Shibing Yang

Sulfonylureas and Risk of Falls and Fractures: A Systematic Review

BackgroundSulfonylureas have been linked to increased risk of hypoglycemia. Hypoglycemia may lead to falls, and falls may lead to fracture. However, studies quantifying the association between sulfonylureas and fractures are sparse and yield inconsistent results.ObjectiveThe purpose of this article was to review the literature regarding sulfonylurea use and falls or fall-related fractures among older adults with type 2 diabetes mellitus and to delineate areas for future research.Data SourcesWe searched MEDLINE (1966–March 2012) and CINAHL (1937–March 2012) for studies of patients with type 2 diabetes mellitus living in the community or nursing homes.Study SelectionThe search algorithms combined three domains: (1) diabetic patients, (2) sulfonylurea medications, and (3) fractures or falls. We included only publications in English that pertained to human subjects. We found 9 randomized trials and 12 non-experimental studies that met the inclusion criteria.Study Appraisal and Synthesis MethodsThe guidelines provided by the Cochrane handbook or Agency for Healthcare Research and Quality (AHRQ) Methods Guide are too general to distinguish the quality of included non-experimental studies, so we developed several specific domains based on those general guidelines. These domains included study design, study population, follow-up time, comparison group, exposure definition, outcome definition, induction period, confounding adjustment, and attrition or missing data. The data were not amenable to a meta-analysis.ResultsNo clinical trials included fracture as a primary endpoint. Most clinical trials excluded older adults. Most studies were not designed to evaluate the risk of sulfonylureas on fractures or falls. Studies did not show an increased risk of falls/fractures with sulfonylurea.LimitationsThe data available from existing studies suffer from methodological limitations including insufficient events, lack of primary endpoints, exclusion of older adults, and lack of clarity or inappropriate comparison groups.ConclusionFuture studies are needed to appropriately estimate the effect of sulfonylureas on falls or fall-related fractures in older adults who are at increased risk for hypoglycemia, the hypothesized mechanism for fractures related to sulfonylurea therapy.

Effects of Prescription Nonsteroidal Antiinflammatory Drugs on Symptoms and Disease Progression Among Patients With Knee Osteoarthritis

The effect of short‐term and long‐term use of nonsteroidal antiinflammatory drugs (NSAIDs) on structural change is equivocal. The aim of this study was to estimate the extent to which short‐ and long‐term use of prescription NSAIDs relieve symptoms and delay structural progression among patients with radiographically confirmed osteoarthritis (OA) of the knee.

Application of marginal structural models in pharmacoepidemiologic studies: a systematic review

We systematically reviewed pharmacoepidemiologic studies published in 2012 that used inverse probability weighted (IPW) estimation of marginal structural models (MSM) to estimate the effect from a time‐varying treatment.

Longitudinal Use of Complementary and Alternative Medicine among Older Adults with Radiographic Knee Osteoarthritis

BACKGROUND Osteoarthritis (OA), a chronic and often painful disease for which there is no cure, accounts for more mobility issues in older adults than any other disease. Cross-sectional studies have found that arthritis is the most common reason for older adults to use complementary and alternative medicine (CAM). Although previous research has profiled the sociodemographic and clinical characteristics of CAM users, few studies have provided information on variation in CAM use over time and most only considered use of any CAM, which was often a mixture of heterogeneous therapies. OBJECTIVES This study sought to describe the longitudinal patterns of CAM use among older adults with knee OA and to identify correlates and predictors of different commonly used CAM therapies. METHODS The Osteoarthritis Initiative included 1121 adults aged ≥65 years with radiographic tibiofemoral OA in one or both knees at baseline. Annual surveys captured current use of conventional therapies and 25 CAM modalities (grouped into 6 categories) for joint pain or arthritis at baseline and during the 4-year follow-up. We assessed longitudinal use of CAM modalities by summing the number of visits with participants reporting use of each modality. Correlates of CAM use under consideration included sociodemographic indicators, body mass index, overall measures of mental and physical well-being, and clinical indices of knee OA. Generalized estimation equations provided adjusted odds ratio estimates and 95% CIs. RESULTS Nearly one-third of older adults reported using ≥1 CAM modality for treating OA at all assessments. With the exception of glucosamine and chondroitin (18%), few were persistent users of other CAM modalities. One in 5 of those using nonsteroidal anti-inflammatory drugs or glucosamine and/or chondroitin were using them concurrently. Adjusted models revealed the following: (1) adults aged ≥75 years were less likely to use dietary supplements than those between ages 65 and 75 years; (2) persons with more severe knee pain or stiffness reported more CAM use; (3) better knee-related physical function was correlated with more use of chiropractic care or massage; and (4) older adults with more comorbidities were less likely to report use of dietary supplements. CONCLUSION Patterns of CAM use are, to some extent, inconsistent with current guidelines for OA treatment. Evaluating the potential risks and benefits in older adults from commonly used CAM modalities, with or without combination use of conventional analgesics, is warranted.

Effects of Glucosamine and Chondroitin Supplementation on Knee Osteoarthritis: An Analysis With Marginal Structural Models

The purpose of this study was to estimate the effectiveness of the combination of glucosamine and chondroitin in relieving knee symptoms and slowing disease progression among patients with knee osteoarthritis (OA).

Gender-Specific Correlates of Complementary and Alternative Medicine Use for Knee Osteoarthritis

BACKGROUND Knee osteoarthritis (OA) increases healthcare use and cost. Women have higher pain and lower quality of life measures compared to men even after accounting for differences in age, body mass index (BMI), and radiographic OA severity. Our objective was to describe gender-specific correlates of complementary and alternative medicine (CAM) use among persons with radiographically confirmed knee OA. METHODS Using data from the Osteoarthritis Initiative, 2,679 women and men with radiographic tibiofemoral OA in at least one knee were identified. Treatment approaches were classified as current CAM therapy (alternative medical systems, mind-body interventions, manipulation and body-based methods, energy therapies, and three types of biologically based therapies) or conventional medication use (over-the-counter or prescription). Gender-specific multivariable logistic regression models identified sociodemographic and clinical/functional correlates of CAM use. RESULTS CAM use, either alone (23.9% women, 21.9% men) or with conventional medications (27.3% women, 19.0% men), was common. Glucosamine use (27.2% women, 28.2% men) and chondroitin sulfate use (24.8% women; 25.7% men) did not differ by gender. Compared to men, women were more likely to report use of mind-body interventions (14.1% vs. 5.7%), topical agents (16.1% vs. 9.5%), and concurrent CAM strategies (18.0% vs. 9.9%). Higher quality of life measures and physical function indices in women were inversely associated with any therapy, and higher pain scores were positively associated with conventional medication use. History of hip replacement was a strong correlate of conventional medication use in women but not in men. CONCLUSIONS Women were more likely than men to use CAM alone or concomitantly with conventional medications.

Racial differences in symptom management approaches among persons with radiographic knee osteoarthritis

BackgroundThe extent to which racial differences exist in use of treatments for osteoarthritis (OA) is debatable. The purpose of this study was to describe the differences between African Americans (AA) and Caucasian Americans (CA) in using treatment approaches to manage symptoms among individuals with radiographic-confirmed knee OA.MethodsA cross-sectional study was conducted. Using data from the Osteoarthritis Initiative, we identified 508 AA and 2,075 CA with radiographic tibiofemoral OA in at least one knee. Trained interviewers asked questions relating to current OA treatments including seven CAM therapy categories—alternative medical systems, mind-body interventions, manipulation and body-based methods, energy therapies, and three types of biologically based therapies, as well as conventional medications. We categorized participants as: conventional medication only users, CAM only users, users of both and users of neither. Multinomial logistic regression models adjusting for sociodemographics and clinical/functional factors provided estimates of the association between race and treatment use.ResultsOverall, 16.5% of AA and 24.2% of CA exclusively used CAM to treat OA, 25.0% of AA and 23.8% of CA used CAM in conjunction with conventional medications, and 24.8% of AA and 14.6% of CA exclusively used conventional medications. After control for sociodemographic and clinical factors, AA were less likely than CA to use CAM therapies alone (adjusted odds ratio (OR) of using CAM alone relative to no CAM or conventional treatments: 0.68, 95% confidence interval (CI): 0.48–0.96) or with conventional medications (adjusted OR relative to no CAM or conventional treatments: 0.59, 95%CI: 0.42–0.83). However, no differences in use of conventional medications alone were observed after adjustment of covariates.ConclusionCAM use is common among people with knee OA, but is less likely to be used by AA relative to CA. For effective CAM therapies, targeted outreach to underserved populations including education about benefits of various CAM treatments and providing accessible care may attenuate observed disparities in effective CAM use by race.

Effects of glucosamine and chondroitin on treating knee osteoarthritis: an analysis with marginal structural models

The purpose of this study was to estimate the effectiveness of the combination of glucosamine and chondroitin in relieving knee symptoms and slowing disease progression among patients with knee osteoarthritis (OA).

Reply to: The effects of glucosamine and chondroitin on treating knee osteoarthritis were underestimated or not?

osteoarthritis were underestimated or not? Shibing Yang, PhD, MS; Charles B. Eaton, MD, MS; Timothy E. McAlindon, MD, MPH; Kate L. Lapane, PhD, MS 1 Division of Epidemiology, Department of Family Medicine and Population Health, Virginia Commonwealth University, Richmond, VA 23298, USA 2 Center for Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, RI 02860, USA 3 Departments of Family Medicine and Epidemiology, Warren Alpert Medical School, School of Public Health, Brown University, Providence, RI 02912, USA 4 Department of Rheumatology, Tufts Medical Center, Boston, MA 02111, USA 5 Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA Corresponding author: Kate L. Lapane, PhD Department of Quantitative Health Sciences University of Massachusetts Medical School 55 Lake Avenue North, Worcester, MA 01655-0002 USA Telephone: 508-856-8965; Fax: 508-856-8993 Email: kate.lapane@umassmed.edu Running title: Reply to Zeng et al. Funding: This article was prepared using an Osteoarthritis Initiative (OAI) public-use data set, and its contents do not necessarily reflect the opinions or views of the NIH or the private funding partners of the OAI. The OAI is a public–private partnership between the NIH (contracts N01AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01AR-2-2261, and N01-AR-2-2262) and private funding partners (Merck Research Laboratories, Novartis Pharmaceuticals, Reply to Letter to the Editor Arthritis & Rheumatology DOI 10.1002/art.39139result in the same underestimation of the treatment effects. Apart from these 2 points, the authors considered a participant to be a nonuser of a supplement if he or she reported using it for 4 days/week or not at all; use of this definition of exposure could likely underestimate the effects observed in the group taking supplements for 4 days/week). The authors admitted that they do not have information on the treatment dosage. In consideration of the various dosages used by the participants taking supplements, even those taking supplements for<4 days/week, is it appropriate to classify participants in that group as nonusers of supplements? To the best of our knowledge, there is no consensus regarding the optimal frequency of glucosamine and chondroitin use as treatment of OA with regard to such long-term use. We are not sure whether it is better to regard a participant who is using supplements for 1–3 days/week to be classified as “low frequency.” We are very much looking forward to the results of reclassification. Furthermore, Yang et al reported that “ 90% of the participants taking either one of the supplements were taking both concurrently.” However, participants taking either one of the supplements or the combination were simply regarded as users of supplements. Like many rheumatologists, we are very interested in the effects of combination treatment with supplements in knee OA compared with the effects of a single supplement or no treatment. The results of such subgroup analysis are also worth the wait. Another concern involves potential confounding factors. Confounders such as diabetes mellitus, hypertension, smoking, and alcohol drinking status need to be addressed. Did the authors not have information regarding these characteristics as well as the glucosamine formulation and treatment dosage? In addition, the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score (3) is one of the most important outcomes. Furthermore, the authors did not exclude participants using analgesics, such as acetaminophen, nonsteroidal antiinflammatory agents, and opioids. At the least, the stability of the results should be assessed by sensitivity analysis, excluding participants using analgesics. Furthermore, the inclusion criteria require further explanation. Participants with a Kellgren/Lawrence grade (4) of 2 in at least one knee were included in the study. The authors did not state clearly, however, whether all of these included participants with radiographic knee OA experienced pain. Finally, the Glucosamine/Chondroitin Arthritis Intervention Trial demonstrated a significant difference between the group receiving the combination of supplements and the placebo group with respect to pain relief in patients with moderate-to-severe pain (5). We agree with the authors that clinical trials have limited external validity (generalizability) (6). Therefore, we would like to know whether this positive result could be observed in the Yang observational study by restricting inclusion of participants to those with more severe pain at baseline. We respect the great contributions of the authors and we are very much looking forward to their supplementary analysis.

Reply to: Is it appropriate to classify all kinds of nonsteroidalanti-inflammatory drugs together for assessing the treatment of kneeosteoarthritis?

To the Editor: We read with great interest the article by Lapane et al (1) regarding the effect of shortand long-term use of prescription nonsteroidal antiinflammatory drugs (NSAIDs) on symptoms and structural progression among patients with radiographically confirmed osteoarthritis (OA) of the knee. This prospective observational study suggested that long-term, but not short-term, NSAID use was associated with an a priori–defined minimally important clinical change in stiffness, physical function, and joint space width, but not pain. We appreciate the authors’ work; however, some worthwhile issues need to be explored. The authors classified 12 different kinds of NSAIDs together to assess the effect on knee OA of these drugs as a whole. Every NSAID has distinguishing characteristics with respect to therapeutic effect, safety, and price. For example, results of a recent high-quality network meta-analysis clearly indicated that naproxen, ibuprofen, and diclofenac, but not celecoxib, were statistically significantly superior to acetaminophen in terms of pain relief for patients with knee OA (2). There are 2 main types of NSAIDs: traditional NSAIDs (ibuprofen, naproxen, diclofenac, etc.) and celecoxib (the only selective NSAID currently available in America) (3). We are interested in learning about the results of this subgroup analysis (traditional versus selective NSAIDs). In addition, no information about the NSAID doses was available. The population of NSAID recipients in this study was largely heterogeneous. Consequently, we are not sure whether such conclusions have instructional significance for clinical practice. Aside from the implications for clinical practice, we are also worried about the reliability of the positive conclusion. The authors stated that long-term NSAID use was associated with clinical changes in stiffness, physical function, and joint space width. However, the 95% confidence intervals included 0, which could be interpreted as evidence that there is no real difference between long-term NSAID recipients and nonrecipients and that long-term NSAID use has no effect (4). The authors admitted that the estimates did not reach statistical significance, which indicates that a Type II error may exist. In other words, a significance test failed to identify the real clinical difference. Although the evidence showed that the a priori–defined minimally important clinical change had been reached, the possibility that the positive results of the study were due to chance could not be ruled out. We admit that the clinical significance is of importance, but we would like to emphasize the fact that statistical significance does not ensure truth and careful attention should be paid to false-positive errors. Furthermore, other issues need to be noted. First, the authors indicated that evidence regarding long-term effects of oral NSAIDs is still lacking, and their effect on structural changes in the joint has not been well established. However, the clinical efficacy and safety of celecoxib, as well as the effects of celecoxib on progression of knee OA over 2 years, have been reported previously (5,6). Second, according to the Osteoarthritis Research Society International atlas (7), joint space narrowing and formation of osteophytes should be determined for knee OA. We are curious about why the progression of osteophytes was not assessed. Third, patients in observational studies differ from those in clinical trials by, for example, the wider spectrum of coexisting illness included in observational studies, which could result in a good generalizability (8). However, the multivariable model was not adjusted for certain underlying diseases, such as diabetes mellitus and hypertension. Finally, it should be noted that safety is an extremely important index for assessing oral NSAIDs, especially for long-term use. The authors admitted that discontinuation rates of prescription NSAIDs have been reported to exceed 85% within 6 months of initiation. We would like more information regarding the side effects of NSAID use in this study. We value the contributions of Lapane et al, and we are very interested in the authors’ response to these issues.