Utility of testing for monoclonal bands in serum of patients with susp
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《英国医生杂志》
1 Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark, 2 Department of Haematology, Odense University Hospital, 3 Department of Clinical Biochemistry, Odense University Hospital
Correspondence to: B Abrahamsen b.abrahamsen@dadlnet.dk
Objective To determine whether measuring monoclonal bands (M component) in serum should be part of the investigation of patients referred to osteoporosis clinics.
Design Retrospective, cross sectional, observational study.
Setting Referral centre for osteoporosis in a university hospital, Denmark.
Participants 799 people (685 women) aged 19 to 94 years newly referred with suspected osteoporosis.
Main outcome measures Proportion of patients fulfilling the Nordic Myeloma Study Group definition for target condition and proportion of patients with other important haematological conditions.
Results 4.9% (18 of 366) of patients with osteoporosis and 2.2% (9 of 408) of patients without osteoporosis had M component in serum (2 = 3.66, P = 0.04). Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%). The relative risk of multiple myeloma in patients presenting with osteoporosis was 75 (10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. 122 blood electrophoreses were carried out for each case of multiple myeloma diagnosed. All patients with multiple myeloma had a history of fragility fractures. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. Monoclonal gammopathy of undetermined significance was diagnosed in 13 (3.6%) participants with osteoporosis and in eight (2.0%) participants with normal bone mineral density or osteopenia.
Conclusions Patients presenting with osteoporosis should be tested for M component in serum, as 1 in 20 patients with newly diagnosed osteoporosis had multiple myeloma or monoclonal gammopathy of undetermined significance.
Osteoporosis is a common disease—a 50 year old white woman has a lifetime risk of 16% for hip fractures, 15% for forearm fractures, and 32% for vertebral fractures.1 About 20-40% of patients have a secondary cause of osteoporosis. The investigation of patients presenting with suspected osteoporosis differs between countries and between clinics within each country.
Compared with osteoporosis, multiple myeloma is a rare disease, yet vertebral fractures and pain are common to both. Multiple myeloma would be expected to be seen more often in osteoporosis clinics than in most other areas of medicine dealing with the care of elderly people. Moreover, monoclonal gammopathy of undetermined significance is a common disorder, with a similar age distribution to that of osteoporosis. The risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance is around 15% over 10 years.2
National guidelines in Denmark do not advocate the routine measurement of monoclonal bands (M component) in the serum or urine of patients presenting with osteoporosis. In the United States, the National Osteoporosis Foundation3 lists protein electrophoresis among tests that could be carried out in patients where a specific secondary, treatable cause of osteoporosis is being considered. The extent to which protein electrophoresis is used routinely is unknown. One survey in the United States found that three out of four bone specialists would refer men with hip fractures for protein electrophoresis.4 We determined the prevalence of multiple myeloma and monoclonal gammopathy of undetermined significance in unselected patients newly referred with osteoporosis to assess whether measurement of M component should form part of the investigation of patients with suspected osteoporosis.
Participants and methods
From March 1999 to March 2001, 1372 patients (1150 women) were referred to our clinic with suspected osteoporosis or osteopenia. The clinic receives all referrals of patients with risk factors for osteoporosis from general practitioners, hospitals, and specialists in a catchment area of 473 000 people. We retrospectively evaluated all first referrals from primary care (n = 799) consecutively by a diagnostic schedule, which included measurement of serum M component and dual energy x ray absorptiometry. The study population consisted of 114 men, mean (SD) age 61.5 (14.0) years (range 19.0 to 89.0 years), and 685 women, mean (SD) age 61.0 (12.0) years (range 20.0 to 94.0 years). Overall, 26% of the participants were aged over 70, 13% over 75, and 5% over 80.
Reference standard
Participants presenting with M component in serum underwent follow-up investigations, including bone marrow examination and skeletal x rays. Multiple myeloma was diagnosed according to the Nordic Myeloma Study Group definition.5 Briefly, the diagnosis was made on the basis of a monoclonal band in serum in excess of 30 g/l (IgG), 20 g/l (IgA), or any level of IgD or IgE monoclonal bands or a urine monoclonal band of kappa or lambda in excess of 1 g/24h. This must be accompanied by osteolytic bone lesions or by more than 10% plasma cells in bone marrow aspirates (or plasmacytosis in soft tissue or skeletal tissue biopsies). A diagnosis of multiple myeloma can be made in the presence of lower monoclonal band concentrations in serum or urine, however, if both osteolytic lesions and high plasma cell content of bone marrow aspirates are present.
Patients were considered to have monoclonal gammopathy of undetermined significance if malignant monoclonal gammopathies were excluded (multiple myeloma, Waldenstr?m's macroglobulinaemia, non-Hodgkin's lymphoma, or other lymphoproliferative disorders).
Test and statistical methods
The index test was for serum M component, assessed using cellulose acetate electrophoresis. This method is less sensitive than the more recent high resolution agarose gel electrophoresis. Urine tests were not carried out.
We calculated confidence intervals using the normal approximation to the binary distribution, and we compared proportions using 2 tests. Anaylses were carried out in SPSS version 10.0. We considered a significance level of 5% as important.
Results
Osteoporosis (T score less than -2.5)6 was diagnosed in 45% (n = 308) of the women and 55% (n = 63) of the men. Twenty five (3.1%) of the referred patients declined dual energy x ray absorptiometry. Thus serum M component was evaluated in 366 participants with osteoporosis detected by densitometry and 408 participants with normal bone mineral density or osteopenia. Overall, 30 participants (3.8%, figure) had a positive index test result. At subsequent visits, three patients with a positive index test result reported that they had a known haematological disorder and another two patients declined further examination. M component was present in 4.9% (n = 18) of patients with osteoporosis and 2.2% (n = 9) of patients without osteoporosis (2 = 3.66, P = 0.04; table 1). Although erythrocyte sedimentation rate was not routinely assessed, six of eight patients with M component had an erythrocyte sedimentation rate of 20 or lower.
Flow of participants through trial
Table 1 Prevalence of serum monoclonal bands (M component) in patients by age and bone mineral density status
Test results
Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%; table 2) but in no participants without osteoporosis. One patient with osteoporosis had a diagnosis of non-Hodgkin's lymphoma.
Table 2 Incidence of multiple myeloma in patients by age and bone mineral density status
We diagnosed monoclonal gammopathy of undetermined significance in 13 (3.6%; table 3) of the participants with osteoporosis and eight (2.0%) of the participants with normal bone mineral density or osteopenia. In patients with osteoporosis, we found no difference in bone mineral density or age (68.1 (10.4) v 65.8 (10.7); P = 0.42) between those with multiple myeloma or monoclonal gammopathy of undetermined significance and those with no M component in serum. The three patients with multiple myeloma had a history of fragility fractures, compared with 28% (95% confidence interval 5% to 70%) in patients with osteoporosis with coexisting monoclonal gammopathy of undetermined significance and 36% (30% to 43%) in patients with osteoporosis but no M component.
Table 3 Prevalence of monoclonal gammopathy of undetermined significance in patients by age and bone mineral density status
Estimation
Compared with the background population, the relative risk of multiple myeloma in patients presenting with osteoporosis in our clinic was 75 (95% confidence interval 10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. In practical terms, 122 blood electrophoreses would need to be carried out for each case of multiple myeloma diagnosed. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. In a large group of patients with multiple myeloma diagnosed at the Mayo clinic,7 20.0% had light chain disease and 2.8% had non-secretory myeloma. Given a similar distribution of multiple myeloma subtypes, our index test would have a sensitivity of 77% and a negative predictive value of 99.7%.
Discussion
Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989;149: 2445-8.
Gregersen H, Mellemkjaer L, Ibsen JS, Dahlerup JF, Thomassen L, Sorensen HT. The impact of M-component type and immunoglobulin concentration on the risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance. Haematologica 2001;86: 1172-9.
Dawson-Hughes B, Gold DT, Rodbard HW, Bonner F, Khosla S, Swift S. Physician's guide to prevention and treatment of osteoporosis. www.nof.org/physguide/diagnosis.htm (accessed 1 December 2004).
Colon-Emeric C, Yballe L, Sloane R, Pieper CF, Lyles KW. Expert physician recommendations and current practice patterns for evaluating and treating men with osteoporotic hip fracture. J Am Geriatr Soc 2000;48: 1261-3.
Nordic Myeloma Study Group. V?rdprogram for myelomatose. www.nordic-myeloma.org (accessed 1 December 2004).
The WHO study group on osteoporosis. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Geneva: WHO, 1994.
Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78: 21-33.
Cancer incidence in Denmark 1999. Copenhagen: National Board of Health, 2003.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996;335: 91-7.
Blade J, Munoz M, Fontanillas M, San Miguel J, Alcala A, Maldonado J, et al. Treatment of multiple myeloma in elderly people: long-term results in 178 patients. Age Ageing 1996;25: 357-61.
Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 1997;79: 1561-7.
Genvresse I, Lange C, Schanz J, Schweigert M, Harder H, Possinger K, et al. Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study. Anticancer Drugs 2001;12: 345-9.
Genvresse I, Wedding U, Bokemeyer C, Spath-Schwalbe E. . Onkologie 2001;24: 386-90.
Sim MF, Stone M, Johansen A, Ho P, Pettit RJ, Evans WD. An analysis of an open access general practitioner bone densitometry service. Int J Clin Pract 2004;58: 300-5.
Nelson DA, Molloy R, Kleerekoper M. Prevalence of osteoporosis in women referred for bone density testing: utility of multiple skeletal sites. J Clin Densitom 1998;1: 5-12.
Ben Sedrine W, Broers P, Devogelaer JP, Depresseux G, Kaufman JM, Goemaere S, et al. Interest of a prescreening questionnaire to reduce the cost of bone densitometry. Osteoporos Int 2002;13: 434-42.
Roux S, Bergot C, Fermand JP, Frija J, Brouet JC, Mariette X. Evaluation of bone mineral density and fat-lean distribution in patients with multiple myeloma in sustained remission. J Bone Miner Res 2003;18: 231-6.
Abildgaard N, Brixen K, Kristensen JE, Vejlgaard T, Charles P, Nielsen JL. Assessment of bone involvement in patients with multiple myeloma using bone densitometry. Eur J Haematol 1996;57: 370-6.
Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem Lab Med 2003;41: 68-73.
((Bo Abrahamsen, consultant1, Ivan Anderse)
Correspondence to: B Abrahamsen b.abrahamsen@dadlnet.dk
Objective To determine whether measuring monoclonal bands (M component) in serum should be part of the investigation of patients referred to osteoporosis clinics.
Design Retrospective, cross sectional, observational study.
Setting Referral centre for osteoporosis in a university hospital, Denmark.
Participants 799 people (685 women) aged 19 to 94 years newly referred with suspected osteoporosis.
Main outcome measures Proportion of patients fulfilling the Nordic Myeloma Study Group definition for target condition and proportion of patients with other important haematological conditions.
Results 4.9% (18 of 366) of patients with osteoporosis and 2.2% (9 of 408) of patients without osteoporosis had M component in serum (2 = 3.66, P = 0.04). Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%). The relative risk of multiple myeloma in patients presenting with osteoporosis was 75 (10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. 122 blood electrophoreses were carried out for each case of multiple myeloma diagnosed. All patients with multiple myeloma had a history of fragility fractures. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. Monoclonal gammopathy of undetermined significance was diagnosed in 13 (3.6%) participants with osteoporosis and in eight (2.0%) participants with normal bone mineral density or osteopenia.
Conclusions Patients presenting with osteoporosis should be tested for M component in serum, as 1 in 20 patients with newly diagnosed osteoporosis had multiple myeloma or monoclonal gammopathy of undetermined significance.
Osteoporosis is a common disease—a 50 year old white woman has a lifetime risk of 16% for hip fractures, 15% for forearm fractures, and 32% for vertebral fractures.1 About 20-40% of patients have a secondary cause of osteoporosis. The investigation of patients presenting with suspected osteoporosis differs between countries and between clinics within each country.
Compared with osteoporosis, multiple myeloma is a rare disease, yet vertebral fractures and pain are common to both. Multiple myeloma would be expected to be seen more often in osteoporosis clinics than in most other areas of medicine dealing with the care of elderly people. Moreover, monoclonal gammopathy of undetermined significance is a common disorder, with a similar age distribution to that of osteoporosis. The risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance is around 15% over 10 years.2
National guidelines in Denmark do not advocate the routine measurement of monoclonal bands (M component) in the serum or urine of patients presenting with osteoporosis. In the United States, the National Osteoporosis Foundation3 lists protein electrophoresis among tests that could be carried out in patients where a specific secondary, treatable cause of osteoporosis is being considered. The extent to which protein electrophoresis is used routinely is unknown. One survey in the United States found that three out of four bone specialists would refer men with hip fractures for protein electrophoresis.4 We determined the prevalence of multiple myeloma and monoclonal gammopathy of undetermined significance in unselected patients newly referred with osteoporosis to assess whether measurement of M component should form part of the investigation of patients with suspected osteoporosis.
Participants and methods
From March 1999 to March 2001, 1372 patients (1150 women) were referred to our clinic with suspected osteoporosis or osteopenia. The clinic receives all referrals of patients with risk factors for osteoporosis from general practitioners, hospitals, and specialists in a catchment area of 473 000 people. We retrospectively evaluated all first referrals from primary care (n = 799) consecutively by a diagnostic schedule, which included measurement of serum M component and dual energy x ray absorptiometry. The study population consisted of 114 men, mean (SD) age 61.5 (14.0) years (range 19.0 to 89.0 years), and 685 women, mean (SD) age 61.0 (12.0) years (range 20.0 to 94.0 years). Overall, 26% of the participants were aged over 70, 13% over 75, and 5% over 80.
Reference standard
Participants presenting with M component in serum underwent follow-up investigations, including bone marrow examination and skeletal x rays. Multiple myeloma was diagnosed according to the Nordic Myeloma Study Group definition.5 Briefly, the diagnosis was made on the basis of a monoclonal band in serum in excess of 30 g/l (IgG), 20 g/l (IgA), or any level of IgD or IgE monoclonal bands or a urine monoclonal band of kappa or lambda in excess of 1 g/24h. This must be accompanied by osteolytic bone lesions or by more than 10% plasma cells in bone marrow aspirates (or plasmacytosis in soft tissue or skeletal tissue biopsies). A diagnosis of multiple myeloma can be made in the presence of lower monoclonal band concentrations in serum or urine, however, if both osteolytic lesions and high plasma cell content of bone marrow aspirates are present.
Patients were considered to have monoclonal gammopathy of undetermined significance if malignant monoclonal gammopathies were excluded (multiple myeloma, Waldenstr?m's macroglobulinaemia, non-Hodgkin's lymphoma, or other lymphoproliferative disorders).
Test and statistical methods
The index test was for serum M component, assessed using cellulose acetate electrophoresis. This method is less sensitive than the more recent high resolution agarose gel electrophoresis. Urine tests were not carried out.
We calculated confidence intervals using the normal approximation to the binary distribution, and we compared proportions using 2 tests. Anaylses were carried out in SPSS version 10.0. We considered a significance level of 5% as important.
Results
Osteoporosis (T score less than -2.5)6 was diagnosed in 45% (n = 308) of the women and 55% (n = 63) of the men. Twenty five (3.1%) of the referred patients declined dual energy x ray absorptiometry. Thus serum M component was evaluated in 366 participants with osteoporosis detected by densitometry and 408 participants with normal bone mineral density or osteopenia. Overall, 30 participants (3.8%, figure) had a positive index test result. At subsequent visits, three patients with a positive index test result reported that they had a known haematological disorder and another two patients declined further examination. M component was present in 4.9% (n = 18) of patients with osteoporosis and 2.2% (n = 9) of patients without osteoporosis (2 = 3.66, P = 0.04; table 1). Although erythrocyte sedimentation rate was not routinely assessed, six of eight patients with M component had an erythrocyte sedimentation rate of 20 or lower.
Flow of participants through trial
Table 1 Prevalence of serum monoclonal bands (M component) in patients by age and bone mineral density status
Test results
Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%; table 2) but in no participants without osteoporosis. One patient with osteoporosis had a diagnosis of non-Hodgkin's lymphoma.
Table 2 Incidence of multiple myeloma in patients by age and bone mineral density status
We diagnosed monoclonal gammopathy of undetermined significance in 13 (3.6%; table 3) of the participants with osteoporosis and eight (2.0%) of the participants with normal bone mineral density or osteopenia. In patients with osteoporosis, we found no difference in bone mineral density or age (68.1 (10.4) v 65.8 (10.7); P = 0.42) between those with multiple myeloma or monoclonal gammopathy of undetermined significance and those with no M component in serum. The three patients with multiple myeloma had a history of fragility fractures, compared with 28% (95% confidence interval 5% to 70%) in patients with osteoporosis with coexisting monoclonal gammopathy of undetermined significance and 36% (30% to 43%) in patients with osteoporosis but no M component.
Table 3 Prevalence of monoclonal gammopathy of undetermined significance in patients by age and bone mineral density status
Estimation
Compared with the background population, the relative risk of multiple myeloma in patients presenting with osteoporosis in our clinic was 75 (95% confidence interval 10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. In practical terms, 122 blood electrophoreses would need to be carried out for each case of multiple myeloma diagnosed. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. In a large group of patients with multiple myeloma diagnosed at the Mayo clinic,7 20.0% had light chain disease and 2.8% had non-secretory myeloma. Given a similar distribution of multiple myeloma subtypes, our index test would have a sensitivity of 77% and a negative predictive value of 99.7%.
Discussion
Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989;149: 2445-8.
Gregersen H, Mellemkjaer L, Ibsen JS, Dahlerup JF, Thomassen L, Sorensen HT. The impact of M-component type and immunoglobulin concentration on the risk of malignant transformation in patients with monoclonal gammopathy of undetermined significance. Haematologica 2001;86: 1172-9.
Dawson-Hughes B, Gold DT, Rodbard HW, Bonner F, Khosla S, Swift S. Physician's guide to prevention and treatment of osteoporosis. www.nof.org/physguide/diagnosis.htm (accessed 1 December 2004).
Colon-Emeric C, Yballe L, Sloane R, Pieper CF, Lyles KW. Expert physician recommendations and current practice patterns for evaluating and treating men with osteoporotic hip fracture. J Am Geriatr Soc 2000;48: 1261-3.
Nordic Myeloma Study Group. V?rdprogram for myelomatose. www.nordic-myeloma.org (accessed 1 December 2004).
The WHO study group on osteoporosis. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Geneva: WHO, 1994.
Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78: 21-33.
Cancer incidence in Denmark 1999. Copenhagen: National Board of Health, 2003.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996;335: 91-7.
Blade J, Munoz M, Fontanillas M, San Miguel J, Alcala A, Maldonado J, et al. Treatment of multiple myeloma in elderly people: long-term results in 178 patients. Age Ageing 1996;25: 357-61.
Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 1997;79: 1561-7.
Genvresse I, Lange C, Schanz J, Schweigert M, Harder H, Possinger K, et al. Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study. Anticancer Drugs 2001;12: 345-9.
Genvresse I, Wedding U, Bokemeyer C, Spath-Schwalbe E. . Onkologie 2001;24: 386-90.
Sim MF, Stone M, Johansen A, Ho P, Pettit RJ, Evans WD. An analysis of an open access general practitioner bone densitometry service. Int J Clin Pract 2004;58: 300-5.
Nelson DA, Molloy R, Kleerekoper M. Prevalence of osteoporosis in women referred for bone density testing: utility of multiple skeletal sites. J Clin Densitom 1998;1: 5-12.
Ben Sedrine W, Broers P, Devogelaer JP, Depresseux G, Kaufman JM, Goemaere S, et al. Interest of a prescreening questionnaire to reduce the cost of bone densitometry. Osteoporos Int 2002;13: 434-42.
Roux S, Bergot C, Fermand JP, Frija J, Brouet JC, Mariette X. Evaluation of bone mineral density and fat-lean distribution in patients with multiple myeloma in sustained remission. J Bone Miner Res 2003;18: 231-6.
Abildgaard N, Brixen K, Kristensen JE, Vejlgaard T, Charles P, Nielsen JL. Assessment of bone involvement in patients with multiple myeloma using bone densitometry. Eur J Haematol 1996;57: 370-6.
Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin Chem Lab Med 2003;41: 68-73.
((Bo Abrahamsen, consultant1, Ivan Anderse)