correspondence
More on Pulmonary Fibrosis Associated with Aluminum Trihydrate (Corian) Dust To the Editor: Raghu et al. (May 29 issue)1 reported a case of pulmonary fibrosis in the context of possible aluminum exposure due to sanding of Corian material. Findings in the lung tissue included both aluminum trihydrate and aluminum oxide. The authors cite the article by Jederlinic et al.2 in support of causation, but this at best shows only analogy, because aluminum trihydrate and aluminum oxide are distinct compounds. Aluminum oxide is a component of sandpaper; with the patient’s history of sanding Corian, it is difficult to determine whether the pulmonary fibrosis is due to the aluminum trihydrate in Corian, the aluminum oxide in sandpaper, or another, unknown environmental exposure. From a toxicologic perspective of chronic aluminum exposure, relevant details of the patient’s disease course are unreported. There is no mention of pertinent positive or negative findings associated with chronic aluminum toxicity such as potroom asthma, osteomalacia, hypochromic microcytic anemia, or encephalopathy.3 The authors prove an exposure pathway but fail to identify the source. Rita McKeever, M.D. Jolene Okaneku, M.D. Gregory S. LaSala, M.D. Drexel University College of Medicine Philadelphia, PA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Raghu G, Collins BF, Xia D, Schmidt R, Abraham JL. Pulmo-
nary fibrosis associated with aluminum trihydrate (Corian) dust. N Engl J Med 2014;370:2154-6. 2. Jederlinic PJ, Abraham JL, Churg A, Himmelstein JS, Epler GR, Gaensler EA. Pulmonary fibrosis in aluminum oxide workers: investigation of nine workers, with pathologic examination and microanalysis in three of them. Am Rev Respir Dis 1990;142: 1179-84. 3. Krewski D, Yokel RA, Nieboer E, et al. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 2007;10:Suppl 1: 1-269. [Erratum, J Toxicol Environ Health B Crit Rev 2008;11:147.] DOI: 10.1056/NEJMc1407658
The authors reply: McKeever et al. and Gannon and Rickard (DuPont, the manufacturer of Corian)1 raise important points. The patient confirmed his
exposures to dust from Corian and sandpaper that he used at his workplace and had no history of other exposures; the settled dust samples contained distinct particles comprised of aluminum trihydrate and methyl methacrylate (matching reference Corian) and aluminum oxide and cellulose (matching reference sandpaper). Both aluminum trihydrate and aluminum oxide were detected in his lungs (methyl methacrylate dissolves during routine processing for histologic examination). Aluminum exposure is among the metal exposures reported as significantly associated with pulmonary fibrosis.2 The patient did not have any of the medical problems suggestive of systemic aluminum toxicity. In addition, we found no substantial silica, aluminum silicates, or metals other than aluminum in his lungs. In 2004, the patient and the last author independently contacted DuPont but received no assistance. The DuPont material safety data sheet for Corian3 does not mention aluminum trihydrate, the major constituent, but advises avoiding dust from grinding and sanding (which would not always be solely from Corian). We agree that the best way to investigate specific causality is to perform an independent epidemiologic study of persons working with Corian in the manufacturing and fabrication operations, as well as relevant inhalation toxicologic analysis. Awareness of pulmonary fibrosis associated with environmental factors and preventive measures to decrease or eliminate such exposures are essential. Ganesh Raghu, M.D. University of Washington Center for Interstitial Lung Diseases Seattle, WA [email protected]
Daniel Xia, M.D. Beth Israel Deaconess Medical Center Boston, MA
Jerrold L. Abraham, M.D. State University of New York Upstate Medical University Syracuse, NY Since publication of their letter, the authors report no further potential conflict of interest. 1. Gannon P, Rickard RW. Pulmonary fibrosis associated with
aluminum trihydrate (Corian) dust — DuPont, the manufacturer of Corian, replies. N Engl J Med 2014;370:2156-7.
n engl j med 371;10 nejm.org september 4, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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The
n e w e ng l a n d j o u r na l
2. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an
environmental disease? Proc Am Thorac Soc 2006;3:293-8. 3. Du Pont. Material safety data sheet: Corian solid surface material (http://www2.dupont.com/Surfaces_Commercial/en_US/
of
m e dic i n e
assets/downloads/pdfs/Corian_Technical_Bulletins/COR001_ CORIAN_MSDS.pdf ). DOI: 10.1056/NEJMc1407658
Risk of Atypical Femoral Fracture during and after Bisphosphonate Use To the Editor: Bisphosphonates prevent clinical fractures in women younger than 80 years of age with documented osteoporosis, according to efficacy trials.1,2 However, adverse events related to these agents may affect all patients, including those in groups in which the benefit of these drugs is less well established. We previously found a strong association between bisphosphonate use and atypical fractures in Swedish women.3 That study of data from 2008 has now been extended to include the period of 2008 through 2010 to investigate the association of potential adverse events with sex, type of bisphosphonate, and timing of use. We reviewed radiographs of 5342 women and men (97% of eligible patients) 55 years of age or older, with a femoral shaft fracture, and found 172 patients with an atypical fracture (according to the American Society for Bone and Mineral Research criteria).4,5 Registry data on medication use since July 2005 and information about coexisting conditions were obtained.3 Nationwide cohort and case–control analyses were performed as described previously.3 However, patients receiving bisphosphonates before October 2005 were defined as longtime users and were excluded from the case–control analysis of current use. In the cohort analysis, the age-adjusted relative risk of an atypical fracture with bisphosphonate use was 55.2 (95% confidence interval [CI], 38.8 to 78.7) among women and 54.1 (95% CI, 15.2 to 192.3) among men. Nevertheless, the absolute risk was three times as high among women as among men; among bisphosphonate users, women as compared with men had a relative risk of 3.1 (95% CI, 1.1 to 8.4). As compared with risedronate users, alendronate users had a relative risk of 1.9 (95% CI, 1.1 to 3.3), which might be related to a higher antiresorptive effect of alendronate with recommended doses. The risk of atypical fracture among women increased progressively with the duration of use, and the relative risk
974
after at least 4 years reached 126.0 (95% CI, 55.1 to 288.1), with an annual absolute risk of 11 fractures (95% CI, 7 to 14) per 10,000 person-years of use. In the case–control analysis, short-term use conferred an increased risk of atypical fracture (Table 1). The multivariable-adjusted odds ratio with 4 to 5 years of current use was 100 times as high as that with nonuse. For each year since the last use, the risk was 70% less. In the multivariable-adjusted analysis, women as compared with men had a risk of atypical fracture of 3.6 (95% CI, 2.5 to 5.3). Bisphosphonate users also commonly used glucocorticoids and proton-pump inhibitors, but these uses did not modify the risk of atypical fracture. There is long-lasting skeletal accumulation of bisphosphonate, but ongoing use seems to be the dominant risk factor for these rare fractures. Oral bisphosphonates might do more harm than good if given to patients without an evidencebased indication, and the evidence base for treatment over many years is weak. Jörg Schilcher, M.D., Ph.D. Veronika Koeppen, M.D. Per Aspenberg, M.D., Ph.D. Linköping University Linköping, Sweden [email protected]
Karl Michaëlsson, M.D., Ph.D. Uppsala University Uppsala, Sweden Drs. Aspenberg and Michaëlsson contributed equally to this letter. Supported by a grant (VR 2009-6725) from the Swedish Research Council and by Linköping University, Östergötland County Council, and the King Gustaf V and Queen Victoria Free Mason Foundation. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. MacLean C, Newberry S, Maglione M, et al. Systematic re-
view: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197-213.
n engl j med 371;10 nejm.org september 4, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
More on Pulmonary Fibrosis Associated with Aluminum Trihydrate (Corian) Dust To the Editor: Raghu et al. (May 29 issue)1 reported a case of pulmonary fibrosis in the context of possible aluminum exposure due to sanding of Corian material. Findings in the lung tissue included both aluminum trihydrate and aluminum oxide. The authors cite the article by Jederlinic et al.2 in support of causation, but this at best shows only analogy, because aluminum trihydrate and aluminum oxide are distinct compounds. Aluminum oxide is a component of sandpaper; with the patient’s history of sanding Corian, it is difficult to determine whether the pulmonary fibrosis is due to the aluminum trihydrate in Corian, the aluminum oxide in sandpaper, or another, unknown environmental exposure. From a toxicologic perspective of chronic aluminum exposure, relevant details of the patient’s disease course are unreported. There is no mention of pertinent positive or negative findings associated with chronic aluminum toxicity such as potroom asthma, osteomalacia, hypochromic microcytic anemia, or encephalopathy.3 The authors prove an exposure pathway but fail to identify the source. Rita McKeever, M.D. Jolene Okaneku, M.D. Gregory S. LaSala, M.D. Drexel University College of Medicine Philadelphia, PA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Raghu G, Collins BF, Xia D, Schmidt R, Abraham JL. Pulmo-
nary fibrosis associated with aluminum trihydrate (Corian) dust. N Engl J Med 2014;370:2154-6. 2. Jederlinic PJ, Abraham JL, Churg A, Himmelstein JS, Epler GR, Gaensler EA. Pulmonary fibrosis in aluminum oxide workers: investigation of nine workers, with pathologic examination and microanalysis in three of them. Am Rev Respir Dis 1990;142: 1179-84. 3. Krewski D, Yokel RA, Nieboer E, et al. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 2007;10:Suppl 1: 1-269. [Erratum, J Toxicol Environ Health B Crit Rev 2008;11:147.] DOI: 10.1056/NEJMc1407658
The authors reply: McKeever et al. and Gannon and Rickard (DuPont, the manufacturer of Corian)1 raise important points. The patient confirmed his
exposures to dust from Corian and sandpaper that he used at his workplace and had no history of other exposures; the settled dust samples contained distinct particles comprised of aluminum trihydrate and methyl methacrylate (matching reference Corian) and aluminum oxide and cellulose (matching reference sandpaper). Both aluminum trihydrate and aluminum oxide were detected in his lungs (methyl methacrylate dissolves during routine processing for histologic examination). Aluminum exposure is among the metal exposures reported as significantly associated with pulmonary fibrosis.2 The patient did not have any of the medical problems suggestive of systemic aluminum toxicity. In addition, we found no substantial silica, aluminum silicates, or metals other than aluminum in his lungs. In 2004, the patient and the last author independently contacted DuPont but received no assistance. The DuPont material safety data sheet for Corian3 does not mention aluminum trihydrate, the major constituent, but advises avoiding dust from grinding and sanding (which would not always be solely from Corian). We agree that the best way to investigate specific causality is to perform an independent epidemiologic study of persons working with Corian in the manufacturing and fabrication operations, as well as relevant inhalation toxicologic analysis. Awareness of pulmonary fibrosis associated with environmental factors and preventive measures to decrease or eliminate such exposures are essential. Ganesh Raghu, M.D. University of Washington Center for Interstitial Lung Diseases Seattle, WA [email protected]
Daniel Xia, M.D. Beth Israel Deaconess Medical Center Boston, MA
Jerrold L. Abraham, M.D. State University of New York Upstate Medical University Syracuse, NY Since publication of their letter, the authors report no further potential conflict of interest. 1. Gannon P, Rickard RW. Pulmonary fibrosis associated with
aluminum trihydrate (Corian) dust — DuPont, the manufacturer of Corian, replies. N Engl J Med 2014;370:2156-7.
n engl j med 371;10 nejm.org september 4, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
973
The
n e w e ng l a n d j o u r na l
2. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an
environmental disease? Proc Am Thorac Soc 2006;3:293-8. 3. Du Pont. Material safety data sheet: Corian solid surface material (http://www2.dupont.com/Surfaces_Commercial/en_US/
of
m e dic i n e
assets/downloads/pdfs/Corian_Technical_Bulletins/COR001_ CORIAN_MSDS.pdf ). DOI: 10.1056/NEJMc1407658
Risk of Atypical Femoral Fracture during and after Bisphosphonate Use To the Editor: Bisphosphonates prevent clinical fractures in women younger than 80 years of age with documented osteoporosis, according to efficacy trials.1,2 However, adverse events related to these agents may affect all patients, including those in groups in which the benefit of these drugs is less well established. We previously found a strong association between bisphosphonate use and atypical fractures in Swedish women.3 That study of data from 2008 has now been extended to include the period of 2008 through 2010 to investigate the association of potential adverse events with sex, type of bisphosphonate, and timing of use. We reviewed radiographs of 5342 women and men (97% of eligible patients) 55 years of age or older, with a femoral shaft fracture, and found 172 patients with an atypical fracture (according to the American Society for Bone and Mineral Research criteria).4,5 Registry data on medication use since July 2005 and information about coexisting conditions were obtained.3 Nationwide cohort and case–control analyses were performed as described previously.3 However, patients receiving bisphosphonates before October 2005 were defined as longtime users and were excluded from the case–control analysis of current use. In the cohort analysis, the age-adjusted relative risk of an atypical fracture with bisphosphonate use was 55.2 (95% confidence interval [CI], 38.8 to 78.7) among women and 54.1 (95% CI, 15.2 to 192.3) among men. Nevertheless, the absolute risk was three times as high among women as among men; among bisphosphonate users, women as compared with men had a relative risk of 3.1 (95% CI, 1.1 to 8.4). As compared with risedronate users, alendronate users had a relative risk of 1.9 (95% CI, 1.1 to 3.3), which might be related to a higher antiresorptive effect of alendronate with recommended doses. The risk of atypical fracture among women increased progressively with the duration of use, and the relative risk
974
after at least 4 years reached 126.0 (95% CI, 55.1 to 288.1), with an annual absolute risk of 11 fractures (95% CI, 7 to 14) per 10,000 person-years of use. In the case–control analysis, short-term use conferred an increased risk of atypical fracture (Table 1). The multivariable-adjusted odds ratio with 4 to 5 years of current use was 100 times as high as that with nonuse. For each year since the last use, the risk was 70% less. In the multivariable-adjusted analysis, women as compared with men had a risk of atypical fracture of 3.6 (95% CI, 2.5 to 5.3). Bisphosphonate users also commonly used glucocorticoids and proton-pump inhibitors, but these uses did not modify the risk of atypical fracture. There is long-lasting skeletal accumulation of bisphosphonate, but ongoing use seems to be the dominant risk factor for these rare fractures. Oral bisphosphonates might do more harm than good if given to patients without an evidencebased indication, and the evidence base for treatment over many years is weak. Jörg Schilcher, M.D., Ph.D. Veronika Koeppen, M.D. Per Aspenberg, M.D., Ph.D. Linköping University Linköping, Sweden [email protected]
Karl Michaëlsson, M.D., Ph.D. Uppsala University Uppsala, Sweden Drs. Aspenberg and Michaëlsson contributed equally to this letter. Supported by a grant (VR 2009-6725) from the Swedish Research Council and by Linköping University, Östergötland County Council, and the King Gustaf V and Queen Victoria Free Mason Foundation. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. MacLean C, Newberry S, Maglione M, et al. Systematic re-
view: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197-213.
n engl j med 371;10 nejm.org september 4, 2014
The New England Journal of Medicine Downloaded from nejm.org on September 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
