Exploratory analysis of osteoarthritis progression among medication users: data from the Osteoarthritis Initiative

BACKGROUND: We conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials. METHODS: We used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee. RESULTS: We screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04). CONCLUSIONS: Users of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers

Experiment II: Training.

<p>(<b>A</b>) Latency to reach the arm, (<b>B</b>) latency to reach the hole, and (<b>C</b>) percentage of time spent at the hole in positive and negative trials across the four days of training for mice being later confronted with the near-negative (NN, n = 7), central (CE, n = 10), or near-positive (NP, n = 11) probe arm. Data are averaged per trial outcome and day and are presented as means ±SEM. Day 1: 5 positive trials, day 2+3: 3 positive and 3 negative trials, day 4: 2 positive and 2 negative trials. Statistics: day 1: ANOVA; day 2–4: Repeated Measures ANOVA for each day, main effect of trial outcome: ***p≤0.001, ^tp≤0.1, effect of group-by-trial outcome interaction: ^#p≤0.1.</p

Cognitive bias test apparatus.

<p>(<b>A</b>) Schematic diagram of the apparatus used in experiment I and II displaying the start box, the starting corridor, the central platform, the positive and negative reference arm, the three probe arms, and the sliding doors. In experiment I both reference arms had either a positive or a negative outcome and only the central probe arm was used for the probe trial. (<b>B</b>) Apparatus used in experiment III with the start cylinder positioned in the starting corridor, the central platform, the positive and negative reference arm, and the ambiguous probe arm. Unused arms were closed by reversing them so that their closed end functioned as barrier. Please note: The position of the positive and negative reference location in experiment II and III was counterbalanced between individuals.</p

Experiment I: Training.

<p>(<b>A</b>) Latency to reach the arm, (<b>B</b>) latency to reach the hole, and (<b>C</b>) percentage of time spent at the hole for mice being confronted with solely positive (optimistically-trained mice, n = 7) or solely negative (pessimistically-trained mice, n = 7) experience across the three days of training. Data are averaged per treatment group and day and are presented as means ±SEM. Day 1: 5 trials, day 2: 6 trials, day 3: 2 trials. See results section for details of statistical analysis.</p

Experiment I: Probe trial.

<p>(<b>A</b>) Latency to reach the arm, (<b>B</b>) latency to reach the hole, and (<b>C</b>) time spent at the hole in the central probe arm for mice that have been confronted with solely positive (optimistically-trained mice, n = 7) or solely negative (pessimistically-trained mice, n = 7) experiences during training. Data are presented as means ±SEM. Statistics: ANOVA, main effect of treatment: *p≤0.05, ^tp≤0.1.</p

Corticosterone stress hormone concentration.

<p>Trunk blood samples were taken 130 sec after the mice were either being placed for 1 min in 21°C water (acute stress) or left untouched in the home-cage for 1 min (control). Bars represent the mean concentration, whiskers express SEM. An ANOVA revealed no significant effect of genotype (F_1,26 = 2.36, P = 0.14) but a trend for increased stress hormone concentrations in mice subjected to acute stress (F_1,26 = 3.21, P = 0.085).</p

Genes included in functional annotation clusters in gene group of 5-HTT <i>KO</i> mice in conditions <i>acute stress</i> vs. <i>control</i> as acquired by DAVID tool.

1<p>Abbreviation: FC, fold change.</p

Genes included in KEGG pathways identified in different gene groups related to condition (<i>acute stress</i> or <i>control</i>) and 5-HTT genotype (<i>WT</i> or <i>KO</i>) acquired by DAVID tool.

1<p>Abbreviation: FC, fold change.</p

Elevated plus-maze test.

<p>a) Activity-related measures exemplified as the path length covered during the test. Bars represent the median values and the dots represent the data of each individual animal. b) Anxiety-related behavior measured as the proportion of time spent in open arms. Serotonintransporter knockout mice (5-HTT <i>KO</i>, n = 17) were less active and spent a lower proportion of time on open arms indicating increased anxiety compared to wild-type (5-HTT <i>WT</i>, n = 14) mice. Statistics: Wilcoxon exact rank sum test: ** = P<0.01, *** = P<0.001.</p

Significant functional annotation clusters in different gene groups related to condition (<i>acute stress</i> or <i>control</i>) and 5-HTT genotype (<i>WT</i> or <i>KO</i>) acquired by DAVID tool.

<p>Significant functional annotation clusters in different gene groups related to condition (<i>acute stress</i> or <i>control</i>) and 5-HTT genotype (<i>WT</i> or <i>KO</i>) acquired by DAVID tool.</p