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Glucocorticoid-induced diabetes mellitus is a risk for vertebral fracture during glucocorticoid treatment
diabetes research and clinical practice 93 (2011) e18–e20
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Glucocorticoid-induced diabetes mellitus is a risk for vertebral fracture during glucocorticoid treatment Ichiro Tatsuno a,*, Takao Sugiyama b a
Department of Clinical Cell Biology, Chiba University Graduate School of Medicine; Department of Clinical Endocrinology and Metabolism, Chiba University Hospital, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan b Department of Rheumatology, Shimoshizu National Hospital, 934-5 Shikawatari, Yotsukaido, Chiba 284-0003, Japan
article info
abstract
Article history:
High-dose glucocorticoid was associated with new-onset diabetes mellitus (NODM) with a
Received 12 January 2011
high prevalence during the early treatment period. Glucocorticoid-induced NODM was an
Received in revised form
independent risk factor for clinical vertebral fracture during high-dose glucocorticoid
30 January 2011
treatment in Chiba-Shimoshizu Rheumatic Cohort of 20 years in Japan. # 2011 Elsevier Ireland Ltd. All rights reserved.
Accepted 1 March 2011 Published on line 26 March 2011 Keywords: Glucocorticoids Diabetes mellitusl Osteoporosis Fracture
Glucocorticoids have numerous adverse effects [1] including glucocorticoid-induced diabetes mellitus (DM) and glucocorticoid-induced osteoporosis [2,3]. Although DM has been demonstrated to be a risk for osteoporotic fractures in both type 1 and 2 [4], glucocorticoid-induced DM is not known to influence glucocorticoid-induced osteoporosis. In the present study, we investigated the role of glucocorticoid-induced DM as a risk factor for clinical vertebral fracture in subjects with collagen vascular diseases treated with long-term high dose glucocorticoid, sub-analyzing the Chiba-Shimoshizu Rheumatic Cohort of 20 years in Japan [5–7]. Collagen vascular diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, polymyositis/dermatomyositis, systemic sclerosis, and granulomatous vasculitic conditions exemplified by Wegener’s granulomatosis are chronic, sometimes involve multiorgans, and are thus occasionally life-threatening. To control disease activity, immuno-suppressive treatment
with glucocorticoid is required [8–10]. In most cases highdoses and long-term glucocorticoids are required although occasionally disease can be controlled with low-doses and in a very small number, glucocorticoid treatment can be temporarily discontinued [5–7]. We analyzed 681 subjects with collagen vascular diseases newly treated with an initial high-dose of 20 mg prednisolone (PSL) equivalent per day for at least 6 months, who did not have previous diagnosis DM (initial age: 46.3 16.7 years; female: 77.4%; BMI: 21.4 3.2, initial PSL dose: 40.0 14.1 mg/ day; cumulative dose of PSL: 31.6 25.1 g; follow-up: 103.9 71.6 months) in the Chiba-Shimoshizu Rheumatic Cohort between 1986 and 2006 [5–7]. New-onset DM (NODM) was defined by two or more glucose with fasting glucose measurement of 7 mmol/l, or 120 min post-load glycaemia >11.1 mmol/l after commencement of glucocorticoid treatment. The glucocorticoid dose increase was defined as the re-introduction of more than 20 mg of glucocorticoid per day
* Corresponding author. Tel.: +81 43 226 2092; fax: +81 43 226 2095. E-mail address: [email protected] (I. Tatsuno). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.03.005
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diabetes research and clinical practice 93 (2011) e18–e20
Table 1 – Characteristics of symptomatic fracture and no fracture groups of vertebrae at baseline and during glucocorticoid treatment.
Number of patients Initial age (years) Female (%) BMI Smoking (%) Alcohol use (%) Follow-up time (months) Initial daily dose of PSL (mg/day) Mean daily dose of PSL (mg/day) Cumulative dose of PSL (g) GC pulse therapy (%) GC dose increase (%) New-onset DM (%)
Fracture group
No fracture group
Difference P value
163 55.4 14.1 76.8 21.1 3.1 24.5 19.6 59.7 63.4 39.1 14.9 20.6 11.7 24.6 21.7 15.3 56.4 42.9
518 41.1 15.0 79.1 21.4 3.2 24.7 17.2 100.7 72.4 40.2 13.8 13.1 6.4 33.8 25.8 14.1 33.8 21.4
P < 0.001a N.S.b N.S.a N.S.b N.S.b P < 0.05a N.S. 1) P < 0.001a P < 0.001a N.S.b P < 0.001b P < 0.001b
Data are expressed as mean SD; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid. Unpaired t test. b x2 test. a
(PSL equivalent) due to increased disease activity in subjects whose doses had been tapered to less than 20 mg of glucocorticoid per day. During the 20 years of following of this cohort, clinical vertebral fractures occurred in 23.9% of the subjects (Table 1). The fracture group was significantly older (P < 0.001), had shorter follow-up time (P < 0.05), higher mean daily glucocorticoid dose (P < 0.001), lower cumulative glucocorticoid dose (P < 0.001), higher glucocorticoid dose increase (P < 0.001), higher NODM (P < 0.001) compared with the no fracture group.
Table 2 – Characteristics of patients with and without new-onset DM at baseline and during glucocorticoid treatment.
Number of patients Initial age (years) BMI Female (%) Smoking (%) Alcohol use (%) Follow-up time (months) Initial daily dose of PSL (mg/day) Mean daily dose of PSL (mg/day) Cumulative dose of PSL (g) GC pulse therapy (%) GC dose increase (%) Vertebral fracture (%)
New-onset DM (+)
New-onset DM ( )
Difference P value
181 53.9 14.4 21.9 3.6 66.3 30.9 23.2 105.2 72.8
500 43.5 16.5 21.2 3.0 81.4 22.4 15.8 103.4 71.2
P < 0.001a P < 0.05b P < 0.001b P < 0.05b P < 0.05b N.S.a
40.5 13.9
39.8 14.2
N.S.a
17.1 10.8
14.1 7.5
P < 0.001a
30.1 24.0
32.2 25.6
N.S.a
16.0
13.8
N.S.b
42.0
38.2
N.S.b
38.7
18.6
P < 0.001b
Data are expressed as mean SD; SLE, systemic lupus erythematosus; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid. a Unpaired t test. b x2 test.
No significant differences were observed between the two groups in sex, BMI, smoking, alcohol use, initial glucocorticoid dose, and glucocorticoid pulse therapy (Table 1). NODM was observed in 26.6% of subjects (Table 2). More than 98% of NODM was diagnosed within 2 months of initiation of glucocorticoid treatment. The NODM group was older (P < 0.001), had higher BMI (P < 0.05), less were females (P < 0.001), had higher rate of smoking (P < 0.05), greater alcohol use (P < 0.05), higher mean glucocorticoid daily dose (P < 0.001), and a higher rate of clinical vertebral fracture (P < 0.001) compared with the non-diabetic group (Table 2). Kaplan–Meier analysis demonstrated that NODM had significantly higher prevalence of fracture (P < 0.001) (Fig. 1); 16.2% vs. 5.5% at 12 months, 30.2% vs.12.3% at 60 months, and 40.3% vs. 19.5% at 120 months, respectively. Cox regression models demonstrated that the risk of fracture was independently higher in NODM with hazard
Fig. 1 – Comparison of clinical vertebral fractures with and without new-onset DM (NODM) in the patients treated with high-dose glucocorticoid in Kaplan–Meier analysis; Kaplan–Meier curve with or without DM; 6 months DM (S) 3.0%: DM (+) 8.3%; 12 months 5.5%: 16.2%; 36 months 9.3%: 23.0%; 60 months 12.3%: 30.2%; 120 months 19.5%: 40.3%; 180 months 26.7%: 46.9%; 240 months 39.2%: 55.2%.
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diabetes research and clinical practice 93 (2011) e18–e20
Table 3 – Evaluation of risk factors for symptomatic vertebral fracture using Cox proportional hazard regression model. Variables
Initial age (every 10 years) BMI (every 1 BMI) Female Smoking Alcohol use Initial dose of PSL (every 10 mg/day) GC pulse therapy GC dose increase Cumulative dose of PSL (every 1 g) New-onset DM
Hazard ratio (95% confidence interval) 1.67 0.98 1.75 1.25 1.12 1.37
bone metabolism such as osteoclast activation, non-enzymatic glycosylation of bone proteins, and impaired PTH/vitamin D system [4]. Further studies are necessary to explore this.
P value
Conflict of interest statement
(1.47–1.90) (0.93–1.03) (1.12–2.72) (0.81–1.93) (0.69–1.84) (1.19–1.57)
P < 0.001 0.480 P < 0.05 0.307 0.643 P < 0.001
1.39 (0.88–2.21) 3.87 (2.77–5.40) 0.93 (0.91–0.94)
0.163 P < 0.001 P < 0.001
1.50 (1.08–2.10)
P < 0.05
BMI, body mass index; PSL, prednisolone; GC; glucocorticoid; Hazard ratio of risk factors was calculated using Cox proportional hazard regression model (confidence interval of 95%).
ratio (HR) 1.50 (P < 0.05), every 10-year increment of initial age (HR 1.67; P < 0.001), female subjects (HR 1.75; P < 0.05), every 10 mg/day of initial glucocorticoid dose (HR 1.37; P < 0.001), and glucocorticoid dose increase (HR 3.87; P < 0.001) (Table 3). However, risk was independently lower for every gram of cumulative glucocorticoid (HR 0.93; P < 0.001) (Table 3). Although it is difficult to determine the reason for the negative correlation between cumulative glucocorticoid dose and fracture risk, there may be some masked genetic or environmental risk factors in the vertebral fracture group, which may have shortened the time period to having a vertebral fracture. As a result, the cumulative dose might be negatively associated with fracture risk. A high prevalence of NODM was observed during glucocorticoid treatment in the present study. This may be due to the high dose of prednisolone used in the treatment of collagen vascular diseases [5–7]. Both higher age and BMI were independent risk factors for NODM [11]. Although the glucocorticoid-induced osteoporosis was first described by Cushing over 70 years ago [1], we have demonstrated for the first time that NODM is an independent risk factor for vertebral fracture during glucocorticoid treatment. While the pathophysiological mechanism cannot be established in the present study, hyperglycemia may have several adverse effects on
There are no conflicts of interest.
references
[1] Cushing H. The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;1:137–92. [2] Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007;18:1319–28. [3] Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract 2009;15:469–74. [4] Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res 2007;22:1317–28. [5] Sugiyama T, Suzuki S, Yoshida T, Suyama K, Tanaka T, Sueishi M, et al. Incidence of symptomatic vertebral fractures in women of child-bearing age newly treated with high-dose glucocorticoid. Gen Med 2010;7:218–29. [6] Tatsuno I, Sugiyama T, Suzuki S, Yoshida T, Tanaka T, Sueishi M, et al. Age-dependent early complication of symptomatic vertebral fracture with high-dose glucocorticoid in treatment for collagen vascular diseases. J Clin Endocrinol Metab 2009;94:1671–7. [7] Tatsuno I, Suzuki S, Yoshida T, Tanaka T, Sueishi M, Sugiyama T. High prevalence and early complication of symptomatic vertebral fracture in the elderly treated with high-dose glucocorticoids. J Am Geriatr Soc 2009;57:188–9. [8] Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299–308. [9] Langford CA. Chronic immunosuppressive therapy for systemic vasculitis. Curr Opin Rheumatol 1997;9:41–7. [10] Nagai S, Izumi T. Immunopathology of collagen vascular disease. Curr Opin Pulm Med 1997;3:356–60. [11] Uzu T, Harada T, Sakaguchi M, Kanasaki M, Isshiki K, Araki S, et al. Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases. Nephron Clin Pract 2007;105:c54–57.
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Glucocorticoid-induced diabetes mellitus is a risk for vertebral fracture during glucocorticoid treatment Ichiro Tatsuno a,*, Takao Sugiyama b a
Department of Clinical Cell Biology, Chiba University Graduate School of Medicine; Department of Clinical Endocrinology and Metabolism, Chiba University Hospital, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan b Department of Rheumatology, Shimoshizu National Hospital, 934-5 Shikawatari, Yotsukaido, Chiba 284-0003, Japan
article info
abstract
Article history:
High-dose glucocorticoid was associated with new-onset diabetes mellitus (NODM) with a
Received 12 January 2011
high prevalence during the early treatment period. Glucocorticoid-induced NODM was an
Received in revised form
independent risk factor for clinical vertebral fracture during high-dose glucocorticoid
30 January 2011
treatment in Chiba-Shimoshizu Rheumatic Cohort of 20 years in Japan. # 2011 Elsevier Ireland Ltd. All rights reserved.
Accepted 1 March 2011 Published on line 26 March 2011 Keywords: Glucocorticoids Diabetes mellitusl Osteoporosis Fracture
Glucocorticoids have numerous adverse effects [1] including glucocorticoid-induced diabetes mellitus (DM) and glucocorticoid-induced osteoporosis [2,3]. Although DM has been demonstrated to be a risk for osteoporotic fractures in both type 1 and 2 [4], glucocorticoid-induced DM is not known to influence glucocorticoid-induced osteoporosis. In the present study, we investigated the role of glucocorticoid-induced DM as a risk factor for clinical vertebral fracture in subjects with collagen vascular diseases treated with long-term high dose glucocorticoid, sub-analyzing the Chiba-Shimoshizu Rheumatic Cohort of 20 years in Japan [5–7]. Collagen vascular diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, polymyositis/dermatomyositis, systemic sclerosis, and granulomatous vasculitic conditions exemplified by Wegener’s granulomatosis are chronic, sometimes involve multiorgans, and are thus occasionally life-threatening. To control disease activity, immuno-suppressive treatment
with glucocorticoid is required [8–10]. In most cases highdoses and long-term glucocorticoids are required although occasionally disease can be controlled with low-doses and in a very small number, glucocorticoid treatment can be temporarily discontinued [5–7]. We analyzed 681 subjects with collagen vascular diseases newly treated with an initial high-dose of 20 mg prednisolone (PSL) equivalent per day for at least 6 months, who did not have previous diagnosis DM (initial age: 46.3 16.7 years; female: 77.4%; BMI: 21.4 3.2, initial PSL dose: 40.0 14.1 mg/ day; cumulative dose of PSL: 31.6 25.1 g; follow-up: 103.9 71.6 months) in the Chiba-Shimoshizu Rheumatic Cohort between 1986 and 2006 [5–7]. New-onset DM (NODM) was defined by two or more glucose with fasting glucose measurement of 7 mmol/l, or 120 min post-load glycaemia >11.1 mmol/l after commencement of glucocorticoid treatment. The glucocorticoid dose increase was defined as the re-introduction of more than 20 mg of glucocorticoid per day
* Corresponding author. Tel.: +81 43 226 2092; fax: +81 43 226 2095. E-mail address: [email protected] (I. Tatsuno). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.03.005
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diabetes research and clinical practice 93 (2011) e18–e20
Table 1 – Characteristics of symptomatic fracture and no fracture groups of vertebrae at baseline and during glucocorticoid treatment.
Number of patients Initial age (years) Female (%) BMI Smoking (%) Alcohol use (%) Follow-up time (months) Initial daily dose of PSL (mg/day) Mean daily dose of PSL (mg/day) Cumulative dose of PSL (g) GC pulse therapy (%) GC dose increase (%) New-onset DM (%)
Fracture group
No fracture group
Difference P value
163 55.4 14.1 76.8 21.1 3.1 24.5 19.6 59.7 63.4 39.1 14.9 20.6 11.7 24.6 21.7 15.3 56.4 42.9
518 41.1 15.0 79.1 21.4 3.2 24.7 17.2 100.7 72.4 40.2 13.8 13.1 6.4 33.8 25.8 14.1 33.8 21.4
P < 0.001a N.S.b N.S.a N.S.b N.S.b P < 0.05a N.S. 1) P < 0.001a P < 0.001a N.S.b P < 0.001b P < 0.001b
Data are expressed as mean SD; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid. Unpaired t test. b x2 test. a
(PSL equivalent) due to increased disease activity in subjects whose doses had been tapered to less than 20 mg of glucocorticoid per day. During the 20 years of following of this cohort, clinical vertebral fractures occurred in 23.9% of the subjects (Table 1). The fracture group was significantly older (P < 0.001), had shorter follow-up time (P < 0.05), higher mean daily glucocorticoid dose (P < 0.001), lower cumulative glucocorticoid dose (P < 0.001), higher glucocorticoid dose increase (P < 0.001), higher NODM (P < 0.001) compared with the no fracture group.
Table 2 – Characteristics of patients with and without new-onset DM at baseline and during glucocorticoid treatment.
Number of patients Initial age (years) BMI Female (%) Smoking (%) Alcohol use (%) Follow-up time (months) Initial daily dose of PSL (mg/day) Mean daily dose of PSL (mg/day) Cumulative dose of PSL (g) GC pulse therapy (%) GC dose increase (%) Vertebral fracture (%)
New-onset DM (+)
New-onset DM ( )
Difference P value
181 53.9 14.4 21.9 3.6 66.3 30.9 23.2 105.2 72.8
500 43.5 16.5 21.2 3.0 81.4 22.4 15.8 103.4 71.2
P < 0.001a P < 0.05b P < 0.001b P < 0.05b P < 0.05b N.S.a
40.5 13.9
39.8 14.2
N.S.a
17.1 10.8
14.1 7.5
P < 0.001a
30.1 24.0
32.2 25.6
N.S.a
16.0
13.8
N.S.b
42.0
38.2
N.S.b
38.7
18.6
P < 0.001b
Data are expressed as mean SD; SLE, systemic lupus erythematosus; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid; BMI, body mass index; PSL, prednisolone; GC, glucocorticoid. a Unpaired t test. b x2 test.
No significant differences were observed between the two groups in sex, BMI, smoking, alcohol use, initial glucocorticoid dose, and glucocorticoid pulse therapy (Table 1). NODM was observed in 26.6% of subjects (Table 2). More than 98% of NODM was diagnosed within 2 months of initiation of glucocorticoid treatment. The NODM group was older (P < 0.001), had higher BMI (P < 0.05), less were females (P < 0.001), had higher rate of smoking (P < 0.05), greater alcohol use (P < 0.05), higher mean glucocorticoid daily dose (P < 0.001), and a higher rate of clinical vertebral fracture (P < 0.001) compared with the non-diabetic group (Table 2). Kaplan–Meier analysis demonstrated that NODM had significantly higher prevalence of fracture (P < 0.001) (Fig. 1); 16.2% vs. 5.5% at 12 months, 30.2% vs.12.3% at 60 months, and 40.3% vs. 19.5% at 120 months, respectively. Cox regression models demonstrated that the risk of fracture was independently higher in NODM with hazard
Fig. 1 – Comparison of clinical vertebral fractures with and without new-onset DM (NODM) in the patients treated with high-dose glucocorticoid in Kaplan–Meier analysis; Kaplan–Meier curve with or without DM; 6 months DM (S) 3.0%: DM (+) 8.3%; 12 months 5.5%: 16.2%; 36 months 9.3%: 23.0%; 60 months 12.3%: 30.2%; 120 months 19.5%: 40.3%; 180 months 26.7%: 46.9%; 240 months 39.2%: 55.2%.
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diabetes research and clinical practice 93 (2011) e18–e20
Table 3 – Evaluation of risk factors for symptomatic vertebral fracture using Cox proportional hazard regression model. Variables
Initial age (every 10 years) BMI (every 1 BMI) Female Smoking Alcohol use Initial dose of PSL (every 10 mg/day) GC pulse therapy GC dose increase Cumulative dose of PSL (every 1 g) New-onset DM
Hazard ratio (95% confidence interval) 1.67 0.98 1.75 1.25 1.12 1.37
bone metabolism such as osteoclast activation, non-enzymatic glycosylation of bone proteins, and impaired PTH/vitamin D system [4]. Further studies are necessary to explore this.
P value
Conflict of interest statement
(1.47–1.90) (0.93–1.03) (1.12–2.72) (0.81–1.93) (0.69–1.84) (1.19–1.57)
P < 0.001 0.480 P < 0.05 0.307 0.643 P < 0.001
1.39 (0.88–2.21) 3.87 (2.77–5.40) 0.93 (0.91–0.94)
0.163 P < 0.001 P < 0.001
1.50 (1.08–2.10)
P < 0.05
BMI, body mass index; PSL, prednisolone; GC; glucocorticoid; Hazard ratio of risk factors was calculated using Cox proportional hazard regression model (confidence interval of 95%).
ratio (HR) 1.50 (P < 0.05), every 10-year increment of initial age (HR 1.67; P < 0.001), female subjects (HR 1.75; P < 0.05), every 10 mg/day of initial glucocorticoid dose (HR 1.37; P < 0.001), and glucocorticoid dose increase (HR 3.87; P < 0.001) (Table 3). However, risk was independently lower for every gram of cumulative glucocorticoid (HR 0.93; P < 0.001) (Table 3). Although it is difficult to determine the reason for the negative correlation between cumulative glucocorticoid dose and fracture risk, there may be some masked genetic or environmental risk factors in the vertebral fracture group, which may have shortened the time period to having a vertebral fracture. As a result, the cumulative dose might be negatively associated with fracture risk. A high prevalence of NODM was observed during glucocorticoid treatment in the present study. This may be due to the high dose of prednisolone used in the treatment of collagen vascular diseases [5–7]. Both higher age and BMI were independent risk factors for NODM [11]. Although the glucocorticoid-induced osteoporosis was first described by Cushing over 70 years ago [1], we have demonstrated for the first time that NODM is an independent risk factor for vertebral fracture during glucocorticoid treatment. While the pathophysiological mechanism cannot be established in the present study, hyperglycemia may have several adverse effects on
There are no conflicts of interest.
references
[1] Cushing H. The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;1:137–92. [2] Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007;18:1319–28. [3] Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract 2009;15:469–74. [4] Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res 2007;22:1317–28. [5] Sugiyama T, Suzuki S, Yoshida T, Suyama K, Tanaka T, Sueishi M, et al. Incidence of symptomatic vertebral fractures in women of child-bearing age newly treated with high-dose glucocorticoid. Gen Med 2010;7:218–29. [6] Tatsuno I, Sugiyama T, Suzuki S, Yoshida T, Tanaka T, Sueishi M, et al. Age-dependent early complication of symptomatic vertebral fracture with high-dose glucocorticoid in treatment for collagen vascular diseases. J Clin Endocrinol Metab 2009;94:1671–7. [7] Tatsuno I, Suzuki S, Yoshida T, Tanaka T, Sueishi M, Sugiyama T. High prevalence and early complication of symptomatic vertebral fracture in the elderly treated with high-dose glucocorticoids. J Am Geriatr Soc 2009;57:188–9. [8] Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299–308. [9] Langford CA. Chronic immunosuppressive therapy for systemic vasculitis. Curr Opin Rheumatol 1997;9:41–7. [10] Nagai S, Izumi T. Immunopathology of collagen vascular disease. Curr Opin Pulm Med 1997;3:356–60. [11] Uzu T, Harada T, Sakaguchi M, Kanasaki M, Isshiki K, Araki S, et al. Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases. Nephron Clin Pract 2007;105:c54–57.