative to ibandronate. Regarding hip fractures, there is a 47% probability that zoledronic acid shows the greatest risk reduction, followed by alendronate (36%) and risedronate (11%). RRs of zoledronic acid relative to placebo, alendronate, and risedronate were 0.58 (0.41-0.82), 0.95 (0.54-1.68), and 0.73 (0.37-1.44), respectively. Risedronate showed the greatest reduction in nonvertebral-nonhip fractures, followed by zoledronic acid. The RR of zoledronic acid relative to risedronate was 1.28 (0.87-1.90). Overall, there was a 94% probability that zoledronic acid showed the greatest reduction in any fracture. Weighting the impact of the different type of fractures by incidence, cost, or quality of life showed similar results. CONCLUSION: Of the available bisphosphonates for osteoporosis, zoledronic acid has the highest probability of offering the best overall fracture protection.

Manipulative therapy in addition to usual medical care accelerates recovery of shoulder complaints at higher costs: economic outcomes of a randomized trial.

BACKGROUND: Shoulder complaints are common in primary care and have unfavourable long term prognosis. Our objective was to evaluate the clinical effectiveness of manipulative therapy of the cervicothoracic spine and the adjacent ribs in addition to usual medical care (UMC) by the general practitioner in the treatment of shoulder complaints. METHODS: This economic evaluation was conducted alongside a randomized trial in primary care. Included were 150 patients with shoulder complaints and a dysfunction of the cervicothoracic spine and adjacent ribs. Patients were treated with UMC (NSAID's, corticosteroid injection or referral to physical therapy) and were allocated at random (yes/no) to manipulative therapy (manipulation and mobilization). Patient perceived recovery, severity of main complaint, shoulder pain, disability and general health were outcome measures. Data about direct and indirect costs were collected by means of a cost diary. RESULTS: Manipulative therapy as add-on to UMC accelerated recovery on all outcome measures included. At 26 weeks after randomization, both groups reported similar recovery rates (41% vs. 38%), but the difference between groups in improvement of severity of the main complaint, shoulder pain and disability sustained. Compared to the UMC group the total costs were higher in the manipulative group (€1167 vs. €555). This is explained mainly by the costs of the manipulative therapy itself and the higher costs due sick leave from work. The cost effectiveness ratio showed that additional manipulative treatment is more costly but also more effective than UMC alone. The cost-effectiveness acceptability curve shows that a 50%-probability of recovery with AMT within 6 months after initiation of treatment is achieved at €2876. CONCLUSION: Manipulative therapy in addition to UMC accelerates recovery and is more effective than UMC alone on the long term, but is associated with higher costs. INTERNATIONAL STANDARD RANDOMIZED CONTROLLED TRIAL NUMBER REGISTER: ISRCTN11216.

Efficacy of vitamin D3 supplementation in preventing fractures in elderly women: a meta-analysis.

BACKGROUND: The efficacy of vitamin D(3) in preventing fractures and falls has been explored in a number of clinical trials. However, recent evidence revealed new questions about the adequate doses of vitamin D(3) supplementation and its efficacy in fracture prevention independent of calcium supplements for various types of fractures. OBJECTIVE: To conduct a meta-analysis to estimate the effectiveness of 800 IU daily vitamin D(3) supplementation for increasing bone mineral density (BMD) and preventing fractures in postmenopausal women. METHODS: Medline and EMBASE were searched for controlled trials comparing the effectiveness of cholecalciferol (vitamin D(3)) against placebo with or without background calcium supplementation in the treatment of postmenopausal women. RESULTS: Eight controlled trials evaluating the effect of vitamin D(3) supplementation with or without calcium were assessed. Of 12 658 women included in a Bayesian meta-analysis, 6089 received vitamin D(3) (with or without calcium) and 6569 received placebo (with or without calcium). Compared to placebo, vitamin D(3) with calcium supplementation showed beneficial effects on the incidence of non-vertebral (odds ratio [OR] 0.77, 95% credibility limit [CL] 0.6-0.93) and hip (OR 0.70, 95% CL 0.53-0.90) fractures, while the effects on non-vertebral-non-hip fractures (OR 0.84, 95% CL 0.67-1.04) % point increase) were associated with more uncertainty. Vitamin D(3) supplementation showed a 70% probability of being a better treatment than placebo for the prevention of non-vertebral fractures, hip fractures, and non-vertebral, non-hip fractures. Compared to calcium supplementation, vitamin D(3) plus calcium reduced non-vertebral fractures (OR 0.68, 95% CL 0.43-1.01) and non-vertebral, non-hip fractures (OR 0.64, 95% CL 0.38-0.99), but did not reduce hip fractures (OR 1.03, 95% CL 0.39-2.25). Key limitations to this analysis include a small number of studies and heterogeneity in the study populations. CONCLUSIONS: This meta-analysis supports the use of vitamin D3 of 800 IU daily to reduce the incidence of osteoporotic non-vertebral, hip, and non-vertebral-non-hip fractures in elderly women. Vitamin D(3) with calcium appears to achieve benefits above those attained with calcium supplementation alone for non-vertebral and non-vertebral-non-hip fractures.

Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs.

OBJECTIVES: To compare the patterns of American College of Rheumatology (ACR) response between tocilizumab and other biologic agents in patients with rheumatoid arthritis who have inadequate response to disease-modifying antirheumatic drugs (DMARD-IR). METHODS: Systematic literature review identified similarly designed double-blind, randomized, placebo-controlled trials over an 18-year period that investigated the effectiveness of abatacept (2), rituximab (2), and TNF-alpha inhibitors etanercept, infliximab, and adalimumab (11) in DMARD-IR patients; data from 3 placebo-controlled, phase 3 trials for tocilizumab, a newly developed IL-6 inhibitor, were included. The endpoint of interest was ACR20/50/70 response criteria at 24 to 30 weeks. Results were analyzed simultaneously using Bayesian mixed-treatment comparison techniques. Nonoverlapping ACR response rates (ACR70) for each agent were compared among treatments to identify differences in ACR response pattern. Separate analyses of overlapping ACR20/50/70 responses were conducted to identify the source of any differences. Results were expressed as relative risk of ACR20/50/70 response and associated 95% credible interval (CrI). RESULTS: Patterns across nonoverlapping ACR response levels varied significantly across treatments. In subsequent analyses, the effectiveness of tocilizumab appeared to be comparable to that of other biologic agents for ACR20 and ACR50 responses but greater for ACR70. Specifically, tocilizumab had greater ACR70 responses than both TNF-alpha inhibitors (relative risk = 1.8; CrI = 1.2, 2.6) and abatacept (relative risk = 2.0; CrI = 1.3, 3.1). CONCLUSIONS: Among DMARD-IR patients, tocilizumab shows a pattern of response that differs from that of other biologic agents. Post-hoc analyses suggest that the difference lies in a higher likelihood of ACR70 response with tocilizumab.

Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies.

OBJECTIVE: The objective was to compare the efficacy of bisphosphonates regarding the prevention of vertebral fractures in postmenopausal women with osteoporosis. METHODS: Seven randomized placebo controlled trials investigating the effects of zoledronic acid (one study), alendronate (three studies), ibandronate (one study), and risedronate (two studies) in terms of fractures with a follow-up of 3 years were identified with a systematic literature search. The endpoint of interest was vertebral fractures. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison (MTC). With MTC the relative treatment effect of one intervention to another can be obtained in the absence of head-to-head evidence. MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics. RESULTS: There is a 98% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all four bisphophonates compared. Zoledronic acid showed an OR of 0.28 (95% Credible Interval 0.22; 0.35) relative to placebo, an OR of 0.57 (0.36; 0.92) relative to ibandronate, an OR of 0.54 (0.39; 0.75) relative to alendronate, and an OR of 0.49 (0.34; 0.69) relative to risedronate. Alendronate, ibandronate, and risedronate showed comparable vertebral fracture reductions. Indirect comparisons using a conservative random effects model supported these findings. CONCLUSION: An indirect comparison of findings from placebo controlled randomized studies indicates that zoledronic acid provides a greater vertebral fracture risk reduction in postmenopausal women with osteoporosis than ibandronate, alendronate, or risedronate.

Interobserver reliability of physical examination of shoulder girdle.

The object of this study was to assess interobserver reliability in 23 tests concerning physical examination of the shoulder girdle. A physical therapist and a physical therapist/manual therapist independently performed a physical examination of the shoulder girdle in 91 patients with shoulder complaints of varying severity and duration. The observers assessed 23 items in total: active and passive abductions, passive external rotation, hand in neck (HIN) test, hand in back (HIB) test, impingement test according to Neer, springing test of the first rib and joint play test of the acromioclavicular joint. The interobserver reliability was evaluated by means of a Cohen's Kappa, the weighted Kappa and the intraclass correlation (ICC). Criteria for acceptable reliability were: Kappa value>or=0.60, ICC>or=0.75 or an absolute agreement>or=80%. The results showed that Kappa values varied from 0.09 (springing test first rib, stiffness) to 0.66 (springing test first rib, pain), weighted Kappa varied from 0.35 (pain during HIB) to 0.73 (range of motion HIB) and ICC varied from 0.54 (abduction passive starting point painful arc) to 0.96 (active and passive ranges of motion in abduction). In total 11 (48%) items fulfilled the criteria of acceptable reliability. In conclusion, there appears to be a great deal of variation in the reliability of the tests used in the physical examination of the shoulder girdle. Over 50% of the tests did not meet the statistical criteria for acceptable reliability.

Assessment of the cervical range of motion over time, differences between results of the Flock of Birds and the EDI-320: a comparison between an electromagnetic tracking system and an electronic inclinometer.

The objective of this study was to analyse cervical range of motion, assessed over time by means of a digital inclinometer (EDI-320) and a three-dimensional electromagnetic tracking device (Flock of Birds). The maximum active cervical range of motion was assessed with two measurement devices in three sessions over time, with 6-week intervals. In total, 26 women and 24 men (mean age: 44.4, SD: 9.9) without known pathology of the cervical spine participated. Four movements were measured axial rotation with the cervical spine in a flexed and in an extended position, flexion-extension, and lateral bending. The results showed that the factor time was significant for rotation in extension and rotation in flexion. The factor device was significant for all movements measured, and the interaction term between time and device was significant for all movements except rotation in extension. The Flock of Birds measured significantly higher ranges of motion on all motions except for lateral bending. A substantial variation in cervical range of motion was observed over time (ranging from -5.6 to 8.1) as well as between devices (ranging from -13.1 to 29.9). Substantial and significant differences in cervical range of motion were found over time as well as differences between the Flock of Birds and the EDI-320.

Interobserver reliability of neck-mobility measurement by means of the flock-of-birds electromagnetic tracking system.

OBJECTIVE: To establish the interobserver reliability for measuring neck mobility in human subjects by means of an electromagnetic tracking device, the Flock-of-Birds system. METHODS: Two observers independently and in random order assessed the cervical range-of-motion in 30 subjects with a dysfunction in the neck and shoulder region (symptomatic subjects) and 30 subjects without known pathology (asymptomatic subjects). Measurements included rotation in neutral position, in flexed position and in extended position, flexion-extension, and lateral bending (all active and passive). Reliability was analyzed by intraclass correlation coefficient (ICC) and agreement by limits of agreement and percentage of paired observations within 5 degrees, 10 degrees, and 15 degrees. RESULTS: For asymptomatic subjects, the ICC varied from 0.57 to 0.85, and the limits of agreement varied between 14.5 degrees and 27.0 degrees. The percentage of paired observations within 5 degrees, 10 degrees, and 15 degrees ranged from 31% to 57%, 58% to 90%, and 78% to 93%, respectively. For symptomatic subjects, the ICC varied from 0.36 to 0.91, and the limits of agreement varied between 9.6 degrees and 37.8 degrees. The percentage of paired observations within 5 degrees, 10 degrees, and 15 degrees ranged from 17% to 60%, 33% to 93%, and 50% to 97%, respectively. CONCLUSIONS: Despite the use of a standardized protocol and a sophisticated measurement system, the interobserver reliability of neck mobility was variable in quality, with reliability being good in rotation in neutral position, flexion-extension, and lateral bending.

Variation in the cervical range of motion over time measured by the "flock of birds" electromagnetic tracking system.

STUDY DESIGN: Observational longitudinal study. OBJECTIVE: To establish the normal variation over time for active and passive cervical range of motion (ROM) measured with the Flock of Birds electromagnetic tracking system (FOB). SUMMARY OF BACKGROUND DATA: Data about normal variation of cervical ROM over time are scarce but important for the interpretation of study results. METHODS: Forty-eight subjects without a manifest dysfunction in neck and shoulder region (asymptomatic group) and 58 subjects with a dysfunction in the neck and shoulder region (symptomatic group) participated in this study. Cervical active and passive ROM was assessed in three different sessions 6 weeks apart. The following movements were measured: flexion-extension, lateral bending, and axial rotation in neutral, flexed, and extended position. RESULTS: A wide range of variation of active and passive cervical ROM was found at the 6- and 12-week measurement in the asymptomatic group as well as in the symptomatic group. Highest variation was found during passive ROM testing as compared with active ROM testing. The symptomatic group showed larger variation than the asymptomatic group. CONCLUSIONS: Cervical range of motion varies considerably over time. This variation should be taken into account when results of therapeutic trials with respect to cervical ROM are interpreted.

Manipulative therapy in addition to usual medical care for patients with shoulder dysfunction and pain: a randomized, controlled trial.

BACKGROUND: Dysfunction of the cervicothoracic spine and the adjacent ribs (also called the shoulder girdle) is considered to predict occurrence and poor outcome of shoulder symptoms. It can be treated with manipulative therapy, but scientific evidence for the effectiveness of such therapy is lacking. OBJECTIVE: To study the effectiveness of manipulative therapy for the shoulder girdle in addition to usual medical care for relief of shoulder pain and dysfunction. DESIGN: Randomized, controlled trial. SETTING: General practices in Groningen, the Netherlands. PATIENTS: 150 patients with shoulder symptoms and dysfunction of the shoulder girdle. INTERVENTIONS: All patients received usual medical care from their general practitioners. Only the intervention group received additional manipulative therapy, up to 6 treatment sessions in a 12-week period. MEASUREMENTS: Patient-perceived recovery, severity of the main complaint, shoulder pain, shoulder disability, and general health. Data were collected during and at the end of the treatment period (at 6 and 12 weeks) and during the follow-up period (at 26 and 52 weeks). RESULTS: During treatment (6 weeks), no significant differences were found between study groups. After completion of treatment (12 weeks), 43% of the intervention group and 21% of the control group reported full recovery. After 52 weeks, approximately the same difference in recovery rate (17 percentage points) was seen between groups. During the intervention and follow-up periods, a consistent between-group difference in severity of the main complaint, shoulder pain and disability, and general health favored additional manipulative therapy. LIMITATIONS: The sample size was small, and assessment of end points was subjective. CONCLUSION: Manipulative therapy for the shoulder girdle in addition to usual medical care accelerates recovery of shoulder symptoms.

Groningen Manipulation Study. The effect of manipulation of the structures of the shoulder girdle as additional treatment for symptom relief and for prevention of chronicity or recurrence of shoulder symptoms. Design of a randomized controlled trial within a comprehensive prognostic cohort study.

BACKGROUND: We present the design of the Groningen Manipulation Study. This randomized controlled trial is part of the Dutch Shoulder Disability Study, a comprehensive prognostic cohort study on shoulder disorders, with randomized controlled interventions in subcohorts. OBJECTIVE: To evaluate the effectiveness of manipulative treatment of the structures of the shoulder girdle, in addition to standard treatment by the general practitioner for relief of shoulder symptoms and prevention of persistent or recurrent shoulder symptoms. METHODS: A total of 250 patients with shoulder symptoms and a functional limitation of the shoulder girdle will be included from 30 general practices in Groningen, The Netherlands. All participating patients receive standard treatment by the general practitioner and will be randomly allocated to additional manipulative treatment. Evaluation measurements take place 6, 12, 26, and 52 weeks after randomization. CONCLUSION: The short-term primary outcome measure is the proportion of patients with relief of shoulder complaints and the long-term primary outcome is the proportion of patients without persistent or recurrent shoulder symptoms. Dependent and independent variables include a structured medical history, a physical examination of the shoulder and shoulder girdle, and a measure of the mobility of the cervico-thoracic spine with a 6-degree-of-freedom electromagnetic tracking device.