Letters COMMENTS
AND
Annals of Internal Medicine RESPONSES
Vitamin D and Calcium Supplementation to Prevent Fractures in Adults TO THE EDITOR: The guideline from the U.S. Preventive Services Task Force (USPSTF) (1) concludes that the current evidence about calcium and vitamin D supplementation to prevent fractures in adults is essentially insufficient. This statement may be partly based on the limited efficacy of calcium and vitamin D supplementation in preventing fractures from skeletal adaptation to mechanical loading, although vitamin D promotes calcium absorption in the gut and supports bone mineralization that is essential for skeletal stiffness. Bone responds to the local mechanical environment at each skeletal site, as evidenced by marked bone gain in the dominant arms of professional tennis players or rapid bone loss in the weight-bearing sites of astronauts during space flight; it has been considered that the skeleton adapts to mechanical stimulation through control of bone strength by resulting elastic deformation (strain) of bone. This feedback control system related to mechanical strain is known as the Harold Frost mechanostat. Recent experimental data in the adult skeleton (2– 4) suggest that control of trabecular and cortical bone related to mechanical strain acts continuously throughout the physiologic range; thus, even slightly increased or decreased bone strain induces site-specific bone gain or loss, respectively, to maintain the strain level. This concept is compatible with clinical reports in adults that high-impact, but not low-impact, exercise results in bone gain (5) because additional mechanical loading (by exercise) will not stimulate bone when the stimulus does not exceed that already derived from existing mechanical loading (by habitual physical activity). Regardless of suppressing bone resorption or promoting bone formation, or increasing bone quantity or quality, an increase in bone strength by nutrients or drugs would decrease bone strain from mechanical stimuli. The mechanostat based on the latest evidence (2– 4) suggests that the decreased bone strain causes the negative feedback of a control system related to mechanical strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by the natural homeostatic system in the skeleton. This hypothesis is consistent with rapid resolution of the effects of most osteoporosis drugs except bisphosphonates that bind to bone mineral and could partly explain the limited effect of calcium plus vitamin D supplementation on fracture prevention.
Toshihiro Sugiyama, MD, PhD Yamaguchi University School of Medicine Yamaguchi, Japan
3. Ellman R, Spatz J, Cloutier A, Palme R, Christiansen BA, Bouxsein ML. Partial reductions in mechanical loading yield proportional changes in bone density, bone architecture, and muscle mass. J Bone Miner Res. 2013;28:875-85. [PMID: 23165526] 4. Schulte FA, Ruffoni D, Lambers FM, Christen D, Webster DJ, Kuhn G, et al. Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. PLoS One. 2013;8:e62172. [PMID: 23637993] 5. Vainionpa¨a¨ A, Korpelainen R, Vihria¨la¨ E, Rinta-Paavola A, Leppa¨luoto J, Ja¨msa¨ T. Intensity of exercise is associated with bone density change in premenopausal women. Osteoporos Int. 2006;17:455-63. [PMID: 16404492]
TO THE EDITOR: I read the USPSTF’s guideline (1) with great
interest. Both the Institute of Medicine report (2) cited in the editorial (3) and the WHI (Women’s Health Initiative) study noted in the guideline as the largest trial of fracture outcomes reported that many persons in the United States are already receiving supplements. Thus, the conclusions refer to persons already having vitamin D and calcium intake at or close to the recommended daily allowance of each, often because they are receiving supplements. Furthermore, the WHI study used the statistical significance value for the intentionto-treat analysis. I recognize the issue of selective withdrawal during a trial so that the groups at the end may not be as comparable as they were at the beginning. In the WHI study, only 59% of the treated participants were receiving the prescribed dose of vitamin D and calcium. As a pharmacologist, I know that if I want to learn a drug’s effects, I have to give the drug and not just intend to do so. One must be cautious in assuming that lack of statistically significant evidence, especially with intention-to-treat analysis with many withdrawals, is evidence of lack of effect. Marcus M. Reidenberg, MD Weill Cornell Medical College New York, New York Potential Conflicts of Interest: Board membership: Aminopterin; Patents
(planned, pending, or issued): National Institutes of Health; Royalties: National Institutes of Health; Stock/stock options: Ascenta; Travel/accommodations/meeting expenses unrelated to activities listed: United States Pharmacopoeia, U.S. Food and Drug Administration Expert Committee. References 1. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158:691-6. [PMID: 23440163] 2. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Pr; 2011. Accessed at www.iom.edu/Reports /2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx on 27 September 2013. 3. Nestle M, Nesheim MC. To supplement or not to supplement: the U.S. Preventive Services Task Force recommendations on calcium and vitamin D [Editorial]. Ann Intern Med. 2013;158:701-2. [PMID: 23440174]
Potential Conflicts of Interest: None disclosed. References 1. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158:691-6. [PMID: 23440163] 2. Sugiyama T, Meakin LB, Browne WJ, Galea GL, Price JS, Lanyon LE. Bones’ adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. J Bone Miner Res. 2012;27:1784-93. [PMID: 22431329]
IN RESPONSE: The USPSTF anticipated the challenges and honest scientific disagreements on the use of vitamin D and calcium supplementation to prevent fractures. Dr. Sugiyama’s suggestion that mechanical effects play a substantial role in bone strength and quality—and therefore in risk for fractures, regardless of or despite supplement use—is an important observation. The Task Force agrees that more research is needed. Dr. Reidenberg highlights the challenges of drawing conclusions from the WHI study and other randomized, controlled trials of vi-
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Letters tamin D and calcium. As he mentions, the standard technique for studying the effectiveness of an intervention is intention-to-treat analysis to avoid bias due to asymmetrical withdrawal from the trial. The Task Force concurs that statistical significance differs from clinical significance, and it is important to understand the meaning of the results. The challenges of determining the effectiveness of nutritional supplements is a broader issue that the field will need to address. The USPSTF relied on 2 systematic reviews and an updated meta-analysis (1–3) to guide development of its recommendation; these are cited in the recommendation statement. In addition, the Task Force considered several other reviews and meta-analyses, including the DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) study (4) and a more recent patient-level metaanalysis by Bischoff-Ferrari and colleagues (5). The Task Force’s systematic review included many of the same studies as DIPART (4) and Tang and associates (6) but excluded others that did not meet inclusion criteria. The 6 trials of vitamin D and calcium that were considered by the Task Force in its final recommendation statement were of fair to good quality and were conducted in community-dwelling adults for the primary prevention of fractures. The large number of studies on vitamin D and calcium supplements would lead one to believe that the question of whether these supplements are effective in preventing fractures should be resolved. However, the body of evidence in this area is exceedingly heterogeneous; therefore, the Task Force used particular caution when drawing conclusions about the population encompassed within its scope, which is asymptomatic, community-dwelling adults. The negative results of the WHI study (without adjusting for outside supplement use, as Dr. Reidenberg noted) clearly show that lower doses of vitamin D and calcium have no effect. Whether an effect is present at higher doses remains uncertain from the Task Force’s perspective. We agree that it can be difficult for the public to understand the nuance of the recommendation, but we are confident that the recommendation is based on a well-done and comprehensive review of the evidence. Virginia A. Moyer, MD, MPH Michael L. LeFevre, MD, MSPH Albert L. Siu, MD, MSPH U.S. Preventive Services Task Force Rockville, Maryland Potential Conflicts of Interest: Disclosure forms from USPSTF mem-
bers can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum⫽M13-0215. References 1. Cranney A, Horsley T, O’Donnell S, Weiler H, Puil L, Ooi D, et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment no. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed at www.ncbi.nlm.nih.gov/books/NBK38410/ on 31 May 2012. 2. Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report/Technology Assessment no. 183. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK32603/ on 31 May 2012. 3. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:82738. [PMID: 22184690] www.annals.org
4. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010;340:b5463. [PMID: 20068257] 5. Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-9. [PMID: 22762317] 6. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370:657-66. [PMID: 17720017]
Lack of Transparency in Emergency Care TO THE EDITOR: I read Kocher and Emanuel’s article (1) with great interest. The discussions of making medical prices and quality measures public to decrease the cost and increase the quality of medical care assumes that the patient can choose where to get care. Friends, relatives, or first responders usually take acutely ill or injured persons to the nearest emergency department. The patient has no choice. This limitation of transparency as a solution to some of our cost and quality problems should not be ignored.
Marcus M. Reidenberg, MD Weill Cornell Medical College New York, New York Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽L13 -1064. Reference 1. Kocher RP, Emanuel EJ. The transparency imperative. Ann Intern Med. 2013;159: 296-7. [PMID: 23712392]
Methylprednisolone Injections for the Carpal Tunnel Syndrome TO THE EDITOR: Atroshi and colleagues’ study (1) shows temporary
but nonpersistent relief of the carpal tunnel syndrome (CTS) after local methylprednisolone injections. In fact, after week 36, the number of patients treated with methylprednisolone injections who had surgery increased (between 73% and 81% at the end of the first year). Moreover, secondary end points (such as the short Disabilities of the Arm, Shoulder and Hand score; Short Form-36 Health Survey bodily pain score; and Short Form-6D score) and treatment satisfaction showed no differences between methylprednisolone and placebo after 10 weeks of corticosteroid injections. Recent studies have found different outcomes. A study (2) comparing local corticosteroid injections with surgical decompression showed that both treatments effectively alleviated symptoms at 2-year follow-up: 60% of patients who received corticosteroid injections versus 69% of patients who had surgery showed a 20% decrease in nocturnal paresthesia. In another study (3), steroid injection was found to be a better treatment in carefully selected patients than in Atroshi and colleagues’ study. The level of surgical decompression was 15% at 1-year follow-up and 33% at 5-year follow-up. That study concluded that women, patients with diabetes, and patients with neurophysiologic confirmation at diagnosis had a higher risk for relapse after local corticosteroid injections. 17 December 2013 Annals of Internal Medicine Volume 159 • Number 12 857
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Letters Another study (4) showed that electromyographic severity of CTS was an important prognostic factor for the long-term effect of local corticosteroid injections. Patients with mild CTS on electromyography responded even better to local corticosteroid injections. A study (5) added ultrasonography to the work-up of patients with CTS. It found that those with less-pronounced median nerve swelling on ultrasonography responded better to corticosteroid injections. In Atroshi and colleagues’ study, more than 80% of patients had severe or moderate results on nerve conduction testing at baseline. This finding could explain the poor response to corticosteroid injections in the first year in accordance with other studies reviewed. It would be interesting to investigate the degree of nerve involvement before local corticosteroid injections. Nerve conduction or ultrasonography may be good predictors of response to nonsurgical treatments. Francisco Ramirez-Lafita, MD, PhD Viamed Monegal Hospital Tarragona, Spain Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1073. References 1. Atroshi I, Flondell M, Hofer M, Ranstam J. Methylprednisolone injections for the carpal tunnel syndrome: a randomized, placebo-controlled trial. Ann Intern Med. 2013;159:309-17. [PMID: 24026316] 2. Ly-Pen D, Andre´u JL, Milla´n I, de Blas G, Sa´nchez-Olaso A. Comparison of surgical decompression and local steroid injection in the treatment of carpal tunnel syndrome: 2-year clinical results from a randomized trial. Rheumatology (Oxford). 2012;51:1447-54. [PMID: 22467087] 3. Jenkins PJ, Duckworth AD, Watts AC, McEachan JE. Corticosteroid injection for carpal tunnel syndrome: a 5-year survivorship analysis. Hand (N Y). 2012;7:151-6. [PMID: 23730233] 4. Visser LH, Ngo Q, Groeneweg SJ, Brekelmans G. Long term effect of local corticosteroid injection for carpal tunnel syndrome: a relation with electrodiagnostic severity. Clin Neurophysiol. 2012;123:838-41. [PMID: 21962473] 5. Meys V, Thissen S, Rozeman S, Beekman R. Prognostic factors in carpal tunnel syndrome treated with a corticosteroid injection. Muscle Nerve. 2011;44:763-8. [PMID: 21953020]
TO THE EDITOR: We read Atroshi and colleagues’ article (1) with great interest. This placebo-controlled trial shows that injections in CTS are useful and safe, at least in the short term. Symptoms of CTS in patients who received corticosteroid injections improved significantly more than those in patients who received placebo, and corticosteroid recipients had no relevant adverse effects. We were surprised at how frequently surgery was required at 1-year follow-up, with 73% of the 80-mg methylprednisolone group versus 92% of the placebo group needing wrist surgery. In our study comparing corticosteroid injections with surgery (2), only 15% of participants who received wrist injections needed additional treatment after 1-year follow-up. Perhaps this discrepancy depends on the corticosteroid preparation used (we used 20 mg in 1 mL of paramethasone acetonide) and on our protocol permitting 2 injections 2 weeks apart in case patients did not fully recover after the first injection. Although the optimal number, dose, and type of corticosteroid injections in the treatment of CTS have not been established, we have the clinical impression that 2 injections work better than 1, without adverse effects.
The role of the dose and potency of the corticosteroid also remains unclear. Although a randomized study in the treatment of CTS (3) showed that injections of 25 mg of hydrocortisone were as effective as higher doses of long-acting triamcinolone at 6-week and 6-month follow-up, studies with longer follow-up are not available. These observations taken together suggest that the relief caused by corticosteroid injections is limited in time. Unfortunately, factors conditioning a more long-lasting effect have not been fully elucidated. Another element that may further complicate comparisons among different trials is the heterogeneous features of enrolled patients. Those recruited from primary care units differ from those seen in a surgery or neurology clinic. We absolutely agree with Atroshi and colleagues’ statement that “[f]uture research should explore how to obtain a consistent durable effect. The goal is to find a medical treatment that effectively resolves CTS without the need to divide the transverse carpal ligament.” Jose´ Luis Andreu, MD, PhD Domingo Ly-Pen, MD, PhD Hospital Universitario Puerta de Hierro Majadahonda Madrid, Spain Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1074. References 1. Atroshi I, Flondell M, Hofer M, Ranstam J. Methylprednisolone injections for the carpal tunnel syndrome: a randomized, placebo-controlled trial. Ann Intern Med. 2013;159:309-17. [PMID: 24026316] 2. Ly-Pen D, Andre´u JL, de Blas G, Sa´nchez-Olaso A, Milla´n I. Surgical decompression versus local steroid injection in carpal tunnel syndrome: a one-year, prospective, randomized, open, controlled clinical trial. Arthritis Rheum. 2005;52:612-9. [PMID: 15692981] 3. O’Gradaigh D, Merry P. Corticosteroid injection for the treatment of carpal tunnel syndrome. Ann Rheum Dis. 2000;59:918-9. [PMID: 11053073]
IN RESPONSE: We appreciate the interest in our randomized,
double-blind, placebo-controlled trial that assessed the efficacy of a single injection of methylprednisolone in patients with CTS not previously treated with steroid injections. Dr. Ramirez-Lafita refers to findings derived from observational studies and 1 randomized, surgery-controlled study. As we highlighted in our article, the Cochrane review of “randomized or quasi-randomized studies” published up to May 2006 that aimed to “evaluate the effectiveness of local corticosteroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions” concluded that “local corticosteroid injection for carpal tunnel syndrome provides greater clinical improvement in symptoms one month after injection compared to placebo,” “significant symptom relief beyond one month has not been demonstrated,” and “two local corticosteroid injections do not provide significant added clinical benefit compared to one injection” (1). We are not aware of any subsequently published studies (involving any type of corticosteroid) that fulfill the review’s criteria of trial quality before our trial that may have changed these conclusions. Our study provides evidence of large effectiveness of methylprednisolone compared with placebo with regard to symptom and function improvement up to 10 weeks and a modest lower need for
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Letters surgery up to 1 year. Our trial did not consider the possible efficacy of repeated steroid injections. The severity of CTS can be based on physical examination findings about thenar muscle strength and finger sensation; results of median nerve conduction tests; or symptom severity measured with validated, patient-reported measures, such as the CTS symptom severity scale. As we described in our study, patients with thenar atrophy and severe sensory deficit were not eligible for inclusion. The prespecified subgroup analysis showed that patients with higher nerve conduction abnormality and higher (worse) CTS symptom severity scores at baseline improved more after a single first-time methylprednisolone injection than patients with lower median nerve conduction abnormality and lower symptom severity scores. The mean pretreatment CTS symptom severity score does not indicate a patient population with predominantly severe CTS. Thus, our results do not support the hypothesis that a steroid injection is more effective in patients with less severe CTS. Ideally, this question should be addressed in a randomized, blinded, placebo-controlled trial with the primary outcome being the response difference according to baseline severity of CTS.
biome might be one of the most important contributors to this association (2, 5). Therefore, administration of broad-spectrum antibiotics and duration of therapy should be judicious, because obese patients might be at increased risk for C. difficile colitis. Tsai and Wadden mention the association between increased body weight and severity of influenza. In a Canadian cohort study over 12 influenza seasons, severe obesity was an independent risk factor for respiratory hospitalizations (3). Even in the absence of comorbid conditions, patients with a body mass index greater than 35 kg/m2 should be approached as a high-risk group, with an emphasis on yearly immunization. Furthermore, empirical administration of oseltamivir should be strongly considered for obese patients, as early as possible in the course of respiratory tract infections, during influenza season (3, 4). Primary care providers should be aware of and consider counseling their obese patients about the increased risk for serious infections. Such information could serve as an additional motive for weight loss. Dimitrios Farmakiotis, MD Baylor College of Medicine Houston, Texas
Isam Atroshi, MD, PhD Jonas Ranstam, PhD Lund University Lund, Sweden
Potential Conflicts of Interest: None disclosed. Forms can be viewed at
Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M12 -3068.
References
Reference 1. Marshall S, Tardif G, Ashworth N. Local corticosteroid injection for carpal tunnel syndrome. Cochrane Database Syst Rev. 2007:CD001554. [PMID: 17443508]
Obesity and Serious Infections TO THE EDITOR: In their recent In the Clinic, Tsai and Wadden (1)
include increased susceptibility to influenza, as well as skin and soft tissue infections, in their comprehensive list of obesity-associated health consequences. I would like to highlight some additional issues of potential clinical significance about the well-described but often underrecognized association between obesity and infection (2). In several studies, obesity has been identified as an important risk factor for higher incidence of and worse outcomes from surgical wound, respiratory, periodontal, and urinary tract infections (2– 4). Those associations are definitely influenced by comorbid conditions and management pitfalls that occur more frequently in obese persons, such as mobility problems and imaging difficulties. However, substantial evidence links excess adiposity with immune system dysfunction, specifically phagocytosis and cytokine production, as well as a decrease in T cells and T-cell activation (2). Thus, prompt initiation of appropriate antibacterials when infection is clinically suspected is paramount in this population to prevent hospitalization and unfavorable outcomes. Nevertheless, findings from a recent report (5) suggest that obesity is also independently associated with a higher risk for Clostridium difficile infection. The exact underlying mechanisms remain to be investigated, but adiposity-related changes in the intestinal microwww.annals.org
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1075.
1. Tsai AG, Wadden TA. In the clinic: obesity. Ann Intern Med. 2013;159:ITC3-1ITC3-15. [PMID: 24026335] 2. Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis. 2006;6:438-46. [PMID: 16790384] 3. Kwong JC, Campitelli MA, Rosella LC. Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study. Clin Infect Dis. 2011; 53:413-21. [PMID: 21844024] 4. Almond MH, Edwards MR, Barclay WS, Johnston SL. Obesity and susceptibility to severe outcomes following respiratory viral infection. Thorax. 2013;68:684-6. [PMID: 23436045] 5. Bishara J, Farah R, Mograbi J, Khalaila W, Abu-Elheja O, Mahamid M, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis. 2013;57:48993. [PMID: 23645850]
IN RESPONSE: Dr. Farmakiotis’s thoughtful letter reminds us about other infectious consequences of obesity, particularly moderate to severe obesity (body mass index ⱖ35 kg/m2), that should concern internal medicine physicians. As with other body systems, physical factors (immobility) and biochemical factors (impaired function of the immune system) increase the risk for these complications.
Adam Gilden Tsai, MD, MSCE University of Colorado School of Medicine Aurora, Colorado Thomas A. Wadden, PhD Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1083. 17 December 2013 Annals of Internal Medicine Volume 159 • Number 12 859
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AND
Annals of Internal Medicine RESPONSES
Vitamin D and Calcium Supplementation to Prevent Fractures in Adults TO THE EDITOR: The guideline from the U.S. Preventive Services Task Force (USPSTF) (1) concludes that the current evidence about calcium and vitamin D supplementation to prevent fractures in adults is essentially insufficient. This statement may be partly based on the limited efficacy of calcium and vitamin D supplementation in preventing fractures from skeletal adaptation to mechanical loading, although vitamin D promotes calcium absorption in the gut and supports bone mineralization that is essential for skeletal stiffness. Bone responds to the local mechanical environment at each skeletal site, as evidenced by marked bone gain in the dominant arms of professional tennis players or rapid bone loss in the weight-bearing sites of astronauts during space flight; it has been considered that the skeleton adapts to mechanical stimulation through control of bone strength by resulting elastic deformation (strain) of bone. This feedback control system related to mechanical strain is known as the Harold Frost mechanostat. Recent experimental data in the adult skeleton (2– 4) suggest that control of trabecular and cortical bone related to mechanical strain acts continuously throughout the physiologic range; thus, even slightly increased or decreased bone strain induces site-specific bone gain or loss, respectively, to maintain the strain level. This concept is compatible with clinical reports in adults that high-impact, but not low-impact, exercise results in bone gain (5) because additional mechanical loading (by exercise) will not stimulate bone when the stimulus does not exceed that already derived from existing mechanical loading (by habitual physical activity). Regardless of suppressing bone resorption or promoting bone formation, or increasing bone quantity or quality, an increase in bone strength by nutrients or drugs would decrease bone strain from mechanical stimuli. The mechanostat based on the latest evidence (2– 4) suggests that the decreased bone strain causes the negative feedback of a control system related to mechanical strain. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by the natural homeostatic system in the skeleton. This hypothesis is consistent with rapid resolution of the effects of most osteoporosis drugs except bisphosphonates that bind to bone mineral and could partly explain the limited effect of calcium plus vitamin D supplementation on fracture prevention.
Toshihiro Sugiyama, MD, PhD Yamaguchi University School of Medicine Yamaguchi, Japan
3. Ellman R, Spatz J, Cloutier A, Palme R, Christiansen BA, Bouxsein ML. Partial reductions in mechanical loading yield proportional changes in bone density, bone architecture, and muscle mass. J Bone Miner Res. 2013;28:875-85. [PMID: 23165526] 4. Schulte FA, Ruffoni D, Lambers FM, Christen D, Webster DJ, Kuhn G, et al. Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. PLoS One. 2013;8:e62172. [PMID: 23637993] 5. Vainionpa¨a¨ A, Korpelainen R, Vihria¨la¨ E, Rinta-Paavola A, Leppa¨luoto J, Ja¨msa¨ T. Intensity of exercise is associated with bone density change in premenopausal women. Osteoporos Int. 2006;17:455-63. [PMID: 16404492]
TO THE EDITOR: I read the USPSTF’s guideline (1) with great
interest. Both the Institute of Medicine report (2) cited in the editorial (3) and the WHI (Women’s Health Initiative) study noted in the guideline as the largest trial of fracture outcomes reported that many persons in the United States are already receiving supplements. Thus, the conclusions refer to persons already having vitamin D and calcium intake at or close to the recommended daily allowance of each, often because they are receiving supplements. Furthermore, the WHI study used the statistical significance value for the intentionto-treat analysis. I recognize the issue of selective withdrawal during a trial so that the groups at the end may not be as comparable as they were at the beginning. In the WHI study, only 59% of the treated participants were receiving the prescribed dose of vitamin D and calcium. As a pharmacologist, I know that if I want to learn a drug’s effects, I have to give the drug and not just intend to do so. One must be cautious in assuming that lack of statistically significant evidence, especially with intention-to-treat analysis with many withdrawals, is evidence of lack of effect. Marcus M. Reidenberg, MD Weill Cornell Medical College New York, New York Potential Conflicts of Interest: Board membership: Aminopterin; Patents
(planned, pending, or issued): National Institutes of Health; Royalties: National Institutes of Health; Stock/stock options: Ascenta; Travel/accommodations/meeting expenses unrelated to activities listed: United States Pharmacopoeia, U.S. Food and Drug Administration Expert Committee. References 1. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158:691-6. [PMID: 23440163] 2. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Pr; 2011. Accessed at www.iom.edu/Reports /2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx on 27 September 2013. 3. Nestle M, Nesheim MC. To supplement or not to supplement: the U.S. Preventive Services Task Force recommendations on calcium and vitamin D [Editorial]. Ann Intern Med. 2013;158:701-2. [PMID: 23440174]
Potential Conflicts of Interest: None disclosed. References 1. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158:691-6. [PMID: 23440163] 2. Sugiyama T, Meakin LB, Browne WJ, Galea GL, Price JS, Lanyon LE. Bones’ adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. J Bone Miner Res. 2012;27:1784-93. [PMID: 22431329]
IN RESPONSE: The USPSTF anticipated the challenges and honest scientific disagreements on the use of vitamin D and calcium supplementation to prevent fractures. Dr. Sugiyama’s suggestion that mechanical effects play a substantial role in bone strength and quality—and therefore in risk for fractures, regardless of or despite supplement use—is an important observation. The Task Force agrees that more research is needed. Dr. Reidenberg highlights the challenges of drawing conclusions from the WHI study and other randomized, controlled trials of vi-
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Letters tamin D and calcium. As he mentions, the standard technique for studying the effectiveness of an intervention is intention-to-treat analysis to avoid bias due to asymmetrical withdrawal from the trial. The Task Force concurs that statistical significance differs from clinical significance, and it is important to understand the meaning of the results. The challenges of determining the effectiveness of nutritional supplements is a broader issue that the field will need to address. The USPSTF relied on 2 systematic reviews and an updated meta-analysis (1–3) to guide development of its recommendation; these are cited in the recommendation statement. In addition, the Task Force considered several other reviews and meta-analyses, including the DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) study (4) and a more recent patient-level metaanalysis by Bischoff-Ferrari and colleagues (5). The Task Force’s systematic review included many of the same studies as DIPART (4) and Tang and associates (6) but excluded others that did not meet inclusion criteria. The 6 trials of vitamin D and calcium that were considered by the Task Force in its final recommendation statement were of fair to good quality and were conducted in community-dwelling adults for the primary prevention of fractures. The large number of studies on vitamin D and calcium supplements would lead one to believe that the question of whether these supplements are effective in preventing fractures should be resolved. However, the body of evidence in this area is exceedingly heterogeneous; therefore, the Task Force used particular caution when drawing conclusions about the population encompassed within its scope, which is asymptomatic, community-dwelling adults. The negative results of the WHI study (without adjusting for outside supplement use, as Dr. Reidenberg noted) clearly show that lower doses of vitamin D and calcium have no effect. Whether an effect is present at higher doses remains uncertain from the Task Force’s perspective. We agree that it can be difficult for the public to understand the nuance of the recommendation, but we are confident that the recommendation is based on a well-done and comprehensive review of the evidence. Virginia A. Moyer, MD, MPH Michael L. LeFevre, MD, MSPH Albert L. Siu, MD, MSPH U.S. Preventive Services Task Force Rockville, Maryland Potential Conflicts of Interest: Disclosure forms from USPSTF mem-
bers can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum⫽M13-0215. References 1. Cranney A, Horsley T, O’Donnell S, Weiler H, Puil L, Ooi D, et al. Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment no. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed at www.ncbi.nlm.nih.gov/books/NBK38410/ on 31 May 2012. 2. Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report/Technology Assessment no. 183. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK32603/ on 31 May 2012. 3. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:82738. [PMID: 22184690] www.annals.org
4. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010;340:b5463. [PMID: 20068257] 5. Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-9. [PMID: 22762317] 6. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370:657-66. [PMID: 17720017]
Lack of Transparency in Emergency Care TO THE EDITOR: I read Kocher and Emanuel’s article (1) with great interest. The discussions of making medical prices and quality measures public to decrease the cost and increase the quality of medical care assumes that the patient can choose where to get care. Friends, relatives, or first responders usually take acutely ill or injured persons to the nearest emergency department. The patient has no choice. This limitation of transparency as a solution to some of our cost and quality problems should not be ignored.
Marcus M. Reidenberg, MD Weill Cornell Medical College New York, New York Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽L13 -1064. Reference 1. Kocher RP, Emanuel EJ. The transparency imperative. Ann Intern Med. 2013;159: 296-7. [PMID: 23712392]
Methylprednisolone Injections for the Carpal Tunnel Syndrome TO THE EDITOR: Atroshi and colleagues’ study (1) shows temporary
but nonpersistent relief of the carpal tunnel syndrome (CTS) after local methylprednisolone injections. In fact, after week 36, the number of patients treated with methylprednisolone injections who had surgery increased (between 73% and 81% at the end of the first year). Moreover, secondary end points (such as the short Disabilities of the Arm, Shoulder and Hand score; Short Form-36 Health Survey bodily pain score; and Short Form-6D score) and treatment satisfaction showed no differences between methylprednisolone and placebo after 10 weeks of corticosteroid injections. Recent studies have found different outcomes. A study (2) comparing local corticosteroid injections with surgical decompression showed that both treatments effectively alleviated symptoms at 2-year follow-up: 60% of patients who received corticosteroid injections versus 69% of patients who had surgery showed a 20% decrease in nocturnal paresthesia. In another study (3), steroid injection was found to be a better treatment in carefully selected patients than in Atroshi and colleagues’ study. The level of surgical decompression was 15% at 1-year follow-up and 33% at 5-year follow-up. That study concluded that women, patients with diabetes, and patients with neurophysiologic confirmation at diagnosis had a higher risk for relapse after local corticosteroid injections. 17 December 2013 Annals of Internal Medicine Volume 159 • Number 12 857
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Letters Another study (4) showed that electromyographic severity of CTS was an important prognostic factor for the long-term effect of local corticosteroid injections. Patients with mild CTS on electromyography responded even better to local corticosteroid injections. A study (5) added ultrasonography to the work-up of patients with CTS. It found that those with less-pronounced median nerve swelling on ultrasonography responded better to corticosteroid injections. In Atroshi and colleagues’ study, more than 80% of patients had severe or moderate results on nerve conduction testing at baseline. This finding could explain the poor response to corticosteroid injections in the first year in accordance with other studies reviewed. It would be interesting to investigate the degree of nerve involvement before local corticosteroid injections. Nerve conduction or ultrasonography may be good predictors of response to nonsurgical treatments. Francisco Ramirez-Lafita, MD, PhD Viamed Monegal Hospital Tarragona, Spain Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1073. References 1. Atroshi I, Flondell M, Hofer M, Ranstam J. Methylprednisolone injections for the carpal tunnel syndrome: a randomized, placebo-controlled trial. Ann Intern Med. 2013;159:309-17. [PMID: 24026316] 2. Ly-Pen D, Andre´u JL, Milla´n I, de Blas G, Sa´nchez-Olaso A. Comparison of surgical decompression and local steroid injection in the treatment of carpal tunnel syndrome: 2-year clinical results from a randomized trial. Rheumatology (Oxford). 2012;51:1447-54. [PMID: 22467087] 3. Jenkins PJ, Duckworth AD, Watts AC, McEachan JE. Corticosteroid injection for carpal tunnel syndrome: a 5-year survivorship analysis. Hand (N Y). 2012;7:151-6. [PMID: 23730233] 4. Visser LH, Ngo Q, Groeneweg SJ, Brekelmans G. Long term effect of local corticosteroid injection for carpal tunnel syndrome: a relation with electrodiagnostic severity. Clin Neurophysiol. 2012;123:838-41. [PMID: 21962473] 5. Meys V, Thissen S, Rozeman S, Beekman R. Prognostic factors in carpal tunnel syndrome treated with a corticosteroid injection. Muscle Nerve. 2011;44:763-8. [PMID: 21953020]
TO THE EDITOR: We read Atroshi and colleagues’ article (1) with great interest. This placebo-controlled trial shows that injections in CTS are useful and safe, at least in the short term. Symptoms of CTS in patients who received corticosteroid injections improved significantly more than those in patients who received placebo, and corticosteroid recipients had no relevant adverse effects. We were surprised at how frequently surgery was required at 1-year follow-up, with 73% of the 80-mg methylprednisolone group versus 92% of the placebo group needing wrist surgery. In our study comparing corticosteroid injections with surgery (2), only 15% of participants who received wrist injections needed additional treatment after 1-year follow-up. Perhaps this discrepancy depends on the corticosteroid preparation used (we used 20 mg in 1 mL of paramethasone acetonide) and on our protocol permitting 2 injections 2 weeks apart in case patients did not fully recover after the first injection. Although the optimal number, dose, and type of corticosteroid injections in the treatment of CTS have not been established, we have the clinical impression that 2 injections work better than 1, without adverse effects.
The role of the dose and potency of the corticosteroid also remains unclear. Although a randomized study in the treatment of CTS (3) showed that injections of 25 mg of hydrocortisone were as effective as higher doses of long-acting triamcinolone at 6-week and 6-month follow-up, studies with longer follow-up are not available. These observations taken together suggest that the relief caused by corticosteroid injections is limited in time. Unfortunately, factors conditioning a more long-lasting effect have not been fully elucidated. Another element that may further complicate comparisons among different trials is the heterogeneous features of enrolled patients. Those recruited from primary care units differ from those seen in a surgery or neurology clinic. We absolutely agree with Atroshi and colleagues’ statement that “[f]uture research should explore how to obtain a consistent durable effect. The goal is to find a medical treatment that effectively resolves CTS without the need to divide the transverse carpal ligament.” Jose´ Luis Andreu, MD, PhD Domingo Ly-Pen, MD, PhD Hospital Universitario Puerta de Hierro Majadahonda Madrid, Spain Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1074. References 1. Atroshi I, Flondell M, Hofer M, Ranstam J. Methylprednisolone injections for the carpal tunnel syndrome: a randomized, placebo-controlled trial. Ann Intern Med. 2013;159:309-17. [PMID: 24026316] 2. Ly-Pen D, Andre´u JL, de Blas G, Sa´nchez-Olaso A, Milla´n I. Surgical decompression versus local steroid injection in carpal tunnel syndrome: a one-year, prospective, randomized, open, controlled clinical trial. Arthritis Rheum. 2005;52:612-9. [PMID: 15692981] 3. O’Gradaigh D, Merry P. Corticosteroid injection for the treatment of carpal tunnel syndrome. Ann Rheum Dis. 2000;59:918-9. [PMID: 11053073]
IN RESPONSE: We appreciate the interest in our randomized,
double-blind, placebo-controlled trial that assessed the efficacy of a single injection of methylprednisolone in patients with CTS not previously treated with steroid injections. Dr. Ramirez-Lafita refers to findings derived from observational studies and 1 randomized, surgery-controlled study. As we highlighted in our article, the Cochrane review of “randomized or quasi-randomized studies” published up to May 2006 that aimed to “evaluate the effectiveness of local corticosteroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions” concluded that “local corticosteroid injection for carpal tunnel syndrome provides greater clinical improvement in symptoms one month after injection compared to placebo,” “significant symptom relief beyond one month has not been demonstrated,” and “two local corticosteroid injections do not provide significant added clinical benefit compared to one injection” (1). We are not aware of any subsequently published studies (involving any type of corticosteroid) that fulfill the review’s criteria of trial quality before our trial that may have changed these conclusions. Our study provides evidence of large effectiveness of methylprednisolone compared with placebo with regard to symptom and function improvement up to 10 weeks and a modest lower need for
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Letters surgery up to 1 year. Our trial did not consider the possible efficacy of repeated steroid injections. The severity of CTS can be based on physical examination findings about thenar muscle strength and finger sensation; results of median nerve conduction tests; or symptom severity measured with validated, patient-reported measures, such as the CTS symptom severity scale. As we described in our study, patients with thenar atrophy and severe sensory deficit were not eligible for inclusion. The prespecified subgroup analysis showed that patients with higher nerve conduction abnormality and higher (worse) CTS symptom severity scores at baseline improved more after a single first-time methylprednisolone injection than patients with lower median nerve conduction abnormality and lower symptom severity scores. The mean pretreatment CTS symptom severity score does not indicate a patient population with predominantly severe CTS. Thus, our results do not support the hypothesis that a steroid injection is more effective in patients with less severe CTS. Ideally, this question should be addressed in a randomized, blinded, placebo-controlled trial with the primary outcome being the response difference according to baseline severity of CTS.
biome might be one of the most important contributors to this association (2, 5). Therefore, administration of broad-spectrum antibiotics and duration of therapy should be judicious, because obese patients might be at increased risk for C. difficile colitis. Tsai and Wadden mention the association between increased body weight and severity of influenza. In a Canadian cohort study over 12 influenza seasons, severe obesity was an independent risk factor for respiratory hospitalizations (3). Even in the absence of comorbid conditions, patients with a body mass index greater than 35 kg/m2 should be approached as a high-risk group, with an emphasis on yearly immunization. Furthermore, empirical administration of oseltamivir should be strongly considered for obese patients, as early as possible in the course of respiratory tract infections, during influenza season (3, 4). Primary care providers should be aware of and consider counseling their obese patients about the increased risk for serious infections. Such information could serve as an additional motive for weight loss. Dimitrios Farmakiotis, MD Baylor College of Medicine Houston, Texas
Isam Atroshi, MD, PhD Jonas Ranstam, PhD Lund University Lund, Sweden
Potential Conflicts of Interest: None disclosed. Forms can be viewed at
Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M12 -3068.
References
Reference 1. Marshall S, Tardif G, Ashworth N. Local corticosteroid injection for carpal tunnel syndrome. Cochrane Database Syst Rev. 2007:CD001554. [PMID: 17443508]
Obesity and Serious Infections TO THE EDITOR: In their recent In the Clinic, Tsai and Wadden (1)
include increased susceptibility to influenza, as well as skin and soft tissue infections, in their comprehensive list of obesity-associated health consequences. I would like to highlight some additional issues of potential clinical significance about the well-described but often underrecognized association between obesity and infection (2). In several studies, obesity has been identified as an important risk factor for higher incidence of and worse outcomes from surgical wound, respiratory, periodontal, and urinary tract infections (2– 4). Those associations are definitely influenced by comorbid conditions and management pitfalls that occur more frequently in obese persons, such as mobility problems and imaging difficulties. However, substantial evidence links excess adiposity with immune system dysfunction, specifically phagocytosis and cytokine production, as well as a decrease in T cells and T-cell activation (2). Thus, prompt initiation of appropriate antibacterials when infection is clinically suspected is paramount in this population to prevent hospitalization and unfavorable outcomes. Nevertheless, findings from a recent report (5) suggest that obesity is also independently associated with a higher risk for Clostridium difficile infection. The exact underlying mechanisms remain to be investigated, but adiposity-related changes in the intestinal microwww.annals.org
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1075.
1. Tsai AG, Wadden TA. In the clinic: obesity. Ann Intern Med. 2013;159:ITC3-1ITC3-15. [PMID: 24026335] 2. Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis. 2006;6:438-46. [PMID: 16790384] 3. Kwong JC, Campitelli MA, Rosella LC. Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study. Clin Infect Dis. 2011; 53:413-21. [PMID: 21844024] 4. Almond MH, Edwards MR, Barclay WS, Johnston SL. Obesity and susceptibility to severe outcomes following respiratory viral infection. Thorax. 2013;68:684-6. [PMID: 23436045] 5. Bishara J, Farah R, Mograbi J, Khalaila W, Abu-Elheja O, Mahamid M, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis. 2013;57:48993. [PMID: 23645850]
IN RESPONSE: Dr. Farmakiotis’s thoughtful letter reminds us about other infectious consequences of obesity, particularly moderate to severe obesity (body mass index ⱖ35 kg/m2), that should concern internal medicine physicians. As with other body systems, physical factors (immobility) and biochemical factors (impaired function of the immune system) increase the risk for these complications.
Adam Gilden Tsai, MD, MSCE University of Colorado School of Medicine Aurora, Colorado Thomas A. Wadden, PhD Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1083. 17 December 2013 Annals of Internal Medicine Volume 159 • Number 12 859
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