Efficacy and safety of ginger in osteoarthritis patients: a meta-analysis of randomized placebo-controlled trials.

The aim of this study was to assess the clinical efficacy and safety of oral ginger for symptomatic treatment of osteoarthritis (OA) by carrying out a systematic literature search followed by meta-analyses on selected studies. Inclusion criteria were randomized controlled trials (RCTs) comparing oral ginger treatment with placebo in OA patients aged >18 years. Outcomes were reduction in pain and reduction in disability. Harm was assessed as withdrawals due to adverse events. The efficacy effect size was estimated using Hedges' standardized mean difference (SMD), and safety by risk ratio (RR). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). Out of 122 retrieved references, 117 were discarded, leaving five trials (593 patients) for meta-analyses. The majority reported relevant randomization procedures and blinding, but an inadequate intention-to-treat (ITT) analysis. Following ginger intake, a statistically significant pain reduction SMD = -0.30 ([95% CI: [(-0.50, -0.09)], P = 0.005]) with a low degree of inconsistency among trials (I(2) = 27%), and a statistically significant reduction in disability SMD = -0.22 ([95% CI: ([-0.39, -0.04)]; P = 0.01; I(2) = 0%]) were seen, both in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to placebo ([RR = 2.33; 95% CI: (1.04, 5.22)]; P = 0.04; I(2) = 0%]). Ginger was modestly efficacious and reasonably safe for treatment of OA. We judged the evidence to be of moderate quality, based on the small number of participants and inadequate ITT populations. Prospero: CRD42011001777.

OARSI Clinical Trials Recommendations: Knee imaging in clinical trials in osteoarthritis.

Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review.

BACKGROUND: Knee osteoarthritis (OA) is one of the leading causes of disability within the adult population. Current treatment options for OA of the knee include intra-articular (IA) hyaluronic acid (HA), a molecule found intrinsically within the knee joint that provides viscoelastic properties to the synovial fluid. A variety of mechanisms in which HA is thought to combat knee OA are reported in the current basic literature. METHODS: We conducted a comprehensive literature search to identify currently available primary non-clinical basic science articles focussing on the mechanism of action of IA-HA treatment. Included articles were assessed and categorized based on the mechanism of action described within them. The key findings and conclusions from each included article were obtained and analyzed in aggregate with studies of the same categorical assignment. RESULTS: Chondroprotection was the most frequent mechanism reported within the included articles, followed by proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, mechanical, subchondral, and analgesic actions. HA-cluster of differentiation 44 (CD44) receptor binding was the most frequently reported biological cause of the mechanisms presented. High molecular weight HA was seen to be superior to lower molecular weight HA products. HA derived through a biological fermentation process is also described as having favorable safety outcomes over avian-derived HA products. CONCLUSIONS: The non-clinical basic science literature provides evidence for numerous mechanisms in which HA acts on joint structures and function. These actions provide support for the purported clinical benefit of IA-HA in OA of the knee. Future research should not only focus on the pain relief provided by IA-HA treatment, but the disease modification properties that this treatment modality possesses as well.

Safety and efficacy of retreatment with a bioengineered hyaluronate for painful osteoarthritis of the knee: results of the open-label Extension Study of the FLEXX Trial.

OBJECTIVE: To evaluate the safety of repeated intra-articular (IA) injections of Euflexxa® (1% sodium hyaluronate; IA--BioHA) for painful knee osteoarthritis (OA). DESIGN: Participants who completed the randomized, double-blind, 26-week FLEXX Trial comparing IA-BioHA to IA saline (IA-SA) for knee OA(1) received three weekly IA-BioHA injections in a 26-week Extension Study. Adverse events (AEs) were recorded and the effect of treatment on knee pain was measured immediately following a 50-foot walk test using a 100 mm visual analog scale (VAS). Responder rate, Medical Outcomes Study Short Form 36 scores, Patient's Global Assessment, and intake of rescue medication were also evaluated. RESULTS: The Extension Study included 433 subjects, 219 who received IA-BioHA and 214 who received IA-SA during the FLEXX Trial. Safety results from the Extension Study indicated that 43.4% (188/433) of subjects had AEs, of which 4.8% (21/433) were deemed treatment-related AEs. Two AEs in the Extension Study led to discontinuation, and no joint effusion was reported. Patients who continued with IA-BioHA in the Extension Study maintained their improvement from baseline, with an average reduction in pain in the VAS score of -3.5 mm. Patients initially treated with IA-SA in the FLEXX Trial also had a reduction in VAS score of -9.0 mm. Secondary efficacy variables also improved during the Extension Study. CONCLUSIONS: Repeat injections of IA-BioHA were effective, safe, well tolerated, and not associated with an increase in AEs, such as synovial effusions. Additional symptom improvements were noted for subjects who received either IA-BioHA or IA-SA in the FLEXX Trial. CLINICAL TRIAL REGISTRATION NUMBER: NCT00379236.

Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials.

OBJECTIVE: To estimate the efficacy and safety of diacerein as a pain-reducing agent in the treatment of osteoarthritis (OA), using meta-analysis of published randomized placebo-controlled trials (RCTs). METHODS: Systematic searches of the bibliographic databases Medline, Embase, Cinahl, Chemical Abstracts, Cochrane and Web of Science for RCTs concerning diacerein treatment of OA. INCLUSION CRITERIA: explicit statement about randomization to either diacerein or placebo, and co-primary outcomes being reduction in pain and improvement in function. Efficacy effect size (ES) was estimated using Hedges's standardized mean difference. Safety was measured via the risk ratio (RR) of patients having at least one episode of diarrhoea, or withdrawal due to adverse events. Trials were combined by using random-effects meta-analysis. Consistency was evaluated via the I-squared index. RESULTS: Six trials (seven sub-studies; 1533 patients) contributed to the meta-analysis, revealing a large degree of inconsistency among the trials (I(2)=56%) in regard to pain reduction: the combined ES was -0.24 [95% confidence intervals (CI): -0.39 to -0.08, P=0.003], favouring diacerein. The statistically significant improvement in function (P=0.01) was based on a small amount of heterogeneity (I(2)=11%), but presented a questionable clinical effect size (ES=-0.14). Risk of publication bias could not be excluded, and trials with duration of more than 6 months did not favour diacerein. There was an increased risk of diarrhoea with diacerein (RR=3.51 [2.55-4.83], P<0.0001), and some withdrawal from therapy following adverse events (RR=1.58 [1.05-2.36], P=0.03). CONCLUSIONS: Diacerein may be an alternative therapy for OA for patients who cannot take paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) because of adverse effects or lack of benefit. However, it is associated with increased risk of diarrhoea, and the symptomatic benefit after 6 months remains unknown.

OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009.

OBJECTIVE: To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. METHODS: A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta-analysis was used to examine the stability of evidence. RESULTS: Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non-pharmacological therapies, ES for pain relief was unchanged for self-management, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) -0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES=0.77, 95% CI 0.36, 1.17) was no longer significant (ES=0.16, 95% CI -0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES=0.10, 95% CI -0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3g/day have been published (HR=1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. CONCLUSION: Publication of a large amount of new research evidence has resulted in changes in the calculated risk-benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice.

A 4-week randomized study of acetaminophen extended-release vs rofecoxib in knee osteoarthritis.

OBJECTIVE: To compare the safety and efficacy of acetaminophen extended-release (APAP ER) with rofecoxib for the management of pain associated with knee osteoarthritis (OA). METHODS: Four hundred and three adult patients with moderate pain secondary to knee OA were randomized to receive APAP ER 1300 mg three times daily, rofecoxib 12.5mg once daily, or rofecoxib 25mg once daily. Primary end point was change from baseline at week 4 in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score using a visual analog scale. This 4-week study was conducted at 23 US research sites from October 1999 to October 2000. RESULTS: APAP ER was noninferior to rofecoxib 12.5mg because the upper 95% confidence limit (CL) for the least squares mean (LSM) change from baseline (35.27 mm at week 4) did not exceed the prespecified noninferiority limit of 50mm. The upper CL (57.39 mm) exceeded the noninferiority limit for APAP ER compared with rofecoxib 25mg at week 4. There were no significant differences among groups in the overall incidence of adverse events. CONCLUSION: APAP ER 3900 mg daily was noninferior to rofecoxib 12.5mg daily, but noninferiority was not established to rofecoxib 25mg daily. APAP ER was well tolerated and no safety issues were identified. Based on the results of this study, APAP ER 3900 mg daily is an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs), such as rofecoxib, in treating pain associated with knee OA.

Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?--a meta-analysis of randomized controlled trials.

OBJECTIVE: Meta-analysis of randomized controlled trials (RCTs)--of a hip powder of Rosa canina (rosehip) preparation for symptomatic treatment of osteoarthritis (OA), in order to estimate the empirical efficacy as a pain reducing compound. METHOD: RCTs from systematic searches were included if they explicitly stated that OA patients were randomized to either rosehip or placebo. The primary outcome was reduction in pain calculated as effect size (ES), defined as the standardized mean difference (SMD). As secondary analysis the number of responders to therapy was analyzed as Odds Ratios (OR), and expressed as the Number Needed to Treat (NNT). Restricted Maximum Likelihood (REML) methods were applied for the meta-analyses using mixed effects models. RESULTS: The three studies (287 patients and a median trial-duration of 3 months)--all supported by the manufacturer (Hyben-Vital International)--showed a reduction in pain scores by rosehip powder (145 patients) compared to placebo (142 patients): ES of 0.37 [95% confidence interval (CI): 0.13-0.60], P=0.002. Test for homogeneity seemed to support that the efficacy was consistent across trials (I(2)=0%). Thus it seems reasonable to assume that the three studies were measuring the same overall effect. It seemed twice as likely that a patient allocated to rosehip powder would respond to therapy, compared to placebo (OR=2.19; P=0.0009); corresponding to a NNT of six (95% CI: 4-13) patients. CONCLUSIONS: Although based on a sparse amount of data, the results of the present meta-analysis indicate that rosehip powder does reduce pain; accordingly it may be of interest as a nutraceutical, although its efficacy and safety need evaluation and independent replication in a future large-scale/long-term trial.

Rheumatic manifestations in HIV-1 infected in-patients and literature review.

OBJECTIVE: To report the rate and spectrum of the rheumatic manifestations of human immunodeficiency virus (HIV) since the advent of highly active anti-retroviral therapy (HAART). METHODS: A retrospective record review of 888 inpatients with HIV for rheumatic manifestations was performed from January 1995 to March 2006. We then searched the 888 records for rheumatic diseases using International Classification Diagnostic (ICD) Codes. The medical records of the cases of HIV with the rheumatic conditions were then reviewed. A computer-assisted search of Medline/Pubmed for the medical literature from January 1981 to August 2007 using the keywords HIV, acquired immune-deficiency syndrome, rheumatic manifestations, combining with text words like systemic lupus erythematosus (SLE). Only English language literature was included. RESULTS: The demographic data of 888 cases of HIV included men (64%) and women (36%) with a mean age of 41.5+/-10.2 years. Race consisted of Black (70%), White (22.8%), Hispanic (6.5%), and others (1.1%). Rheumatic manifestations were present in 80 (9%) with arthritis/arthralgia 49 (5.5%), septic arthritis 9 (1%), and osteomyelitis 8 (0.9%), connective tissue diseases (CTDs) 6 (0.7%) (SLE 3, rheumatoid arthritis 1, polymyositis 1, and systemic sclerosis 1), avascular necrosis 6 (0.7%) (hips 3, knees 2, and shoulder 1). There were no cases of seronegative spondyloarthritis or Sjögren's syndrome. CONCLUSIONS: There was an association of HIV with rheumatic conditions in 9%, including CTDs and avascular necrosis. In addition, there were no cases of the seronegative spondyloarthritis subsets. This change in spectrum from prior reports suggests the rheumatic manifestations of HIV have changed, perhaps related to HAART.

The action of cathepsin D in human articular cartilage on proteoglycans.

In recent years the lysosomal cathepsins have been implicated as important agents in the physiological degradation of various cartilages. In the present study, the nature of cathepsin present in human articular cartilage was investigated by microtechniques and a possible role for cathepsins in the cartilage degradation observed in osteoarthritis was sought. The results of this study indicated that the hemoglobin and proteoglycan-digesting activity in the human cartilage observed is predominantly that of a cathepsin D-type enzyme. This cathepsin D-type enzyme activity was present in two to three times greater amounts in yellowish or ulcerated articular cartilage from patients with primary osteoarthritis than in control "normal" human cartilages. The human cathepsin D-type enzyme, as well as a highly purified cathepsin D from bovine uterus degraded proteoglycan subunit (PGS) maximally at pH 5. Both enzyme preparations were inactive on hemoglobin at pH 6-8, but degraded PGS considerably at neutral pH. The activity of the human cathepsin extract was not affected by reagents which inhibit or activate cathepsins A and B. Neutral proteases which are active on hemoglobin or are inhibited by diisopropylfluorophosphate (DFP) were not detected in these preparations, but contamination by another type of neutral protease cannot be excluded. Chloroquine inhibited the degradation of PGS at neutral pH by the human cartilage enzyme extract.

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).

Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1*0301(DQw7) was significantly increased. The presence of HLA-DQB1*0301(DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.

Synthetic human calcitonin in refractory Paget's disease of bone.

Fourteen patients with symptomatic and active Paget's disease of bone who had demonstrated resistance to parenteral synthetic salmon calcitonin, oral disodium etidronate, or both in combination were treated with parenteral synthetic human calcitonin. Eleven patients (79%) demonstrated clinical and chemical improvement for up to five years. Two patients received additional benefit with combined synthetic human calcitonin and etidronate disodium.

Screening nonimmigrant visitors to the United States for tuberculosis: report of the Council on Scientific Affairs.

OBJECTIVE: To assess the desirability of requiring proof of tuberculosis (TB) screening for nonimmigrant visitors to the United States. DATA SOURCES: Literature review using the MEDLINE database for 1966 to 1999 and the Lexis-Nexis database for 1998 to 1999 on the terms tuberculosis and transmission, combined with the qualifiers foreign visitors, foreign students, foreign born, and policy. Experts in TB control from the Centers for Disease Control and Prevention, Atlanta, Ga, and the Canadian government were consulted. The World Wide Web was searched using the terms tuberculosis and transmission. DATA EXTRACTION: English-language articles with information directly related to control of TB transmission among foreign-born persons were selected. RESULTS AND CONCLUSIONS: Eliminating TB in the United States will depend significantly on the ability to control it within the foreign-born population; however, strict border screening guidelines used as exclusionary measures can actually worsen the epidemic. Overseas TB screening of nonimmigrant visitors, who are unlikely to have active TB and even less likely to transmit it, will be of extremely low yield, would significantly deviate from the US "open-door" policy for nonimmigrants, and would have great logistical and political implications. Foreign-born persons 15 years and older who intend to stay in the United States are the high-risk population most likely to affect public health and thus will provide the best yield for TB control resources. Screening and monitoring the nonimmigrant foreign-born population would divert valuable resources from now established, successful TB control programs for foreign-born immigrants.

Prevalence of pelvic Paget's disease of bone in the United States.

The objective of this article was to estimate the prevalence of Paget's disease of bone in the United States from a statistically derived sample of the general population. Pelvic radiographs obtained in the First National Health and Nutrition Examination Survey (NHANES-I) were reviewed for the presence of Paget's disease. Age, sex, and geographic distribution of Paget's disease of the pelvic region were determined. The overall prevalence of Paget's disease in the United States was estimated. Pelvic Paget's disease is estimated to be present in 0.71 + 0.18% of the radiographs of the general population. The disease was higher in frequency in people who were in the older decades of life with the highest prevalence of 2.32 + 0.54% in the 65- to 74-year-old people. There is a slight male predominance in the 45- to 74-year age group. The regional distribution suggests the highest prevalence in the Northeast (1.48 + 0.52%) with the lowest prevalence in the South (0.26+0.25%). The prevalence was equal in white people and black people. An estimate of the overall prevalence of Paget's disease in the United States was at least 1% and perhaps as much as 2 % of the general population with near equal sex distribution and the highest prevalence in the northeastern United States.

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Paget's disease of bone: rheumatologic complications.

Pain is the most common reason people consult a physician when suffering from Paget's disease of bone. The most common reason for patients' pain is osteoarthritis, either directly or indirectly induced by Paget's disease. The physician should make a concerted effort to target the origin of the pain, because effective treatments for the two conditions seem to be different. Back pain is particularly common and one must be careful before attributing back pain to Paget's disease; otherwise, both the physician and patient may be disappointed in the results of therapy.

Hepatocyte growth factor and its actions in growth plate chondrocytes.

Hepatocyte growth factor (HGF) has been implicated as a paracrine regulator of organogenesis and repair in many tissues. Here we have studied the expression and actions of HGF in intact rachitic rat growth plate and derived cultures of proliferative zone chondrocytes. In vivo and in vitro chondrocytes express HGF mRNA; 1,25(OH)2 has a three-fold maximal stimulatory effect, which can be blocked by H-7, an inhibitor of protein kinase C. Although HGF elaboration and action generally follow a paracrine model, chondrocytes appear capable of both expressing and responding to HGF. mRNA encoding the HGF receptor (c-met) was detected in both growth cartilage and derived chondrocyte cultures. HGF addition to chondrocyte cultures increased collagen II mRNA and alkaline phosphatase enzymatic activity to degrees comparable to that observed for active vitamin D metabolites. Combining HGF and 1,25-D evoked a synergistic response (ninefold) of alkaline phosphatase activity. To assess whether a similar stimulatory effect might be seen with bioactive peptides and HGF, we investigated the effect of HGF pretreatment on acute responses of chondrocytes to synthetic human calcitonin, an anabolic chondrocyte regulator whose skeletal action are mediated principally by cAMP elevation and subsequent protein kinase A activation. CT's maximal activation of protein kinase A was increased by prior HGF treatment from 56% to 78%. In concert, our findings indicate that in addition to HGF's classical paracrine role during skeletal growth, this growth factor may modulate hormonal sensitivity of the chondrocyte during proliferation, differentiation, and/or apoptosis.

Overview of osteoarthritis.

Osteoarthritis is a disease characterized by defects in articular cartilage with involvement of the tissues about the joint. The disease is frequent in the population over the age of 40 and is a major public health problem. Development of disease is due to cartilagenous, bony, synovial, mechanical, and other factors operating independently, as well as in combination. Therapeutic programs should be an integration of physical measures, medicinal agents, psychosocial interventions, and surgery. Therapy should be directed at the pathophysiologic causes of the patients' symptoms.

Review of ibuprofen for osteoarthritis.

Pain is the predominant reason for seeking treatment in patients with osteoarthritis. Management is multifactorial, involving psychological, physical, pharmaceutical, and sometimes surgical measures. Nonsteroidal anti-inflammatory agents play a valuable role in the overall treatment program. A review of 28 clinical trials involving ibuprofen for osteoarthritis shows sometimes conflicting results in efficacy, often because of inadequacies in study design or dosage. In fact, 17 of these 28 studies employed doses of less than 1,600 mg/day. Nonetheless, several trends are clear. Ibuprofen at a dose of over 1,200 mg daily was superior to placebo and at doses of 1,200 to 1,800 mg/day was as effective or more effective than 3,200 to 3,600 mg/day of aspirin or 4,500 mg/day of aspirin plus acetaminophen. In trials with a wide variety of other nonsteroidal anti-inflammatory drugs, ibuprofen was often as effective as the comparison agent. Tolerability was consistently excellent with ibuprofen, and adverse reactions were few.

Long-term follow-up of therapy with intermittent etidronate disodium in Paget's disease of bone.

A long-term trial of etidronate disodium therapy in 93 patients with Paget's disease of bone yielded generally favorable results. Treatment or retreatment was initiated for symptomatic Paget's disease with elevated serum alkaline phosphatase and urinary hydroxyproline values. Improvement occurred in 60 percent of patients even in the presence of secondary osteoarthritis. There appeared to be three types of responses: (1) Patients with prolonged clinical and chemical improvement after a single course of therapy (40 percent); these patients tended to have less active disease on the basis of initial alkaline phosphatase and hydroxyproline values, with suppression to normal in 76 percent of patients after etidronate disodium therapy. (2) Patients with response to retreatment (45 percent); these patients had modest disease on the basis of alkaline phosphatase and hydroxyproline values and required retreatment less often than once a year. (3) Patients with response to retreatment but eventual development of resistance to etidronate disodium (15 percent); these patients had the most severe disease clinically and on the basis of alkaline phosphatase and hydroxyproline values. In this last group, resistance to etidronate disodium (5 mg/kg per day) was common and early, and patients received etidronate disodium more often than one course per year; alkaline phosphatase response was transient, often of less than three months' duration.