Letters
Corresponding Author: Joslyn S. Kirby, MD, Penn State Milton S. Hershey Medical Center, Department of Dermatology, 500 University Dr, Hershey, PA 17033 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581. 2. Yosipovitch G. Chronic pruritus: a paraneoplastic sign. Dermatol Ther. 2010;23 (6):590-596. 3. Fukuoka M, Miyachi Y, Ikoma A. Mechanically evoked itch in humans. Pain. 2013; 154(6):897-904. 4. Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol. 2009;161(5):1072-1080. 5. Misery L, Alexandre S, Dutray S, et al. Functional itch disorder or psychogenic pruritus: suggested diagnosis criteria from the French psychodermatology group. Acta Derm Venereol. 2007;87(4):341-344. 6. Leader B, Carr CW, Chen SC. Pruritus epidemiology and quality of life. Handb Exp Pharmacol. 2015;226:15-38.
Shared Decision-Making for Cancer Screening: Visual Tools and a 4-Step Method To the Editor Caverly’s concerns for promoting shared decisionmaking and selecting the best candidates for lung cancer screening deserve comment.1 First, it is untrue that developing a shared decisionmaking tool is complex.1 Common sense pictographs that use absolute numbers with a consistent denominator (ie, /1000 screened), time frames, and visuals employing the same scale for information on gains and losses of the options have been shown to change and improve decision-making.2,3 Such pictographs for breast cancer screening are already implemented in the small country of Belgium.4 It is puzzling why national health care agencies from so many countries enduringly fail to do this job properly. Second, to address whether a shared decision requires many more tools, a simple 4-step method can be employed: (1) Indicate that all options are acceptable; (2) administer the information (as above); (3) promote active participation of the patient by the expression of his or her values; and (4) analyze if the patient is comfortable with the decision by rephrasing. Finally, blood tests might be a cost-effective means to select candidates for computed tomography in the near future.5 Alain Braillon, MD, PhD Susan Bewley, MD, FRCOG, MA Author Affiliations: Amiens University Hospital, 80000 Amiens, France (Braillon); Women's Health Academic Centre, St Thomas' Hospital, London, England (Bewley). Corresponding Author: Alain Braillon, MD, PhD, Amiens University Hospital, 80000 Amiens, France ([email protected]). Conflict of Interest Disclosures: None reported. Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors. 1. Caverly T. Selecting the best candidates for lung cancer screening. JAMA Intern Med. 2015;175(6):898-900. 2. Zikmund-Fisher BJ, Fagerlin A, Ubel PA. A demonstration of “less can be more” in risk graphics. Med Decis Making. 2010;30(6):661-671. 3. Johansson M, Brodersen J. Informed choice in screening needs more than information. Lancet. 2015;385(9978):1597-1599.
1862
4. Belgian Health Care Knowledge Center (KCE). Report 216 [Breast cancer screening: messages for an informed choice]. 2014. http://kce.fgov.be/fr /publication/report/d%C3%A9pistage-du-cancer-du-sein-messages-en -support-d%E2%80%99un-choix-inform%C3%A9#.VQa0tPmG_6J. Accessed April 13, 2015. 5. Montani F, Marzi MJ, Dezi F, et al. miR-Test: a blood test for lung cancer early detection. J Natl Cancer Inst. 2015;107(6):djv063.
Physical Activity and Successful Aging: Even a Little Is Good To the Editor Recently in JAMA Internal Medicine, two studies1,2 highlighted the need of vigorous-intensity and/or long durations of physical activity for older adults. However, this is hardly feasible. Less than 50% are able to achieve the recommended minimum of 150 minutes of moderate-intensity physical activity, 75 minutes of vigorous-intensity physical activity, or an equivalent combination of moderate and vigorous physical activity (MVPA) per week.3,4 In a cohort of 204 542 middleaged and older Australians followed over the course of 6.5 years (7435 deaths included), Gebel et al1 reported significant benefits of vigorous-intensity physical activity in reducing mortality. Thus, they encourage vigorous intensity in activity guidelines to maximize benefits of physical activity in older adults.1 Can we recommend running to older adults for whom brisk walking is too demanding? Arem et al2 pooled data from 6 studies (5 American, 1 Swedish), including 661 137 middle-aged and older adults with 14.2 follow-up years (116 686 deaths registered) and reported an optimal threshold between 3 to 5 times the physical activity recommendations.2 Can we recommend 150 min/d physical activity to older adults who are not able to achieve 150 min/wk? Recommendations in the United States for older adults are similar to those for middle-aged adults.3 The only adaptation to the potential limitations of older adults is when older adults cannot do 150 minutes of moderate-intensity activity a week, they should be as physically active as their abilities and conditions allow.3 Doing little is better than doing nothing. The prescription of physical activity for older adults needs to be clarified (ie, the dose of physical activity required). We think that focusing on the current guidelines or on the upper threshold of physical activity may mean that the benefits of low-dose MVPA are overlooked in older adults. We think that older adults should increase physical activities progressively in their daily lives rather than changing their daily habits dramatically by adhereing to current recommendations. Based on the dose-response relationship between physical activity and mortality, we demonstrated that among the different bouts of daily exercise, the end of the first 15 minutes of MVPA yielded the largest increase in benefits, tapering off for subsequent 15-minute increments.5 Fifteen minutes per day could be a reasonable target dose for older adults. Small increases in physical activity may enable some older adults to incorporate more moderate activity and get closer to the recommended 150 min/wk.3 David Hupin, MD, MSc Frédéric Roche, MD, PhD Pascal Edouard, MD, PhD
JAMA Internal Medicine November 2015 Volume 175, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
jamainternalmedicine.com
Letters
Author Affiliations: Department of Clinical and Exercise Physiology, Autonomic Nervous System and Exercise Physiology Laboratories, University Hospital of Saint-Etienne, PRES Lyon, Jean Monnet University, Saint-Etienne, France. Corresponding Author: David Hupin, MD, MSc, Department of Clinical and Exercise Physiology, University Hospital of Saint-Etienne, PRES Lyon, Jean Monnet University, CHU Saint-Etienne, Hôpital Nord, Service de Physiologie Clinique et de l’Exercice, Centre VISAS, Bâtiment A-3è étage, 42055 SaintEtienne CEDEX 2, France ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gebel K, Ding D, Chey T, Stamatakis E, Brown WJ, Bauman AE. Effect of moderate to vigorous physical activity on all-cause mortality in middle-aged and older older Australians. JAMA Intern Med. 2015;175(6):970-977. 2. Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175(6):959-967. 3. Physical Activity Guidelines Advisory Committee. 2008 Physical Activity Guidelines for Americans. Washington, DC; US Dept of Health and Human Services; 2008. http://www.health.gov/PAGuidelines. Accessed June 13, 2015. 4. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U; Lancet Physical Activity Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet. 2012;380(9838): 247-257. 5. Hupin D, Roche F, Gremeaux V et al Even low-dose of moderate-to-vigorous physical activity reduces mortality in adults aged > 60 years by 22%: a systematic review and meta-analysis [published online August 3, 2015]. Br J Sports Med. doi:10.1136/bjsports-2014-094306.
In Reply We thank Dr Hupin and colleagues for their comment on the health-related importance of even low levels of moderate- to vigorous-intensity physical activity (MVPA) in older adults. We agree that amounts of MVPA as low as 15 min/d (about 70% of the recommended minimum) can provide important health benefits for older adults. A previous publication by our group1 examined in detail the low end of the dose-response relationship between physical activity and years of life gained, reporting a benefit of approximately 2 years of life with even 0.1 to 3.75 metabolic equivalent h/wk of leisure time MVPA (ie, ≤50% of the recommended minimum). Thus, previous findings in our pooled analytic cohort support the emphasis on the importance of even low levels of MVPA by Hupin et al. The 2008 Physical Activity Guidelines for Americans3 suggested “additional” health benefits beyond 2 times the recommended LTPA minimum but lacked evidence for a definition of the health benefits beyond this threshold. Our recent article in JAMA Internal Medicine2 built on our previous analysis1 to further understand the upper threshold of benefit from physical activity. Our study findings informed individuals at both ends of the physical activity spectrum, providing evidence of a 20% lower mortality risk with activity less than the recommended minimum while reassuring those at the highest activity levels that there was no increased risk of death. Furthermore, in our study, total volume of leisure time physical activity was more important for mortality benefits than activity intensity, supporting the mortality benefit accrued by moderate-intensity activities such as brisk walking. In our current study,2 we also found that significant benefit was obtained from doing any leisure time MVPA (23% lower mortality risk) in older adults (≥70 years) and also noted that additional benefit was gained from meeting the recommenjamainternalmedicine.com
dations for this age group (35% lower mortality risk). Some exercise is better than none, and more exercise is better, even for older adults. Future studies may further delve into the health benefits associated with specific types of activities or interventions to increase activity levels in older adults. Hannah Arem, MHS, PhD Charles E. Matthews, PhD I-Min Lee, MBBS, ScD Author Affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Arem, Matthews); Harvard Medical School, Boston, Massachusetts (Lee). Corresponding Author: Hannah Arem, MHS, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Rm 6E314, MSC 9768, Bethesda, MD 20892-9768 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Moore SC, Patel AV, Matthews CE, et al. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med. 2012;9(11):e1001335. 2. Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175(6):959-967. 3. Office of Disease Prevention and Health Promotion. Physical Activity Guidelines for Americans. http://health.gov/paguidelines/guidelines/. 2008. Updated September 2, 2015. Accessed September 2, 2015.
In Reply The response from Hupin and colleagues to our recent article1 in JAMA Internal Medicine underlines the interest in our findings and their potential implications on future physical activity guidelines. Unfortunately, it also seems to underline the common misinterpretation of our research findings, which is that we would like to encourage older adults to abandon moderate physical activity and start running and sweating.2 A key finding in our article was that, similar to other studies, we found the total volume of physical activity to be a strong predictor of mortality and that even low volumes of activity significantly reduce risk of mortality, which supports the argument by Hupin and colleagues that even a little activity is better than none. The more novel finding of our study was that, independent of the amount of physical activity, engaging in any vigorous activity added further protection against all-cause mortality risk. Our findings are in line with other epidemiological and experimental studies that found that higher proportions of vigorous activity have multiple health benefits,3 including prevention of functional decline.4 Functional limitations can make vigorous activity difficult or impossible. However, as we argued previously,4 for middle-aged and older adults who are able to engage in vigorous physical activity, it might be important to promote vigorous activity for maintaining physical function, independence, and successful aging. Hupin and colleagues noted that moderate-intensity activity is challenging for older adults and, therefore, vigorous activity is even more so. We fully agree with their notion that low doses of activity yield the largest increases in health benefits and are more achievable for older adults than the uppervolume threshold and more vigorous activities, as reflected in the activity guidelines for older adults. We also agree that some older adults are too frail to engage in vigorous activity or very (Reprinted) JAMA Internal Medicine November 2015 Volume 175, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
1863
Letters
high volumes of activity. However, we acknowledge that at the population level there is a spectrum of capability to perform physical activity at an older age. As public health professionals, we believe that it is important to apply a population strategy where we shift the population distribution of physical activity rather than focusing solely on high-risk population subgroups.5 The population strategy to promote physical activity among older adults should be to get those who are inactive to do some physical activity and those who currently only engage in moderate activity to incorporate even a little vigorous activity if feasible. A balanced and inclusive approach is needed for physical activity recommendations that takes into account variation in physical and functional abilities. Therefore, to maximize population health benefits for older adults, we believe that in addition to the volume, the intensity of physical activity should be considered. As stated in our original article,1(p975) “in future activity guidelines, it may be reasonable to encourage wider consideration of vigorous activities for those who are capable of doing so by including statements such as ‘If you can, enjoy some regular vigorous-intensity activity for extra health and fitness benefits.’” Klaus Gebel, PhD Ding Ding, PhD Adrian E Bauman, PhD Author Affiliations: Centre for Chronic Disease Prevention, College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, Queensland, Australia (Gebel, Ding); Prevention Research Collaboration, Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia (Gebel, Ding, Bauman). Corresponding Author: Klaus Gebel, PhD, Centre for Chronic Disease Prevention, College of Public Health, Medical and Veterinary Sciences, James Cook University, PO Box 6811, Cairns QLD 4870, Australia ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Heart Foundation of Australia (grant No. G170286). Role of the Funder/Sponsor: The Heart Foundation of Australia had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Gebel K, Ding D, Chey T, Stamatakis E, Brown WJ, Bauman AE. Effect of moderate to vigorous physical activity on all-cause mortality in middle-aged and older Australians. JAMA Intern Med. 2015;175(6):970-977. 2. Ding D, Gebel K, Freeman B, Bauman AE. Vigorous physical activity and all-cause mortality: a story that got lost in translation. J Phys Act Health. 2015;12 (4):445-446. 3. Swain DP, Franklin BA. Comparison of cardioprotective benefits of vigorous versus moderate intensity aerobic exercise. Am J Cardiol. 2006;97(1):141-147. 4. Gebel K, Ding D, Bauman AE. Volume and intensity of physical activity in a large population-based cohort of middle-aged and older Australians: prospective relationships with weight gain, and physical function. Prev Med. 2014;60(3):131-133. 5. Rose G. Sick individuals and sick populations. Int J Epidemiol. 2001;30(3):427432.
Dosing Strategies of Bone-Targeting Agents To the Editor We read with interest the study by Greenspan and colleagues1 that evaluated the clinical benefits of a single dose of intravenous zoledronate (with daily calcium and vitamin D) on bone mineral density and safety for 2 years in frail elderly 1864
women in long-term care facilities. This study provides further motivation for patients, clinicians, and researchers to study the optimal dosing interval of increasingly potent bonetargeting agents such as zoledronate and denosumab. It is interesting and perhaps disturbing that, despite the widespread use of these agents for several decades, so few trials have been performed examining optimal dosing intervals. For example, in the setting of cancer therapy–induced bone loss, these agents continue to be given every 6 to 12 months despite data showing that a single injection of zoledronate is associated with prolonged bone density and biomarker response for at least 3 years.2 Similarly, the 3- to 4-week dosing intervals for bonetargeted agent use in metastatic breast and prostate cancers were developed from studies in patients with hypercalcemia and for the convenience of coadministration with standard anticancer agents (eg, chemotherapy). These schedules ignore the long half-life many of these agents have in bone and bone turnover marker studies—a surrogate of skeletal-related event risk—that have consistently shown rapid falls in biomarker levels sustained at significantly lower doses for longer durations than 3 to 4 weeks for both bisphosphonates and denosumab.3 We are currently in the process of updating a 2013 systematic review4 that assesses the evidence comparing the clinical benefits and harms of standard (3- to 4-week doses) vs deescalated (12-week doses) bone-targeting agents in breast cancer patients. While trends from existing randomized clinical trials of pamidronate,5 zoledronate (EudraCT2005-0049425-15), and denosumab (NCT02051218, NCT00091832, NCT00104650) suggest comparable benefits and potential reductions in harms for deescalated treatment, most studies have been of small sample size. The Swiss Group for Clinical Cancer Research have recently initiated a large randomized clinical trial (NCT02051218) that will compare the clinical benefits and harms of standard vs deescalated treatment with bone-targeting agents in patients with breast or prostate cancer, which will be instrumental in addressing this issue. If similar benefits could be attained with a reduced frequency of drug administration and reduced risk of harms (eg, renal toxic effects and osteonecrosis of the jaw) then there will be increased benefits for patients in terms of quality of life, and reduced health care costs can be achieved. Brian Hutton, PhD Sasha Mazzarello, BSc Mark Clemons, MD Author Affiliations: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (Hutton); Division of Medical Oncology, Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada (Mazzarello, Clemons). Corresponding Author: Mark Clemons, MD, Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada ([email protected]). Conflict of Interest Disclosures: None reported. 1. Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med. 2015;175(6):913-921. 2. Brown JE, Ellis SP, Lester JE, et al. Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res. 2007;13(18, pt 1):5406-5410. 3. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27(10):1564-1571.
JAMA Internal Medicine November 2015 Volume 175, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
jamainternalmedicine.com
Corresponding Author: Joslyn S. Kirby, MD, Penn State Milton S. Hershey Medical Center, Department of Dermatology, 500 University Dr, Hershey, PA 17033 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581. 2. Yosipovitch G. Chronic pruritus: a paraneoplastic sign. Dermatol Ther. 2010;23 (6):590-596. 3. Fukuoka M, Miyachi Y, Ikoma A. Mechanically evoked itch in humans. Pain. 2013; 154(6):897-904. 4. Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol. 2009;161(5):1072-1080. 5. Misery L, Alexandre S, Dutray S, et al. Functional itch disorder or psychogenic pruritus: suggested diagnosis criteria from the French psychodermatology group. Acta Derm Venereol. 2007;87(4):341-344. 6. Leader B, Carr CW, Chen SC. Pruritus epidemiology and quality of life. Handb Exp Pharmacol. 2015;226:15-38.
Shared Decision-Making for Cancer Screening: Visual Tools and a 4-Step Method To the Editor Caverly’s concerns for promoting shared decisionmaking and selecting the best candidates for lung cancer screening deserve comment.1 First, it is untrue that developing a shared decisionmaking tool is complex.1 Common sense pictographs that use absolute numbers with a consistent denominator (ie, /1000 screened), time frames, and visuals employing the same scale for information on gains and losses of the options have been shown to change and improve decision-making.2,3 Such pictographs for breast cancer screening are already implemented in the small country of Belgium.4 It is puzzling why national health care agencies from so many countries enduringly fail to do this job properly. Second, to address whether a shared decision requires many more tools, a simple 4-step method can be employed: (1) Indicate that all options are acceptable; (2) administer the information (as above); (3) promote active participation of the patient by the expression of his or her values; and (4) analyze if the patient is comfortable with the decision by rephrasing. Finally, blood tests might be a cost-effective means to select candidates for computed tomography in the near future.5 Alain Braillon, MD, PhD Susan Bewley, MD, FRCOG, MA Author Affiliations: Amiens University Hospital, 80000 Amiens, France (Braillon); Women's Health Academic Centre, St Thomas' Hospital, London, England (Bewley). Corresponding Author: Alain Braillon, MD, PhD, Amiens University Hospital, 80000 Amiens, France ([email protected]). Conflict of Interest Disclosures: None reported. Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors. 1. Caverly T. Selecting the best candidates for lung cancer screening. JAMA Intern Med. 2015;175(6):898-900. 2. Zikmund-Fisher BJ, Fagerlin A, Ubel PA. A demonstration of “less can be more” in risk graphics. Med Decis Making. 2010;30(6):661-671. 3. Johansson M, Brodersen J. Informed choice in screening needs more than information. Lancet. 2015;385(9978):1597-1599.
1862
4. Belgian Health Care Knowledge Center (KCE). Report 216 [Breast cancer screening: messages for an informed choice]. 2014. http://kce.fgov.be/fr /publication/report/d%C3%A9pistage-du-cancer-du-sein-messages-en -support-d%E2%80%99un-choix-inform%C3%A9#.VQa0tPmG_6J. Accessed April 13, 2015. 5. Montani F, Marzi MJ, Dezi F, et al. miR-Test: a blood test for lung cancer early detection. J Natl Cancer Inst. 2015;107(6):djv063.
Physical Activity and Successful Aging: Even a Little Is Good To the Editor Recently in JAMA Internal Medicine, two studies1,2 highlighted the need of vigorous-intensity and/or long durations of physical activity for older adults. However, this is hardly feasible. Less than 50% are able to achieve the recommended minimum of 150 minutes of moderate-intensity physical activity, 75 minutes of vigorous-intensity physical activity, or an equivalent combination of moderate and vigorous physical activity (MVPA) per week.3,4 In a cohort of 204 542 middleaged and older Australians followed over the course of 6.5 years (7435 deaths included), Gebel et al1 reported significant benefits of vigorous-intensity physical activity in reducing mortality. Thus, they encourage vigorous intensity in activity guidelines to maximize benefits of physical activity in older adults.1 Can we recommend running to older adults for whom brisk walking is too demanding? Arem et al2 pooled data from 6 studies (5 American, 1 Swedish), including 661 137 middle-aged and older adults with 14.2 follow-up years (116 686 deaths registered) and reported an optimal threshold between 3 to 5 times the physical activity recommendations.2 Can we recommend 150 min/d physical activity to older adults who are not able to achieve 150 min/wk? Recommendations in the United States for older adults are similar to those for middle-aged adults.3 The only adaptation to the potential limitations of older adults is when older adults cannot do 150 minutes of moderate-intensity activity a week, they should be as physically active as their abilities and conditions allow.3 Doing little is better than doing nothing. The prescription of physical activity for older adults needs to be clarified (ie, the dose of physical activity required). We think that focusing on the current guidelines or on the upper threshold of physical activity may mean that the benefits of low-dose MVPA are overlooked in older adults. We think that older adults should increase physical activities progressively in their daily lives rather than changing their daily habits dramatically by adhereing to current recommendations. Based on the dose-response relationship between physical activity and mortality, we demonstrated that among the different bouts of daily exercise, the end of the first 15 minutes of MVPA yielded the largest increase in benefits, tapering off for subsequent 15-minute increments.5 Fifteen minutes per day could be a reasonable target dose for older adults. Small increases in physical activity may enable some older adults to incorporate more moderate activity and get closer to the recommended 150 min/wk.3 David Hupin, MD, MSc Frédéric Roche, MD, PhD Pascal Edouard, MD, PhD
JAMA Internal Medicine November 2015 Volume 175, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
jamainternalmedicine.com
Letters
Author Affiliations: Department of Clinical and Exercise Physiology, Autonomic Nervous System and Exercise Physiology Laboratories, University Hospital of Saint-Etienne, PRES Lyon, Jean Monnet University, Saint-Etienne, France. Corresponding Author: David Hupin, MD, MSc, Department of Clinical and Exercise Physiology, University Hospital of Saint-Etienne, PRES Lyon, Jean Monnet University, CHU Saint-Etienne, Hôpital Nord, Service de Physiologie Clinique et de l’Exercice, Centre VISAS, Bâtiment A-3è étage, 42055 SaintEtienne CEDEX 2, France ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gebel K, Ding D, Chey T, Stamatakis E, Brown WJ, Bauman AE. Effect of moderate to vigorous physical activity on all-cause mortality in middle-aged and older older Australians. JAMA Intern Med. 2015;175(6):970-977. 2. Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175(6):959-967. 3. Physical Activity Guidelines Advisory Committee. 2008 Physical Activity Guidelines for Americans. Washington, DC; US Dept of Health and Human Services; 2008. http://www.health.gov/PAGuidelines. Accessed June 13, 2015. 4. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U; Lancet Physical Activity Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet. 2012;380(9838): 247-257. 5. Hupin D, Roche F, Gremeaux V et al Even low-dose of moderate-to-vigorous physical activity reduces mortality in adults aged > 60 years by 22%: a systematic review and meta-analysis [published online August 3, 2015]. Br J Sports Med. doi:10.1136/bjsports-2014-094306.
In Reply We thank Dr Hupin and colleagues for their comment on the health-related importance of even low levels of moderate- to vigorous-intensity physical activity (MVPA) in older adults. We agree that amounts of MVPA as low as 15 min/d (about 70% of the recommended minimum) can provide important health benefits for older adults. A previous publication by our group1 examined in detail the low end of the dose-response relationship between physical activity and years of life gained, reporting a benefit of approximately 2 years of life with even 0.1 to 3.75 metabolic equivalent h/wk of leisure time MVPA (ie, ≤50% of the recommended minimum). Thus, previous findings in our pooled analytic cohort support the emphasis on the importance of even low levels of MVPA by Hupin et al. The 2008 Physical Activity Guidelines for Americans3 suggested “additional” health benefits beyond 2 times the recommended LTPA minimum but lacked evidence for a definition of the health benefits beyond this threshold. Our recent article in JAMA Internal Medicine2 built on our previous analysis1 to further understand the upper threshold of benefit from physical activity. Our study findings informed individuals at both ends of the physical activity spectrum, providing evidence of a 20% lower mortality risk with activity less than the recommended minimum while reassuring those at the highest activity levels that there was no increased risk of death. Furthermore, in our study, total volume of leisure time physical activity was more important for mortality benefits than activity intensity, supporting the mortality benefit accrued by moderate-intensity activities such as brisk walking. In our current study,2 we also found that significant benefit was obtained from doing any leisure time MVPA (23% lower mortality risk) in older adults (≥70 years) and also noted that additional benefit was gained from meeting the recommenjamainternalmedicine.com
dations for this age group (35% lower mortality risk). Some exercise is better than none, and more exercise is better, even for older adults. Future studies may further delve into the health benefits associated with specific types of activities or interventions to increase activity levels in older adults. Hannah Arem, MHS, PhD Charles E. Matthews, PhD I-Min Lee, MBBS, ScD Author Affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Arem, Matthews); Harvard Medical School, Boston, Massachusetts (Lee). Corresponding Author: Hannah Arem, MHS, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Rm 6E314, MSC 9768, Bethesda, MD 20892-9768 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Moore SC, Patel AV, Matthews CE, et al. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med. 2012;9(11):e1001335. 2. Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med. 2015;175(6):959-967. 3. Office of Disease Prevention and Health Promotion. Physical Activity Guidelines for Americans. http://health.gov/paguidelines/guidelines/. 2008. Updated September 2, 2015. Accessed September 2, 2015.
In Reply The response from Hupin and colleagues to our recent article1 in JAMA Internal Medicine underlines the interest in our findings and their potential implications on future physical activity guidelines. Unfortunately, it also seems to underline the common misinterpretation of our research findings, which is that we would like to encourage older adults to abandon moderate physical activity and start running and sweating.2 A key finding in our article was that, similar to other studies, we found the total volume of physical activity to be a strong predictor of mortality and that even low volumes of activity significantly reduce risk of mortality, which supports the argument by Hupin and colleagues that even a little activity is better than none. The more novel finding of our study was that, independent of the amount of physical activity, engaging in any vigorous activity added further protection against all-cause mortality risk. Our findings are in line with other epidemiological and experimental studies that found that higher proportions of vigorous activity have multiple health benefits,3 including prevention of functional decline.4 Functional limitations can make vigorous activity difficult or impossible. However, as we argued previously,4 for middle-aged and older adults who are able to engage in vigorous physical activity, it might be important to promote vigorous activity for maintaining physical function, independence, and successful aging. Hupin and colleagues noted that moderate-intensity activity is challenging for older adults and, therefore, vigorous activity is even more so. We fully agree with their notion that low doses of activity yield the largest increases in health benefits and are more achievable for older adults than the uppervolume threshold and more vigorous activities, as reflected in the activity guidelines for older adults. We also agree that some older adults are too frail to engage in vigorous activity or very (Reprinted) JAMA Internal Medicine November 2015 Volume 175, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
1863
Letters
high volumes of activity. However, we acknowledge that at the population level there is a spectrum of capability to perform physical activity at an older age. As public health professionals, we believe that it is important to apply a population strategy where we shift the population distribution of physical activity rather than focusing solely on high-risk population subgroups.5 The population strategy to promote physical activity among older adults should be to get those who are inactive to do some physical activity and those who currently only engage in moderate activity to incorporate even a little vigorous activity if feasible. A balanced and inclusive approach is needed for physical activity recommendations that takes into account variation in physical and functional abilities. Therefore, to maximize population health benefits for older adults, we believe that in addition to the volume, the intensity of physical activity should be considered. As stated in our original article,1(p975) “in future activity guidelines, it may be reasonable to encourage wider consideration of vigorous activities for those who are capable of doing so by including statements such as ‘If you can, enjoy some regular vigorous-intensity activity for extra health and fitness benefits.’” Klaus Gebel, PhD Ding Ding, PhD Adrian E Bauman, PhD Author Affiliations: Centre for Chronic Disease Prevention, College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, Queensland, Australia (Gebel, Ding); Prevention Research Collaboration, Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia (Gebel, Ding, Bauman). Corresponding Author: Klaus Gebel, PhD, Centre for Chronic Disease Prevention, College of Public Health, Medical and Veterinary Sciences, James Cook University, PO Box 6811, Cairns QLD 4870, Australia ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Heart Foundation of Australia (grant No. G170286). Role of the Funder/Sponsor: The Heart Foundation of Australia had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Gebel K, Ding D, Chey T, Stamatakis E, Brown WJ, Bauman AE. Effect of moderate to vigorous physical activity on all-cause mortality in middle-aged and older Australians. JAMA Intern Med. 2015;175(6):970-977. 2. Ding D, Gebel K, Freeman B, Bauman AE. Vigorous physical activity and all-cause mortality: a story that got lost in translation. J Phys Act Health. 2015;12 (4):445-446. 3. Swain DP, Franklin BA. Comparison of cardioprotective benefits of vigorous versus moderate intensity aerobic exercise. Am J Cardiol. 2006;97(1):141-147. 4. Gebel K, Ding D, Bauman AE. Volume and intensity of physical activity in a large population-based cohort of middle-aged and older Australians: prospective relationships with weight gain, and physical function. Prev Med. 2014;60(3):131-133. 5. Rose G. Sick individuals and sick populations. Int J Epidemiol. 2001;30(3):427432.
Dosing Strategies of Bone-Targeting Agents To the Editor We read with interest the study by Greenspan and colleagues1 that evaluated the clinical benefits of a single dose of intravenous zoledronate (with daily calcium and vitamin D) on bone mineral density and safety for 2 years in frail elderly 1864
women in long-term care facilities. This study provides further motivation for patients, clinicians, and researchers to study the optimal dosing interval of increasingly potent bonetargeting agents such as zoledronate and denosumab. It is interesting and perhaps disturbing that, despite the widespread use of these agents for several decades, so few trials have been performed examining optimal dosing intervals. For example, in the setting of cancer therapy–induced bone loss, these agents continue to be given every 6 to 12 months despite data showing that a single injection of zoledronate is associated with prolonged bone density and biomarker response for at least 3 years.2 Similarly, the 3- to 4-week dosing intervals for bonetargeted agent use in metastatic breast and prostate cancers were developed from studies in patients with hypercalcemia and for the convenience of coadministration with standard anticancer agents (eg, chemotherapy). These schedules ignore the long half-life many of these agents have in bone and bone turnover marker studies—a surrogate of skeletal-related event risk—that have consistently shown rapid falls in biomarker levels sustained at significantly lower doses for longer durations than 3 to 4 weeks for both bisphosphonates and denosumab.3 We are currently in the process of updating a 2013 systematic review4 that assesses the evidence comparing the clinical benefits and harms of standard (3- to 4-week doses) vs deescalated (12-week doses) bone-targeting agents in breast cancer patients. While trends from existing randomized clinical trials of pamidronate,5 zoledronate (EudraCT2005-0049425-15), and denosumab (NCT02051218, NCT00091832, NCT00104650) suggest comparable benefits and potential reductions in harms for deescalated treatment, most studies have been of small sample size. The Swiss Group for Clinical Cancer Research have recently initiated a large randomized clinical trial (NCT02051218) that will compare the clinical benefits and harms of standard vs deescalated treatment with bone-targeting agents in patients with breast or prostate cancer, which will be instrumental in addressing this issue. If similar benefits could be attained with a reduced frequency of drug administration and reduced risk of harms (eg, renal toxic effects and osteonecrosis of the jaw) then there will be increased benefits for patients in terms of quality of life, and reduced health care costs can be achieved. Brian Hutton, PhD Sasha Mazzarello, BSc Mark Clemons, MD Author Affiliations: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (Hutton); Division of Medical Oncology, Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada (Mazzarello, Clemons). Corresponding Author: Mark Clemons, MD, Division of Medical Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada ([email protected]). Conflict of Interest Disclosures: None reported. 1. Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med. 2015;175(6):913-921. 2. Brown JE, Ellis SP, Lester JE, et al. Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res. 2007;13(18, pt 1):5406-5410. 3. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27(10):1564-1571.
JAMA Internal Medicine November 2015 Volume 175, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Central Michigan University User on 11/03/2015
jamainternalmedicine.com
