ABSTRACT: Cannabidiol (CBD) is increasingly used as analgesic medication even though the recent International Association for the Study of Pain presidential task force on cannabis and cannabinoid analgesia found a lack of trials examining CBD for pain management. The present trial examines CBD as add on analgesic therapy in patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain intensity despite therapy. Using a randomized double-blind, placebo-controlled design, patients received synthetic CBD 20-30mg or placebo daily for 12 weeks. Primary outcome was pain intensity during the last 24 hours (0-100mm); safety outcomes were percentage of patients experiencing adverse events and a characterization of serious adverse events. Explorative outcomes included change in Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS) and Health Assessment Questionnaire (HAQ-DI).One hundred and thirty-six patients were randomized 129 were included in the primary analysis. Between group difference in pain intensity at 12 weeks was 0.23mm (95%CI -9.41 to 9.90; p = 0.96). 22% patients receiving CBD and 21% receiving placebo experienced a reduction in pain intensity of more than 30mm. We found neither clinically nor statistically significant effect of CBD for pain intensity in patients with hand osteoarthritis and psoriatic arthritis when compared to placebo. Additionally, no statistically significant effects were found on sleep quality, depression, anxiety, or pain catastrophizing scores.
osteoarthritis
Immune Function Has Key Role in OA
Monocytes influence pain and disease progression
Monocyte activation plays a pivotal role in the degree of pain and disease progression associated with osteoarthritis (OA), according to Canadian researchers.
Monocytes were more activated and pro-inflammatory in women with OA, and that elevated inflammation and BMI were associated with this increased activation, reported Dawn Bowdish, PhD, of McMaster University and McMaster Institute for Research on Aging in Hamilton, Ontario, Canada, and colleagues, in Osteoarthritis and Cartilage.
The study included 22 women with OA, and 22 healthy age- and sex-matched controls. The researchers measured markers of soluble and cellular inflammation in the peripheral blood.
Serum C-reactive protein (CRP) levels were elevated in participants with OA, who also had a lower proportion of circulating monocytes. Increased expression of the activation markers CD16, CCR2, and HLA-DR was found in monocytes from women with OA; these monocytes induced greater production of tumor necrosis factor (TNF) and interleukin-1β than in healthy controls. BMI and higher serum TNF levels were correlated with increased monocyte expression of CCR2.
“It is the first study, to our knowledge, to specifically characterize changes in circulating monocytes in individuals with OA compared to healthy women,” said Bowdish. “We know that changes in monocytes contribute to the development of chronic inflammatory conditions. If we can target these monocytes in OA, we may be able to slow down disease progression or decrease the risk of other chronic inflammatory diseases.”
Impact of total knee replacement practice: cost effectiveness analysis of data from the Osteoarthritis Initiative
Abstract
Objectives To evaluate the impact of total knee replacement on quality of life in people with knee osteoarthritis and to estimate associated differences in lifetime costs and quality adjusted life years (QALYs) according to use by level of symptoms.
Design Marginal structural modeling and cost effectiveness analysis based on lifetime predictions for total knee replacement and death from population based cohort data.
Setting Data from two studies—Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST)—within the US health system.
Participants 4498 participants with or at high risk for knee osteoarthritis aged 45-79 from the OAI with no previous knee replacement (confirmed by baseline radiography) followed up for nine years. Validation cohort comprised 2907 patients from MOST with two year follow-up.
Intervention Scenarios ranging from current practice, defined as total knee replacement practice as performed in the OAI (with procedural rates estimated by a prediction model), to practice limited to patients with severe symptoms to no surgery.
Main outcome measures Generic (SF-12) and osteoarthritis specific quality of life measured over 96 months, model based QALYs, costs, and incremental cost effectiveness ratios over a lifetime horizon.
Results In the OAI, total knee replacement showed improvements in quality of life with small absolute changes when averaged across levels of confounding variables: 1.70 (95% uncertainty interval 0.26 to 3.57) for SF-12 physical component summary (PCS); −10.69 (−13.39 to −8.01) for Western Ontario and McMaster Universities arthritis index (WOMAC); and 9.16 (6.35 to 12.49) for knee injury and osteoarthritis outcome score (KOOS) quality of life subscale. These improvements became larger with decreasing functional status at baseline. Provision of total knee replacement to patients with SF-12 PCS scores <35 was the optimal scenario given a cost effectiveness threshold of $200 000/QALY, with cost savings of $6974 ($5789 to $8269) and a minimal loss of 0.008 (−0.056 to 0.043) QALYs compared with current practice. These findings were reproduced among patients with knee osteoarthritis from the MOST cohort and were robust against various scenarios including increased rates of total knee replacement and mortality and inclusion of non-healthcare costs but were sensitive to increased deterioration in quality of life without surgery. In a threshold analysis, total knee replacement would become cost effective in patients with SF-12 PCS scores ≤40 if the associated hospital admission costs fell below $14 000 given a cost effectiveness threshold of $200 000/QALY.
Conclusion Current practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life and QALYs at the group level. If the procedure were restricted to more severely affected patients, its effectiveness would rise, with practice becoming economically more attractive than its current use.
Abstract
Objectives To evaluate the impact of total knee replacement on quality of life in people with knee osteoarthritis and to estimate associated differences in lifetime costs and quality adjusted life years (QALYs) according to use by level of symptoms.
Design Marginal structural modeling and cost effectiveness analysis based on lifetime predictions for total knee replacement and death from population based cohort data.
Setting Data from two studies—Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST)—within the US health system.
Participants 4498 participants with or at high risk for knee osteoarthritis aged 45-79 from the OAI with no previous knee replacement (confirmed by baseline radiography) followed up for nine years. Validation cohort comprised 2907 patients from MOST with two year follow-up.
Intervention Scenarios ranging from current practice, defined as total knee replacement practice as performed in the OAI (with procedural rates estimated by a prediction model), to practice limited to patients with severe symptoms to no surgery.
Main outcome measures Generic (SF-12) and osteoarthritis specific quality of life measured over 96 months, model based QALYs, costs, and incremental cost effectiveness ratios over a lifetime horizon.
Results In the OAI, total knee replacement showed improvements in quality of life with small absolute changes when averaged across levels of confounding variables: 1.70 (95% uncertainty interval 0.26 to 3.57) for SF-12 physical component summary (PCS); −10.69 (−13.39 to −8.01) for Western Ontario and McMaster Universities arthritis index (WOMAC); and 9.16 (6.35 to 12.49) for knee injury and osteoarthritis outcome score (KOOS) quality of life subscale. These improvements became larger with decreasing functional status at baseline. Provision of total knee replacement to patients with SF-12 PCS scores <35 was the optimal scenario given a cost effectiveness threshold of $200 000/QALY, with cost savings of $6974 ($5789 to $8269) and a minimal loss of 0.008 (−0.056 to 0.043) QALYs compared with current practice. These findings were reproduced among patients with knee osteoarthritis from the MOST cohort and were robust against various scenarios including increased rates of total knee replacement and mortality and inclusion of non-healthcare costs but were sensitive to increased deterioration in quality of life without surgery. In a threshold analysis, total knee replacement would become cost effective in patients with SF-12 PCS scores ≤40 if the associated hospital admission costs fell below $14 000 given a cost effectiveness threshold of $200 000/QALY.
Conclusion Current practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life and QALYs at the group level. If the procedure were restricted to more severely affected patients, its effectiveness would rise, with practice becoming economically more attractive than its current use.
Introduction
Osteoarthritis is a leading cause of disability worldwide,1 resulting in pain, structural changes in the bone and joint space, and limitation of motion. Disease onset is gradual and usually begins after the age of 40. Osteoarthritis of the knee has a variable prognosis. Once present, improvement of joint structure is rare when assessed by radiography, but abatement of joint pain and disability occurs frequently.2 About 12% of adults in the US are affected.3 The annual rate of total knee replacement in the US has doubled since 2000, especially in those aged 45-64.45 This disproportionate increase in this practice has been attributed to expansion of eligibility to people with less severe symptoms.6 The total number of procedures performed each year now exceeds 640 000, at a total annual cost of about $10.2bn (£8.3bn, €9.6bn).5
The potential benefit of total knee replacement in patients with knee osteoarthritis should outweigh the associated costs. A recent randomized controlled trial looked at replacement compared with non-surgical management alone in 95 patients and showed large improvements in pain and physical limitations and significant increases in quality of life at 12 months.7 The trial population predominantly included patients with severe preoperative symptoms, as shown by low mean quality of life utility values at baseline.7 Many previously published uncontrolled before-after studies showed similarly large effects.89 In particular, the systematic review by Shan and colleagues described 19 studies that showed substantial improvements from baseline status, both in the intermediate and long term, for disease specific and generic health related quality of life across a broad range of domains.9 It is estimated, however, that up to a third of recipients of total knee replacement experience chronic pain postoperatively,1011 and the health benefits of the procedure are assumed to be higher in those with poor physical functioning before surgery.121314 This would imply that patients undergoing the procedure because of the recently expanded practice in the US might show less significant improvement in symptoms. Yet, the effectiveness of total knee replacement has been understudied in patients who are representative for the current practice population.1011
We used data from the Osteoarthritis Initiative (OAI) to estimate the effect of total knee replacement according to patients’ functional status by looking at longitudinal health outcomes of patients with knee osteoarthritis with heterogeneous symptoms who underwent the procedure compared with those who did not.15 We subsequently performed a decision modeling study to evaluate the impact of the procedure on lifetime costs and quality adjusted life years (QALYs) while varying its use by level of symptoms.
Methods
Study populations
We obtained the data for our analysis from the Osteoarthritis Initiative (OAI) database, which is available for public access at http://www.oai.ucsf.edu/. The OAI is a multi-center cohort study of 4796 individuals with knee osteoarthritis or at risk for knee osteoarthritis who were recruited from the general population in 2005-06 across four US centers. Study participants were aged 45-79 at enrolment and were tracked with repeated follow-up evaluations for nine years. These evaluations included physical examinations, radiographs of both knees, and questionnaires on risk factors, symptoms, medical history, and quality of life. Knee osteoarthritis was defined as the patient having pain, aching, or stiffness in or around the knee on most days for at least one month during the past 12 months, and radiographically confirmed tibiofemoral osteophytes of grades 1-3 according to the Osteoarthritis Research Society International (OARSI) atlas.1617 Patients eligible for the current analysis were those included in the outcomes dataset released 11 October 2015 (n=4796). To develop a decision model for estimating lifetime outcomes, we excluded participants who had already undergone TKR at baseline, confirmed by radiography (n=62) and participants from the low osteoarthritis risk, “non-exposed” control group (n=122) who had no established risk factors, symptoms or radiographic findings of knee osteoarthritis.18 This resulted in a development sample of 4498 (table 1⇓). OAI participants classified as having knee osteoarthritis at baseline (n=1327), as opposed to participants who were at high risk for knee osteoarthritis,were defined as the study population for estimation of the effect of total knee replacement on quality of life and use ofnon-surgical treatment for osteoarthritis pain, and for the base case cost effectiveness analysis. To validate the effect estimates, we repeated similar analyses with 30 months’ follow-up data on 965 participants with knee osteoarthritis at baseline of the Multicenter Osteoarthritis Study (MOST).23 To show generalizability of the base case cost effectiveness analysis, we performed a scenario analysis using the 965 MOST patients.
Modeling effect of total knee replacement on quality of life and use of non-surgical treatment
Outcomes were defined as the SF-12 physical component summary (PCS) score, the SF-12 mental component summary (MCS) score, the SF-6D utility index, the Western Ontario and McMaster Universities arthritis index (WOMAC), the quality of life subscale on the knee injury and osteoarthritis outcome score (KOOS), and self reported use of pain medication for osteoarthritis, all measured at 12, 24, 36, 48, 72, and 96 months. We evaluated the effect of total knee replacement on use of non-pharmacological treatments with measurements at 24, 48, and 96 months, as questions on these treatments were not included at the other study visits. The SF-12 instrument is a single page questionnaire measuring generic quality of life.24 To estimate this, we calculated the SF-6D utility index, which can be directly derived from SF-12 by using a previously published algorithm.25 The KOOS and WOMAC instruments are validated questionnaires measuring quality of life, pain, stiffness, and functionality specific for osteoarthritis.242627 We chose to use only the KOOS quality of life subscale, which measures knee related quality of life and mental and social aspects such as awareness and lifestyle changes. These items are not well captured by the WOMAC total score, which focuses on knee symptoms and functioning. The Pearson product moment correlation coefficient for the two scores in the 1327 OAI participants with knee osteoarthritis was −0.67. Osteoarthritis pain medication included acetaminophen (paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs), and cyclo-oxygenase-2 (COX-2) inhibitors. Non-pharmacological treatments included massage, chiropractic, acupuncture treatments, and other less commonly used complementary treatment options such as acupressure, chelation therapy, folk medicine, and homeopathic treatment.
To estimate the effect of total knee replacement on these longitudinally measured outcomes compared with no/delayed procedure, we used marginal structural models for repeated measures defined as weighted generalized estimating equations (GEEs) with each outcome as the dependent variable.28 Marginal structural models are warranted when outcome values can vary over time and can predict future treatment assignment along with other time varying confounders. For example, an increase in use of osteoarthritis pain medication could be associated with a higher likelihood of receiving total knee replacement. Each GEE included a treatment variable for the procedure, which was set to one after performance, a study visit indicator, the outcome’s baseline value, and other baseline variables including age, sex, race, income, education, knee injury in medical history, knee surgery in medical history, body mass index (BMI), Charlson comorbidity score,29 use of osteoarthritis pain medication, doctor’s diagnosis of knee osteoarthritis, Kellgren-Lawrence radiographic grade, SF-12 scores, WOMAC total score, and KOOS quality of life. To evaluate the effectiveness of total knee replacement according to preoperative physical functioning, we included an interaction term for the procedure with baseline SF-12 PCS.3031 Within these GEEs, we included weights for treatment propensity (that is, the likelihood of having received total knee replacement) for each study visit. Weights were estimated by logistic regression models pooled for study visits with the above mentioned baseline variables, study visit, longitudinally measured BMI, Charlson comorbidity score, doctor’s diagnosis of knee osteoarthritis, Kellgren-Lawrence radiographic grade, and all outcome variables. The main treatment effect estimate obtained from the marginal structural modeling should be interpreted as a “time averaged” causal effect.28
Missing values were imputed 20 times with a flexible additive model including status variables and the Nelson-Aalen estimator of the cumulative hazard for total knee replacement and death. To estimate parameter uncertainty, we re-fitted imputation, pooled logistic regression, and GEE models in 500 bootstrap datasets. We used the 2.5th and 97.5th centiles of bootstrap effect estimates for uncertainty interval limits. To validate the effect estimates from models developed with OAI patients, we performed multivariable adjusted analyses for SF-12 scores, SF-6D utility index, WOMAC, and use of osteoarthritis pain medication using 30 months’ follow-up data on 965 MOST participants with knee osteoarthritis at baseline. All statistical analyses were performed with R version 3.2.0 (2015, R Foundation for Statistical Computing). For more information on these statistical analyses see appendix 1.
Modeling of lifetime outcomes and cost effectiveness of total knee replacement
We developed the KOSMOS (Knee OSteoarthritis MicrOSimulation) model to simulate the virtual life course of 1327 OAI patients by modeling the occurrence of primary total knee replacement, revision procedure, and death up to age 100. Rates of primary total knee replacement and death were modeled by cause specific multivariable Cox regression with chronological age as time scale. Revision rates were based on the literature19 using the log cumulative hazard of revision procedure as reported for different age groups, which was modeled as a linear function of log time since the primary procedure. Health related SF-6D utility scores, use of osteoarthritis pain medication, and use of non-pharmacological treatment were based on the patients’ baseline and predicted 96 month values taken from the output of the GEEs with and without total knee replacement. We used linear interpolation to calculate patients’ values through eight years. We estimated SF-12 PCS, SF-12 MCS, and SF-6D scores for patients alive longer than eight years by linear extrapolation, based on the observed steady changes over time (figs A-C in appendix 3). Use of osteoarthritis pain medication and non-pharmacological treatments was assumed to remain stable after eight years (figs F and G in appendix 3), and the predicted 96 month probability of use was carried forward.
For simulated patients who survived each cycle of the model, we calculated an undiscounted QALY as the predicted SF-6D score multiplied by one year, thus resulting in a different QALY outcome for patients receiving total knee replacement in that cycle. Patients could accrue QALYs in the model until death or age 100. We calculated effect modification of procedure by SF-12 PCS scores using the latest predicted score, which was updated every eighth year until total knee replacement. We assumed that with revision procedure a beneficial effect on SF-12 PCS, use of osteoarthritis pain medication, and non-pharmacological treatment would be cancelled out by deterioration and improvement before and after the revision.3233
Costs associated with care of knee osteoarthritis and total knee replacement procedures were estimated from a US health system perspective (table 2⇓) and were either applied for each model cycle (annual costs associated with pharmacological and non-pharmacological treatment, physician office visits, and imaging) or as a one off cost penalty (costs associated with primary and revision procedures and rehabilitation including physiotherapy). All costs were expressed in 2013 $, with inflation rates reported in the US healthcare consumer price index.34 We recalibrated the average life expectancy predicted by the KOSMOS model for the modeled patient cohort to reflect the average life expectancy as predicted by age and sex specific US 2011 life tables and validated the KOSMOS model’s predictive performance in OAI and MOST data. More details on the development and validity of the KOSMOS model are provided in appendix 1.
For the base case analysis, we modeled 10 scenarios, ranging from current practice with rates as observed in the OAI, to lower rates of practice in which the procedure was performed only in individuals with lower SF-12 PCS levels (from <55-<20), to a scenario without total knee replacement. In the restricted scenarios, the underlying annual rate was kept the same as modeled for the current practice scenario, but no effects on quality of life, use of non-surgical treatment, and costs, and no procedural mortality rates were incorporated if the preceding SF-12 PCS level was greater than or equal to the threshold value.
For each scenario, we performed microsimulation of 1327 individuals for each set of 500 bootstrap equations and calculated the accrued QALYs and costs using the recommended 3% discount rate.35 We calculated 95% uncertainty intervals by using the 2.5th and 97.5th centiles of 500 modeled outcomes, each averaged across 1327 individuals. We calculated incremental cost effectiveness ratios (ICERs), defined as the difference in average costs divided by the difference in average QALYs, after ranking scenarios according to increasing costs and exclusion of dominated scenarios. Dominated scenarios were defined as programs less effective and more costly than the previous program (absolutely dominated) and programs with a larger incremental cost effectiveness ratio than the next not dominated program (extendedly dominated). We considered cost effectiveness thresholds of $50 000, $100 000, and $200 000 per QALY for decision making.36
Sensitivity analyses
In threshold analyses, we varied the hospital admission costs of primary and revision total knee replacement and used various percentages up to 100% for a further decline in quality of life (SF-12 PCS, SF-12 MCS, and SF-6D) in patients who were simulated to receive the procedure in the current practice scenario but were modeled to not receive the procedure in the other scenarios. For modeling the additional decline, we multiplied the main effect of follow-up time by values from 1 to 2. We used a time lag of four years after total knee replacement (equal to the difference in last follow-up measurement and median time to the procedure), so that the further decrease would reflect a long term effect of total knee replacement that we could have missed using OAI data.
We performed a scenario analysis using the 965 MOST patients after recalibration of hazard rates for total knee replacement and an analysis using EuroQol (EQ)-5d utility values as a substitute for SF-6D values by conversion of SF-12 MCS and PCS scores by a published equation.373839 In additional analyses, we modeled an increased rate of primary total knee replacement up to 30% to investigate the impact of a further increase in procedure rates as observed in the US after 2006.5 We also increased the background mortality rate based on findings that patients with osteoarthritis might have an excess all cause mortality compared with the general population by multiplying mortality rates by standardized mortality ratios sampled from a lognormal distribution (mean 1.55, 95% confidence interval 1.41 to 1.70).40 Finally, we performed an analysis exploring the potential influence of non-healthcare costs and loss of productivity not captured by a decrease in health utility,41 through inclusion of costs due to work time lost by patients and cost of informal caregiving. More details on these sensitivity analyses are provided in appendix 1.
Patient involvement
No patients were involved in developing plans for recruitment, design, or implementation of the studies, nor were they involved in developing the research questions and outcome measures. No patients were asked to advice on interpretation or writing up of results. Plans are in place for dissemination of the results of the research to the patient community. These plans include providing manuscript summaries to media sources, osteoarthritis charities, provider bodies, and patient organizations, in addition to social media announcements and institutional provision of pamphlets in health system waiting areas.
Results
Study populations
The 1327 OAI participants with knee osteoarthritis at baseline had worse SF-12 PCS, SF-6D, and osteoarthritis specific quality of life scores than the 3171 at high risk for knee osteoarthritis (P<0.001, table 1⇑). There were 382 total knee replacements, of which 319 were done before the 96 month visit, and 255 were in the 1327 with knee osteoarthritis at baseline. In the MOST cohort (table A, appendix 2), 135 total knee replacements were performed in 965 participants with knee osteoarthritis at baseline, and 16 were performed in 1719 individuals at high risk of knee osteoarthritis, all before the 30 month visit.
Effect of total knee replacement on quality of life and use of non-surgical treatment
Figures A-G in appendix 3 show time trends of SF-12 PCS, SF-12 MCS, SF-6D, WOMAC, KOOS quality of life, use of osteoarthritis pain medication, and non-pharmacological treatments, specified for those who did and did not undergo total knee replacement. After adjustment for baseline and time varying confounders, the main effects of total knee replacement (that is, treatment effects averaged across confounding variable levels and follow-up time) comprised an absolute improvement of 1.70 points (95% uncertainty interval 0.26 to 3.57) on SF-12 PCS, and changes in SF-12 MCS of −0.22 (−1.49 to 1.31) and SF-6D of 0.008 (−0.008 to 0.028) point. For each unit decrease in baseline SF-12 PCS, the effect on SF-6D increased and could be calculated as 0.098−0.002×(SF-12 PCS), suggesting that total knee replacement would become more effective if it was restricted to patients with SF-12 PCS scores <50. For osteoarthritis specific measures of quality of life, the procedure’s main effects included improvement of the WOMAC score by 10.69 (8.01 to 13.39) and KOOS quality of life of 9.16 (6.35 to 12.49) points. Total knee replacement reduced the odds of use of medication for osteoarthritis pain, but this effect was uncertain, with an odds ratio of 0.81 (0.55 to 1.12). Use of non-pharmacological treatment did not significantly seem to change with total knee replacement (0.91, 0.55 to 1.77). These effects were generally consistent with those obtained from multivariable adjusted analyses of MOST data, although in MOST the effect on SF-12 MCS was positive in contrast with the effect in OAI (table 3⇓).
Table 3
Changes in quality of life measures and use of non-surgical treatment after total knee replacement (TKR) in four models*. Figures are effect estimates with 95% uncertainty intervals based on refitting all modeling steps in 500 bootstrap datasets given for 1327 Osteoarthritis Initiative (OAI) participants with knee osteoarthritis at baseline who were repeatedly followed up until 96 months v 965 Multicenter Osteoarthritis Study (MOST) participants with knee osteoarthritis at baseline who were followed up until 30 months
Lifetime outcomes and cost effectiveness of total knee replacement practice
In the current practice scenario, the lifetime likelihood of undergoing total knee replacement, as predicted for OAI, was 39.9% (95% uncertainty interval 34.5 to 45.3), and the average undiscounted life expectancy was 22.39 years (21.13 to 23.85 years). Modeled quality of life values and proportions of use of non-surgical treatments over time were generally most favorable in the current practice scenario, except for SF-12 MCS scores (figs I-M, appendix 3). The mean discounted QALYs in the current practice scenario were 11.18 (10.66 to 11.70) and costs were $17 168 ($15 307 to $19 124).
In the base case cost effectiveness analysis, only the ICER of total knee replacement for those with SF-12 PCS <20 fell below $100 000/QALY. The optimal scenario given a cost effectiveness threshold of $200 000/QALY was surgery for those with SF-12 PCS scores <35; surgery for those with SF-12 PCS <40 was borderline cost effective. Compared with current practice, restriction of surgery to those with SF-12 PCS <35 would decrease the lifetime likelihood of total knee replacement to 10.2% (95% uncertainty 8.1 to 12.4), and would save $6974 ($5789 to $8269) per patient, whereas the effectiveness would be only slightly lower at −0.008 (−0.056 to 0.043) QALYs. The ICER of this strategy compared with the previous best scenario was $160 974/QALY (table 4⇓ and fig 1⇓). The current practice scenario was less effective and more expensive than the more restrictive scenarios with SF-12 PCS threshold values of 40-55 and therefore dominated. None of the ICERs fell below the $50 000/QALY threshold. The likelihood that the current practice scenario would be considered to be cost effective was low for cost effectiveness thresholds below $200 000/QALY (fig N, appendix 3).
Table 4
Lifetime cost effectiveness outcomes for different scenarios for determining which patients are eligible for undergoing total knee replacement (TKR) with 95% uncertainty intervals based on 500 bootstrap datasets for simulations of 1327 participants from the Osteoarthritis Initiative (OAI) with knee osteoarthritis at baseline
Fig 1 Base case analysis cost effectiveness at different levels of SF-12 PCS (physical component summary). Costs ($) and QALYs are means in OAI study population. Incremental cost effectiveness ratios (ICERs) not shown for dominated scenarios
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Fig 1 Base case analysis cost effectiveness at different levels of SF-12 PCS (physical component summary). Costs ($) and QALYs are means in OAI study population. Incremental cost effectiveness ratios (ICERs) not shown for dominated scenarios
Sensitivity analyses
With a cost effectiveness threshold of $200 000/QALY, restriction of surgery to those withSF-12 PCS <40 became attractive if the hospital admission costs of primary total knee replacement fell below $14 000. If the admission costs of primary total knee replacement fell below $8000, restriction of surgery to those withSF-12 PCS <30 would become economically attractive given a cost effectiveness threshold of $100 000/QALY. Cost effectiveness outcomes were not sensitive to the admission costs of revision procedures.
Simulation of the MOST population with knee osteoarthritis provided much higher lifetime likelihoods of total knee replacement, but similar ICERs, although restriction of surgery to those withSF-12 PCS <40 now became the optimal scenario at a cost effectiveness threshold of $200 000/QALY (table E in appendix 2). Use of EQ-5D utility values improved ICERs, with the ICER of restriction of surgery to those withSF-12 PCS <40 now amply falling below $200 000/QALY (table F in appendix 2). Increasing rates of primary total knee replacement or background mortality only minimally affected incremental cost effectiveness outcomes, and restriction of surgery to those withSF-12 PCS <35 remained the optimal scenario at a cost effectiveness threshold of $200 000/QALY (tables G and H in appendix 2).
Inclusion of costs associated with work days lost (see table D in appendix 2) and informal caregiving did not have a major impact on the cost effectiveness results: again restriction of surgery to those withSF-12 PCS <35 was the optimal scenario at a cost effectiveness threshold of $200 000/QALY (table I in appendix 2). If patients who would receive total knee replacement in current practice, but not in the more restrictive scenarios, experienced an additional decline of 50% in quality of life over the long term, all scenarios of performing total knee replacement including current practice became economically attractive given a cost effectiveness threshold of $200 000/QALY and with an additional decline of 80% given a cost effectiveness threshold of $100 000/QALY.
Discussion
Principal findings
We evaluated the effectiveness of total knee replacement on quality of life and use of non-surgical treatment in a recent US cohort of patients with knee osteoarthritis. Compared with patients who did not undergo total knee replacement, generic quality of life scores (on SF-12 physical) and those related to osteoarthritis improved with performance of the procedure, with larger improvements generally in those with a lower SF-12 physical score at baseline. Changes in use of osteoarthritis pain medication and SF-12 mental scores were small and heterogeneous across the two cohorts. In a cost effectiveness analysis modeling the life courses of OAI patients with knee osteoarthritis with inclusion of utility values derived from the SF-12, current practice was more expensive and in some cases even less effective compared with scenarios in which total knee replacement was performed only in patients with lower physical functioning. At the group level, the economically most attractive strategy was performing the procedure in those with a SF-12 PCS <35, assuming a cost effectiveness threshold of $200 000 per QALY. These findings were reproduced among knee osteoarthritis patients from the MOST cohort. Extension of the use of total knee replacement to those with a SF-12 physical score of ≤40 would become financially attractive if the hospital admission costs fell below $14 000.
Comparison with other studies
Scenarios of total knee replacement restricted to those with lower SF-12 PCS scores provided higher QALYs in our cost effectiveness analysis because small improvements in quality of life after the procedure became more prominent in people with lower baseline scores. A recently published randomized controlled trial showed larger effects of total knee replacement on quality of life measures than we found. 7 The OAI patient population undergoing total knee replacement, however, had on average less severe symptoms before surgery compared with the population from that randomized controlled trial, and the mean follow-up duration was longer in the OAI. Moreover, measures of quality of life were assessed independently of care providers in the OAI, contributing to a more limited potential for reporting desirable answers on quality of life scores before and after surgery.4243 Recent uncontrolled before-after studies have also shown larger effects of total knee replacement, generally including improvements in SF-12 PCS scores of 5-15 points.3244454647484950515253 In these studies, changes in SF-12 MCS were heterogeneous and varied from no improvement to 5 points.4749 Similar to SF-12 PCS, larger effects have been shown in before-after studies for quality of life measures specific to osteoarthritis.1332445455 As with the study population in the randomized controlled trial, however, the preoperative quality of life scores for these studies were on average worse than those of our study population and the duration of follow-up was generally shorter, possibly explaining the larger effects.
In addition to our analysis, three observational studies have compared quality of life outcomes in patients who did and did not undergo total knee replacement.125657 Two of these studies were not designed to prospectively collect data on generic and osteoarthritis related quality of life measures in people who did not and did undergo the procedure.1256 In a single hospital prospective cohort study (n=174) including 30 patients who received total knee replacement, there were large improvements in SF-12 PCS (9.6 points) and total WOMAC (24.2 points) scores at 12 months after joint replacement. The effect estimation, however, included effects of hip replacements (n=21), which generally have much larger effects than knee replacements.4749 Modeling studies that investigated the cost effectiveness of total knee replacement all used effects from before-after studies with larger marginal effects on quality of life, contributing to much lower estimated ICERs than we found.135859
Strengths and limitations of study
We estimated the effectiveness of total knee replacement versus no or delayed surgery in a large population based sample, the OAI cohort study, adjusting for baseline and time varying variables using marginal structural models. Marginal structural modeling has been shown to produce unbiased estimates of causal treatment effects.28 The larger number of procedures in our analysis enabled us to evaluate effect modification by baseline symptoms. Effect estimates and modification by baseline physical functional scores obtained in OAI were generally consistent with those found in the MOST population. Nevertheless, our findings should be interpreted in light of several limitations. First, the knee osteoarthritis populations of the OAI and MOST might not be representative of the current total population of patients with knee osteoarthritis in the US, limiting the generalizability of our findings. For example, younger patients might have been under-represented, contributing to fewer lower quality of life values from symptoms affecting work and other regular activities. Yet, both studies recruited participants from the general population across different regions in the US and obtained detailed information on risk factors, total knee replacements, and outcome measures independently from the hospital in which procedures were performed. Furthermore, our conclusions were unaffected by an increase in the rate of total knee replacement, resembling the most recent increase in use on a national level. Second, the study visits performed within OAI and MOST did not allow for measurement of outcomes immediately before procedures, and ignoring worsening symptoms just before could cause an underestimation of the true effect. We, however, adjusted for differences in 12 month changes in use of osteoarthritis pain medication, Kellgren-Lawrence radiographic grade, and quality of life scores assessed at the visit preceding total knee replacement. In addition, no changes in quality of life are observed at 12 months before procedures versus at one month before,50 and an immediate worsening of symptoms as a reason for undergoing total knee replacement is not likely as patients generally defer surgery for years before finally proceeding.606162 Third, as our study was based on analyses of non-randomized data without an intention to treat principle, residual confounding by indication and selection bias could be possible. Fourth, the self reported outcomes available in the retrospective data, such as use of osteoarthritis pain medication and loss of productivity, could potentially have influenced outcomes because of reporting bias or non-differential overestimation and underestimation. Finally, we made several assumptions in our cost effectiveness analysis. In any modeling study, a trade-off must be made between comprehensively including consequences of each strategy and their relevance to the decision problem at hand. We developed our decision model using individual level data on quality of life, treatment use, and survival, which allowed us to incorporate correlation between the model parameters while assessing uncertainty. Unfortunately, the OAI and MOST studies did not include collection of cost data. We therefore had to estimate costs using the best available external data sources, which might not have been representative for our patient cohort.
Conclusions and policy implications
Improvements in quality of life with total knee replacement were on average smaller than previously shown. Given its limited effectiveness in individuals with less severely affected physical function, performance of total knee replacement in these patients seems to be economically unjustifiable. Considerable cost savings could be made by limiting eligibility to patients with more symptomatic knee osteoarthritis. Only one randomized controlled trial has so far been published evaluating total knee replacement as an adjunct treatment to optimized non-surgical treatment, but it did not include results according to symptom status.7 Our findings emphasize the need for more research comparing total knee replacement with less expensive, more conservative interventions, particularly in patients with less severe symptoms, and research aiming to develop individualized prediction models for a better selection of patients with a predicted large net benefit from the procedure. These interventions can then be compared within cost effectiveness analyses, for which non-US data sources should be considered as well. In conclusion, the practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life. If the procedure were restricted to patients with more severe functional status, however, its effectiveness would rise, with practice becoming economically more attractive.
What is already known on this topic
-
Rates of total knee replacement in the US have more than doubled since 2000, primarily because of expanding eligibility to patients with less symptomatic knee osteoarthritis
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Up to a third of recipients of total knee replacement experience chronic pain postoperatively, and health benefits are assumed to be higher in those with poor preoperative physical functioning
What this study adds
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Quality of life outcomes generally improve after total knee replacement, with small effects becoming larger with decreasing preoperative functional status
-
The practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on QALYs at the group level and was found to be economically unattractive
-
Total knee replacement practice, however, could be considered cost effective if the procedure were restricted to patients with more severely affected functional status.
Soure: BMJ
The Need for Predictive, Prognostic, Objective and Complementary Blood-Based Biomarkers in Osteoarthritis (OA)
Osteoarthritis (OA) has traditionally been viewed as a non-inflammatory arthropathy and has not been considered a ‘serious disease’. However, this view has radically changed in recent years, due to the complexity and heterogeneity of the patient populations, spiralling socio-economical costs and long-term impact on the quality of life of affected individuals. There is an acute need for objective and non-invasive diagnostic biomarkers in OA, markers that can stratify patient subtypes and thereby direct therapeutic treatments at an earlier disease stage (read personal health care (PHC)) (Conaghan, 2013). Increased interest in the development of new diagnostic and prognostic tests for early forms of OA may incorporate the use of blood-based biomarkers; however, both research and regulated development and approval are still needed to reach a diagnostically important significant point where a given biomarker will benefit the clinical management of the patient.
1. The OA Biomarker Landscape Today
There are currently no disease-modifying osteoarthritis drugs (DMOAD) available for treatment of OA patients (Mobasheri, 2013, Qvist et al., 2008). This may be due to the heterogeneity of the OA population, where the origin and driver of disease progression is often poorly understood. The main treatment options for OA presently are pain relief, physical therapy and nutritional supplements (nutraceuticals). However, none of these can halt or reverse disease progression. In addition, diagnosis is often subjective, due to the lack of objective, precise and accurate diagnostic devices. Thus the limited clinical diagnosis and characterization of the individual patient will adversely influence healthcare management and the recruitment of the right patient cohorts for the testing of drugs in clinical trials. There is a medical need for objective, precise and accurate in vitro diagnostic devices for clinical trial enrichment (Kraus et al., 2015, Karsdal et al., 2013).
2. What Is the Medical Need for Biomarkers?
The lack of approved DMOADs in OA drags a long tail of failed clinical drug trials. Recently the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and other regulatory agencies have published guidelines on how biomarkers should be defined. Different groups and public-private partnerships have proposed different models for classifying OA biomarkers for clinical use (Bauer et al., 2006, Kraus et al., 2011, Bay-Jensen et al., 2016a, Bay-Jensen et al., 2016b). There is a general consensus on the medical need for biomarker development which may be summarized as seven key points:
- 1.
Translational biomarkers, which allow better characterization of a drug in preclinical development, ensuring of selection of the most viable projects
- 2.
Early identification of efficacy of intervention; Go/no-go decision-making already in phase 1b/2a studies, which normally do not include efficacy measures.
- 3.
Phase II and Phase III trial enrichment; reduction in study size, and a particular OA phenotype tailored for a selective interventions, which will recuse length of the clinical study to allow more efficient and less costly trials
- 4.
Identification of patients who are fast progressors and as such in greatest need of treatment.
- 5.
Identification of super responders to a specific treatment; patients with high efficacy and low safety concerns
- 6.
Biomarkers of disease activity; as OA is not a stabile disease, there is a need for devices for identification with high disease activity and potential progression
- 7.
Easy accessible monitoring devices – point of care; post marketing patient care and personalized medicine
Although there are clear overlaps in the above, it is clear that no single biomarker will be the answer for all.
3. Message From the Regulators
The public attention to biomarkers is increasing, recently further emphasized by the “white house” initiate focusing on quantifiable tools for patient election and monitoring.2
2The White house, 2015. Precision Medicine Initiative | The White House [WWW Document]. White house. URL https://www.whitehouse.gov/precision-medicine (accessed 2.5.16).
On the regulatory side, the FDA issued a position document describing the need and road ahead for personalized medicine “FDA: Paving the Way for Personalized Medicine”,3
3FDA, 2013. Paving the Way for Personalized Medicine [WWW Document]. URL http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf(accessed 2.5.16).
which later resulted in new guidelines to faster biomarker tool development by the guidelines “Identifying Potential Biomarkers for Qualification and Describing Contexts of Use To Address Areas Important to Drug Development”,4
4FDA, 2015. Identifying Potential Biomarkers for Qualification and Describing Contexts of Use To Address Areas Important to Drug Development; Request for Comments [WWW Document]. FDA. URL https://www.federalregister.gov/articles/2015/02/13/2015-02976/identifying-potential-biomarkers-for-qualification-and-describing-contexts-of-use-to-address-areas (accessed 2.5.16)
which are in addition to the standard guidelines for in vitro companion diagnostic device. This has led to the discussion on prospective-retrospective biomarker analysis for regulatory consideration, by the white paper from the industry pharmacogenomics working group (Patterson et al., 2011). This will greatly assist precision medicine and PHC by guiding the discussion on how to implement a “prospective-retrospective biomarker analysis”. The prospective-retrospective biomarker analysis approach is developed to “rescue” failed phase III trials. Qualified biomarkers are to be measured in certified, high-quality laboratories and analyzed using predefined statistical analysis plans to test hypotheses related to retrospective analysis of technically and biologically validated biomarkers.
According to the FDA, a prognostic in vitro diagnostic biomarker would need a 510 K or de novo approval (class II device), whereas a predictive biomarker would need ldt pre-market approval (PMA, class III device). The main separating factor is that a prognostic biomarker provides you with an estimate for progression, whereas a predictive biomarker would be used to decide the exact treatment regimen for individual patients, and would therefore have a significant impact on the patient’s life. A predictive biomarker will often become a companion diagnostic.5
5FDA, 2014. In Vitro Companion Diagnostic Devices. Guidance for Industry and Food and Drug Administration Staff.
In addition, the recent “drug development tool (DDT) box” guidelines are also allowing for regulatory assessment of tools to assist in clinical drug development, such as the fibrinogen enrichment of patients in COPD clinical studies with a more severe outcome (fast progressors), which is now classified as a DDT.
No biomarkers have yet been qualified as biomarkers for OA, however several biomarkers have been developed targeting cartilage degradation and formation (e.g. CTX-II, ARGS, PIIANP), joint inflammation (e.g.C3M, Col2-NO2), bone remodelling (e.g. alpha CTX I, osteocalcin) as well as inflammation and metabolic factors (Bay-Jensen et al., 2016a, Bay-Jensen et al., 2016b). The scientists and clinicians working in the biomarker field cannot expect a “one size fits all” solution for OA. Consequently it is important to test and validate a biomarker to a specific hypothesis. This can be done under the laboratory-developed test (LDT) (Sarata and Johnson, 2014), which is a type of in vitro diagnostic test that is designed, manufactured and used within a single laboratory.
4. How Do We Move Forward?
Different approaches, techniques and better-stratified patient samples are needed to move biomarker development towards qualification, which means that new partners need to come together and collaborate. For example development of a novel blood-based and cartilage-derived protein biomarker requires application of advanced analytical techniques such as proteomics and mass spectrometry, whereas development of the biomarker assay requires knowhow of biochemical and immunological assessment platforms. Furthermore, testing, validation and qualification requires access to high quality clinical samples from several independent retrospective or prospective cohorts. In the end a commercialisation plan needs to be established to push forwards and finance the qualification of biomarkers. Thus it is most likely that no single entity, public or private, will be able to complete these development steps alone. There is a need for i) Formation of public-private partnerships to develop, test, validate and qualify biomarkers for use in clinical trial and patient management, ii) Design of clinical studies that stratify patients and investigate trends and characteristics of specific OA cohorts and study populations, and iii) Collaboration between biotech and pharmaceutical companies to support the commercialization of biomarkers.
In summary, a great deal of collaborative work needs to be done in this area to develop more predictive, prognostic, objective and complementary biomarkers for OA management and DMOAD development.
Rheumatologists more likely to underestimate impact of osteoarthritis than rheumatoid arthritis
Despite having a higher burden of disease, individuals with osteoarthritis (OA) are more likely to have their condition underestimated by rheumatologists than individuals with rheumatoid arthritis (RA), according to a study presented at the European League Against Rheumatism Annual Congress (EULAR 2016) held in London, UK.
To analyse the discordance between physician global estimates (DOCGL) and patient global estimates (PATGL) in patients with RA (n=216) or OA (n=243), patients were asked to complete a multidimensional health assessment questionnaire/routine assessment of patient index data (MDHAQ/RAPID3) while physicians used the RheuMetric checklist, both of which enabled evaluation of disease severity on a visual analogue scale (VAS). [EULAR 2016, abstract OP0094]
Patients with RA were more likely to be in concordance with their physicians (67 percent, n=144) compared to OA patients (56 percent; n=136).
Patient perception of disease severity exceeded that of physician perception (PATGL>DOCGL) in 82 OA patients (34 percent) and 39 (18 percent) RA patients, while physician perception was higher than patient perception of disease severity (DOCGL>PATGL) in 33 RA (15 percent) and 25 OA patients (10 percent).
There was an almost two-fold greater likelihood that rheumatologists would underrate OA compared to RA, said study author Dr. Isabel Castrejón from the Rush University Medical Center, Chicago, Illinois, US who presented the results.
In both diagnosis groups, higher perception of disease severity was more likely in patients with lower education levels, higher levels of pain, disability, fatigue, and joint counts, and more symptoms. Experiencing higher levels of pain was found to be a significant predictor of discordance for both diagnosis groups, said Castrejón.
Previous studies have pointed to discordance between patient and physician assessment of rheumatic disease severity. [Arthritis Care Res (Hoboken) 2014;66:934-942; Arthritis Care Res (Hoboken)2012;64:206-214]
“Concordance by patients and physicians has been associated with greater expectations for improvement and better outcomes. It is important to be able to recognize discordance by patients and physicians because that can influence treatment adherence, compliance, and future outcomes,” said Castrejón.
“RA is generally thought to be more severe than OA, not only by physicians but also by patients and the public,” said Castrejón. “Rheumatologists need to revise their generally held views that OA is less severe than RA,” she said, while stressing on the importance of good communication between patients and physicians.
Turmeric Extract Puts Drugs For Knee Osteoarthritis To Shame
Millions take non-steroidal anti-inflammatory drugs (NSAIDs) daily for arthritis and related inflammatory conditions, but are completely unaware that far safer, and at least as effective, natural alternatives already exist — and are as easily accessible and inexpensive as the spices found in your kitchen cupboard.
Human research on the health benefits of turmeric is sparse, mainly due to the lack of capital available to fund expensive clinical trials.[i] Despite many decades of investigation as a lead drug compound, and the availability of thousands of preclinical studies indicating turmeric’s therapeutic value, few yet realize that this common kitchen spice may provide a suitable drug alternative for common health conditions.
The latest human study to clinically confirm turmeric’s medicinal value was published in theIndonesian Journal of Internal Medicine in April, 2012 and found the curcuminoid extract of turmeric was able to reduce inflammation in patients suffering from knee osteoarthritis.
Researchers compared the effect of a curcuminoid extract to the NSAID drug diclofenac sodium in reducing cycloxygenase -2 (COX-2) secretion by synovial fluid’s monocytes in two, randomly divided, groups suffering with knee osteoarthritis.
The synovial fluid is an egg yolk-like liquid within the cavities of the synovial joints, which serves to reduce friction between articular cartilage during movement. In knee osteoarthritis, a condition that afflicts 1 in 2 people by the age of 85 years, the immune cells known as monocytes express increased inflammatory COX-2 enzyme activity within the synovial fluid.
In the study, subjects were given either 30 mg 3 times daily of turmeric extract (curcuminoid) or 25 mg 3 times daily of diclofenac sodium for 4 weeks. After the treatment period, aspiration of the joint as performed and the secretion of cycloxygenase-2 enzyme by synovial fluid’s monocytes was evaluated.
Results were reported as follows:
In curcuminoid group the average scores were 1.84±0.37 and 1.15±0.28 respectively (p<0.001). In diclofenac group the average scores were 1.79±0.38 and 1.12±0.27 respectively (p<0.001). In curcuminoid group the decreasing score of cycloxygenase-2 secretion was 0.70±0.51 while in diclofenac group was 0.67±0.45. There was no significant difference in decreasing the score of cycloxygenase enzyme secretion between both treatment groups (p=0.89).
In summary, both curcuminoid and diclofenac sodium were capable of significantly decreasing the secretion of the inflammatory COX-2 enzyme, with nearly identical potency.
Discussion
This is not the first human study to confirm turmeric is at least as effective as an NSAID drug in reducing the symptoms associated with knee osteoarthritis. A 2010 study published in the Journal of Alternative and Complementary Medicine found 2,000 mg of turmeric extract was as effective as 800 mg of ibuprofen in reducing symptoms of pain and inflammation.[ii]
What is most remarkable about the more recent study is not that turmeric curcuminoids have potent anti-inflammatory properties – there are already hundreds of studies confirming its COX-2 reducing and otherwise anti-inflammary effects — but rather how much safer they are relative to NSAID drugs like diclofenac, which like most pharmaceutical anti-inflammatory drugs have been linked to adverse health effects such as increased cardiac mortality, miscarriage and seizure.
One way to assess the relative toxicity of these two compounds is to compare the primary polyphenol in turmeric, curcumin, with diclofenac sodium through their respective Material Safety Data Sheets, which contain detailed information on the toxicity of these substances.
Diclofenac Sodium: The LD50 for mice is 95 mg/kg, meaning that it only takes 95 mg/kg of mouse to acutely kill 50% of an exposed group.
Curcumin: The LD50 for mice is >2,000 mg/kg, meaning that it would take more than 2,000 mg/kg of mouse to acutely kill 50% of an exposed group.
In order to get perspective on how toxic an LD50 of 95 mg/kg is, let’s first calculate how much of this chemical it would take in milligrams to kill an average sized mouse. Mice are between 15-27 grams, depending on their age, strain and diet. If we take the average between the two, at 21 grams, our mouse would weigh 0.021 kilograms. This means that it only takes 1.9 milligrams to acutely kill 50% of the mice given such a dose.
Extrapolating to humans, an average 150 lb adult weighs 68.03 kilograms, it would only take 6462 milligrams, or 6.46 grams to kill 50% of the humans given the dose. This is less than the weight of three pennies (7.5 grams). Compare this to the LD50 of curcumin (2,000 mg/kg), where it would take more than 136,000 mgs (4.86 ounces) to kill 50% of the humans given it – and even this estimation is doubtful, since it is likely that it would simply be vomited up, or expelled through the gastrointestinal tract, and other organs of elimination, before reaching lethal levels in the body. Also, remember that it only took 90 mg a day in the aforementioned study to reduce inflammation as effectively as diclofenac sodium. The difference between the 90 mg required to produce an effective response, and a (theoretical) 136,000 mg threshold for lethal toxicity, is four orders of magnitude.
In practical terms, the chance of you hurting yourself with a drug like diclofenac sodium — ironically, in an attempt to reduce pain — as compared to a simple kitchen spice like turmeric, is infinitely higher. Consider too, that there are over 100 known adverse health effects associated with this chemical class of drugs, whereas turmeric (and curcumin) has been linked to over 600 beneficial ones — not exactly a hard choice to make, when it comes to risk-benefit analysis.
Vitamin D a No Go for Arthritic Knees, Study Finds .
Vitamin D supplements didn’t relieve pain or slow the progression of knee osteoarthritis in a new study, even though the patients involved had low levels of the vitamin.
Osteoarthritis is a progressive disease, and currently no treatment is available that will stop the loss of cartilage. Eventually, many patients are headed for knee replacements, the Australian researchers said.
“These data suggest a lack of evidence to support vitamin D supplementation for slowing disease progression or structural change in knee osteoarthritis,” said lead researcher Dr. Changhai Ding, a professor at the University of Tasmania in Hobart.
The use of vitamin D supplements to reduce pain and slow the progression of knee osteoarthritis has been controversial in the past, with studies showing conflicting results, he said.
This new study put vitamin D supplements to the test by randomly assigning some osteoarthritis sufferers to receive supplements while others received a placebo. In the context of this type of definitive study, vitamin D failed to have any beneficial effect, Ding’s team found.
Knee osteoarthritis affects about 10 percent of men and 13 percent of women aged 60 and older, according to background information in the report. The study was published in the March 8 issue of the Journal of the American Medical Association.
The study findings did not come as a surprise to Dr. Neil Roth, an orthopedic surgeon at Lenox Hill Hospital in New York City.
“Osteoarthritis is a progressive disease and any medications patients take, orally or injected, won’t alter the disease,” he said. “The best we can do without a joint replacement is to modify some of the symptoms.”
These treatments include anti-inflammatory drugs, painkillers and cortisone injections, he said. These therapies do not stop the disease from getting worse and only relieve some of the symptoms, Roth said.
For the study, Ding and colleagues randomly assigned just over 400 patients with knee osteoarthritis and low vitamin D levels to monthly treatment with either 50,000 International Units of vitamin D a month or a placebo.
Over two years of follow-up, the investigators did not see any difference between the groups in reduced pain, loss of cartilage or improvement in bone marrow in the thigh or shin bone.
“That’s not to say that vitamin D doesn’t play a role in other aspects of bone health — because it does,” Roth said.
It is important for men and women to have the appropriate levels of vitamin D to build and maintain bone mass, he said.
“Vitamin D is an important part of any well-balanced diet,” Roth said. “But the notion that it is going to alter your arthritis and minimize some of the symptoms or the progression isn’t sound. I wouldn’t be taking vitamin D supplements if that’s what your goal is.”
A group that represents the vitamin supplement industry said the study did find slight improvements in some who were given vitamin D supplementation.
“This study demonstrates the potential benefit of vitamin D for patients with knee osteoarthritis as patients supplementing with vitamin D experienced pain reduction and a slightly smaller loss of cartilage over time,” said Andrea Wong, vice president of scientific and regulatory affairs at the Coucil for Responsible Nutrition. “Even though the numbers are not statistically significant, these are positive trends that should encourage further research.”
Scientists discover first biomarkers predictive of severe OA
The presence of micro RNA (miRNA) biomarkers in the blood is correlated to the development of severe osteoarthritis (OA) of the knee or hip, according to new research. [Abstract OP0003]
“The findings indicate that for the first time we will be able to predict the risk of severe osteoarthritis, before the disease starts to significantly impact a person’s life, allowing us to take preventative action early on,” said lead author Dr. Christian Beyer from University Erlangen-Nuremberg, Germany. “Through the early identification of osteoarthritis we can decrease both the impact of the disease on individuals and the major socio-economic burden severe disease poses.”
The researchers analyzed blood samples from patients with OA over a follow-up period of 15 years, testing for the presence of miRNAs and occurrence of OA. Out of the 816 patients followed, 67 had ≥1 total joint replacement for severe knee or hip OA. The results of serum analyses demonstrated that severe OA was correlated with three miRNA biomarkers known as let-7e, miR-454 and miR-885-5p.
Prevention and early treatment is considered the most effective approach for the management of OA. However, there has been no way to identify severe OA early, when the disease is still clinically silent.
“We need to identify those individuals who are at risk of developing this disease. This is crucially important,” said Beyer. “At the moment, there are no markers or indicators that will show us who is at risk of that and we need to develop biomarkers that can predict the development of this disease.”
However, this new study suggests that three miRNAs could be used as biomarkers to predict severe OA, said Beyer, adding that: “let-7e was our most promising single micro-RNA and we also found a nice correlation between let-7e levels and the number of joint replacement surgeries due to severe OA. We found that the lower those let-7e levels were, the higher was the risk for receiving more than one joint replacement because of severe osteoarthritis of the knee or the hip.”
OA is a common musculoskeletal disorder affecting 10 percent of people worldwide. It is one of the top 10 most disabling diseases in developed countries and a major cause of knee and hip replacements. “Osteoarthritis is the most common form of arthritis and it is a major socioeconomic burden,” said Beyer. “Our study now opens many new questions that need to be addressed by future studies.”
Does Cracking Your Knuckles Cause Arthritis?.
Do you crack or “pop” your knuckles? Some believe it may cause, or worsen, joint conditions such as arthritis. However, according to the featured research,1, 2knuckle-cracking does not appear to be a risk factor for osteoporosis in that joint.
About one in five adults, or nearly 50 million Americans, have been diagnosed with arthritis, the most common form of which is osteoarthritis.3
If you have osteoarthritis, the cartilage within your joints is progressively being damaged, and the synovial fluid that keeps your joints lubricated and cushioned is typically reduced as well.
The pain and joint stiffness that you feel is a result of your bones starting to come into contact with each other as cartilage and synovial fluid is reduced, and if you don’t take action, it can become progressively worse until you are unable to carry out your normal daily activities.
In conclusion, the authors stated that:
“Total past duration (in years) and volume (daily frequency ‘- years) of knuckle-cracking (KC) of each joint type also was not significantly correlated with OA at the respective joint. A history of habitual KC – including the total duration and total cumulative exposure ‘does not seem to be a risk factor for hand OA.'”
Twenty years ago, I co-authored a paper titled “Cracking down on ‘neck cracking,’ which was published in the journal American Family Physician.4 In it, I argued that self-manipulation can lead to lax ligaments. Personally, I don’t think it’s wise to crack your joints on a regular basis, even if it doesn’t directly lead to arthritis of the joint. That said, what can make arthritis worse, and how can you address arthritic conditions?
What’s the Difference Between Osteoarthritis and Rheumatoid Arthritis?
Osteoarthritis usually occurs in older individuals, but can also be caused by repetitive stress or acute trauma. Rheumatoid arthritis, on the other hand, can affect you at any age, including children. Fortunately, juvenile rheumatoid arthritis (JRA) is relatively rare.
Understanding the differences between the two types of arthritis will help you distinguish which one you have.
Osteoarthritis – Degenerative joint disease usually affects the distal joints, or the joints at the end of your fingers and toes, not the middle ones. Additionally, it’s not symmetrical, so typically you may have it on just one joint, or on one hand or foot and not the other.
Rheumatoid arthritis – RA, on the other hand, is an autoimmune disease that causes your body to break itself down. Therefore, it tends to be bilateral and symmetrical, meaning it’s the same on both sides of your body. If you only have a specific joint affected on one side of your body, it is far less likely to be RA. It also affects your middle joints, and is associated with joint deformities, especially your hands and fingers. It can be very crippling, and people do die from rheumatoid arthritis, so it’s not something to be treated lightly.
Little-Known Risk Factors for Rheumatoid Arthritis and Osteoarthritis
Recent research5 has identified several lifestyle factors and pre-existing conditions that may increase your risk of developing rheumatoid arthritis, including:
- Smoking
- Obesity
- Diabetes
As for osteoarthritis, a recent analysis6 found that the greater a woman’s exposure to perfluorinated compounds (PFCs), the greater her risk for developing osteoarthritis. Interestingly, the same correlation was not found in men. It’s believed the reason for this is the impact of these chemicals on women’s hormones. PFC’s are commonly found in nonstick cookware, takeout containers and carpeting, just to name a few.
Even though osteoarthritis and rheumatoid arthritis are two entirely different diseases, they can be treated in much the same way as foundationally inflammation as at the core of the pain. So even though osteoarthritis is typically caused by wear-and-tear on your joints due to lifestyle, diet and aging, and rheumatoid arthritis is an autoimmune disease in which your body starts destroying itself, you may gain relief from the following treatments regardless of which type of arthritis you have.
First: Basic Lifestyle Changes to Address Arthritis
I believe improving your diet using my nutritional guidelines is crucial for your success. It addresses all of the nutritional guidelines presented in this article, and more. In addition, there are some general principles that seem to hold true for virtually everyone and these include:
- Eliminating sugar, especially fructose, and most grains. For most people with rheumatoid arthritis, you’ll want to be very careful to limit fructose to just 15 grams per day or less, and this includes fructose from whole fruit.
- Opting for organic food, preferably locally grown, and eat your food as close to raw as possible
- Incorporating regular exercise into your daily schedule. Weight training has been found to be of particular benefit for those with rheumatoid arthritis and, contrary to popular belief, if you have osteoarthritis exercise is absolutely crucial to your well-being. Naturally, if you’re in pain, you need to take certain precautions, so for more information on how to adjust your exercise if you have either of these conditions, please follow the links provided
The Importance of Sulfur
Sulfur is just now becoming more widely appreciated as a really critical nutrient, without which many other things don’t work properly, and many are not getting enough sulfur from their diet anymore. Sulfur is found in over 150 different compounds within the human body. There are sulfur components in virtually every type of cell, so it’s extremely important. It plays a critical role in inflammatory conditions such as arthritis, as well as detoxification. Two ways to increase your sulfur intake include:
- MSM, either from food or supplement: A metabolite of DMSO, MSM primarily impacts your health by reducing inflammation. MSM is 34 percent sulfur by weight, but it’s more than just a simple sulfur donor. It affects sulfur metabolism in your body, although it’s still not entirely clear how. Perhaps most important, MSM helps protect against oxidative damage, and is widely used as a supplement for arthritic conditions.
While many opt for a supplement, MSM is in most raw foods, such as leafy green vegetables. Raw milk has the highest naturally occurring content of MSM.
One caveat is cooking and pasteurization. While MSM is stable to extremes of pH and temperature, it volatilizes and turns to gas very easily. It’s also very water-soluble. So when cooked at high temperatures, it simply wafts off in the steam. That’s why it’s easily removed during cooking and processing. Pasteurization cuts the MSM content by approximately 50 percent. So, in order to ensure you’re getting the most MSM from any food, it must be either raw or as minimally processed as possible.
Fortunately, toxicity studies have shown that MSM is extremely safe and can be taken at very, very high doses. Even if you have a very rich diet full of raw vegetables and MSM-rich foods, you can still supplement and not hit that toxicity level. Clinical research studies have found that the effective amounts range from about 1.5 grams to 6 grams. For comparison, intake of MSM from natural sources such as fruits and vegetables would be in the milligram per day range of about 2.3 to 5.6 mg/day.
- Bone broth: Simmering leftover bones over very low heat for an entire day will create one of the most nutritious and healing foods known to man. Make sure the bones are from organically raised animals. The connective tissues are sulfur-rich, and when you slow-cook the bones, you dissolve these nutrients out of the bone and into the water.
You can use this broth for soups, stews, or drink it straight. Remember that the “skin” that forms on the top is the best part—this is what contains the most valuable nutrients, including sulfur, along with healthful fats—so make sure to stir it back into the broth.
- Source: mercola.com
at F�te�� ��� 2 hours before eating them. This will help to get rid of the phytic acid and enzyme inhibitors, which can interfere with the function of your own digestive and metabolic enzymes, in the nuts. To make them more palatable you can you a dehydrator (I like the Excalibur) to improve the texture.
Enzyme inhibitors in nuts (and seeds) help protect the nut as it grows, helping to decrease enzyme activity and prevent premature sprouting. When nuts are soaked, the germination process begins, allowing the enzyme inhibitors to be deactivated and increasing the nutrition of the nut significantly, as well as making them much easier to digest. Macadamia nuts (and other white nuts) have only negligible amounts of enzyme inhibitors, so soaking is not as necessary.
Choose Raw Organic Nuts, Ideally
To increase the positive impacts on your health, look for nuts that are organic and raw, not irradiated or pasteurized. Be aware that pasteurized almonds sold in North America can still be labeled “raw” even though they’ve been subjected to one of the following pasteurization methods:
- Oil roasting, dry roasting or blanching
- Steam processing
- Propylene Oxide (PPO) treatment (PPO is a highly toxic flammable chemical compound, once used as a racing fuel before it was prohibited for safety reasons)
There are generally no truly “raw” almonds sold in North America, so don’t be misled. It is possible to purchase raw almonds in the US, but it has to be done very carefully from vendors selling small quantities that have a waiver from the pasteurization requirement. The key is to find a company with the waiver that is not pasteurizing them.
When consumed with these guidelines in mind, raw, organic nuts are a convenient and enjoyable superfood to add to your diet. And this is precisely why they’re recommended as one of the best sources of healthy fats in my nutrition plan.
Source: mercola.com
Cartilage Gives Early Warning of Arthritis, Study Finds.
Damage to the tissue that cushions joints occurs even before people feel pain, research shows.
By Robert Preidt, HealthDay News
Exercise-related damage in cartilage can help identify people with the earliest stages of osteoarthritis, a new study reveals.
The findings could improve early detection of the painful joint disease and could also be used to improve methods of repairing damaged cartilage, said study senior author Alan Grodzinsky, of the Massachusetts Institute of Technology, and colleagues.
For the study, the researchers developed a method that identifies osteoarthritis-related changes that occur in cartilage in response to high-load activities such as running and jumping.
Cartilage is firm, rubbery tissue that cushions bones and keeps them from rubbing together. When osteoarthritis begins to develop, the ability of cartilage to resist physical-activity-related impact is reduced. This is now known to be due to the loss of molecules called glycosaminoglycans (GAGs)
Using their new system, the researchers found that GAG-depleted cartilage loses its ability to stiffen under the forces of high-load activities. GAG loss also caused an increase in the depletion of fluids from the cartilage, which likely reduces protection against the impact of high-load activities.
The findings show how GAG loss at the earliest disease stages reduces the ability of this tissue to withstand high-load activities, according to the study, which was published in the April 2 issue of theBiophysical Journal.
“This finding suggests that people with early degradation of cartilage, even before such changes would be felt as pain, should be careful of dynamic activities such as running or jumping,” Grodzinsky said in a journal news release.
Osteoarthritis affects about one-third of older adults and is the most common type of joint disorder.
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