User login
Vertebroplasty for osteoporotic fracture? Think twice
Think twice before recommending vertebroplasty (VP) for symptomatic osteoporotic compression fractures. New studies suggest that it has little benefit; thus, VP should be considered only after other, more conservative options fail.1,2
STRENGTH OF RECOMMENDATION
A: Consistent, high-quality randomized controlled trials (RCTs)
Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
ILLUSTRATIVE CASE
A 72-year-old woman with a history of osteoporosis is being treated with a bisphosphonate, calcium, and vitamin D. She’s in your office today because of the sudden onset of midline lower back pain after minor trauma. X-ray reveals an uncomplicated osteoporotic fracture of L2, with 50% loss of vertebral height. When she returns in a few weeks, the patient still has significant pain (7 on a scale of 0-10) that is not well controlled with hydrocodone and acetaminophen. Should you refer her for vertebroplasty?
Each year in the United States, approximately 750,000 vertebral fractures occur.3 The traditional treatments for osteoporotic vertebral compression fractures include bed rest, pain medication, braces, and therapy for osteoporosis. Since the late 1990s, however, vertebroplasty (VP)—the percutaneous injection of acrylic bone cement (polymethylmethacrylate, or PMMA) into the affected vertebra under radiologic guidance—has become the preferred treatment, particularly for painful vertebral fractures that do not respond to conservative treatment.
Widely used, but not much evidence
Despite a lack of rigorous scientific evidence of VP’s efficacy, the number of procedures nearly doubled from 2001 to 2005 among Medicare enrollees—from 45 per 100,000 to 87 per 100,000.4 A meta-analysis of 74 (mostly observational) studies of VP for osteoporotic compression fractures found good evidence for improved pain control in the first 2 weeks. At 3 months, the analysis found only fair evidence of benefit, and at 2 years, there was no apparent benefit.5
Complications are primarily related to cement extravasation, but are usually not symptomatic. The overall symptomatic complication rate is less than 4%.6 There is conflicting evidence regarding whether VP increases the risk of fracture in other vertebrae.7
Prior to the 2 studies reviewed in this PURL, there were only 2 RCTs comparing vertebroplasty with conservative medical management. The VERTOS trial8 randomized 34 people with osteoporotic vertebral compression fractures (of 6 weeks’ to 6 months’ duration and refractory to medical therapy) to either VP or conservative treatment. The VP patients had improved pain scores and decreased use of analgesic agents at 24 hours, compared with the conservative treatment group. But at the end of the 2-week trial, there was no difference in pain scores between the 2 groups.
The other RCT of VP vs conservative therapy randomized 50 patients with acute or subacute osteoporotic fractures (the average age of fracture was 6-8 days) to VP or conservative care.9 There was significant pain improvement in VP patients at 24 hours, but no significant difference in pain scores between the 2 groups at 3 months. This study was significantly flawed, however, because the researchers failed to collect pain measurements at study entry for a substantial number of patients.
STUDY SUMMARIES: Vertebroplasty lacks benefits
Both INVEST (the Kallmes study)1 and the Buchbinder study2 were blinded, randomized, placebo-controlled trials of VP. INVEST, performed at 11 sites in the United States, United Kingdom, and Australia, enrolled 131 patients. The Buchbinder study enrolled 78 patients at 4 sites in Australia. Both enrolled patients with painful osteoporotic fractures of less than 1 year’s duration. Exclusions for both trials included a suspicion of neoplasm in the vertebral body, substantial retropulsion of bony fragments, medical conditions that would preclude surgery, and an inability to obtain consent or conduct follow-up.
Participants in both trials had similar baseline characteristics: They were primarily Caucasian and female, with an average age in the mid-70s. The average pain intensity at enrollment was about 7 on a 0- to 10-point visual analog scale (VAS). The average time since the fracture causing the pain was 4 to 5 months in INVEST and about 2 months in the Buchbinder study. Both trials used appropriate randomization, blinding, and intention-to-treat analysis.
Blinding featured sham procedures. In both studies, the researchers used elaborate measures to ensure blinding: The control patients were prepped in the fluoroscopy suite as if they were about to undergo VP. They received local anesthesia down to the periosteum of the vertebra. The PMMA was opened and mixed in the room to allow its distinctive smell to permeate. Patients also received verbal and physical cues that simulated the procedure, and spinal images were obtained.
INVEST used pain and disability at 1 month as the primary end points. There was minimal difference in pain intensity (3.9 on VAS for the VP group, vs 4.6 for the controls). There was also little difference in back pain-related disability at 1 month, with scores on the Roland Morris Disability scale decreasing (from a baseline of 16.6 for the VP group and 17.5 for the control group) to 12 and 13, respectively (P=.49). Nor were there any statistically significant differences in pain or disability at earlier intervals (the researchers compared the scores of the VP and control groups at 3 days and 14 days.) The authors also looked at 7 other measures of pain and functioning and found no significant differences in any of them at the end of 1 month.
To encourage enrollment, patients in the INVEST trial were allowed to cross over after 1 month. At that time, 12% of those in the VP group and 43% of those in the control group took advantage of this provision and had the alternate “procedure.” Both groups of cross-over patients had more pain than those who did not make the switch. Although both of these groups showed improvement at the 3-month mark, they still had higher pain levels than their counterparts who did not cross over.
The Buchbinder study used overall pain on a 10-point VAS at 3 months as its primary end point. The researchers also recorded 7 other measurements and assessed participants at 1 week, 1 month, 3 months, and 6 months. At 3 months, there was no significant difference in the change in pain scores between the treatment and placebo groups: Mean pain scores for those who underwent VP decreased from 7.4 to 5.1, while the placebo group’s average pain scores went from 7.1 to 5.4. Similarly, there was no difference between the treatment and placebo groups in the change in pain scores at 1 week or 6 months—and no difference between the groups at any time for the other 7 measures of pain and function.
WHAT’S NEW: Trials cast doubt on established procedure
VP has essentially become the standard of care for painful osteoporotic vertebral fractures, bolstered by a long list of methodologically inferior studies that have lent support to the procedure’s efficacy. These 2 studies are the first to incorporate a sham procedure that supports true placebo control. The complete lack of benefit for VP compared with conservative management in these well-done trials calls into question the results of prior reports.
CAVEATS: Sample size, study design
Researchers in both studies had considerable difficulty enrolling patients. Both were multi center trials and enrolled patients over a 4-year period; nonetheless, taken together, only about 200 patients consented. The researchers faced opposition from referring doctors and patients alike, who believed that the possibility of receiving a placebo treatment rather than VP constituted inferior care.
In addition to their relatively small size, these studies enrolled patients with fairly chronic fractures. It has been postulated that VP has a higher likelihood of success with acute fractures, but that was not the focus of these trials. The majority of the fractures in trial participants were not acute (<4 weeks). Neither trial was designed for analysis based on the chronicity of the fracture, and neither found a difference in outcome based on fracture duration.
Because these trials were not designed, or robust enough, for subgroup analysis, we don’t know if there is a population that might benefit (ie, severity of the compression, acuteness of the fracture, or premorbid health, etc). In addition, these results do not apply to the use of VP for other reasons—malignant spinal neoplasms or vertebral hemangiomas, for example.
Finally, it is important to remember that these trials did not strictly compare VP with conservative treatment. The sham treatment may have had significant placebo power that is greater than that of typical conservative treatment.
CHALLENGES TO IMPLEMENTATION: Support for VP is well established
Anecdotal results, established treatment patterns, and numerous low-quality studies support the use of VP for vertebral compression fracture. Medicare and other insurers had reviewed the evidence prior to these 2 trials and agreed to reimburse for the procedure. It remains to be seen whether these 2 trials will be sufficient to overcome these barriers and change practice patterns.
At a minimum, however, it is prudent to reserve VP for patients who have intractable symptoms until further trials are undertaken to determine whether VP really works, and if so, for which patients.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
2. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
3. Weinstein JN. Balancing science and informed choice in decisions about vertebroplasty. N Engl J Med. 2009;361:619-621.
4. Gray DT, Hollingworth W, Onwudiwe N, et al. Thoracic and lumbar vertebroplasties performed in US Medicare enrollees, 2001-2005. JAMA. 2007;298:1760-1762.
5. McGirt MJ, Parker SL, Wolinsky JP, et al. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9:501-508.
6. Lee MJ, Dumonski M, Cahill P, et al. Percutaneous treatment of vertebral compression fractures: a meta-analysis of complications. Spine. 2009;34:1228-1232.
7. Hulme PA, Krebs J, Ferguson S, et al. Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies. Spine. 2006;31:1983-2001.
8. Voormolen MH, Mali WP, Lohle PN, et al. Percutaneous vertebroplasty compared with optimal pain medication treatment: short-term clinical outcome of patients with subacute or chronic painful osteoporotic vertebral compression fractures. The VERTOS study. AJNR Am J Neuroradiol. 2007;28:555-560.
9. Rousing R, Andersen MO, Jespersen SM, et al. Percutaneous vertebroplasty compared to conservative treatment in patients with painful acute or subacute osteoporotic vertebral fractures: three-months follow-up in a clinical randomized study. Spine. 2009;34:1349-1354.
Think twice before recommending vertebroplasty (VP) for symptomatic osteoporotic compression fractures. New studies suggest that it has little benefit; thus, VP should be considered only after other, more conservative options fail.1,2
STRENGTH OF RECOMMENDATION
A: Consistent, high-quality randomized controlled trials (RCTs)
Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
ILLUSTRATIVE CASE
A 72-year-old woman with a history of osteoporosis is being treated with a bisphosphonate, calcium, and vitamin D. She’s in your office today because of the sudden onset of midline lower back pain after minor trauma. X-ray reveals an uncomplicated osteoporotic fracture of L2, with 50% loss of vertebral height. When she returns in a few weeks, the patient still has significant pain (7 on a scale of 0-10) that is not well controlled with hydrocodone and acetaminophen. Should you refer her for vertebroplasty?
Each year in the United States, approximately 750,000 vertebral fractures occur.3 The traditional treatments for osteoporotic vertebral compression fractures include bed rest, pain medication, braces, and therapy for osteoporosis. Since the late 1990s, however, vertebroplasty (VP)—the percutaneous injection of acrylic bone cement (polymethylmethacrylate, or PMMA) into the affected vertebra under radiologic guidance—has become the preferred treatment, particularly for painful vertebral fractures that do not respond to conservative treatment.
Widely used, but not much evidence
Despite a lack of rigorous scientific evidence of VP’s efficacy, the number of procedures nearly doubled from 2001 to 2005 among Medicare enrollees—from 45 per 100,000 to 87 per 100,000.4 A meta-analysis of 74 (mostly observational) studies of VP for osteoporotic compression fractures found good evidence for improved pain control in the first 2 weeks. At 3 months, the analysis found only fair evidence of benefit, and at 2 years, there was no apparent benefit.5
Complications are primarily related to cement extravasation, but are usually not symptomatic. The overall symptomatic complication rate is less than 4%.6 There is conflicting evidence regarding whether VP increases the risk of fracture in other vertebrae.7
Prior to the 2 studies reviewed in this PURL, there were only 2 RCTs comparing vertebroplasty with conservative medical management. The VERTOS trial8 randomized 34 people with osteoporotic vertebral compression fractures (of 6 weeks’ to 6 months’ duration and refractory to medical therapy) to either VP or conservative treatment. The VP patients had improved pain scores and decreased use of analgesic agents at 24 hours, compared with the conservative treatment group. But at the end of the 2-week trial, there was no difference in pain scores between the 2 groups.
The other RCT of VP vs conservative therapy randomized 50 patients with acute or subacute osteoporotic fractures (the average age of fracture was 6-8 days) to VP or conservative care.9 There was significant pain improvement in VP patients at 24 hours, but no significant difference in pain scores between the 2 groups at 3 months. This study was significantly flawed, however, because the researchers failed to collect pain measurements at study entry for a substantial number of patients.
STUDY SUMMARIES: Vertebroplasty lacks benefits
Both INVEST (the Kallmes study)1 and the Buchbinder study2 were blinded, randomized, placebo-controlled trials of VP. INVEST, performed at 11 sites in the United States, United Kingdom, and Australia, enrolled 131 patients. The Buchbinder study enrolled 78 patients at 4 sites in Australia. Both enrolled patients with painful osteoporotic fractures of less than 1 year’s duration. Exclusions for both trials included a suspicion of neoplasm in the vertebral body, substantial retropulsion of bony fragments, medical conditions that would preclude surgery, and an inability to obtain consent or conduct follow-up.
Participants in both trials had similar baseline characteristics: They were primarily Caucasian and female, with an average age in the mid-70s. The average pain intensity at enrollment was about 7 on a 0- to 10-point visual analog scale (VAS). The average time since the fracture causing the pain was 4 to 5 months in INVEST and about 2 months in the Buchbinder study. Both trials used appropriate randomization, blinding, and intention-to-treat analysis.
Blinding featured sham procedures. In both studies, the researchers used elaborate measures to ensure blinding: The control patients were prepped in the fluoroscopy suite as if they were about to undergo VP. They received local anesthesia down to the periosteum of the vertebra. The PMMA was opened and mixed in the room to allow its distinctive smell to permeate. Patients also received verbal and physical cues that simulated the procedure, and spinal images were obtained.
INVEST used pain and disability at 1 month as the primary end points. There was minimal difference in pain intensity (3.9 on VAS for the VP group, vs 4.6 for the controls). There was also little difference in back pain-related disability at 1 month, with scores on the Roland Morris Disability scale decreasing (from a baseline of 16.6 for the VP group and 17.5 for the control group) to 12 and 13, respectively (P=.49). Nor were there any statistically significant differences in pain or disability at earlier intervals (the researchers compared the scores of the VP and control groups at 3 days and 14 days.) The authors also looked at 7 other measures of pain and functioning and found no significant differences in any of them at the end of 1 month.
To encourage enrollment, patients in the INVEST trial were allowed to cross over after 1 month. At that time, 12% of those in the VP group and 43% of those in the control group took advantage of this provision and had the alternate “procedure.” Both groups of cross-over patients had more pain than those who did not make the switch. Although both of these groups showed improvement at the 3-month mark, they still had higher pain levels than their counterparts who did not cross over.
The Buchbinder study used overall pain on a 10-point VAS at 3 months as its primary end point. The researchers also recorded 7 other measurements and assessed participants at 1 week, 1 month, 3 months, and 6 months. At 3 months, there was no significant difference in the change in pain scores between the treatment and placebo groups: Mean pain scores for those who underwent VP decreased from 7.4 to 5.1, while the placebo group’s average pain scores went from 7.1 to 5.4. Similarly, there was no difference between the treatment and placebo groups in the change in pain scores at 1 week or 6 months—and no difference between the groups at any time for the other 7 measures of pain and function.
WHAT’S NEW: Trials cast doubt on established procedure
VP has essentially become the standard of care for painful osteoporotic vertebral fractures, bolstered by a long list of methodologically inferior studies that have lent support to the procedure’s efficacy. These 2 studies are the first to incorporate a sham procedure that supports true placebo control. The complete lack of benefit for VP compared with conservative management in these well-done trials calls into question the results of prior reports.
CAVEATS: Sample size, study design
Researchers in both studies had considerable difficulty enrolling patients. Both were multi center trials and enrolled patients over a 4-year period; nonetheless, taken together, only about 200 patients consented. The researchers faced opposition from referring doctors and patients alike, who believed that the possibility of receiving a placebo treatment rather than VP constituted inferior care.
In addition to their relatively small size, these studies enrolled patients with fairly chronic fractures. It has been postulated that VP has a higher likelihood of success with acute fractures, but that was not the focus of these trials. The majority of the fractures in trial participants were not acute (<4 weeks). Neither trial was designed for analysis based on the chronicity of the fracture, and neither found a difference in outcome based on fracture duration.
Because these trials were not designed, or robust enough, for subgroup analysis, we don’t know if there is a population that might benefit (ie, severity of the compression, acuteness of the fracture, or premorbid health, etc). In addition, these results do not apply to the use of VP for other reasons—malignant spinal neoplasms or vertebral hemangiomas, for example.
Finally, it is important to remember that these trials did not strictly compare VP with conservative treatment. The sham treatment may have had significant placebo power that is greater than that of typical conservative treatment.
CHALLENGES TO IMPLEMENTATION: Support for VP is well established
Anecdotal results, established treatment patterns, and numerous low-quality studies support the use of VP for vertebral compression fracture. Medicare and other insurers had reviewed the evidence prior to these 2 trials and agreed to reimburse for the procedure. It remains to be seen whether these 2 trials will be sufficient to overcome these barriers and change practice patterns.
At a minimum, however, it is prudent to reserve VP for patients who have intractable symptoms until further trials are undertaken to determine whether VP really works, and if so, for which patients.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Think twice before recommending vertebroplasty (VP) for symptomatic osteoporotic compression fractures. New studies suggest that it has little benefit; thus, VP should be considered only after other, more conservative options fail.1,2
STRENGTH OF RECOMMENDATION
A: Consistent, high-quality randomized controlled trials (RCTs)
Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
ILLUSTRATIVE CASE
A 72-year-old woman with a history of osteoporosis is being treated with a bisphosphonate, calcium, and vitamin D. She’s in your office today because of the sudden onset of midline lower back pain after minor trauma. X-ray reveals an uncomplicated osteoporotic fracture of L2, with 50% loss of vertebral height. When she returns in a few weeks, the patient still has significant pain (7 on a scale of 0-10) that is not well controlled with hydrocodone and acetaminophen. Should you refer her for vertebroplasty?
Each year in the United States, approximately 750,000 vertebral fractures occur.3 The traditional treatments for osteoporotic vertebral compression fractures include bed rest, pain medication, braces, and therapy for osteoporosis. Since the late 1990s, however, vertebroplasty (VP)—the percutaneous injection of acrylic bone cement (polymethylmethacrylate, or PMMA) into the affected vertebra under radiologic guidance—has become the preferred treatment, particularly for painful vertebral fractures that do not respond to conservative treatment.
Widely used, but not much evidence
Despite a lack of rigorous scientific evidence of VP’s efficacy, the number of procedures nearly doubled from 2001 to 2005 among Medicare enrollees—from 45 per 100,000 to 87 per 100,000.4 A meta-analysis of 74 (mostly observational) studies of VP for osteoporotic compression fractures found good evidence for improved pain control in the first 2 weeks. At 3 months, the analysis found only fair evidence of benefit, and at 2 years, there was no apparent benefit.5
Complications are primarily related to cement extravasation, but are usually not symptomatic. The overall symptomatic complication rate is less than 4%.6 There is conflicting evidence regarding whether VP increases the risk of fracture in other vertebrae.7
Prior to the 2 studies reviewed in this PURL, there were only 2 RCTs comparing vertebroplasty with conservative medical management. The VERTOS trial8 randomized 34 people with osteoporotic vertebral compression fractures (of 6 weeks’ to 6 months’ duration and refractory to medical therapy) to either VP or conservative treatment. The VP patients had improved pain scores and decreased use of analgesic agents at 24 hours, compared with the conservative treatment group. But at the end of the 2-week trial, there was no difference in pain scores between the 2 groups.
The other RCT of VP vs conservative therapy randomized 50 patients with acute or subacute osteoporotic fractures (the average age of fracture was 6-8 days) to VP or conservative care.9 There was significant pain improvement in VP patients at 24 hours, but no significant difference in pain scores between the 2 groups at 3 months. This study was significantly flawed, however, because the researchers failed to collect pain measurements at study entry for a substantial number of patients.
STUDY SUMMARIES: Vertebroplasty lacks benefits
Both INVEST (the Kallmes study)1 and the Buchbinder study2 were blinded, randomized, placebo-controlled trials of VP. INVEST, performed at 11 sites in the United States, United Kingdom, and Australia, enrolled 131 patients. The Buchbinder study enrolled 78 patients at 4 sites in Australia. Both enrolled patients with painful osteoporotic fractures of less than 1 year’s duration. Exclusions for both trials included a suspicion of neoplasm in the vertebral body, substantial retropulsion of bony fragments, medical conditions that would preclude surgery, and an inability to obtain consent or conduct follow-up.
Participants in both trials had similar baseline characteristics: They were primarily Caucasian and female, with an average age in the mid-70s. The average pain intensity at enrollment was about 7 on a 0- to 10-point visual analog scale (VAS). The average time since the fracture causing the pain was 4 to 5 months in INVEST and about 2 months in the Buchbinder study. Both trials used appropriate randomization, blinding, and intention-to-treat analysis.
Blinding featured sham procedures. In both studies, the researchers used elaborate measures to ensure blinding: The control patients were prepped in the fluoroscopy suite as if they were about to undergo VP. They received local anesthesia down to the periosteum of the vertebra. The PMMA was opened and mixed in the room to allow its distinctive smell to permeate. Patients also received verbal and physical cues that simulated the procedure, and spinal images were obtained.
INVEST used pain and disability at 1 month as the primary end points. There was minimal difference in pain intensity (3.9 on VAS for the VP group, vs 4.6 for the controls). There was also little difference in back pain-related disability at 1 month, with scores on the Roland Morris Disability scale decreasing (from a baseline of 16.6 for the VP group and 17.5 for the control group) to 12 and 13, respectively (P=.49). Nor were there any statistically significant differences in pain or disability at earlier intervals (the researchers compared the scores of the VP and control groups at 3 days and 14 days.) The authors also looked at 7 other measures of pain and functioning and found no significant differences in any of them at the end of 1 month.
To encourage enrollment, patients in the INVEST trial were allowed to cross over after 1 month. At that time, 12% of those in the VP group and 43% of those in the control group took advantage of this provision and had the alternate “procedure.” Both groups of cross-over patients had more pain than those who did not make the switch. Although both of these groups showed improvement at the 3-month mark, they still had higher pain levels than their counterparts who did not cross over.
The Buchbinder study used overall pain on a 10-point VAS at 3 months as its primary end point. The researchers also recorded 7 other measurements and assessed participants at 1 week, 1 month, 3 months, and 6 months. At 3 months, there was no significant difference in the change in pain scores between the treatment and placebo groups: Mean pain scores for those who underwent VP decreased from 7.4 to 5.1, while the placebo group’s average pain scores went from 7.1 to 5.4. Similarly, there was no difference between the treatment and placebo groups in the change in pain scores at 1 week or 6 months—and no difference between the groups at any time for the other 7 measures of pain and function.
WHAT’S NEW: Trials cast doubt on established procedure
VP has essentially become the standard of care for painful osteoporotic vertebral fractures, bolstered by a long list of methodologically inferior studies that have lent support to the procedure’s efficacy. These 2 studies are the first to incorporate a sham procedure that supports true placebo control. The complete lack of benefit for VP compared with conservative management in these well-done trials calls into question the results of prior reports.
CAVEATS: Sample size, study design
Researchers in both studies had considerable difficulty enrolling patients. Both were multi center trials and enrolled patients over a 4-year period; nonetheless, taken together, only about 200 patients consented. The researchers faced opposition from referring doctors and patients alike, who believed that the possibility of receiving a placebo treatment rather than VP constituted inferior care.
In addition to their relatively small size, these studies enrolled patients with fairly chronic fractures. It has been postulated that VP has a higher likelihood of success with acute fractures, but that was not the focus of these trials. The majority of the fractures in trial participants were not acute (<4 weeks). Neither trial was designed for analysis based on the chronicity of the fracture, and neither found a difference in outcome based on fracture duration.
Because these trials were not designed, or robust enough, for subgroup analysis, we don’t know if there is a population that might benefit (ie, severity of the compression, acuteness of the fracture, or premorbid health, etc). In addition, these results do not apply to the use of VP for other reasons—malignant spinal neoplasms or vertebral hemangiomas, for example.
Finally, it is important to remember that these trials did not strictly compare VP with conservative treatment. The sham treatment may have had significant placebo power that is greater than that of typical conservative treatment.
CHALLENGES TO IMPLEMENTATION: Support for VP is well established
Anecdotal results, established treatment patterns, and numerous low-quality studies support the use of VP for vertebral compression fracture. Medicare and other insurers had reviewed the evidence prior to these 2 trials and agreed to reimburse for the procedure. It remains to be seen whether these 2 trials will be sufficient to overcome these barriers and change practice patterns.
At a minimum, however, it is prudent to reserve VP for patients who have intractable symptoms until further trials are undertaken to determine whether VP really works, and if so, for which patients.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
2. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
3. Weinstein JN. Balancing science and informed choice in decisions about vertebroplasty. N Engl J Med. 2009;361:619-621.
4. Gray DT, Hollingworth W, Onwudiwe N, et al. Thoracic and lumbar vertebroplasties performed in US Medicare enrollees, 2001-2005. JAMA. 2007;298:1760-1762.
5. McGirt MJ, Parker SL, Wolinsky JP, et al. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9:501-508.
6. Lee MJ, Dumonski M, Cahill P, et al. Percutaneous treatment of vertebral compression fractures: a meta-analysis of complications. Spine. 2009;34:1228-1232.
7. Hulme PA, Krebs J, Ferguson S, et al. Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies. Spine. 2006;31:1983-2001.
8. Voormolen MH, Mali WP, Lohle PN, et al. Percutaneous vertebroplasty compared with optimal pain medication treatment: short-term clinical outcome of patients with subacute or chronic painful osteoporotic vertebral compression fractures. The VERTOS study. AJNR Am J Neuroradiol. 2007;28:555-560.
9. Rousing R, Andersen MO, Jespersen SM, et al. Percutaneous vertebroplasty compared to conservative treatment in patients with painful acute or subacute osteoporotic vertebral fractures: three-months follow-up in a clinical randomized study. Spine. 2009;34:1349-1354.
1. Kallmes DF, Comstock BA, Heagerty PJ, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361:569-579.
2. Buchbinder R, Osborne RH, Ebeling PR, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361:557-568.
3. Weinstein JN. Balancing science and informed choice in decisions about vertebroplasty. N Engl J Med. 2009;361:619-621.
4. Gray DT, Hollingworth W, Onwudiwe N, et al. Thoracic and lumbar vertebroplasties performed in US Medicare enrollees, 2001-2005. JAMA. 2007;298:1760-1762.
5. McGirt MJ, Parker SL, Wolinsky JP, et al. Vertebroplasty and kyphoplasty for the treatment of vertebral compression fractures: an evidenced-based review of the literature. Spine J. 2009;9:501-508.
6. Lee MJ, Dumonski M, Cahill P, et al. Percutaneous treatment of vertebral compression fractures: a meta-analysis of complications. Spine. 2009;34:1228-1232.
7. Hulme PA, Krebs J, Ferguson S, et al. Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies. Spine. 2006;31:1983-2001.
8. Voormolen MH, Mali WP, Lohle PN, et al. Percutaneous vertebroplasty compared with optimal pain medication treatment: short-term clinical outcome of patients with subacute or chronic painful osteoporotic vertebral compression fractures. The VERTOS study. AJNR Am J Neuroradiol. 2007;28:555-560.
9. Rousing R, Andersen MO, Jespersen SM, et al. Percutaneous vertebroplasty compared to conservative treatment in patients with painful acute or subacute osteoporotic vertebral fractures: three-months follow-up in a clinical randomized study. Spine. 2009;34:1349-1354.
Copyright © 2009 The Family Physicians Inquiries Network.
All rights reserved.
Does neonatal circumcision decrease morbidity?
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
Evidence suggests that neonatal circumcision decreases the incidence of childhood urinary tract infections, phimosis, paraphimosis, balanitis and other genital dermatoses, invasive penile cancer, and the sexually transmitted diseases human papilloma virus (HPV) and HIV (strength of recommendation [SOR]: B, based on case control and cohort studies). The benefits of decreased incidence of HPV and HIV infections go beyond the index patient and have public health implications on the transmission of these diseases (SOR: B). Further, a decrease in HPV incidence and transmission may lead to a lower incidence of cervical cancer (SOR: B).
While there appears to be some evidence for reduced morbidity with routine circumcision, decisions regarding routine neonatal circumcision requires balancing risks and benefits of the procedure with the alternatives in the context of social, familial, and religious beliefs.
Evidence summary
Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.1 The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.4 It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.
Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.5 In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.6 Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.7 In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).7
The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).8 A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).9 This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.
A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.10 The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.11
Recommendations from others
Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”12 The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.13-15
Explain risks and benefits of circumcision to parents so they make informed decisions
A dilemma exists in the practice of recommending circumcision to parents of newborn males. Although the evidence shows that morbidity is decreased in circumcised males, the occurrence of complications (such as UTI or balanitis) is believed to be preventable through good hygiene, and the incidence of the preventable disease (such as penile cancer) is so low in the general population as to not justify the procedure. The challenge is there because the procedure is not without pain or risk of complications.
This is the basis for the American Academy of Pediatrics not recommending routine neonatal circumcision. The consensus was that the evidence was not sufficient to support it. Since then, many studies have been published on HPV and HIV transmission, the incidence of phimosis and paraphimosis, UTI, and balanitis, and how circumcision reduces the incidence of these diseases. Again, these are believed to be preventable through hygiene and condom use. In practice, it is difficult to persuade parents because these complications usually occur much later in life. Most patients made their decisions on circumcision based on religious or cultural experiences.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
1. Wiswell TE. The prepuce, urinary tract infections, and the consequences. Pediatrics 2000;105:860-862.
2. Sethi N, Schwierling K, Kim J, et al. Newborn circumcision and urinary tract infections. Pediatrics 2001;107:212.-
3. Christakis DA, Harvey E, Zerr DM, Feudtner C, Wright JA, Connell FA. A trade off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249.
4. Nayir A. Circumcision for the prevention of significant bacteriuria in boys. Pediatr Nephrol 2001;16:1129-1134.Erratum in: Pediatr Nephrol. 2002; 17: 307.
5. Lerman SE, Liao JC. Neonatal circumcision. Pediatr Clin North Am 2001;48:1539-557.
6. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol 2000;136:350-354.
7. Schoen EJ. The relationship between circumcision and cancer of the penis. CA Cancer J Clin 1991;41:306-309.
8. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics 2000;105:E36.-
9. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-1112.
10. Weiss HA, Quigley MA, Hayes RJ. Male circumcision and risk of HIV infection in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2000;14:2361-2370.
11. Reynolds SJ, Shepherd ME, Risbud AR, et al. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet 2004;363:1039-1040.
12. American Academy of Pediatrics. Task Force on Circumcision. Circumcision policy statement. Pediatrics 1999;103:686-693.
13. American Medical Association. Report 10 of the Council on Scientific Affairs (I-99) Neonatal Circumcision. Available at: www.ama-assn.org/ama/pub/category/ 13585.html. Accessed on December 8, 2004.
14. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 260: Circumcision. Obstet Gynecol 2001;98:707-708.
15. American Academy of Family Physicians. Position Paper on Neonatal Circumcision. Available at: www.aafp.org/ x1462.xml. Accessed on December 8, 2004.
Evidence-based answers from the Family Physicians Inquiries Network