OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hand osteoarthritis.

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis.

OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. METHODS: PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. RESULTS: There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. CONCLUSION: At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

Relief of acute low back pain with diclofenac-K 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial.

OBJECTIVE: To assess efficacy and safety of diclofenac-K 12.5 mg tablets in the treatment of acute low back pain (low back pain). MATERIAL/METHOD: A multiple dose, double-blind, double-dummy, randomized, placebo-controlled, parallel group trial compared diclofenac-K (12.5 mg; n = 124) with ibuprofen (200 mg; n = 122) and placebo (n = 126) in patients with moderate-to-severe acute low back pain. The treatment consisted of an initial dose of 2 tablets followed by 1 or 2 tablets every 4-6 hours as needed (maximum 6 tablets/day) for 7 days. The primary efficacy outcome for the initial dose was TOTPAR-3, the summed total pain relief over the first 3 hours. Secondary initial dose outcomes included TOTPAR-6, summed pain intensity differences SPID-3 and SPID-6, time to rescue medication or remedicate, and the End of First Dose global efficacy assessment. The primary efficacy outcome for the flexible multiple dosing regimen was the End of Study global efficacy assessment. Secondary outcomes for multiple dosing included time to rescue medication over the entire study, the End of Day global efficacy assessments (daily over Days 1-7), pain intensity differences on the VAS measured at Visit 2 and 3, and change in Eifel algofunctional index. Safety/tolerability was assessed by recording adverse events. RESULTS: Diclofenac-K 12.5 mg demonstrated superiority vs placebo on the primary efficacy parameter and almost all secondary initial dose outcomes. With respect to the initial dose, diclofenac-K 12.5 mg was also significantly superior to ibuprofen 200 mg on SPID-3. Ibuprofen 200 mg was superior to placebo only on the End of First Dose global efficacy assessment. The flexible multiple dosing regimens of diclofenac-K and ibuprofen were both significantly superior to placebo on the End of Study global efficacy assessment, time to rescue medication over the entire study period, the End of Day global efficacy assessment on Days 1-2, pain intensity difference on the VAS at Visit 3 and the Eifel algofunctional index at Visit 3 (also at Visit 2 in diclofenac-K 12.5 mg group). Both active treatments were as well tolerated as placebo. CONCLUSIONS: The flexible multiple dosing regimen of diclofenac-K 12.5 mg (initial dose of 2 tablets followed by 1-2 tablets every 4-6 hours, max. 75 mg/day) is an effective and safe treatment of acute low back pain.

Guidelines for clinical studies assessing the efficacy of drugs for the management of acute low back pain.

In this paper we propose guidelines for clinical trials aimed at assessing the efficacy of drugs for acute non-specific low back pain (LBP) with or without radicular pain, preliminary to their approval and registration. To this end, consensus statements were obtained from a group of experts in the fields of rheumatology, clinical medicine, public health and epidemiology. EBM resources were systematically used as references. Four diagnostic categories were defined: type 1--LBP with no radiation; type 2--LBP radiating no further than the knee; type 3--LBP radiating beyond the knee, but with no neurologic signs; and type 4--LBP radiating to a specific and entire leg dermatome, with or without neurologic signs. Studies should be designed on the basis of the claimed indications for the drug, but must be double-blinded whatever the indication. The duration of the study may be shorter for LBP type 1 or 2 (one week) than for LBP types 3 and 4 (up to one month), depending on the aim of the study and the indications for the drug. The comparator may be inactive (placebo) or active (for a superiority trial, e.g., versus paracetamol). Specific inclusion and exclusion criteria have been defined here for each category. An appropriate wash-out period for any drugs that could affect the pain status should be planned. Paracetamol may be allowed as rescue medication. The primary endpoint should be based on a validated pain assessment tool that may be either generic (type 1 or 2) or oriented (back and knee for types 3 and 4). Secondary endpoints could include the assessment of functional performance; the duration of any period of bed-rest; work limitation; a global assessment comprising pain at rest, standing and walking; the time elapsed before epidural injection, the prescription of other therapeutic agents, or surgery; and the use of rescue medication. Adverse events (AE) should be monitored systematically using a methodology that reflects the mode of action of the tested drug. With the application of these guidelines, LBP could serve as an appropriate disease for testing analgesic drugs. Rigorous evaluation may also help to improve the management of acute LBP.

Lowest effective single dose of diclofenac for antipyretic and analgesic effects in acute febrile sore throat.

OBJECTIVE: To compare the antipyretic and analgesic effects of a single oral dose of diclofenac potassium 6.25, 12.5 or 25mg with paracetamol 1000mg and placebo in patients with fever resulting from acute febrile sore throat. DESIGN AND SETTING: This was a multicentre, double-blind, double-dummy, randomised, placebo-controlled, parallel group study conducted at 21 primary-care centres throughout France. PATIENTS: In total, 343 adult patients with acute febrile sore throat (fever >/=38.0 degrees C) were randomised to the five treatment groups. INTERVENTIONS: Patients received one oral dose of medication. Fever, spontaneous throat pain and pain on swallowing were recorded over 6 hours. If acute symptoms persisted 2 hours after study drug administration, the patient was allowed to take rescue medication and discontinue the trial. RESULTS: The antipyretic effects of diclofenac potassium 6.25, 12.5 and 25mg and paracetamol 1000mg were significantly greater than placebo. The antipyretic effects of diclofenac potassium 12.5 and 25mg were numerically greater than paracetamol 1000mg, which was comparable to the effect of diclofenac potassium 6.25mg. The analgesic effects of the higher doses, diclofenac potassium 12.5 and 25mg, and of paracetamol 1000mg were significantly better than placebo. Summary efficacy measures over the first 4 hours post-dose showed a dose-response relationship among the diclofenac doses, with statistically significant differences on some outcomes between the 25mg and the 6.25mg doses. On the global efficacy evaluation for relief of fever and throat pain, patients rated both diclofenac potassium 12.5 and 25mg significantly higher than paracetamol 1000mg (p

Oral meloxicam is effective in acute sciatica: two randomised, double-blind trials versus placebo or diclofenac.

OBJECTIVE: Two randomised, double-blind, double-dummy trials evaluated the efficacy and tolerability of meloxicam compared with placebo or diclofenac in patients with acute sciatica. SUBJECTS: 1021 patients with acute sciatica. TREATMENT AND METHODS: In the first study, 532 patients received meloxicam 7.5 mg, meloxicam 15 mg, or placebo for 7 days. The second study randomised 489 patients to meloxicam 7.5 mg, meloxicam 15 mg, or diclofenac 150 mg for 14 days. RESULTS: Meloxicam 7.5 mg and 15 mg significantly improved overall pain between baseline and day 7 (p < 0.05) compared with placebo. Furthermore, both meloxicam doses showed similar improvements on all primary and secondary efficacy endpoints compared with diclofenac 150 mg. No significant differences in tolerability were observed between any of the treatment groups in either study. CONCLUSIONS: Meloxicam (7.5 mg or 15 mg) was well tolerated and was more effective than placebo, and as effective as diclofenac, in acute sciatica.

Sensitivity to change of the functional index for hand osteoarthritis.

BACKGROUND: The functional index for hand osteoarthritis (FIHOA), a 10-item investigator-administered questionnaire, was validated in 1995. It is relevant, reliable and has good external and internal validities. OBJECTIVE: To assess the sensitivity to change over time of the FIHOA. PATIENTS: symptomatic [visual analog scale (VAS) > or = 30 mm, FIHOA > or = 5] hand OA patients [American College of Rheumatology (ACR) criteria, > or = 2 radiologically affected joints] were included in a 6-month randomized, double-blind, placebo-controlled trial. Recorded parameters: Pain on VAS, FIHOA score, morning stiffness duration, grip strength. STATISTICAL ANALYSIS: mean standardized response (MSR = delta DO-M6/S.D. of delta) was calculated for each parameter in an intention-to-treat (ITT) population before breaking the randomization code. RESULTS: 239 women, 22 men, mean age 61 +/- 7.5 years were recruited. Characteristics of HOA: 88% of patients were right-handed, 48% had a family history of hand OA. The location of OA was the first trapezo-metacarpal (TMC) joint (62%), proximal interphalangeal (PIP) joint (47.5%), distal interphalangeal (DIP) joint (67.6%). The mean number of painful flares (previous 12 months) was 4.4, that of painful joints was 3.7, that of nodal joints in the right hand 3.1, and that of radiologically affected joints was 4.4. Baseline symptomatic severity assessment gave pain on VAS=54.4 +/- 14 mm, FIHOA score=10.4 +/- 3.7, morning stiffness duration=20 +/- 27.6 min and grip strength=59.3 +/- 21.2 mm Hg. The MSR value was 0.58 for the FIHOA and 0.87 for pain on VAS. CONCLUSION: The sensitivity to change of the FIHOA over 6 months is high, but inferior to that of pain on VAS in this trial.

Hand osteoarthritis patients characteristics according to the existence of a hormone replacement therapy.

BACKGROUND: Hand osteoarthritis (hand OA) mostly occurs in women around the time of menopause, but its relationship with sexual hormones remains a controversial issue. The eventual influence of hormone replacement therapy (HRT) on the incidence and progression of hand OA is still debated. OBJECTIVE: To assess whether HRT influences the occurrence and disease activity of hand OA. METHODS/PATIENTS: Epidemiological prospective cross-sectional study. PATIENTS: Menopausal women, aged 50-75, consulting for painful hand OA, for another rheumatic condition with hand OA or controls (no disease of the upper limbs). ELIGIBILITY CRITERIA: hand OA [American College Rheumatology (ACR) criteria] with X-ray evidence. PATIENTS with 'painful' hand OA defined by a Dreiser's functional index score > or = 6 and pain on VAS > or = 35 mm. Study parameters: Demographics, personal histories and gynaecologic data for patients and controls including the administration of HRT (+) or not (-). For patients, description and symptom activity of hand OA. STATISTICS: Descriptive analysis in the studied population and in subsets taking into account treatment and disease activity factors. RESULTS: 711 women were studied: 238 with 'painful' hand OA, 240 with 'quiescent' and 233 controls. Baseline characteristics were similar for patients and controls except for age (patients were older). HRT+ patients were younger (-5 years) (P < 0.0001), slightly taller (P < 0.0045) and more often cigarettes smokers (P < 0.012) than HRT- patients. They did not differ in gynecologic characteristics with the exception that the women in the HRT+ group had been menopausal for a shorter period of time, probably because of their younger age. There were no differences between HRT+ and HRT- patients, whatever the symptom activity, on the characteristics of hand OA: Dreiser's index scores were, respectively, 11.3 +/- 3.8 vs 12.3 +/- 4.5 in 'painful' patients, 3.6 +/- 2.5 vs 3.7 +/- 2.7 in 'quiescent' patients. Pain on VAS showed no difference between the two groups. CONCLUSION: Few differences were found between hand OA patients receiving HRT or not. HRT did not seem to influence the severity or the symptom activity of hand OA. Further prospective studies are required in order to evaluate the exact effect of HRT on hand OA.

Medico-economic analysis of diacerein with or without standard therapy in the treatment of osteoarthritis.

This 9-month pragmatic study compared 2 therapeutic regimens in the management of osteoarthritis of the hip and knee. Patients received either diacerein 100 mg/day plus standard osteoarthritic therapy for 6 months, followed by a 3-month monitoring period without diacerein, or standard therapy alone for the entire 9-month period. A total of 207 patients with osteoarthritis of the knee and hip were enrolled. Improvements in Lequense's functional index and quality-of-life scores (revised Arthritis Impact Measurement Scales Health Status Questionnaire and Nottingham Health Profile), and decreases in nonsteroidal anti-inflammatory drug and analgesic consumption were significantly greater with diacerein plus standard therapy than with standard therapy alone. The overall assessment of therapy by patients was good or excellent for 60% of those who received diacerein plus standard therapy, compared with 26% who received standard therapy alone. Medical and paramedical procedures carried out in addition to those stipulated in the protocol (medical consultations, physiotherapy, nursing, etc.), osteoarthritis-related, were fewer and less costly in the diacerein plus standard therapy group than in the standard therapy group. The average outpatient cost (in 1995 French francs) of osteoarthritis treatment in the standard therapy group was FF2272 compared with FF2360 in the diacerein plus standard therapy group. The cost-effectiveness ratios per point scored on Lequesne's index were FF1893 for the standard therapy group and FF1072 for the diacerein plus standard therapy group, leading to a saving of 43% with diacerein plus standard therapy. The marginal cost (additional cost corresponding to the clinical benefit obtained by adding diacerein to standard treatment) was FF88 per point scored on Lequesne's index.

An epidemiological study of diagnostic and therapeutic strategies in office practice patients with subacute or chronic pain in the thoracic or low back. Comparison of practices in primary care and rheumatology settings.

UNLABELLED: There is a paucity of epidemiological data on diagnostic and therapeutic practices in office practice patients with subacute or chronic pain in the thoracic or low back. STUDY OBJECTIVE: to describe diagnostic and therapeutic strategies used in such patients. PATIENTS AND METHODS: descriptive, prospective, two-month epidemiological study in 50 general practitioners and 50 rheumatologists. Each physician was asked to provide data on the demographics, clinical features, history of spinal disease, investigations, prior treatments and treatments prescribed on D0 and D30 in two patients with low back pain and two with thoracic back pain, of one to 12 months' duration. RESULTS: A total of 352 patients were included. In the 217 patients with low back pain, including 107 women and 110 men, duration of the pain was 4.3 +/- 0.2 months and mean age was 49.6 +/- 1 years; 67% of these patients were economically active and 22% were retired; 59% were recruited by rheumatologists. In the thoracic back pain group, there were 135 patients, including 82 women (61%) and 53 men, with a mean duration of pain of 3.8 +/- 0.3 months and a mean age of 47.7 +/- 1.4 years; 60% were economically active and 22% were retired; 49% were recruited by rheumatologists. A history of conservatively-treated low or thoracic back pain was reported for 95.4% of patients in the low back pain group and 94% in the thoracic back pain group. Of the patients with low back pain, 6.3% had had spinal surgery. Investigations were as follows: roentgenograms in 85% of low back pain and 75% of thoracic back pain patients, computed tomography in 11% and 5.8%, magnetic resonance imaging in 2% and 1% and laboratory tests in 14% and 20%. Ninety-one per cent of low back pain and 84% of thoracic back pain patients were already under therapy on D0. Ninety-six per cent of patients overall were given a prescription at the end of the D0 visit, for a nonsteroidal antiinflammatory drug or an analgesic in 80% of low back pain and 63% of thoracic back pain patients, for muscle relaxants in 62% and 69%, for drugs aimed at preventing gastric side effects in 19% and 9.5%, for myotonic agents in 10% and 8% and for sedatives in 5% and 11%. A local steroid injection was given to 20% of low back pain patients. Twenty-four per cent of low back pain and 14% of thoracic back pain patients missed days of work (mean, 11 +/- 1.7 days and 13 +/- 4.6 days, respectively). Physical therapy was prescribed to 36% of low back pain and 27% of thoracic back pain patients and a lumbar support belt to 17% of low back pain patients. On D30, the pain had abated in 86% of low back pain and 89% of thoracic back pain patients and complete freedom from pain was reported by 28% and 32% of patients in these two groups, respectively. Treatments prescribed on D30 were physical therapy (43% and 31%), analgesics (40% and 36%) muscle relaxants (25% and 30%), and nonsteroidal antiinflammatory drugs (23% and 12%). Conclusion. This preliminary study provides data on common practices in subacute and chronic low back and back pain and may prove useful for health care cost estimations.

Therapeutic equivalence of diclofenac sustained-released 75 mg tablets and diclofenac enteric-coated 50 mg tablets in the treatment of painful osteoarthritis.

Efficacy and tolerability of diclofenac sustained-released (SR) 75 mg tablets taken b.i.d. were compared with that of enteric-coated diclofenac sodium 50 mg tablets given t.i.d. in a seven-day, randomised, double-blind, double-dummy, parallel groups study in 294 outpatients suffering from painful femorotibial or hip osteoarthritis. Primary efficacy criteria were spontaneous joint pain assessed on serial visual analogue scales during the first 36 hours and after 48 hours of treatment. The two treatments had equivalent efficacy since all the 90% confidence intervals of differences between means for pain intensity between the two groups were included within the interval (-10 mm; +10 mm). Rates of overall efficacy judged good to excellent ranged from 74.3-78.5% in both groups. One or more drug-related adverse events, mainly gastrointestinal, was reported by 24.5% and 27.2% of patients in diclofenac SR 75 mg and diclofenac 50 mg groups, respectively. Percentage of good compliance (i.e. > 90%) was higher with diclofenac SR 75 mg (p < 0.001).

Therapeutic trials in digital osteoarthritis. A critical review.

Although common, hand osteoarthritis is controversial and rarely used as a model for clinical trials in osteoarthritis. We found only 13 therapeutic trials conducted in digital or trapeziometacarpal osteoarthritis between 1983 and 1994. Eleven of these trials were published. Seven were on nonsteroidal antiinflammatory drugs given either per os (two trials, meclofenamate and ibuprofen) or percutaneously (one trial each on etofenamate, ibuprofen, and ketoprofen gel, and two trials on niflumic acid gel), three were on symptomatic slow-acting drugs (glycosaminoglycanes in two trials and chondroitin sulfate in one), and three were on miscellaneous agents (the muscle relaxant idrocilamide, as a gel; the antisubstance P agent capsaicin, also as a gel; and a spa treatment). We have reviewed the methodology and findings of these trials with the goal of determining the optimal approach to realize better standardized trials in the next future for identifying symptomatic slow-acting drugs and/or "chondroprotective" agents with beneficial effects in digital osteoarthritis.

Validation of an algofunctional index for osteoarthritis of the hand.

Although hand osteoarthritis is common, it has been the focus of few therapeutic trials. In addition to the problems raised by clinical trials in osteoarthritis in general and to the difficulties due to the unforeseeable course of osteoarthritis of the trapezometacarpal and finger joints, the lack of a clinical tool for assessing pain and function over time is an additional obstacle. We propose an algofunctional index designed for evaluation and symptomatic follow-up of patients with digital osteoarthritis. The index is based on a physician-administered questionnaire on 10 daily activities involving the hands. The patient is asked to answer each item using a 4-point verbal scale, from "possible without difficulty" (0) to "impossible" (3 points); thus, total scores range from 0 to 30. This index has been used in a few clinical placebo-controlled trials and was found sensitive to change. The aim of this study was to assess the metrological qualities of this index, including consistency (internal and external), sensitivity and specificity (by scoring the index in different groups of subjects), intra-observer reproducibility, and ease of use. Three hundred patients were recruited by 25 rheumatologists: 100 had a painful attack of digital and/or trapezometacarpal osteoarthritis (mean age: 64.9 years) with a score of more than 40 mm on a visual analog scale for overall pain severity (mean: 57.3 +/- 14 mm), 100 had "inactive" hand osteoarthritis (mean age 67.0 years), and 100 had no diseases of the upper limbs. Specificity/sensitivity: the mean index score was 12.41 +/- 5.41 in patients with painful OA, 4.28 +/- 3.87 in "inactive" cases, and 0.59 +/- 1.23 in controls. External consistency: the overall mean score was well correlated with pain severity: r = 0.49 (p < 0.001). Internal consistency: principal component analysis identified a primary axis responsible for 44.2% of the variance and two secondary axes each responsible for slightly more than 9% of the variance. None of the questions seemed redundant. Intra-observer reproducibility: two evaluations done one hour apart in symptomatic patients yielded the following scores: 12.32 +/- 5.41 and 12.5 +/- 5.51 (correlation: 0.95; mean difference: 0.17 +/- 1.64; coefficient of variation: 9.32%). Kappa values for both measurements of each item ranged from 0.68 to 0.87. Ease of use: mean time needed to determine the score 2.5 +/- 2 min. The scoring process was considered simple by 100% of investigators and easy/very easy by 98% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Methodology of clinical trials in hand osteoarthritis. Issues and proposals.

Although very common, hand osteoarthritis has rarely been the focus of clinical trials aimed at determining whether old or new drugs are effective on its symptoms or anatomical course. In addition to the difficulties inherent to studies of osteoarthritis in general, the highly unpredictable course of hand osteoarthritis poses specific challenges. Hand osteoarthritis is only beginning to be considered a potentially useful model for therapeutic trials and clinical research, in addition to the two widely-used models, knee and hip osteoarthritis. Recent studies have provided new information on the clinical and roentgenographic course of hand osteoarthritis. An algofunctional index and a quantitative roentgenographic score have been developed and validated as tools for evaluating and monitoring hand osteoarthritis. These tools are now available for use during therapeutic trials. In this article, we will make a number of recommendations about the selection of patients and of quantitative evaluation methods. These recommendations take into account the specific features of hand osteoarthritis and of the various categories of drugs for osteoarthritis; they place special emphasis on the most recent drug classes, namely symptomatic slow-acting drugs for osteoarthritis and potentially "chondroprotective" agents.