Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2025;15(2):5050 1 Risk of Osteoporosis Associated with Glucocorticoid Use in Pemphigus Vulgaris: Insights from a Retrospective Cohort Study Merve Kaya1, Gülhan Aksoy Saraç1, Onur Acar2, Selma Emre3, Akın Aktaş3 1 Department of Dermatology, Bilkent City Hospital, Ankara, Turkey 2 Orhangazi District Health Directorate, Bursa, Turkey 3 Department of Dermatology, Ankara Yıldırım Beyazıt University, Medical School, Ankara, Turkey Key words: pemphigus vulgaris, glucocorticoids, bone mineral density, osteoporosis, bone loss, corticosteroid-induced osteoporosis, retrospective cohort Citation: Kaya M, Saraç GA, Acar O, Emre S, Aktaş A. Risk of Osteoporosis Associated with Glucocorticoid Use in Pemphigus Vulgaris: Insights from a Retrospective Cohort Study. Dermatol Pract Concept. 2025;15(2):5050. DOI: https://doi.org/10.5826/dpc.1502a5050 Accepted: January 2, 2025; Published: April 2025 Copyright: ©2025 Kaya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Merve Kaya, Department of Dermatology, Bilkent City Hospital, 06800, Ankara, Turkey. ORCID ID: 0000-0002- 5188-1245. E-mail: mervekaya203@gmail.com Introduction: Pemphigus vulgaris (PV) is an autoimmune bullous disease affecting the skin and mucous membranes. Osteoporosis, a significant side effect of commonly used glucocorticoids in treat- ment, can adversely contribute to the existing morbidity. Objectives: This study aimed to assess the impact of glucocorticoid therapy on bone mineral density in patients with PV. Methods: Patients newly diagnosed with PV were included in this study. Femur and lumbar T-scores, serum calcium, vitamin D, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) levels were analyzed before and one year after therapy. Results: Among 66 patients, the average time to diagnosis was 10.14 months, and the average daily dose of prednisone was 16.95 mg, with 63.6% of patients receiving medium doses. Our data showed no significant change in lumbar T-scores after one year of glucocorticoid treatment, but a significant decrease in femur density was observed. The decrease in femur T-scores was significant in the medium-dose group, while the lumbar T-scores decreased significantly in the high-dose group. There was no significant correlation between T-scores and sex, menopausal state, diagnosis time, or obesity. Additionally, vitamin D and LDH levels significantly increased after treatment, while changes in serum calcium and ALP levels were not significant. Conclusion: Given the multiple factors that reduce bone mineral density in PV patients, the current strategies for glucocorticoid-induced osteoporosis prophylaxis in this group may need re-evaluation, with potential for additional recommendations to be included in pemphigus guidelines. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2025;15(2):5050 Introduction Pemphigus vulgaris (PV) is an autoimmune bullous disease affecting the skin and mucous membranes. It is characterized by acantholysis resulting from antibodies against desmoglein 1 and desmoglein 3 [1,2]. Clinically, this typically presents as flaccid vesicles, bullae, or erosions on the skin and mucous membranes, with the oral mucosa being the primary site of onset [3]. Although its incidence worldwide is 2.83 per mil- lion person-years, it is a life-threatening disease [4]. While corticosteroids have been the first choice of treatment for many years, they have been ranked alongside rituximab in new guidelines due to the risk of morbidity and mortality [5,6]. Osteoporosis, a known side effect of corticosteroids, can occur due to senility, reduced mechanical stimulation/ immobilization, bone and hormone metabolism disorders, inflammatory diseases, and malnutrition [7]. Various guide- lines are being developed for the prophylaxis and treatment of corticosteroid-induced osteoporosis [8,9]. However, these guidelines are not disease-specific. Current PV guidelines in- clude recommendations for calcium and vitamin D supple- mentation, screening for osteoporosis, and bisphosphonates in patients at risk [5]. The clinical impact of adhering to PV guidelines on bone mineral density needs to be investigated since there is a lack of studies on this topic. Objectives Our study aimed to retrospectively evaluate the bone min- eral density changes in patients diagnosed with PV who were taking corticosteroids, receiving treatment and lifestyle mod- ifications according to osteoporosis prevention measures within the first year. Methods Study Design This retrospective study was conducted in dermatology in- patient and outpatient clinics between June 2019 and May 2024 in a training and research hospital in Ankara, Turkey. The study was approved by the hospital’s ethics and scien- tific committee (approval date: 29.05.2024, decision num- ber: 2-24-206). Study Population Newly diagnosed pemphigus vulgaris patients who were glucocorticoid-naive and whose diagnosis was confirmed by biopsy were included in our study. Patients with endocrino- logical, rheumatological, and inflammatory diseases, malig- nancies, having a history of antiepileptic or benzodiazepine usage, having diseases causing malnutrition, or with a his- tory of gastrointestinal surgery were excluded. Patients who were not documented to have regularly taken daily calcium and vitamin D supplements or to adhere to daily lifestyle and diet recommendations or patients with incomplete doc- uments were also excluded from the study. All patients were provided with a daily supplement of 1200 mg of calcium and 800 IU of vitamin D in accordance with current guide- lines, along with dietary and exercise recommendations [8]. Additionally, further treatment options were discussed with the physical therapy and rehabilitation department when necessary. Studied Variables The charts of pemphigus vulgaris patients were reviewed from the medical records. Age, sex, body mass index (BMI), menopausal status of female patients, lumbar and femur T-scores, serum 25-hydroxyvitamin D (25(OH)D), serum calcium corrected for serum albumin (reference interval 8.4- 10.2 mg/dL), serum total alkaline phosphatase (ALP) (refer- ence interval 53–128 UI/L), and serum lactate dehydrogenase (reference interval 120-246 U/L) levels before and one year after treatment were obtained from the data system. Addi- tionally, the cumulative and daily prednisone doses were also evaluated. The average daily glucocorticoid dose was classi- fied as low (≤ 7.5 mg/day), medium (> 7.5 mg/day but ≤ 30 mg/day), or high (> 30 mg/day) [10]. Bone mineral density (BMD) was measured by Dual-energy X-ray Absorptiometry (DXA) (GE Healthcare, Madison WI, USA) at lumbar spine and femoral neck and expressed as standard deviation (SD) units in relation to the reference healthy population of the same age (Z-score) and of the young adults (T-score). Os- teopenia was defined as a T-score between -1.0 and -2.5 and osteoporosis as a T-score of -2.5 and less. Serum 25 (OH)D levels were measured by competitive immunoassay (Atellica IM, Siemens Healthineers, Forchheim, Germany) (reference interval: 30–100 μg/L). Statistical Analysis The data were analyzed using SPSS version 26.0 for Win- dows (IBM SPSS Statistics, Armonk, NY). Categorical vari- ables are expressed as numbers and percentages. Continuous variables are expressed as mean and standard deviation. For normal distributions, continuous variables were compared using independent samples t-test and paired sample t-test. For non-parametric distributions, Mann-Whitney U test was used. A p-value of 0.05 was considered the threshold for sta- tistical significance. Results A total of 73 patients were included in this study, with 66  patients evaluated due to exclusion criteria. Of the 66  patients (39 females, 27 males), the mean age of females Original Article | Dermatol Pract Concept. 2025;15(2):5050 3 was 53.15 ± 17.06 and of males was 54.8 ± 14.9 years. The age of these patients ranged from 18 to 83 years, with a mean of 53.83 ± 16.15 years. The mean BMI was 27.61 ± 5.06. Ac- cording to BMI, 66.7% (N=44) were overweight and obese, while 33.3% (N=22) were of normal weight. Among the female patients, 45.5% (N=30) were postmenopausal. The average time to diagnosis was 10.14 ± 13.89 months, and the daily dose of prednisone was 16.95 ± 16.10 mg. When categorized according to daily prednisone doses, 18.2% (N=12) were on low, 63.6% (N=42) were on medium, and 18.2% (N=12) were on high doses. The mean cumulative prednisone dose was 6190.08 ± 3598.4 mg (Table 1). Our results show that the lumbar T-scores did not differ before and after one year of glucocorticoid treatment (P=0.102). In contrast, there was a significant decrease in femur den- sity (P=0.001). After one year of glucocorticoid therapy, the changes in mean serum calcium and serum ALP levels were not significant (P=0.819, P=0.724, respectively). A signif- icant increase in 25 (OH)D levels (P=0.018) and in LDH levels (P<0.001) were observed after treatment compared to pre-treatment levels (Table 2). There was no significant correlation between T-scores and sex, diagnosis time, or obe- sity (Table 3). Although femur and lumbar T-scores were low both before and after treatment in the menopausal group, the difference was not significant (Table 4). Vitamin D val- ues of non-menopausal patients increased significantly com- pared to menopausal patients (P=0.044). When analyzing glucocorticoid dose categories, a significant decrease in fe- mur T-scores was observed in patients receiving moderate doses, while a significant decrease in lumbar T-scores was found in the high-dose group (P=0.000 and P=0.018, respec- tively). No significant decrease in T-scores was observed in the low-dose group (Table 5). Conclusions This study describes the change in bone mineral density sta- tus in a population of 66 PV patients treated with glucocor- ticoids. Although corticosteroids have been prioritized with rituximab in the treatment of moderate-to-severe pemphigus vulgaris in recent years, they are still among the chronically used medications [5]. Previous studies have shown that oste- oporosis, one of the well-known side effects of systemic glu- cocorticoids, is increased in PV patients compared to healthy volunteers even before treatment [11]. This difference could not be confirmed in our case series since our study lacked a control group. Similar to our study, Marzano et al. found that PV patients have lower serum calcium and vitamin D levels compared to controls before treatment. Along with this result, they suggested that low vitamin D might play a role in the pathogenesis of pemphigus vulgaris [12,13]. Although the absence of a significant decrease in calcium and vitamin D levels post-treatment suggests that prophylaxis may be ad- equate, low vitamin D levels before treatment, malnutrition, Table 1. Characteristics of the Study Population. Variable Total (N=66) Mean (SD) Male (N=27) Mean (SD) Female (N=39) Mean (SD) P-value Age (years) 53.83 (16.15) 54.8 (14.9) 53.15 (17.06) 0.685 BMI (mg/m2) 27.61 (5.06) 26.7 (3.72) 28.2 (5.79) 0.228 Time before diagnosis (months) 10.14 (13.89) 10.78 (12.7) 9.69 (14.7) 0.758 Cumulative prednisone dose (mg) 6190.08 (3598.4) 6828.8 (4030.1) 5747.88 (3247.4) 0.233 Daily prednisone dose (mg) 16.95 (16.10) 20.78 (10.84) 17.76 (9.53) 0.236 Abbreviations: BMI = body mass index; SD = standard deviation. Table 2. Comparison of T-scores and Laboratory Values Before and After Treatment. Variable Before Treatment Mean ± SD After Treatment Mean ± SD P-value Lumbar T-score −0.91 ± 1.56 −1.06 ± 1.44 0.102 Femur T-score −0.64 ± 1.10 −0.87 ± 1.09 0.001 ALP 69.90 ± 26.22 68.83 ± 22.87 0.724 Calcium 9.43 ± 0.48 9.41 ± 0.48 0.819 Vitamin D 34.64 ± 15.62 39.49 ± 19.40 0.018 LDH 203.03 ± 41.79 232.01 ± 59.54 <0.001 Abbreviations: ALP = alkaline phosphatase; LDH = lactate dehydrogenase; SD = standard deviation. 4 Original Article | Dermatol Pract Concept. 2025;15(2):5050 T ab le 3 . C om pa ri so n of B on e M in er al D en si ty V al ue s B ef or e an d A ft er T re at m en t A cc or di ng t o Se x an d B od y M as s In de x. V ar ia bl e Se x M ea n ± SD B od y M as s In de x M ea n ± SD M al e Fe m al e P- va lu e ≥3 0 m g/ m 2 <3 0 m g/ m 2 P- va lu e Fe m ur T -s co re B ef or e -0 .6 7± 0. 93 -0 .6 1± 1. 22 0. 82 4 -0 .4 3± 1. 06 -0 .7 4± 1. 12 0. 29 3 A ft er -0 .7 0± 1. 06 -0 .9 8± 1. 12 0. 31 8 -0 .8 1± 0. 89 -0 .8 9± 1. 19 0. 78 5 L um ba r T- sc or e B ef or e -0 .7 9± 1. 41 -1 .0 0± 1. 67 0. 60 3 -0 .7 7± 1. 53 -0 .9 9± 1. 59 0. 59 8 A ft er -0 .8 2± 1. 21 -1 .2 3± 1. 57 0. 25 6 -1 .1 ±1 .3 9 -1 .0 5± 1. 48 0. 89 6 A L P B ef or e 69 .0 7± 25 .5 6 70 .4 8± 26 .9 9 0. 83 2 77 .8 1± 35 .2 5 65 .9 ±1 9. 61 0. 15 3 A ft er 69 .8 5± 22 .6 6 68 .1 2± 23 .2 9 0. 76 5 70 .6 3± 24 .3 1 67 .9 3± 22 .3 5 0. 65 4 C al ci um B ef or e 9. 45 ±0 .3 8 9. 41 ±0 .5 5 0. 79 2 9. 4± 0. 31 9. 44 ±0 .5 6 0. 79 2 A ft er 9. 41 ±0 .3 9 9. 41 ±0 .5 5 0. 97 5 9. 38 ±0 .5 1 9. 43 ±0 .4 7 0. 73 5 V it am in D B ef or e 41 .7 4± 15 .1 2 29 .7 2± 14 .1 6 0. 00 2 35 .1 3± 14 .3 3 34 .3 9± 16 .3 8 0. 85 8 A ft er 46 .8 9± 21 .4 8 34 .3 6± 16 .2 0 0. 01 4 38 .6 5± 18 .4 1 39 .9 1± 20 .0 8 0. 80 7 L D H B ef or e 20 2. 51 ±3 8. 86 20 3. 38 ±4 4. 20 0. 93 5 20 6. 86 ±4 1. 29 20 1. 11 ±4 2. 38 0. 60 2 A ft er 21 8. 96 ±4 1. 83 24 1. 05 ±6 8. 28 0. 10 9 23 5. 31 ±5 6. 67 23 0. 36 ±6 1. 50 0. 75 3 A bb re vi at io ns : A L P = al ka lin e ph os ph at as e; L D H = la ct at e de hy dr og en as e; S D = s ta nd ar d de vi at io n. Original Article | Dermatol Pract Concept. 2025;15(2):5050 5 Table 4. Comparison of Bone Mineral Density Values Before and After Treatment According to Menopausal State. Variable Menopausal State Mean ± SD Menopausal Non-Menopausal P-value Femur T-score Before -0.66±1.30 -0.61±0.93 0.869 After -0.97±1.25 -0.78±0.96 0.493 Lumbar T-score Before -1.17±1.76 -0.70±1.36 0.224 After -1.25±1.74 0.91±1.13 0.370 ALP Before 71.76±24.88 68.36±27.55 0.603 After 70.23±25.24 67.66±20.99 0.653 Calcium Before 9.37±0.51 9.48±0.46 0.353 After 9.40±0.51 9.42±0.47 0.823 Vitamin D Before 30.54±14.91 38.06±15.58 0.051 After 34.25±17.15 43.85±20.31 0.044 LDH Before 207.60±41.58 199.22±42.17 0.422 After 246.86±68.01 219.63±49.04 0.064 Abbreviations: ALP = alkaline phosphatase; LDH = lactate dehydrogenase; SD = standard deviation. Table 5. Comparison of T-scores Before and After Treatment According to Dose Categories. Before Treatment Mean (SD) After Treatment Mean (SD) P-value Low Dose Femur T-score -0.49 (0.89) -0.4 (1.11) 0.571 Lumbar T-score -0.63 (1.25) -0.6 (1.47) 0.908 Medium dose Femur T-score -0.8 (1.13) -1.02 (1.09) 0.000 Lumbar T-score -1.26 (1.5) -1.24 (1.47) 0.785 High dose Femur T-score -0.2 (1.15) -0.79 (1.02) 0.018 Lumbar T-score -0.01 (1.73) -0.89 (1.29) 0.059 Abbreviation: SD = standard deviation. and pre-existing inflammation may contribute to the sig- nificant decrease in femur T-scores in PV patients and that there may be a need to initiate additional anti-resorptive treatments earlier [12,14,15]. Additionally, glucocorticoids directly affect osteoclasts and osteoblasts, reducing bone mineral density, which negatively contributes to the current condition of bone mineral density [16-18]. This study has po- tential limitations. First, the retrospective design of our study limited our ability to clearly evaluate the presence of malnu- trition in the patients. The compliance with physical activity and dietary follow-up could not be monitored. Second, the lack of control group limits establishing causal relationships and comparing outcomes with alternative treatment strat- egies. Third, since disease severity was not included in the study, its relationship with bone mineral density could not be determined. Van Staa et al. demonstrated that the risk of 6 Original Article | Dermatol Pract Concept. 2025;15(2):5050 Venereol. 2015;29(3):405-414. DOI: 10.1111/jdv.12772. PMID: 25338479. 7. Armas LA, Recker RR. Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol Metab Clin North Am. 2012;41(3):475-486. DOI: 10.1016/j.ecl.2012.04.006. PMID: 22877425. 8. Humphrey MB, Russell L, Danila MI, et al. 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2023;75(12):2088-2102. DOI: 10.1002/art.42646. PMID: 37845798. 9. Park SY, Gong HS, Kim KM, et al. 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The Study of Osteoporotic both hip and vertebral fractures was significantly higher in patients receiving moderate-to-high daily doses of glucocor- ticoids (7.5 mg and above) compared to those on low doses (below 2.5 mg) [19]. Although fracture incidence was not included in our study, previous studies have shown that low BMD is a crucial determinant of fragility fractures, and DXA measurements of BMD are strong predictors of fracture risk in individuals [20-22]. Patients with a BMI < 30 kg/m² had lower femur and lumbar T-scores before treatment com- pared to those with a BMI > 30 kg/m². After treatment, the BMD scores decreased in both groups, with no significant difference between them. Previous studies have shown that a low body mass index causes osteoporosis and a decrease in BMD [23]. 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