L.L. Price

Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE To compare the efficacy of intraarticular hyaluronic acid with corticosteroids for knee osteoarthritis (OA). METHODS Our data sources were Medline, EMBASE, CINAHL, BIOSIS, and the Cochrane database, as well as hand- searched reviews, manuscripts, and supplements. For unpublished data we used author contacts. Randomized trials that reported effects of intraarticular hyaluronic acid versus corticosteroids on knee OA were selected based on inclusion criteria. Two reviewers extracted data independently. Using a random-effects model, we computed effect sizes for pain change from baseline at 2, 4, 8, 12, and 26 weeks. We also performed multivariate analyses accounting for within and between-study covariance. We performed sensitivity analyses for trials that reported intent-to-treat (ITT) analysis and blinding, and directly compared Hyalgan with methylprednisolone. RESULTS The 7 eligible trials included 606 participants. Five reported ITT analyses. At week 2 the effect size was -0.39 (95% confidence interval [95% CI], -0.65, -0.12) favoring corticosteroids; at week 4 it was -0.01 (95% CI -0.23, 0.21) suggesting equal efficacy. At week 8 the effect size was 0.22 (95% CI -0.05, 0.49) favoring hyaluronic acid, and at week 12 it was 0.35 (95% CI 0.03, 0.66) favoring hyaluronic acid. At week 26 the effect size was 0.39 (95% CI 0.18, 0.59), favoring hyaluronic acid. The multivariate analyses and sensitivity analyses generated consistent results. CONCLUSION From baseline to week 4, intraarticular corticosteroids appear to be relatively more effective for pain than intraarticular hyaluronic acid. By week 4, the 2 approaches have equal efficacy, but beyond week 8, hyaluronic acid has greater efficacy. Understanding this trend is useful to clinicians when treating knee OA.

Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial

OBJECTIVE To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate. DESIGN Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use. RESULTS Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes. CONCLUSIONS These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks.

Use of pimobendan in 170 cats (2006–2010)

HYPOTHESIS/OBJECTIVES To describe the therapeutic use of pimobendan in cats, describe the patient population to which it was administered, document potential side effects and report the clinical course following administration of pimobendan in conjunction with standard heart failure therapy. It is hypothesized that cats with advanced heart disease including congestive heart failure from a variety of causes will tolerate pimobendan with a minimum of side effects when used in treatment in conjunction with a variety of other medications. ANIMALS, MATERIALS AND METHODS One hundred and seventy client owned cats with naturally occurring heart disease, one hundred and sixty four of which had congestive heart failure. Medical records were reviewed and owners and referring veterinarians were contacted for follow-up data. Data collected included pimobendan dose, other medications administered concurrently, data collected at physical examination, presence or absence of heart failure, adverse effects, classification of heart disease, echocardiographic data and survival time. The data were analyzed for significance between the initial visit and any follow-up visits. RESULTS All cats were treated with pimobendan. The median pimobendan dose was 0.24 mg/kg q 12 h. Pimobendan was used in combination with multiple concurrent medications including angiotensin converting enzyme inhibitors, diuretics and anti-thrombotics. Five cats (3.0%) had potential side effects associated with pimobendan. One cat (0.6%) had presumed side effects severe enough to discontinue pimobendan use. Median survival time for 164 cats with congestive heart failure after initiation of pimobendan was 151 days (range 1-870). CONCLUSION Pimobendan appears to be well tolerated in cats with advanced heart disease when used with a variety of concurrent medications. Randomized controlled studies need to be performed to accurately assess whether it is efficacious for treatment of congestive heart failure in cats.

Relationship of bone mineral density to progression of knee osteoarthritis

OBJECTIVE To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes. METHODS We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans in each subject. Multivariable linear regression models were used to examine the associations of baseline BMD and BMD change with the cartilage outcomes, adjusting for baseline age, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated. RESULTS A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β = 1.25 per 0.1 gm/cm(2) , P = 0.02) and loss of tibial cartilage thickness (β = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (<-4.7%) was associated with 1.02% cartilage volume loss per year (P = 0.005), 0.014 mm femoral cartilage thickness loss (P = 0.04), and 0.021 mm tibial cartilage thickness loss per year (P = 0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes. CONCLUSION Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could reveal novel therapeutic targets for knee OA.

Metabolites related to gut bacterial metabolism, peroxisome proliferator-activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults

Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6‐month change in serum mass spectrometry‐obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6‐month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400‐m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally‐limited older adults (SPPB ≤ 10; 70–85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p‐cresol sulfate, 3‐indoxyl sulfate, serotonin, N‐methylproline, hydrocinnamate, dimethylglycine, trans‐urocanate, valerate) that are altered in response to peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) activation (α‐hydroxyisocaproate, α‐hydroxyisovalerate, 2‐hydroxy‐3‐methylvalerate, indolelactate, serotonin, 2‐hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5‐dodecenoate, myristoleate, palmitoleate; γ‐glutamylamino acids: γ‐glutamylglutamine, γ‐glutamylalanine, γ‐glutamylmethionine, γ‐glutamyltyrosine; branched‐chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6‐month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR‐α activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally‐limited older adults.

An evaluation of the reliability of muscle fiber cross-sectional area and fiber number measurements in rat skeletal muscle

BackgroundThe reliability of estimating muscle fiber cross-sectional area (measure of muscle fiber size) and fiber number from only a subset of fibers in rat hindlimb muscle cross-sections has not been systematically evaluated. This study examined the variability in mean estimates of fiber cross-sectional area as a function of the number of fibers measured, and tested whether counting a subset of fibers in a cross-section could predict total fiber number in middle-aged rats.ResultsSoleus and extensor digitorum longus (EDL) muscle cross-sections from 23-month-old, male Fisher 344 x Brown Norway rats were stained for myofibrillar ATPase activity to identify muscle fiber type (either type I [slow-twitch] or II [fast-twitch]) and laminin to facilitate fiber cross-sectional measurements. We outlined the circumference of 1000 to 1600 single muscle fibers for measurement of fiber cross-sectional area within muscle sections. Mean type I fiber cross-sectional area was based on soleus muscle sections which were predominantly composed of type I muscle fibers. Mean type II fiber cross-sectional area was based on EDL muscle sections which were predominantly composed of type II muscle fibers. A bootstrapping resampling technique demonstrated that variability in sampling distribution of mean type I and II fiber cross-sectional areas decreased and gradually stabilized as the number of fibers measured increased with large declines in variability occurring at numbers below 150 fibers. Coefficients of variation for bootstrapped mean type I fiber cross-sectional areas were lower than for type II. In the same muscle sections, total fiber number was compared to fiber numbers within 1, 2, 3, and 4 fixed field areas (10x magnification; 1000 x 1500 pixels in size/field) on the cross-section. Fiber numbers from 3 to 4 fields (approximating 15 to 20% of the cross-section) provided a reasonably predictive value of total fiber number (r=0.57-0.59, P=0.003).ConclusionsThese data describe a pattern of improved precision in estimating mean fiber cross-sectional area as sample size of fibers measured increases to at least 150 in this rat model. Counting 15-20% of the fibers in cross-sections provides a reasonably reliable estimate of the total fiber number.

Eighteen Year (1985–2002) Analysis of Incidence, Mortality, and Cardiac Procedure Outcomes of Acute Myocardial Infarction in Patients ≥ 65 Years of Age

The temporal patterns of outcomes and therapy in patients aged > or =65 years with acute myocardial infarctions (AMIs) from a national database were examined to better understand this increasingly important demographic group. The National Hospital Discharge Survey (NHDS), a nationally representative sample of acute care hospitals in the United States, was used for analysis. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, hospitalizations with first-listed diagnoses of AMI from 1985 to 2002 were identified. A multivariate logistic regression model was developed to identify predictors of mortality in these patients. The logit of propensity score was used as an adjuster for reducing the bias of nonrandom assignment of cardiovascular procedures. Although the number of patients aged > or =65 years admitted with AMIs increased over the study period, the incidence in patients aged > or =65 years decreased by 1.5%. In patients aged <65 years, the incidence was significantly lower for any year and decreased by 17.5%. The in-hospital mortality rate in patients aged > or =65 years decreased (from 22.0% in 1985 to 11.5% in 2002) but remained significantly higher compared with younger patients (from 7.0% in 1985 to 3.2% in 2002). Overall cardiac procedure use increased from 18.0% in 1985 to 50.7% in 2002, but patients aged > or =65 years consistently underwent fewer procedures than younger patients. After taking 12 covariates into consideration, not undergoing a cardiac procedure remained a significant risk factor for mortality (odds ratio 3.13, p <0.0001). Acute renal failure (odds ratio 4.64, p <0.0001) and age > or =65 years (odds ratio 2.14, p <0.0001) were the other 2 strongest independent predictors of mortality. In conclusion, the incidence of AMI is decreasing. Over the 18-year period from 1985 to 2002, there was a significant reduction in mortality, but patients aged > or =65 years remained at particular risk. Multivariate analysis suggests that a lack of the use of procedures in these patients may at least partially explain their higher mortality.

Risk factors can classify individuals who develop accelerated knee osteoarthritis: Data from the osteoarthritis initiative

We assessed which combinations of risk factors can classify adults who develop accelerated knee osteoarthritis (KOA) or not and which factors are most important. We conducted a case‐control study using data from baseline and the first four annual visits of the Osteoarthritis Initiative. Participants had no radiographic KOA at baseline (Kellgren‐Lawrence [KL]<2). We classified three groups (matched on sex): (i) accelerated KOA: >1 knee developed advance‐stage KOA (KL = 3 or 4) within 48 months; (ii) typical KOA: >1 knee increased in radiographic scoring (excluding those with accelerated KOA); and (iii) No KOA: no change in KL grade by 48 months. We selected eight predictors: Serum concentrations for C‐reactive protein, glycated serum protein (GSP), and glucose; age; sex; body mass index; coronal tibial slope, and femorotibial alignment. We performed a classification and regression tree (CART) analysis to determine rules for classifying individuals as accelerated KOA or not (no KOA and typical KOA). The most important baseline variables for classifying individuals with incident accelerated KOA (in order of importance) were age, glucose concentrations, BMI, and static alignment. Individuals <63.5 years were likely not to develop accelerated KOA, except when overweight. Individuals >63.5 years were more likely to develop accelerated KOA except when their glucose levels were >81.98 mg/dl and they did not have varus malalignment. The unexplained variance of the CART = 69%. These analyses highlight the complex interactions among four risk factors that may classify individuals who will develop accelerated KOA but more research is needed to uncover novel risk factors.

405 EVALUATION OF THE ABILITY OF DELAYED GADOLINIUM-ENHANCED MRI (DGEMRIC) TO DETECT CHANGE IN CARTILAGE CHARACTERISTICS AMONG INDIVIDUALS WITH KNEE OSTEOARTHRITIS (OA) RECEIVING A COLLAGEN HYDROLYSATE FORMULATION

N. Krishnan, T. McAlindon, M. Nuite, K. Carr, D. Burstein, L. Price, and K. Flechsenhar Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, United States, Division of Rheumatology, Tufts Medical Center, Boston, MA, United States, Tufts Medical Center, Boston, MA, United States, Health Sciences and Technology, Harvard Medical School, Boston, MA, United States, Research & Development, Gelita AG, Eberbach, Germany