Safety and efficacy of long‐term intraarticular steroid injections in osteoarthritis of the knee: A randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the safety and efficacy of long‐term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA).

Methods

In a randomized, double‐blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50‐foot walking time. Clinical symptoms were assessed just before each injection.

Results

At the 1‐year and 2‐year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid‐injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline‐injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2‐year study by repeated injections of triamcinolone acetonide, but not saline (P < 0.05).

Conclusion

Our findings support the long‐term safety of IA steroid injections for patients with symptomatic knee OA. No deleterious effects of the long‐term administration of IA steroids on the anatomical structure of the knee were noted. Moreover, long‐term treatment of knee OA with repeated steroid injections appears to be clinically effective for the relief of symptoms of the disease.

     

Combining two hyaluronic acids in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial

Synovial fluid in patients may differ in molecular weight depending on the presence and degree of osteoarthritis. Treatment is not directed at this relationship. Patients with osteoarthritis of the knee with resting visual analogue scale (VAS) pain of >45 mm were included in a randomized, prospective, double-blind cohort followed for 16 weeks. Patients were randomized at baseline to receive a three intra-articular injection series with one of: dual molecular weight (DMW; 580-780 kDa + 1.2 to 2.0 million Da); low molecular weight (LMW; 500-730 kDa); high molecular weight (HMW; 6 million Da); or saline placebo over 3 weeks. Patients completed baseline assessment of rest and walking VAS pain (primary efficacy variable), collection of a 5-point categorical global satisfaction score, and record of adverse events. Two-hundred and twenty-five patients (age 68 +/- 8 y) were screened and 200 were randomized to one of the four groups. There were no differences at baseline between groups. At 4, 12 and 16 weeks, respectively, walking VAS pain was significantly improved in all treatment groups vs. placebo: DMW (79.6%, p < 0.001; 85.6, p < 0.001; 89.3%, p < 0.001); LMW (73.6%, p < 0.001; 76.4, p < 0.001; 81.3%, p < 0.001) and HMW (69.1%, p < 0.001; 81.0, p < 0.001; 79.1%, p < 0.001). Patients in the DMW group had significantly greater improvement (p < 0.007) in VAS walking pain by 3 weeks (following the second injection) compared to all groups. This difference was persistent at 16 weeks. Greater improvement in patients who received the DMW product was achieved by the second injection persistent at 16 weeks.     

Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized,double-blind,placebo-controlled comparison trial with diclofenac sodium

BACKGROUND: Recommendations state that acetaminophen should be used in preference to nonsteroidal anti-inflammatory drugs in the initial treatment of symptomatic osteoarthritis (OA) of the hip or knee, because of lesser toxicity and the pervasive belief that acetaminophen is not only effective in treating OA pain but is of equal analgesic efficacy as nonsteroidal anti-inflammatory drugs. METHODS: This was a randomized, double-blind, placebo-controlled trial of diclofenac sodium, 75 mg twice daily, vs acetaminophen, 1000 mg 4 times daily, in 82 subjects with symptomatic OA of the medial knee. Osteoarthritis was quantitated radiographically, and subjects met stringent baseline pain criteria. The primary evaluation of efficacy used the Western Ontario and McMaster Universities Osteoarthritis Index, with evaluations at screening, baseline, and 2 and 12 weeks after treatment. Intention-to-treat analysis was used. RESULTS: Twenty-five subjects were randomized to diclofenac, 29 to acetaminophen, and 28 to placebo. The groups were closely matched for age, sex, body mass index, prior use of OA medications, baseline pain, and radiographic features. At 2 and 12 weeks, clinically and statistically significant (P<.001) improvements were seen in the diclofenac-treated group; however, no significant improvements were seen in the acetaminophen-treated group (P =.92 at 2 weeks and.19 at 12 weeks). Stratification of subjects according to baseline pain, prestudy OA medication, and radiographic grade showed no clear pattern of preferential response to diclofenac, and did not reveal a subset of subjects who responded to acetaminophen. CONCLUSIONS: Diclofenac is effective in the symptomatic treatment of OA of the knee, but acetaminophen is not. A review of the literature reveals that there is scanty published evidence for a therapeutic effect of acetaminophen relative to placebo in patients with OA of the knee, because most published studies use active comparators (ie, nonsteroidal anti-inflammatory drugs) only. The advocacy of acetaminophen use in subjects with OA of the knee should be reconsidered pending further placebo-controlled studies.     

Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis

OBJECTIVE: To assess the efficacy of glucosamine sulfate in knee osteoarthritis (OA). METHODS: A 4-center, 6-month, randomized, double-blind, placebo-controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in knee pain after starting glucosamine. Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study (maximum 1,500 mg/day). Followup continued for 6 months or until disease flare, whichever occurred first. The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent-to-treat analysis. Secondary outcomes included time to disease flare; analgesic medication use; severity of disease flare; and change in pain, stiffness, function and quality of life in the glucosamine and placebo groups. RESULTS: Disease flare was seen in 28 (42%) of 66 placebo patients and 32 (45%) of 71 glucosamine patients (difference -3%; 95% confidence interval [95% CI] -19, 14; P = 0.76). In the Cox regression analysis, after adjustment for sex, study site, and OA radiographic severity, time to disease flare was not significantly different in the glucosamine compared with placebo group (hazard ratio of flare = 0.8; 95% CI 0.5, 1.4; P = 0.45). At final study visit, acetaminophen was used in 27% and 21% of placebo and glucosamine patients, respectively (P = 0.40), nonsteroidal antiinflammatory drugs were used in 29% and 30% (P = 0.92), and both were used in 20% and 21% (P = 0.84). No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients. CONCLUSION: In patients with knee OA with at least moderate subjective improvement with prior glucosamine use, this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate.     

Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial

Pubertal gynecomastia is thought to result from transient imbalances between estrogen and androgen concentrations. Anastrozole (ARIMIDEX), a potent and selective aromatase inhibitor, decreases estrogen and increases testosterone concentrations in pubertal boys. The safety and efficacy of anastrozole for the treatment of pubertal gynecomastia were evaluated. In a randomized, double-blind, placebo-controlled study of 80 boys, aged 11-18 yr, with pubertal gynecomastia that had not reduced over a 3-month interval, subjects received either anastrozole (1 mg) or placebo once daily for 6 months. A response was defined as a 50% or greater reduction in the calculated volume of both breasts combined using ultrasonography measurements. A comparison of response rates was performed using logistic regression analysis. Secondary end points included changes in serum hormone concentrations. The percentage of patients with a response was 38.5% for the anastrozole group and 31.4% for the placebo group (odds ratio, 1.513; 95% confidence interval, 0.496-4.844; P = 0.47). At 6 months, the median percent change in the testosterone/estradiol ratio was 166% for the anastrozole group and 39% for the placebo group. Anastrozole treatment was well tolerated. In patients with pubertal gynecomastia, no significant difference in the percentage of patients with a 50% or greater reduction in total breast volume, as calculated from ultrasonography measurements, was demonstrated between the anastrozole and placebo groups.     

The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat osteoarthritis (OA), though their long-term efficacy is uncertain. We report a comparison of the symptomatic responses to therapy with tiaprofenic acid, indomethacin and placebo over 5 yr. METHODS: A parallel-group, randomized, single-blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patients received tiaprofenic acid (300 mg b.d.), 202 indomethacin (25 mg t.d.s.) and 303 matching placebo for up to 5 yr. At the end of the parallel-group study, patients receiving tiaprofenic acid or placebo entered a 4-week blinded cross-over study of tiaprofenic acid or placebo, both given for 2 weeks. Assessments were at baseline, 4 weeks, then at 6-month intervals for up to 5 yr in the parallel group study and at 2-week intervals in the cross-over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes. RESULTS: There were significant falls in overall pain scores in patients receiving NSAIDs compared with placebo at 4 weeks in the parallel-group phase. Thereafter there were no advantages favouring active therapy. In the cross-over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. Patients who had been receiving long-term tiaprofenic acid showed significant rises in their pain scores when receiving placebo therapy and vice versa. Adverse events were reported by 61% of patients receiving tiaprofenic acid, 63% on indomethacin and 51% on placebo. Potentially severe side-effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. The pattern of withdrawal was similar in patients taking NSAIDs and placebo in the parallel-group study; at 48 weeks 53% of the patients remained on tiaprofenic acid, 50% on indomethacin and 54% on placebo. CONCLUSIONS: NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.     

Steroid injection for osteoarthritis of the hip: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis (OA) in a randomized, double-blind, placebo-controlled trial. METHODS: Fifty-two patients with symptomatic hip OA were randomly allocated to receive placebo (10 mg bipuvicaine, 2 ml saline) (n = 21) or corticosteroid treatment (10 mg bipuvicaine, 40 mg triamcinolone hexacetonide) (n = 31). Patients were followed up for 1, 2, 3, and 6 months. The primary outcome measure was the pain improvement response, defined as a 20% decrease in the Western Ontario and McMaster Universities OA Index (WOMAC) pain score (on 5 100-mm visual analog scales [VAS]) (WOMAC20) from baseline to 2 months postinjection. Secondary outcomes were a 50% decrease in the WOMAC pain score (WOMAC50), changes in other WOMAC subscale scores, patient's global assessment of health (on a 100-mm VAS), and Short Form 36 (SF-36) quality of life indices. Analyses were based on the intent-to-treat principle. RESULTS: The mean WOMAC pain score fell 49.2% (decreasing from 310.1 mm to 157.4 mm) at 2 months postinjection in patients receiving corticosteroid, compared with a decrease of 2.5% (from 314.3 mm to 306.5 mm) in the placebo group (P < 0.0001). The proportion of WOMAC20 responders at 2 months' followup was significantly higher in the corticosteroid group (67.7%) compared with the placebo group (23.8%) (P = 0.004); similar proportions of WOMAC50 responders were observed between groups (61.3% in the corticosteroid group versus 14.3% in the placebo group; P = 0.001). Response differences were maintained at 3 months' followup (58.1% responders in the corticosteroid group versus 9.5% responders in the placebo group; P = 0.004). Significant differences in the WOMAC stiffness and physical function scores (P < 0.0001), patient's global health scores (P = 0.005), and SF-36 physical component scores (P = 0.04) were observed, with patients in the corticosteroid group showing greater improvements. There were no differences in the frequency of adverse events between groups. CONCLUSION: This placebo-controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA, with benefits lasting up to 3 months in many cases. Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification.     

A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee

OBJECTIVES: A randomized, placebo-controlled, double-blind trial of the relative effectiveness of glucosamine sulphate and placebo in managing pain in osteoarthritis (OA) of the knee. METHODS: Eighty patients with OA of the knee were recruited from a rheumatology out-patient clinic and received either glucosamine sulphate 1500 mg daily for 6 months or dummy placebo. The primary outcome measure was patients' global assessment of pain in the affected knee. RESULTS: Area under the curve analysis for the primary outcome measure showed no difference between placebo and glucosamine [mean difference 0.15 mm, 95% confidence interval (CI) -8.78 to 9.07]. The placebo response was 33%. There was a statistically significant difference between groups in knee flexion (mean difference 13 degrees, 95% CI -23.13 to -1.97), but this difference was small and could have been due to measurement error. CONCLUSIONS: As a symptom modifier in OA patients with a wide range of pain severities, glucosamine sulphate was no more effective than placebo.     

Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial

BACKGROUND: Intra-articular hyaluronate sodium is a relatively new therapy for the treatment of osteoarthritis of the knee. This randomized, double-blind clinical trial was conducted at a large primary care medical center to determine the impact of hyaluronate sodium vs conventional therapy on measures of pain, stiffness, and disability at rest and following functionally relevant walking and stepping activities. METHODS: A total of 120 patients (mean age, 67 years) with unilateral grades 1 to 3 medial compartment knee osteoarthritis were randomized to 1 of 4 treatment groups: group 1, 2 mL of hyaluronate sodium at a concentration of 10 mg/mL and placebo (100 mg of lactose); group 2, nonsteroidal anti-inflammatory drugs (NSAIDs) (75 mg of diclofenac and 200 microg of misoprostol) and hyaluronate sodium; group 3, NSAIDs and placebo (2 mL of isotonic sodium chloride solution [saline]); and group 4, placebo (lactose and saline). Intra-articular hyaluronate sodium or saline (2 mL) was administered once weekly over 3 weeks while NSAIDs or lactose were administered twice daily over 12 weeks. MAIN OUTCOME MEASURES: (1) Western Ontario McMaster Universities Index (WOMAC) global measure of pain, stiffness, and disability; (2) visual analog scale (VAS) scores for pain at rest and following functional walking and stepping activities (self-paced walking and stepping); and (3) functional performance (exercise time, heart rate, and predicted maximum oxygen uptake) at baseline and weeks 4 and 12. RESULTS: At week 4, significant improvement in WOMAC scores for pain and disability and VAS score for resting pain was observed in groups 1 to 3 compared with baseline measures. Groups 1 and 2 showed significantly lower self-paced stepping pain, while no change was observed in group 4. At week 12, groups 1 to 3 showed significantly greater improvement in WOMAC pain subscale score and VAS score for resting pain; however, these differences did not vary from week 4. Following self-paced walking and stepping, groups 1 and 2 reported significantly less activity pain, while group 1 showed significantly faster self-paced walking and stepping test results. Groups 1 to 3 improved self-paced walking and stepping time at week 12 compared with baseline measures, while predicted maximum oxygen uptake was significantly higher in the hyaluronate sodium groups 1 and 2 at weeks 4 and 12 compared with baseline measures. CONCLUSIONS: For resting pain relief, hyaluronate sodium seems to be as effective as NSAIDs. Further, for pain with physical activity and functional performance, hyaluronate sodium may be superior to placebo alone or NSAIDs alone.     

Efficacy and safety of diacerein in early knee osteoarthritis: a randomized placebo-controlled trial

The objective of this study was to evaluate the efficacy and safety of diacerein in early, symptomatic knee osteoarthritis in Indian population. Sixty-four patients of knee osteoarthritis fulfilling American College of Rheumatology Criteria were randomized to receive either diacerein or placebo for 8 weeks, followed by 4 weeks “treatment-free” follow-up in this single-blind, parallel group, post-marketing trial. Primary efficacy variable was visual analogue scale (VAS) assessment of pain on movement; secondary efficacy variables included Western Ontario and Mc Master Universities Osteoarthritis Index (WOMAC) subscores for stiffness and physical function, rescue medication use and physician's clinical global impression (CGI). Compared to placebo, diacerein showed highly significant (p < 0.01) reductions in VAS pain scores, significant (p < 0.05) reductions in WOMAC physical function scores, significantly lower requirement for rescue medication, and significantly better CGI grades. Incidence of adverse events were significantly (p < 0.01) higher in diacerein arm with urine discoloration and soft stool being the most common ones. However, most events were of mild to moderate intensity. In Indian patients with knee osteoarthritis, diacerein effectively reduces pain and improves physical function, and despite frequent adverse events, overall tolerability seemed to be good.     

A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee

OBJECTIVE: To assess the efficacy of intraarticular (IA) injections of hyaluronic acid (HA) compared to placebo in patients with osteoarthritis (OA) of the knee; and to assess patient satisfaction with treatment relative to placebo, and whether there is a difference between a series of 3 versus 6 consecutive IA injections. METHODS: We conducted a randomized, double-blind, placebo controlled, 2-arm parallel design trial of 106 patients with radiologically confirmed knee OA. Two-milliliter IA injections using 20 mg/ml HA sodium salt or saline placebo were administered once weekly over 3 weeks (HA and placebo groups), followed by once weekly IA injection with 2.0 ml (20 mg/ml) HA for a further 3 consecutive weeks. The primary efficacy assessment included Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score for knee pain (Week 3 score). Secondary efficacy assessments included WOMAC scores for knee pain at Weeks 6 and 12 (followup), as well as WOMAC stiffness, physical function and quality of life scores, visual analog scale (VAS) scores for pain at rest and following walking and stepping activity, range of knee joint motion, and global patient satisfaction with treatment and quality of life using the SF-36. RESULTS: After 3 weeks of study treatment, both treatment groups showed improvements in knee function, the HA group showing a greater improvement compared to placebo in WOMAC knee pain score (p < 0.01). The HA group showed greater (p < 0.05) improvement in the overall WOMAC score and VAS pain following walking and stepping activity at Week 3. Results from all other secondary efficacy assessments at Weeks 6 and 12 including patient satisfaction were similar and were not statistically significant between treatment groups, and there were no significant differences between groups for adverse events. CONCLUSION: Intraarticular HA was superior to placebo in improving knee pain and function, with no difference between 3 or 6 consecutive injections for the primary efficacy assessment.     

Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.     

The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial

In this study, we planned to investigate the effects of pulse electromagnetic field (PEMF) on pain relief and functional capacity of patients with knee osteoarthritis (OA). Fifty-five patients with knee OA were included in a randomized, placebo-controlled study. At the end of the therapy, there was statistically significant improvement in pain scores in both groups (P < 0.05). However, no significant difference was observed within the groups (P > 0.05). We observed statistically significant improvement in some of the subgroups of Lequesne index. These are morning stiffness and activities of daily living activities compared to placebo group. However, we could not observe statistically significant differences in total of the scale between two groups (P > 0.05). Applying between-group analysis, we were unable to demonstrate a beneficial symptomatic effect of PEMF in the treatment of knee OA in all patients. Further studies using different types of magnetic devices, treatment protocols and patient populations are warranted to confirm the general efficacy of PEMF therapy in OA and other conditions.     

Topical diclofenac patch in patients with knee osteoarthritis: a randomized,double-blind,controlled clinical trial

OBJECTIVE: To assess the efficacy and safety of a diclofenac hydroxyethylpyrrolidine (DHEP) patch in the treatment of symptomatic osteoarthritis (OA) of the knee joint. METHODS: A double-blind, randomised, placebo-controlled trial was carried out on 103 outpatients for 2 weeks. The main efficacy parameters were spontaneous pain and Lequesne's Index. Secondary endpoints were walking time over a standard distance, global assessment of efficacy and tolerability, and paracetamol consumption. RESULTS: The active treatment group showed a significant improvement in pain, Lequesne's Index, and the physician's and patient's global assessment of efficacy. For these parameters the difference between groups was statistically significant in favour of the DHEP patch. Adverse reactions were seen in a small number of probands and were similar in both groups. CONCLUSIONS: The results of this trial suggest that the DHEP patch appears to be an effective and safe treatment for patients suffering from symptomatic knee OA.     

Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam Osteoarthritis Investigators

BACKGROUND: Meloxicam (Mobic; Boehringer Ingelheim, Ridgefield, Conn) is an enolic acid derivative of the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs) whose mechanism of action may be related to prostaglandin (cyclooxygenase) synthetase inhibition. In previous studies, meloxicam has been found to be safe and effective in the treatment of osteoarthritis (OA) at doses of 7.5 to 15 mg daily. To evaluate a lower dose and a different patient population, we evaluated the efficacy and safety of 3 doses of meloxicam vs placebo and diclofenac for the treatment of OA among patients with symptom exacerbations. METHODS: In this double-blind, double-dummy, parallel-group, multicenter study, 774 patients with confirmed OA of the hip or knee and a flare were randomized and treated with daily oral administration of meloxicam tablets (at dosages of 3.75, 7.5, or 15 mg/d), diclofenac (100 mg [50 mg twice daily]), or placebo. Treatment was for 12 weeks, with regular assessments for drug safety and efficacy. Safety was assessed by evaluation of adverse events, vital signs, and laboratory data. Primary efficacy variables included the Western Ontario and McMaster University Osteoarthritis (WOMAC) index, the patient's overall assessment of pain, and the patient's and investigator's overall assessment of disease activity. RESULTS: The incidence of all adverse events was lower at each dosage of meloxicam than for diclofenac but greater than for placebo. However, the incidence of gastrointestinal adverse events and dropout rates because of such events was the same for meloxicam as for placebo and lower than for diclofenac. Meloxicam, at 7.5 and 15 mg/d, and diclofenac were statistically significantly more effective than placebo for all end points, while the 3.75-mg/d dosage of meloxicam did not always reach statistical significance for all end points. Efficacy was evident after 2 weeks of treatment, improved with increasing doses, and was maintained until the end of the trial. CONCLUSIONS: Meloxicam is a safe and effective medication for the symptomatic treatment of OA. The data support consideration of 7.5 to 15 mg of meloxicam once daily to treat the pain and stiffness of OA, with gastrointestinal tolerability comparable to that of placebo. Arch Intern Med. 2000;160:2947-2954     

Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial

Primary hyperparathyroidism (PHPT) is often associated with reduced bone mineral density (BMD). A randomized, double-blind, placebo-controlled trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with PHPT. Eligible patients had asymptomatic PHPT and did not meet surgical guidelines or refused surgery. Forty-four patients randomized to placebo or active treatment arms were stratified for gender. At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in yr 2. The primary outcome index, BMD, at the lumbar spine (LS), femoral neck, total hip, and distal one third radius was measured every 6 months by dual-energy x-ray absorptiometry. Calcium, phosphorous, PTH, bone-specific alkaline phosphatase (BSAP) activity, urinary calcium, and urinary N-telopeptide (NTX) excretion were monitored every 3 months. Treatment with alendronate over 2 yr was associated with a significant (6.85%; micro(d) = 0.052; +/-0.94% se; P < 0.001) increase in LS BMD in comparison with baseline. Total hip BMD increased significantly at 12 months with alendronate by 4.01% (micro(d) = 0.027; +/-0.77% se; P < 0.001) from baseline and remained stable over the next 12 months of therapy. BMD at the one third radius site did not show any statistically significant change in the alendronate-treated group at 12 or 24 months of therapy. At 24 months, the alendronate-treated group showed a 3.67% (micro(d) = 0.022; +/-1.63% se; P = 0.038) gain in bone density at the femoral neck site in comparison with baseline. The placebo group, when crossed over to alendronate at 12 months, showed a significant change of 4.1% (micro(d) = 0.034; +/-1.12% se; P = 0.003) in the LS BMD and 1.7% (micro(d) = 0.012; +/-0.81% se; P = 0.009) at the total hip site in comparison with baseline. There was no statistically significant change seen in the placebo group at 12 months at any BMD site and no significant change at 24 months for the distal one third radius or femoral neck sites. Alendronate was associated with marked reductions in bone turnover markers with rapid decreases in urinary NTX excretion by 66% (micro(d) = -60.27; +/-13.5% se; P < 0.001) at 3 months and decreases in BSAP by 49% at 6 months (micro(d) = -15.98; +/-6.32% se; P < 0.001) and by 53% at 9 and 12 months (micro(d) = -17.11; +/-7.85% se; P < 0.001; micro(d) = -17.36; +/-6.96% se; P < 0.001, respectively) of therapy. In the placebo group, NTX and BSAP levels remained elevated. Serum calcium (total and ionized), PTH, and urine calcium did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS at 12 and 24 months from baseline values. Significant reductions in bone turnover occur with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD.     

The efficacy and safety of Xianling Gubao capsules in the treatment of knee osteoarthritis: A protocol for a randomized,double-blind,controlled trial

Background:Knee osteoarthritis (KOA) is a chronic degenerative joint disease, which is the most common type of osteoarthritis. The clinical manifestations are pain, swelling, and dysfunction of the knee joint, which seriously reduces the quality of life of patients and causes a huge social burden. At present, western medicine mainly focuses on symptomatic treatment, such as anti-inflammatory and pain relief, joint cavity injection, joint replacement, etc. The curative effect has certain limitations. Xianling Gubao capsule has some advantages in the treatment of KOA, but it lacks high-quality clinical research to verify it. Therefore, the purpose of this study is to evaluate the efficacy and safety of Xianling Gubao capsule in the treatment of KOA.Methods:A randomized, double-blind, double-simulation, parallel controlled trial design was used to study the efficacy and safety of Xianling Gubao capsules in the treatment of KOA. The patients were randomly divided into a treatment group and the control group according to 1:1. The treatment group: Xianling Gubao capsule + glucosamine hydrochloride capsule simulation agent treatment; the control group: glucosamine hydrochloride capsule + Xianling Gubao capsule simulation agent treatment. Both groups received standard treatment for 8 weeks and followed up for 30 days. And at the same time, pay attention to its efficacy and safety indicators. Observation indicators include: the western Ontario and McMaster universities osteoarthritis index, hospital for special surgery knee score, liver and kidney function, adverse reactions, etc. Data analysis was performed using SPSS 25.0 software.Discussion:This study will evaluate the efficacy and safety of Xianling Gubao capsule in the treatment of KOA. The results of this experiment will provide evidence support for Xianling Gubao capsule in the treatment of KOA.Trial registration:OSF Registration number: DOI 10.17605/OSF.IO/ERM9C