Clinical Inquiries

Evidence summary

Most studies of ADHD medication have lasted fewer than 4 months. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with Attention Deficit/Hyperactivity Disorder (known as the MTA study) is the longest treatment study of children to date. This study—a 28-day, double-blind placebo-controlled trial—enrolled children aged 7 to 9 years with ADHD and compared 4 treatment strategies (including medication and behavioral interventions) over 14 months.^1-3

Of particular interest was the dose-titration evaluation at the beginning of the study. Daily dose-switching titration of methylphenidate was used to identify the optimal starting dose for each child assigned to receive medication. In all, 289 children were randomized to receive methylphenidate, and 256 completed the titration (17 children refused to take medication, 1 moved, 4 had side effects, 4 had missing data, and 7 stopped mid-titration because of inability to follow the titration protocol).

Of the 256 children who completed titration, 198 (77%) responded favorably to 1 of the following doses: low (15 mg/day), intermediate (25 mg/day), or high (35 mg/day for children weighing less than 25 kg; or 50 mg/day for children weighing 25 kg or more). Of the remaining 23%, 32 children responded best to placebo and 26 were methylphenidate nonresponders and were subsequently placed on dextroamphetamine.

Children who responded to methylphenidate entered the 13-month maintenance phase on the optimal dose identified in the titration trial. They were monitored by monthly re-examination and review of information from parents and teachers regarding ADHD symptoms and potential drug side effects. The dose was changed if symptoms were not well controlled or if side effects were present. Subsequently, if no effective and well-tolerated dose of methylphenidate could be identified, the drug was deemed ineffective for that child and was replaced by another medication.

Of the children who responded to methylphenidate, 88% were still taking it at the end of the maintenance trial; 29% were still taking the titration-determined dose of methylphenidate, 18% took a lower dose, and 41% took a higher dose as their “optimal” dose, at which there were no clinically significant symptoms, or “no room for improvement.” The mean dose increased from 31 mg/day at the start to 34 mg/day at the end of the study. Of the 430 total changes in dose made during the maintenance period, 62% were dose increases.

While commendable for its design and large study population, the MTA study had several limitations. The titration trial’s complex method of determining each child’s “best dose” may not be feasible in clinical practice. Furthermore, the study enrolled only children aged 7 to 9 years, while ADHD affects a much broader age range. Finally, the chronic nature of ADHD limits the generalizability of this study beyond 14 months. Additional long-term studies are needed.

Recommendations from others

The most common strategy for managing children taking methylphenidate is to start with a low dose and gradually adjust upward, as required by residual symptoms and as allowed by side effects. This escalating-dose titration reflects typical practice in the United States, as described in several clinical guides.^4,5 The Physician’s Desk Reference states that the maximum total daily dose is 60 mg for methylphenidate, and experts often limit the upper range to 25 mg for a single dose.⁶

The American Academy of Child and Adolescent Psychiatry suggests using a consistent titration schedule with weekly increases in increments of 5–10 mg per dose to achieve symptom control. Alternatively, a fixed-dose titration trial similar to that found in the MTA study may be employed, in which a full set of different doses is switched on a weekly basis. If the top recommended dose does not help, a change in drug or psychosocial intervention may be more beneficial than an increase in methylphenidate dose.⁶

Evidence summary

Most studies of ADHD medication have lasted fewer than 4 months. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with Attention Deficit/Hyperactivity Disorder (known as the MTA study) is the longest treatment study of children to date. This study—a 28-day, double-blind placebo-controlled trial—enrolled children aged 7 to 9 years with ADHD and compared 4 treatment strategies (including medication and behavioral interventions) over 14 months.^1-3

Of particular interest was the dose-titration evaluation at the beginning of the study. Daily dose-switching titration of methylphenidate was used to identify the optimal starting dose for each child assigned to receive medication. In all, 289 children were randomized to receive methylphenidate, and 256 completed the titration (17 children refused to take medication, 1 moved, 4 had side effects, 4 had missing data, and 7 stopped mid-titration because of inability to follow the titration protocol).

Of the 256 children who completed titration, 198 (77%) responded favorably to 1 of the following doses: low (15 mg/day), intermediate (25 mg/day), or high (35 mg/day for children weighing less than 25 kg; or 50 mg/day for children weighing 25 kg or more). Of the remaining 23%, 32 children responded best to placebo and 26 were methylphenidate nonresponders and were subsequently placed on dextroamphetamine.

Children who responded to methylphenidate entered the 13-month maintenance phase on the optimal dose identified in the titration trial. They were monitored by monthly re-examination and review of information from parents and teachers regarding ADHD symptoms and potential drug side effects. The dose was changed if symptoms were not well controlled or if side effects were present. Subsequently, if no effective and well-tolerated dose of methylphenidate could be identified, the drug was deemed ineffective for that child and was replaced by another medication.

Of the children who responded to methylphenidate, 88% were still taking it at the end of the maintenance trial; 29% were still taking the titration-determined dose of methylphenidate, 18% took a lower dose, and 41% took a higher dose as their “optimal” dose, at which there were no clinically significant symptoms, or “no room for improvement.” The mean dose increased from 31 mg/day at the start to 34 mg/day at the end of the study. Of the 430 total changes in dose made during the maintenance period, 62% were dose increases.

While commendable for its design and large study population, the MTA study had several limitations. The titration trial’s complex method of determining each child’s “best dose” may not be feasible in clinical practice. Furthermore, the study enrolled only children aged 7 to 9 years, while ADHD affects a much broader age range. Finally, the chronic nature of ADHD limits the generalizability of this study beyond 14 months. Additional long-term studies are needed.

Recommendations from others

The most common strategy for managing children taking methylphenidate is to start with a low dose and gradually adjust upward, as required by residual symptoms and as allowed by side effects. This escalating-dose titration reflects typical practice in the United States, as described in several clinical guides.^4,5 The Physician’s Desk Reference states that the maximum total daily dose is 60 mg for methylphenidate, and experts often limit the upper range to 25 mg for a single dose.⁶

The American Academy of Child and Adolescent Psychiatry suggests using a consistent titration schedule with weekly increases in increments of 5–10 mg per dose to achieve symptom control. Alternatively, a fixed-dose titration trial similar to that found in the MTA study may be employed, in which a full set of different doses is switched on a weekly basis. If the top recommended dose does not help, a change in drug or psychosocial intervention may be more beneficial than an increase in methylphenidate dose.⁶

Evidence summary

Most studies of ADHD medication have lasted fewer than 4 months. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with Attention Deficit/Hyperactivity Disorder (known as the MTA study) is the longest treatment study of children to date. This study—a 28-day, double-blind placebo-controlled trial—enrolled children aged 7 to 9 years with ADHD and compared 4 treatment strategies (including medication and behavioral interventions) over 14 months.^1-3

Of particular interest was the dose-titration evaluation at the beginning of the study. Daily dose-switching titration of methylphenidate was used to identify the optimal starting dose for each child assigned to receive medication. In all, 289 children were randomized to receive methylphenidate, and 256 completed the titration (17 children refused to take medication, 1 moved, 4 had side effects, 4 had missing data, and 7 stopped mid-titration because of inability to follow the titration protocol).

Of the 256 children who completed titration, 198 (77%) responded favorably to 1 of the following doses: low (15 mg/day), intermediate (25 mg/day), or high (35 mg/day for children weighing less than 25 kg; or 50 mg/day for children weighing 25 kg or more). Of the remaining 23%, 32 children responded best to placebo and 26 were methylphenidate nonresponders and were subsequently placed on dextroamphetamine.

Children who responded to methylphenidate entered the 13-month maintenance phase on the optimal dose identified in the titration trial. They were monitored by monthly re-examination and review of information from parents and teachers regarding ADHD symptoms and potential drug side effects. The dose was changed if symptoms were not well controlled or if side effects were present. Subsequently, if no effective and well-tolerated dose of methylphenidate could be identified, the drug was deemed ineffective for that child and was replaced by another medication.

Of the children who responded to methylphenidate, 88% were still taking it at the end of the maintenance trial; 29% were still taking the titration-determined dose of methylphenidate, 18% took a lower dose, and 41% took a higher dose as their “optimal” dose, at which there were no clinically significant symptoms, or “no room for improvement.” The mean dose increased from 31 mg/day at the start to 34 mg/day at the end of the study. Of the 430 total changes in dose made during the maintenance period, 62% were dose increases.

While commendable for its design and large study population, the MTA study had several limitations. The titration trial’s complex method of determining each child’s “best dose” may not be feasible in clinical practice. Furthermore, the study enrolled only children aged 7 to 9 years, while ADHD affects a much broader age range. Finally, the chronic nature of ADHD limits the generalizability of this study beyond 14 months. Additional long-term studies are needed.

Recommendations from others

The most common strategy for managing children taking methylphenidate is to start with a low dose and gradually adjust upward, as required by residual symptoms and as allowed by side effects. This escalating-dose titration reflects typical practice in the United States, as described in several clinical guides.^4,5 The Physician’s Desk Reference states that the maximum total daily dose is 60 mg for methylphenidate, and experts often limit the upper range to 25 mg for a single dose.⁶

The American Academy of Child and Adolescent Psychiatry suggests using a consistent titration schedule with weekly increases in increments of 5–10 mg per dose to achieve symptom control. Alternatively, a fixed-dose titration trial similar to that found in the MTA study may be employed, in which a full set of different doses is switched on a weekly basis. If the top recommended dose does not help, a change in drug or psychosocial intervention may be more beneficial than an increase in methylphenidate dose.⁶

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²

Evidence summary

Osteoporosis results in significant morbidity and mortality. In a prospective observational study of women over 50 years of age, 39.6% had osteopenia and 7.2% had osteoporosis. Osteoporosis was associated with a fracture rate 4 times that of normal bone mineral density.¹ People with vertebral or hip fractures have a reduced relative 5-year survival of 0.81. Excess mortality occurred within the first 6 months following fracture.²

One prospective cohort study identified 14 independent risk factors for hip fracture.³ The best predictors were female gender, age, low weight, and no current estrogen use. For women aged >65 years with no other risks, 12% to 28% have osteoporosis.⁴ Multiple risk assessment scales have been studied to identify women aged >65 years who are at increased risk; however, none of the scales had good discriminatory performance.⁵ As a result, it is unclear which factors for women under 65 years should trigger screening.

While multiple technologies exist to measure bone mineral density, dual-energy x-ray absorptiometry (DEXA) has been the most validated test for predicting fractures. A meta-analysis of 11 prospective cohort trials showed that all sites of bone mineral density measurements correlated with fractures (relative risk [RR], 1.5; 95% confi-dence interval [CI], 1.4–1.6.). However, DEXA of the femoral neck predicted hip fracture better than other measures (RR, 2.6; 95% CI, 2.0–3.5).⁶

Additionally, heel ultrasonography was compa-rable with hip DEXA for predicting hip fractures for women over 65 years (probability of fracture 0.018 vs. 0.023); no studies have compared effec-tiveness for women under 65 years.

Multiple therapeutic interventions for osteo-porosis have been demonstrated to reduce frac-tures. Adequate calcium and vitamin D appear to prevent fractures. Alendronate and rise-dronate are the only prescription medications with evidence showing they prevent hip fractures.

A meta-analysis of 11 randomized controlled trials including 11,808 women found fewer hip fractures in women taking 10 mg/day of alendronate (RR, 0.51; 95% CI, 0.38–0.69; number needed to treat [NNT]=24), and fewer vertebral fractures in women taking 5 mg/day of alendronate (RR, 0.52; 95% CI, 0.43–0.65; NNT=72).⁷

For these results to apply to screening, study participants must be similar to those identified by general population screening. All trials included healthy women with low bone mineral density who were not using estrogen, which is similar to women identified by general screening. However, 57% of women recruited for the second Fracture Intervention Trial (FIT-II), the largest study, were classified as ineligible. This raises concern about the study’s generalizability.⁸

The US Preventive Services Task Force did an outcomes estimation of screening effectiveness, combining all of the above data (Table).⁹ Screening 731 women aged 65 to 69 years would prevent 1 hip fracture if those with indications for treat-ment took it; screening 248 women would prevent 1 vertebral fracture. As the table demonstrates, benefits increase with age. For women under 65 years, benefits are relatively small, unless they have other risk factors for osteoporosis.

TABLE
Hip and vertebral fracture outcomes for osteoporosis screening in 10,000 postmenopausal women ⁹

Recommendations from others

Based on their outcomes model, the US Preventive Services Task Force recommends screening for women aged >65 years, and those aged 60 to 65 years who have risk factors.⁹ In 1998, the National Osteoporosis Foundation, in collaboration with many other professional organ-izations, recommended bone mineral density test-ing for all women aged >65 years and younger postmenopausal women who have had or are at risk for fractures.¹⁰ The 2000 Consensus Development Conference from the National Institutes of Health recommended an individual-ized approach to screening, stating evidence for universal osteoporosis screening is inconclusive.¹¹ The American Association of Clinical Endo-crinologists revised guidelines in 2001 to include screening younger postmenopausal women with a body weight <127 lbs or a family history of nontraumatic spine or hip fracture.¹²

Evidence summary

Graduated elastic compression stockings improve lower-extremity hemodynamics (including reflux and residual volume measured by color flow duplex scanning) in patients with varicosities, and can improve symptoms such as swelling, discomfort, and leg tightness.^1,2

A Cochrane review concluded that existing evidence supports the use of sclerotherapy for recurrent varicose veins after surgery and for relatively minor “thread” veins.³ Data did not show that any particular type of sclerosant or pressure dressing or duration of post-treatment compression have significant effect on outcomes, such as disappearance of varicosities and cosmetic improvement.³

A Cochrane protocol is in progress regarding comparison of the outcomes of surgery and sclerotherapy.⁴ Few randomized trials have compared surgery and sclerotherapy.

Belcaro reported results of a 10-year randomized trial including 121 subjects, 96 of whom completed the study.⁵ Surgery consisted of ligation of the saphenopopliteal junction without stripping. At 10 years, 16.1% of patients receiving surgery plus sclerotherapy had distal venous incompetence (assessed with color duplex scanning and ambulatory venous pressure measurement), compared with 36.4% of those who underwent surgery alone and 43.8% of those who received sclerotherapy alone. The authors concluded that long-term outcomes (defined as saphenofemoral junction competence) are superior with strategies that included surgery, but at greater cost.

Beresford and colleagues also concluded that surgery lessened the likelihood of additional treatment.⁶ Another randomized trial showed that saphenous vein stripping reduced by two thirds the need for reoperation due to recurrent saphenofemoral incompetence, compared with saphenofemoral junction ligation alone.⁷

A meta-analysis studied the effectiveness of venotonic medications (such as rutoside, flunarizine, and dihydroergotamine) in chronic venous insufficiency.⁸ These agents significantly reduced pain, leg heaviness, cramps, and paresthesias. However, a Cochrane Collaboration reviewer questioned the validity of pooling results from this heterogeneous group of studies into a single meta-analysis.⁹

A Cochrane Review did find that horse chestnut seed extract significantly improves leg pain, edema, pruritus, and lower leg volume and circumference, but suggests that larger randomized trials are needed to establish conclusively this agent’s efficacy.¹⁰

Recommendations from others

A recent clinical review indicated that patients whose main symptoms are swelling or aching can be treated with compression stockings alone; trunk varicosities should be treated with saphenofemoral or saphenopopliteal ligation, plus stripping of the long saphenous vein for long saphenous varicosities.¹¹ They suggest that sclerotherapy should be reserved for varicosities that persist after surgery.

The Venous Insufficiency Epidemiologic and Economic Studies (VEINES) program recommends sclerotherapy for telangiectasias and reticular veins, and surgery for saphenous varicosities.¹² However, they noted the need for randomized trials to compare therapies.

Evidence summary

Graduated elastic compression stockings improve lower-extremity hemodynamics (including reflux and residual volume measured by color flow duplex scanning) in patients with varicosities, and can improve symptoms such as swelling, discomfort, and leg tightness.^1,2

A Cochrane review concluded that existing evidence supports the use of sclerotherapy for recurrent varicose veins after surgery and for relatively minor “thread” veins.³ Data did not show that any particular type of sclerosant or pressure dressing or duration of post-treatment compression have significant effect on outcomes, such as disappearance of varicosities and cosmetic improvement.³

A Cochrane protocol is in progress regarding comparison of the outcomes of surgery and sclerotherapy.⁴ Few randomized trials have compared surgery and sclerotherapy.

Belcaro reported results of a 10-year randomized trial including 121 subjects, 96 of whom completed the study.⁵ Surgery consisted of ligation of the saphenopopliteal junction without stripping. At 10 years, 16.1% of patients receiving surgery plus sclerotherapy had distal venous incompetence (assessed with color duplex scanning and ambulatory venous pressure measurement), compared with 36.4% of those who underwent surgery alone and 43.8% of those who received sclerotherapy alone. The authors concluded that long-term outcomes (defined as saphenofemoral junction competence) are superior with strategies that included surgery, but at greater cost.

Beresford and colleagues also concluded that surgery lessened the likelihood of additional treatment.⁶ Another randomized trial showed that saphenous vein stripping reduced by two thirds the need for reoperation due to recurrent saphenofemoral incompetence, compared with saphenofemoral junction ligation alone.⁷

A meta-analysis studied the effectiveness of venotonic medications (such as rutoside, flunarizine, and dihydroergotamine) in chronic venous insufficiency.⁸ These agents significantly reduced pain, leg heaviness, cramps, and paresthesias. However, a Cochrane Collaboration reviewer questioned the validity of pooling results from this heterogeneous group of studies into a single meta-analysis.⁹

A Cochrane Review did find that horse chestnut seed extract significantly improves leg pain, edema, pruritus, and lower leg volume and circumference, but suggests that larger randomized trials are needed to establish conclusively this agent’s efficacy.¹⁰

Recommendations from others

A recent clinical review indicated that patients whose main symptoms are swelling or aching can be treated with compression stockings alone; trunk varicosities should be treated with saphenofemoral or saphenopopliteal ligation, plus stripping of the long saphenous vein for long saphenous varicosities.¹¹ They suggest that sclerotherapy should be reserved for varicosities that persist after surgery.

The Venous Insufficiency Epidemiologic and Economic Studies (VEINES) program recommends sclerotherapy for telangiectasias and reticular veins, and surgery for saphenous varicosities.¹² However, they noted the need for randomized trials to compare therapies.

Evidence summary

Graduated elastic compression stockings improve lower-extremity hemodynamics (including reflux and residual volume measured by color flow duplex scanning) in patients with varicosities, and can improve symptoms such as swelling, discomfort, and leg tightness.^1,2

A Cochrane review concluded that existing evidence supports the use of sclerotherapy for recurrent varicose veins after surgery and for relatively minor “thread” veins.³ Data did not show that any particular type of sclerosant or pressure dressing or duration of post-treatment compression have significant effect on outcomes, such as disappearance of varicosities and cosmetic improvement.³

A Cochrane protocol is in progress regarding comparison of the outcomes of surgery and sclerotherapy.⁴ Few randomized trials have compared surgery and sclerotherapy.

Belcaro reported results of a 10-year randomized trial including 121 subjects, 96 of whom completed the study.⁵ Surgery consisted of ligation of the saphenopopliteal junction without stripping. At 10 years, 16.1% of patients receiving surgery plus sclerotherapy had distal venous incompetence (assessed with color duplex scanning and ambulatory venous pressure measurement), compared with 36.4% of those who underwent surgery alone and 43.8% of those who received sclerotherapy alone. The authors concluded that long-term outcomes (defined as saphenofemoral junction competence) are superior with strategies that included surgery, but at greater cost.

Beresford and colleagues also concluded that surgery lessened the likelihood of additional treatment.⁶ Another randomized trial showed that saphenous vein stripping reduced by two thirds the need for reoperation due to recurrent saphenofemoral incompetence, compared with saphenofemoral junction ligation alone.⁷

A meta-analysis studied the effectiveness of venotonic medications (such as rutoside, flunarizine, and dihydroergotamine) in chronic venous insufficiency.⁸ These agents significantly reduced pain, leg heaviness, cramps, and paresthesias. However, a Cochrane Collaboration reviewer questioned the validity of pooling results from this heterogeneous group of studies into a single meta-analysis.⁹

A Cochrane Review did find that horse chestnut seed extract significantly improves leg pain, edema, pruritus, and lower leg volume and circumference, but suggests that larger randomized trials are needed to establish conclusively this agent’s efficacy.¹⁰

Recommendations from others

A recent clinical review indicated that patients whose main symptoms are swelling or aching can be treated with compression stockings alone; trunk varicosities should be treated with saphenofemoral or saphenopopliteal ligation, plus stripping of the long saphenous vein for long saphenous varicosities.¹¹ They suggest that sclerotherapy should be reserved for varicosities that persist after surgery.

The Venous Insufficiency Epidemiologic and Economic Studies (VEINES) program recommends sclerotherapy for telangiectasias and reticular veins, and surgery for saphenous varicosities.¹² However, they noted the need for randomized trials to compare therapies.

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Longitudinal studies show spontaneous resolution in more than half of children within 3 months of the development of the effusion. After 3 months, the rate of spontaneous resolution remains constant, so that only a small percentage of children have OME a year or longer. There is a theoretical basis for the use of antibiotics for OME, since between 27%–50% of middle-ear aspirates of patients with OME contain bacteria.¹

In the last 10 years, 4 meta-analyses reported mild short-term improvement in OME with antibiotic treatment (effusion clearance rates of 23%,² 16%,³ 14%,¹ and 4%,⁴ respectively—see Table). The last study was the only meta-analysis that restricted inclusion to only randomized, blinded, placebo-controlled trials. The small difference reported (4%) was not significant. None of the studies that assessed outcomes beyond a month showed a significant difference in the persistence of OME.

The meta-analyses vary significantly in methodology, inclusion/exclusion criteria, and interpretation, making a definitive conclusion on treatment results difficult. The included trials varied in antibiotics chosen, use of placebo, duration of therapy, time to measurement of OME resolution, and method of diagnosis (tympanography, otoscopy, audiometry).

The reviews commented on potential harms of antibiotic therapy, including medication cost and the development of antibiotic resistance. Nausea, vomiting, and diarrhea were reported in 2%–30% of children on antibiotic therapy.¹ The reviews did not address the treatment of OME in the nonpediatric population or such long-term patient-oriented outcomes as hearing loss or speech delay.

Recommendations from others

The American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American Academy of Otolaryngology– Head and Neck Surgery participated in the meta-analysis by Stool et al,¹ under contract with the Agency for Health Care Policy and Research. The resulting clinical practice guideline has been adopted by the AAP, AAFP, and the Centers for Disease Control and Prevention. The guideline stresses that observation or antibiotics are treatment options for children with OME present less than 4 to 6 months. Antibiotic therapy is never considered a required treatment for OME of any duration. All published guidelines are applicable to the pediatric population only.

Conflicting evidence indicates short-term or no benefit for antibiotics, and complications such as nausea, vomiting, diarrhea, and rash have been reported in 2%–32% of children. Long-term antibiotics lead to poor adherence, more office visits, and antibiotic resistance.⁵

TABLE
Meta-analyses of otitis media with effusion

Otitis media with effusion

Evidence summary

Longitudinal studies show spontaneous resolution in more than half of children within 3 months of the development of the effusion. After 3 months, the rate of spontaneous resolution remains constant, so that only a small percentage of children have OME a year or longer. There is a theoretical basis for the use of antibiotics for OME, since between 27%–50% of middle-ear aspirates of patients with OME contain bacteria.¹

In the last 10 years, 4 meta-analyses reported mild short-term improvement in OME with antibiotic treatment (effusion clearance rates of 23%,² 16%,³ 14%,¹ and 4%,⁴ respectively—see Table). The last study was the only meta-analysis that restricted inclusion to only randomized, blinded, placebo-controlled trials. The small difference reported (4%) was not significant. None of the studies that assessed outcomes beyond a month showed a significant difference in the persistence of OME.

The meta-analyses vary significantly in methodology, inclusion/exclusion criteria, and interpretation, making a definitive conclusion on treatment results difficult. The included trials varied in antibiotics chosen, use of placebo, duration of therapy, time to measurement of OME resolution, and method of diagnosis (tympanography, otoscopy, audiometry).

The reviews commented on potential harms of antibiotic therapy, including medication cost and the development of antibiotic resistance. Nausea, vomiting, and diarrhea were reported in 2%–30% of children on antibiotic therapy.¹ The reviews did not address the treatment of OME in the nonpediatric population or such long-term patient-oriented outcomes as hearing loss or speech delay.

Recommendations from others

The American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American Academy of Otolaryngology– Head and Neck Surgery participated in the meta-analysis by Stool et al,¹ under contract with the Agency for Health Care Policy and Research. The resulting clinical practice guideline has been adopted by the AAP, AAFP, and the Centers for Disease Control and Prevention. The guideline stresses that observation or antibiotics are treatment options for children with OME present less than 4 to 6 months. Antibiotic therapy is never considered a required treatment for OME of any duration. All published guidelines are applicable to the pediatric population only.

Conflicting evidence indicates short-term or no benefit for antibiotics, and complications such as nausea, vomiting, diarrhea, and rash have been reported in 2%–32% of children. Long-term antibiotics lead to poor adherence, more office visits, and antibiotic resistance.⁵

TABLE
Meta-analyses of otitis media with effusion

Otitis media with effusion

Evidence summary

Longitudinal studies show spontaneous resolution in more than half of children within 3 months of the development of the effusion. After 3 months, the rate of spontaneous resolution remains constant, so that only a small percentage of children have OME a year or longer. There is a theoretical basis for the use of antibiotics for OME, since between 27%–50% of middle-ear aspirates of patients with OME contain bacteria.¹

In the last 10 years, 4 meta-analyses reported mild short-term improvement in OME with antibiotic treatment (effusion clearance rates of 23%,² 16%,³ 14%,¹ and 4%,⁴ respectively—see Table). The last study was the only meta-analysis that restricted inclusion to only randomized, blinded, placebo-controlled trials. The small difference reported (4%) was not significant. None of the studies that assessed outcomes beyond a month showed a significant difference in the persistence of OME.

The meta-analyses vary significantly in methodology, inclusion/exclusion criteria, and interpretation, making a definitive conclusion on treatment results difficult. The included trials varied in antibiotics chosen, use of placebo, duration of therapy, time to measurement of OME resolution, and method of diagnosis (tympanography, otoscopy, audiometry).

The reviews commented on potential harms of antibiotic therapy, including medication cost and the development of antibiotic resistance. Nausea, vomiting, and diarrhea were reported in 2%–30% of children on antibiotic therapy.¹ The reviews did not address the treatment of OME in the nonpediatric population or such long-term patient-oriented outcomes as hearing loss or speech delay.

Recommendations from others

The American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American Academy of Otolaryngology– Head and Neck Surgery participated in the meta-analysis by Stool et al,¹ under contract with the Agency for Health Care Policy and Research. The resulting clinical practice guideline has been adopted by the AAP, AAFP, and the Centers for Disease Control and Prevention. The guideline stresses that observation or antibiotics are treatment options for children with OME present less than 4 to 6 months. Antibiotic therapy is never considered a required treatment for OME of any duration. All published guidelines are applicable to the pediatric population only.

Conflicting evidence indicates short-term or no benefit for antibiotics, and complications such as nausea, vomiting, diarrhea, and rash have been reported in 2%–32% of children. Long-term antibiotics lead to poor adherence, more office visits, and antibiotic resistance.⁵

TABLE
Meta-analyses of otitis media with effusion

Otitis media with effusion

Evidence summary

Calcium supplementation lessens bone loss in postmenopausal women. One double-blind, randomized controlled trial included healthy women who were 6 or more years postmenopausal and had a dietary intake of less than 400 mg of calcium per day.¹ Women who received daily calcium citrate (500 mg) for 2 years had significantly less bone loss at the spine, hip, and radius than women taking placebo. In addition, calcium carbonate supplementation maintained bone density at the hip and radius but not the spine when compared with placebo. This dose of calcium was not associated with better outcomes in women within the first 5 years after menopause, but the dose was less than most generally recommended ranges.

Another randomized controlled trial of healthy women, postmenopausal for at least 3 years, showed that calcium supplementation at 1000 mg per day for 2 years decreased bone density loss in the hip and eliminated loss in the spine.² The effect may be greatest in the first year of supplementation and less in subsequent years.³

Several studies have shown calcium supplementation has a beneficial effect on reducing fractures in postmenopausal women. A randomized controlled trial of healthy, community-dwelling people 65 years of age and older (55% women) showed daily supplementation with 500 mg calcium and 700 IU vitamin D for 3 years decreased nonvertebral fractures vs. placebo (response rate [RR]=0.54; 95% confidence interval [CI], 0.12–0.77; number needed to treat [NNT]=15).⁴

Another randomized controlled trial of elderly ambulatory women showed that supplementation with 1200 mg calcium and 800 IU vitamin D per day for 18 months decreased hip fractures (RR=0.26; 95% CI, 0.03–0.44; NNT=48) and other nonvertebral fractures (RR=0.25; 95% CI, 0.09–0.38; NNT=26).⁵

A third randomized controlled trial in post-menopausal women with low calcium intake and previous vertebral fractures showed that 1200 mg of calcium supplementation reduced the incidence of additional fractures (RR=0.23).⁶

Not all studies agree. The Study of Osteoporotic Fractures showed no beneficial effect of calcium supplements on fracture risk. This cohort study found that calcium supplements were actually associated with an increased risk of hip fracture (RR=1.5; 95% CI, 1.1–2.0) and vertebral fracture (RR=1.4; 95% CI, 1.1–1.9).⁷

Observational studies like this are subject to bias; reviews of the more rigorous randomized trials support calcium supplementation in order to decrease the risk of vertebral fracture by approximately 35% and nonvertebral fractures by approximately 25%.^8,9 Daily supplementation of calcium (500–1200 mg) along with vitamin D (700–800 IU) is the regimen best supported by the evidence. Since the absorption of calcium decreases with single doses above 500 mg, the studies that used 1000–1200 mg of calcium split the daily doses.¹⁰

Recommendations from others

Guidelines have been published by the National Osteoporosis Foundation (1999),¹¹ the National Institutes of Health Consensus Development Panel on Osteoporosis (2000),¹² and others, all recommending 1200–1500 mg of elemental calcium and 400–800 IU of vitamin D be taken daily through a combination of diet and supplementation. The United States Preventive Services Task Force¹³ recommends that 1000–1500 mg of calcium be used daily; they make no specific recommendation regarding vitamin D supplementation.

Evidence summary

Calcium supplementation lessens bone loss in postmenopausal women. One double-blind, randomized controlled trial included healthy women who were 6 or more years postmenopausal and had a dietary intake of less than 400 mg of calcium per day.¹ Women who received daily calcium citrate (500 mg) for 2 years had significantly less bone loss at the spine, hip, and radius than women taking placebo. In addition, calcium carbonate supplementation maintained bone density at the hip and radius but not the spine when compared with placebo. This dose of calcium was not associated with better outcomes in women within the first 5 years after menopause, but the dose was less than most generally recommended ranges.

Another randomized controlled trial of healthy women, postmenopausal for at least 3 years, showed that calcium supplementation at 1000 mg per day for 2 years decreased bone density loss in the hip and eliminated loss in the spine.² The effect may be greatest in the first year of supplementation and less in subsequent years.³

Several studies have shown calcium supplementation has a beneficial effect on reducing fractures in postmenopausal women. A randomized controlled trial of healthy, community-dwelling people 65 years of age and older (55% women) showed daily supplementation with 500 mg calcium and 700 IU vitamin D for 3 years decreased nonvertebral fractures vs. placebo (response rate [RR]=0.54; 95% confidence interval [CI], 0.12–0.77; number needed to treat [NNT]=15).⁴

Another randomized controlled trial of elderly ambulatory women showed that supplementation with 1200 mg calcium and 800 IU vitamin D per day for 18 months decreased hip fractures (RR=0.26; 95% CI, 0.03–0.44; NNT=48) and other nonvertebral fractures (RR=0.25; 95% CI, 0.09–0.38; NNT=26).⁵

A third randomized controlled trial in post-menopausal women with low calcium intake and previous vertebral fractures showed that 1200 mg of calcium supplementation reduced the incidence of additional fractures (RR=0.23).⁶

Not all studies agree. The Study of Osteoporotic Fractures showed no beneficial effect of calcium supplements on fracture risk. This cohort study found that calcium supplements were actually associated with an increased risk of hip fracture (RR=1.5; 95% CI, 1.1–2.0) and vertebral fracture (RR=1.4; 95% CI, 1.1–1.9).⁷

Observational studies like this are subject to bias; reviews of the more rigorous randomized trials support calcium supplementation in order to decrease the risk of vertebral fracture by approximately 35% and nonvertebral fractures by approximately 25%.^8,9 Daily supplementation of calcium (500–1200 mg) along with vitamin D (700–800 IU) is the regimen best supported by the evidence. Since the absorption of calcium decreases with single doses above 500 mg, the studies that used 1000–1200 mg of calcium split the daily doses.¹⁰

Recommendations from others

Guidelines have been published by the National Osteoporosis Foundation (1999),¹¹ the National Institutes of Health Consensus Development Panel on Osteoporosis (2000),¹² and others, all recommending 1200–1500 mg of elemental calcium and 400–800 IU of vitamin D be taken daily through a combination of diet and supplementation. The United States Preventive Services Task Force¹³ recommends that 1000–1500 mg of calcium be used daily; they make no specific recommendation regarding vitamin D supplementation.

Evidence summary

Calcium supplementation lessens bone loss in postmenopausal women. One double-blind, randomized controlled trial included healthy women who were 6 or more years postmenopausal and had a dietary intake of less than 400 mg of calcium per day.¹ Women who received daily calcium citrate (500 mg) for 2 years had significantly less bone loss at the spine, hip, and radius than women taking placebo. In addition, calcium carbonate supplementation maintained bone density at the hip and radius but not the spine when compared with placebo. This dose of calcium was not associated with better outcomes in women within the first 5 years after menopause, but the dose was less than most generally recommended ranges.

Another randomized controlled trial of healthy women, postmenopausal for at least 3 years, showed that calcium supplementation at 1000 mg per day for 2 years decreased bone density loss in the hip and eliminated loss in the spine.² The effect may be greatest in the first year of supplementation and less in subsequent years.³

Several studies have shown calcium supplementation has a beneficial effect on reducing fractures in postmenopausal women. A randomized controlled trial of healthy, community-dwelling people 65 years of age and older (55% women) showed daily supplementation with 500 mg calcium and 700 IU vitamin D for 3 years decreased nonvertebral fractures vs. placebo (response rate [RR]=0.54; 95% confidence interval [CI], 0.12–0.77; number needed to treat [NNT]=15).⁴

Another randomized controlled trial of elderly ambulatory women showed that supplementation with 1200 mg calcium and 800 IU vitamin D per day for 18 months decreased hip fractures (RR=0.26; 95% CI, 0.03–0.44; NNT=48) and other nonvertebral fractures (RR=0.25; 95% CI, 0.09–0.38; NNT=26).⁵

A third randomized controlled trial in post-menopausal women with low calcium intake and previous vertebral fractures showed that 1200 mg of calcium supplementation reduced the incidence of additional fractures (RR=0.23).⁶

Not all studies agree. The Study of Osteoporotic Fractures showed no beneficial effect of calcium supplements on fracture risk. This cohort study found that calcium supplements were actually associated with an increased risk of hip fracture (RR=1.5; 95% CI, 1.1–2.0) and vertebral fracture (RR=1.4; 95% CI, 1.1–1.9).⁷

Observational studies like this are subject to bias; reviews of the more rigorous randomized trials support calcium supplementation in order to decrease the risk of vertebral fracture by approximately 35% and nonvertebral fractures by approximately 25%.^8,9 Daily supplementation of calcium (500–1200 mg) along with vitamin D (700–800 IU) is the regimen best supported by the evidence. Since the absorption of calcium decreases with single doses above 500 mg, the studies that used 1000–1200 mg of calcium split the daily doses.¹⁰

Recommendations from others

Guidelines have been published by the National Osteoporosis Foundation (1999),¹¹ the National Institutes of Health Consensus Development Panel on Osteoporosis (2000),¹² and others, all recommending 1200–1500 mg of elemental calcium and 400–800 IU of vitamin D be taken daily through a combination of diet and supplementation. The United States Preventive Services Task Force¹³ recommends that 1000–1500 mg of calcium be used daily; they make no specific recommendation regarding vitamin D supplementation.

Evidence summary

Radiologic imaging of any kind is seldom needed in the evaluation of acute low back pain unless there are “red flags” suggestive of cancer, infection, or fracture (Table). Conduct a thorough history and review of systems to risk-stratify patients that may benefit from imaging.

One study of patients with low back pain identified risk factors for cancer, including age >50 years, prior cancer, unexplained weight loss, pain lasting >1 month, and no relief with bed rest.⁴ An elevated erythrocyte sedimentation rate of >50 mm/hr in the setting of these risk factors should prompt the clinician to order an MRI or bone scan.⁵

An analysis of systematic reviews and original articles by Jarvik and Deyo reported sensitivities for MRI (83% to 93%) and for radionucleotide scanning (74% to 98%) in detecting cancer.⁶ MRI exhibits the best sensitivity (96%) and specificity (92%) for infection. MRI may be helpful for further evaluation of an acute neurologic deficit, suspected cauda equina syndrome, suspected active sacroiliitis, and worsening low back pain not responding to 4 or more weeks of conservative therapy.^7,8

Consider contrast enhancement with gadolinium when evaluating inflammatory conditions, or for patients who have had spine surgery.⁹ The lower specificity of MRI for radiculopathy means that MRI can detect disk herniations that do not cause the patient’s signs or symptoms. In one study, MRI demonstrated herniated disks in 25% of asymptomatic persons.¹

Unfortunately, there are too few studies to guide clinicians in the appropriate use of MRI in the evaluation of low back pain.^2,4 Higher quality evidence is needed before firm guidelines can be made for the use of MRI in the evaluation of low back pain.

TABLE
Red flags for underlying causes of low back pain

Recommendations from others

Institute for Clinical Systems Improvement guidelines recommend considering plain films for patients with risk factors for cancer or infection.

Additional indications are listed in the Table. Plain films, however, do not rule out cancer. With patients who warrant a high level of suspicion of cancer, consider using MRI, computed tomography, or bone scan. Consider MRI or computed tomography also for patients with cauda equina syndrome or a rapidly progressing neurologic deficit, while concurrently consulting neurosurgery or surgery.¹⁰

Evidence summary

Radiologic imaging of any kind is seldom needed in the evaluation of acute low back pain unless there are “red flags” suggestive of cancer, infection, or fracture (Table). Conduct a thorough history and review of systems to risk-stratify patients that may benefit from imaging.

One study of patients with low back pain identified risk factors for cancer, including age >50 years, prior cancer, unexplained weight loss, pain lasting >1 month, and no relief with bed rest.⁴ An elevated erythrocyte sedimentation rate of >50 mm/hr in the setting of these risk factors should prompt the clinician to order an MRI or bone scan.⁵

An analysis of systematic reviews and original articles by Jarvik and Deyo reported sensitivities for MRI (83% to 93%) and for radionucleotide scanning (74% to 98%) in detecting cancer.⁶ MRI exhibits the best sensitivity (96%) and specificity (92%) for infection. MRI may be helpful for further evaluation of an acute neurologic deficit, suspected cauda equina syndrome, suspected active sacroiliitis, and worsening low back pain not responding to 4 or more weeks of conservative therapy.^7,8

Consider contrast enhancement with gadolinium when evaluating inflammatory conditions, or for patients who have had spine surgery.⁹ The lower specificity of MRI for radiculopathy means that MRI can detect disk herniations that do not cause the patient’s signs or symptoms. In one study, MRI demonstrated herniated disks in 25% of asymptomatic persons.¹

Unfortunately, there are too few studies to guide clinicians in the appropriate use of MRI in the evaluation of low back pain.^2,4 Higher quality evidence is needed before firm guidelines can be made for the use of MRI in the evaluation of low back pain.

TABLE
Red flags for underlying causes of low back pain

Recommendations from others

Institute for Clinical Systems Improvement guidelines recommend considering plain films for patients with risk factors for cancer or infection.

Additional indications are listed in the Table. Plain films, however, do not rule out cancer. With patients who warrant a high level of suspicion of cancer, consider using MRI, computed tomography, or bone scan. Consider MRI or computed tomography also for patients with cauda equina syndrome or a rapidly progressing neurologic deficit, while concurrently consulting neurosurgery or surgery.¹⁰

Evidence summary

Radiologic imaging of any kind is seldom needed in the evaluation of acute low back pain unless there are “red flags” suggestive of cancer, infection, or fracture (Table). Conduct a thorough history and review of systems to risk-stratify patients that may benefit from imaging.

One study of patients with low back pain identified risk factors for cancer, including age >50 years, prior cancer, unexplained weight loss, pain lasting >1 month, and no relief with bed rest.⁴ An elevated erythrocyte sedimentation rate of >50 mm/hr in the setting of these risk factors should prompt the clinician to order an MRI or bone scan.⁵

An analysis of systematic reviews and original articles by Jarvik and Deyo reported sensitivities for MRI (83% to 93%) and for radionucleotide scanning (74% to 98%) in detecting cancer.⁶ MRI exhibits the best sensitivity (96%) and specificity (92%) for infection. MRI may be helpful for further evaluation of an acute neurologic deficit, suspected cauda equina syndrome, suspected active sacroiliitis, and worsening low back pain not responding to 4 or more weeks of conservative therapy.^7,8

Consider contrast enhancement with gadolinium when evaluating inflammatory conditions, or for patients who have had spine surgery.⁹ The lower specificity of MRI for radiculopathy means that MRI can detect disk herniations that do not cause the patient’s signs or symptoms. In one study, MRI demonstrated herniated disks in 25% of asymptomatic persons.¹

Unfortunately, there are too few studies to guide clinicians in the appropriate use of MRI in the evaluation of low back pain.^2,4 Higher quality evidence is needed before firm guidelines can be made for the use of MRI in the evaluation of low back pain.

TABLE
Red flags for underlying causes of low back pain

Recommendations from others

Institute for Clinical Systems Improvement guidelines recommend considering plain films for patients with risk factors for cancer or infection.

Additional indications are listed in the Table. Plain films, however, do not rule out cancer. With patients who warrant a high level of suspicion of cancer, consider using MRI, computed tomography, or bone scan. Consider MRI or computed tomography also for patients with cauda equina syndrome or a rapidly progressing neurologic deficit, while concurrently consulting neurosurgery or surgery.¹⁰

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹

Evidence summary

A systematic review of glucosamine sulfate use for osteoarthritis, based on early research (1956–1991), found that it has anti-inflammatory properties and rebuilds damaged cartilage.¹ These studies evaluated chondrocytes grown in culture and animal models.^1,2 Chondroitin sulfate also stimulates chondrocyte biosynthesis in both animal and in vitro studies. There is insufficient evidence to demonstrate glucosamine sulfate or chondroitin sulfate stimulates chrondrocyte growth in humans with osteoarthritis.^2,3

Joint space narrowing on radiographs suggests progression of osteoarthritis. This narrowing is thought to imply cartilage destruction or loss due to osteoarthritis. A double-blinded randomized controlled trial studied the effect of glucosamine sulfate on tibial-femoral compartment joint space narrowing in 212 patients older than 50 with mild to moderate knee osteoarthritis.⁴ Patients took either 1500 mg/day of glucosamine sulfate or placebo over 3 years. Knee radiographs in a standing anterior-posterior view, using visual and digital analysis, were used to assess joint space narrowing.⁵ The average mean joint space loss was 0.31 mm in the placebo group and 0.07 mm in the treatment group (P<.05; 95% confidence interval, 0.13–0.48).

The clinical relevance of knee joint space narrowing is undetermined. Radiographic evaluation of a weight-bearing joint space may not be an accurate or reproducible technique. A study of 15 patients with mild to moderate knee osteoarthritis used standing and semi-flexed radiographic views after an analgesic and nonsteroid anti-inflammatory drug washout period, and 1 to 12 weeks after resumption of analgesic therapy (mean 6.0 weeks).⁶ Knee pain significantly decreased radiographic joint space in the standing anteriorposterior position, but not in the semiflexed position. Using the standing anterior-posterior method may confound accurate interpretation of joint space narrowing and changes in articular cartilage since glucosamine may have an anti-inflammatory effect.⁶

One double-blinded randomized controlled trial, comparing chondroitin sulfate with placebo, evaluated joint space in patients with symptomatic hand osteoarthritis.⁷ One hundred sixty-five Caucasian patients, aged 40 to 70 years, were randomized to receive either a 50-mg intramuscular injection of chondroitin polysulfate, twice weekly, for 8 weeks, every 4 months, versus placebo, or 400 mg of oral chondroitin sulfate, 3 times a day, versus placebo.

Osteoarthritis progression in the metacarpalphalangeal and interphalangeal joints was assessed with radiographs over 3 years. Evaluators used the Anatomic Lesion Progression Scale to assess the development of osteophytes and joint space narrowing, with or without subchondral bone changes, to determine osteoarthritis progression. This scale makes it very difficult to determine whether improvements are clinically significant.

Chondroitin sulfate and polysulfate did not prevent osteoarthritis from occurring in previously normal joints. In joints already affected, intramuscular chondroitin polysulfate significantly reduced progression of distal interphalangeal, proximal interpharangeal, and metacarpophalangeal joint space narrowing (P<.013), using the progression scale. Oral chondroitin sulfate did not prevent progression.⁷

Recommendations from others

The American College of Rheumatology stated in 2000 that recommending glucosamine sulfate or chondroitin sulfate for osteoarthritis might be premature due to the methodology, lack of standardization, and insufficient information on study designs. More research was recommended.⁸

These products are sold as supplements in the United States. Their purity is often questionable and thus may affect study results. When studying glucosamine, the National Institutes of Health was forced to manufacture the drug itself due to lack of a reliable amount present in commercial products.⁹

Evidence summary

A systematic review of glucosamine sulfate use for osteoarthritis, based on early research (1956–1991), found that it has anti-inflammatory properties and rebuilds damaged cartilage.¹ These studies evaluated chondrocytes grown in culture and animal models.^1,2 Chondroitin sulfate also stimulates chondrocyte biosynthesis in both animal and in vitro studies. There is insufficient evidence to demonstrate glucosamine sulfate or chondroitin sulfate stimulates chrondrocyte growth in humans with osteoarthritis.^2,3

Joint space narrowing on radiographs suggests progression of osteoarthritis. This narrowing is thought to imply cartilage destruction or loss due to osteoarthritis. A double-blinded randomized controlled trial studied the effect of glucosamine sulfate on tibial-femoral compartment joint space narrowing in 212 patients older than 50 with mild to moderate knee osteoarthritis.⁴ Patients took either 1500 mg/day of glucosamine sulfate or placebo over 3 years. Knee radiographs in a standing anterior-posterior view, using visual and digital analysis, were used to assess joint space narrowing.⁵ The average mean joint space loss was 0.31 mm in the placebo group and 0.07 mm in the treatment group (P<.05; 95% confidence interval, 0.13–0.48).

The clinical relevance of knee joint space narrowing is undetermined. Radiographic evaluation of a weight-bearing joint space may not be an accurate or reproducible technique. A study of 15 patients with mild to moderate knee osteoarthritis used standing and semi-flexed radiographic views after an analgesic and nonsteroid anti-inflammatory drug washout period, and 1 to 12 weeks after resumption of analgesic therapy (mean 6.0 weeks).⁶ Knee pain significantly decreased radiographic joint space in the standing anteriorposterior position, but not in the semiflexed position. Using the standing anterior-posterior method may confound accurate interpretation of joint space narrowing and changes in articular cartilage since glucosamine may have an anti-inflammatory effect.⁶

One double-blinded randomized controlled trial, comparing chondroitin sulfate with placebo, evaluated joint space in patients with symptomatic hand osteoarthritis.⁷ One hundred sixty-five Caucasian patients, aged 40 to 70 years, were randomized to receive either a 50-mg intramuscular injection of chondroitin polysulfate, twice weekly, for 8 weeks, every 4 months, versus placebo, or 400 mg of oral chondroitin sulfate, 3 times a day, versus placebo.

Osteoarthritis progression in the metacarpalphalangeal and interphalangeal joints was assessed with radiographs over 3 years. Evaluators used the Anatomic Lesion Progression Scale to assess the development of osteophytes and joint space narrowing, with or without subchondral bone changes, to determine osteoarthritis progression. This scale makes it very difficult to determine whether improvements are clinically significant.

Chondroitin sulfate and polysulfate did not prevent osteoarthritis from occurring in previously normal joints. In joints already affected, intramuscular chondroitin polysulfate significantly reduced progression of distal interphalangeal, proximal interpharangeal, and metacarpophalangeal joint space narrowing (P<.013), using the progression scale. Oral chondroitin sulfate did not prevent progression.⁷

Recommendations from others

The American College of Rheumatology stated in 2000 that recommending glucosamine sulfate or chondroitin sulfate for osteoarthritis might be premature due to the methodology, lack of standardization, and insufficient information on study designs. More research was recommended.⁸

These products are sold as supplements in the United States. Their purity is often questionable and thus may affect study results. When studying glucosamine, the National Institutes of Health was forced to manufacture the drug itself due to lack of a reliable amount present in commercial products.⁹

Evidence summary

A systematic review of glucosamine sulfate use for osteoarthritis, based on early research (1956–1991), found that it has anti-inflammatory properties and rebuilds damaged cartilage.¹ These studies evaluated chondrocytes grown in culture and animal models.^1,2 Chondroitin sulfate also stimulates chondrocyte biosynthesis in both animal and in vitro studies. There is insufficient evidence to demonstrate glucosamine sulfate or chondroitin sulfate stimulates chrondrocyte growth in humans with osteoarthritis.^2,3

Joint space narrowing on radiographs suggests progression of osteoarthritis. This narrowing is thought to imply cartilage destruction or loss due to osteoarthritis. A double-blinded randomized controlled trial studied the effect of glucosamine sulfate on tibial-femoral compartment joint space narrowing in 212 patients older than 50 with mild to moderate knee osteoarthritis.⁴ Patients took either 1500 mg/day of glucosamine sulfate or placebo over 3 years. Knee radiographs in a standing anterior-posterior view, using visual and digital analysis, were used to assess joint space narrowing.⁵ The average mean joint space loss was 0.31 mm in the placebo group and 0.07 mm in the treatment group (P<.05; 95% confidence interval, 0.13–0.48).

The clinical relevance of knee joint space narrowing is undetermined. Radiographic evaluation of a weight-bearing joint space may not be an accurate or reproducible technique. A study of 15 patients with mild to moderate knee osteoarthritis used standing and semi-flexed radiographic views after an analgesic and nonsteroid anti-inflammatory drug washout period, and 1 to 12 weeks after resumption of analgesic therapy (mean 6.0 weeks).⁶ Knee pain significantly decreased radiographic joint space in the standing anteriorposterior position, but not in the semiflexed position. Using the standing anterior-posterior method may confound accurate interpretation of joint space narrowing and changes in articular cartilage since glucosamine may have an anti-inflammatory effect.⁶

One double-blinded randomized controlled trial, comparing chondroitin sulfate with placebo, evaluated joint space in patients with symptomatic hand osteoarthritis.⁷ One hundred sixty-five Caucasian patients, aged 40 to 70 years, were randomized to receive either a 50-mg intramuscular injection of chondroitin polysulfate, twice weekly, for 8 weeks, every 4 months, versus placebo, or 400 mg of oral chondroitin sulfate, 3 times a day, versus placebo.

Osteoarthritis progression in the metacarpalphalangeal and interphalangeal joints was assessed with radiographs over 3 years. Evaluators used the Anatomic Lesion Progression Scale to assess the development of osteophytes and joint space narrowing, with or without subchondral bone changes, to determine osteoarthritis progression. This scale makes it very difficult to determine whether improvements are clinically significant.

Chondroitin sulfate and polysulfate did not prevent osteoarthritis from occurring in previously normal joints. In joints already affected, intramuscular chondroitin polysulfate significantly reduced progression of distal interphalangeal, proximal interpharangeal, and metacarpophalangeal joint space narrowing (P<.013), using the progression scale. Oral chondroitin sulfate did not prevent progression.⁷

Recommendations from others

The American College of Rheumatology stated in 2000 that recommending glucosamine sulfate or chondroitin sulfate for osteoarthritis might be premature due to the methodology, lack of standardization, and insufficient information on study designs. More research was recommended.⁸

These products are sold as supplements in the United States. Their purity is often questionable and thus may affect study results. When studying glucosamine, the National Institutes of Health was forced to manufacture the drug itself due to lack of a reliable amount present in commercial products.⁹