Dermatology: Practical and Conceptual


Original Article | Dermatol Pract Concept. 2023;13(2):e2023121 1

Skeletal Side Effects of Systemic Isotretinoin 
Treatment: Do They Depend on Age, Gender, 

Treatment Duration, Daily Dose and 
Isotretinoin-Naiveness?

Defne Özkoca1, Nazlı Caf2, Nazan Nur Alacagöz Yılmaz3, Tuğba Kevser Uzunçakmak4, 
Ayşenur Özdil5, Ayşe Nilhan Atsü6

1 Zonguldak Atatürk State Hospital, Dermatology and Venerology Clinic, Zonguldak, Turkey

2 Diyarbakır Dağkapı Military Hospital, Dermatology and Venerology Clinic, Diyarbakır, Turkey

3 Zonguldak Atatürk State Hospital, Physical Therapy and Rehabilitation Clinic, Zonguldak, Turkey

4 Şişli Memorial Hospital, Dermatology and Venerology Clinic, İstanbul, Turkey

5 İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Department of Public Health, İstanbul, Turkey

6 İstanbul Kent University, Department of Dermatology and Venerology, İstanbul, Turkey

Key words: acne vulgaris, fatigue, low back pain, isotretinoin, myalgia

Citation: Özkoca D, Caf N, Alacagöz Yılmaz NN, Uzunçakmak TK, Özdil A, Atsü AN. Skeletal Side Effects of Systemic Isotretinoin 
Treatment: Do They Depend on Age, Gender, Treatment Duration, Daily Dose and Isotretinoin-Naiveness? Dermatol Pract Concept. 
2023;13(2):e2023121. DOI: https://doi.org/10.5826/dpc.1302a121

Accepted: November 14, 2022; Published: April 2023

Copyright: ©2023 Özkoca 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: Defne Özkoca, MD, Zonguldak Atatürk Devlet Hastanesi, Site Ek Binası, Bahçelievler, Zonguldak, Turkey.  
Phone: 00905366561000 E-mail: defneozkoca@yahoo.com

Introduction: Systemic isotretinoin is the most effective treatment modality in acne vulgaris; however, 
both patients and physicians hesitate to use it due its side effects.

Objectives: The aim of this study is to determine the prevalence of fatigue, myalgia and low back pain 
during systemic isotretinoin treatment; and to determine their relationship with age, gender, treatment 
duration, daily isotretinoin dose and isotretinoin-naiveness of the patient.

Methods: This is a cross sectional study including the acne vulgaris patients, aged between 13 to 
40 years, who have at least received one month of oral isotretinoin treatment. Patients were questioned 
for side effects during their follow-up visits; a physical therapy and rehabilitation specialist further 
evaluated patients complaining of low back pain.

Results: Fatigue was reported by 4.4% of the patients, myalgia by 2.8% and low back pain by 25% of 
the patients; 2.2% had inflammatory and 22.8% had mechanical low back pain. None of the patients 

ABSTRACT



2 Original Article | Dermatol Pract Concept. 2023;13(2):e2023121

Introduction

Systemic isotretinoin (13-cis retinoic acid) is the most ef-

fective treatment modality for acne vulgaris given that it is 

the only treatment method that targets all four of the major 

etiological factors of acne vulgaris. The US Food and Drug 

Administration have approved its use for the treatment of 

severe acne vulgaris in 1982 [1]. The common side effects of 

systemic isotretinoin treatment are cheilitis, xerosis, xeroph-

thalmia, and myalgias. Its tendency for causing depression, 

and suicidal ideation still remains controversial [2]. Arthral-

gia may also be experienced by the patients during systemic 

isotretinoin therapy; 20% of the patients complain of either 

myalgia or arthralgia [3]. Inflammatory low back pain is a 

very common side effect of systemic isotretinoin therapy; 

sacroiliitis and tendinitis may also occur although much 

rare. The low back pain ceases with dose reduction [4,5].

Objectives

The aim of this study is to determine the incidence of fatigue, 

myalgia and low back pain (inflammatory or mechanical) 

in acne vulgaris patients receiving oral isotretinoin therapy; 

and to determine the relationship of these side-effects to the 

age and the gender of the patient, the isotretinoin dosing reg-

imen, the duration of isotretinoin therapy and the isotreti-

noin-naiveness of the patient.

Methods

Patient Selection

Acne vulgaris patients, aged between 13 to 40 years, who have 

at least received one month of oral isotretinoin treatment in 

the dermatology outpatient clinic of Zonguldak Atatürk State 

Hospital and who were willing to participate in this study 

were included in this cross-sectional study. Patients with al-

ready diagnosed rheumatic diseases, musculoskeletal diseases, 

inflammatory bowel disease, hormonal disturbances, psychi-

atric comorbidities and who were using non-steroidal anti-in-

flammatory drugs regularly were excluded from this study.

Data Acquisition

The blood chemistry including lipids and beta-human cho-

rionic globulin (for female patients only) of the patients 

receiving oral isotretinoin were evaluated during monthly 

consultations. The age, gender, isotretinoin dosage (mg/kg/

day), treatment duration (weeks) and whether the patient is 

using isotretinoin the first or the second time for acne vul-

garis were noted during the monthly consultations. The pa-

tients were questioned for the presence of fatigue, myalgia 

or low back pain; and the patients with low back pain were 

referred to the physical therapy and rehabilitation outpatient 

clinic for further evaluation.

The physical therapy and rehabilitation specialist has 

evaluated the patients to determine the character of low back 

pain (inflammatory or mechanical) along with performing 

physical examination of the range of motion, muscle power 

and lordosis. Magnetic resonance imaging of the lumber ver-

tebrae was performed on the patients who had inflammatory 

low back pain in order to evaluate sacroiliitis.

Statistical Analysis

SPSS version 21 was used for the statistical analyses. 

Mann-Whitney U test was used to determine the relation-

ship of age, isotretinoin dosage and treatment duration to 

all of the side effects studied (fatigue, myalgia and low back 

pain). Pearson chi-square test was used to determine the re-

lationship of gender to fatigue and low back pain; and of 

isotretinoin-naiveness to low back pain. Fisher exact test was 

used to determine the relationship of gender to myalgia; and 

of isotretinoin-naiveness to fatigue and myalgia.

Ethics

The approval of İstanbul Kent University Ethics Committee 

was obtained before the initiation of the study (27.05.2022). 

Informed consent was taken from all of the patients who 

were willing to participate in this study; and the study was 

conducted in accordance with the Helsinki Declaration.

Results

Patient Characteristics and Side Effects

A total of 180 patients were included in this study. The mean 

age of the patients was 20.3 years with a standard deviation 

of 5 years. Of all the patients, 57 (31.7%) were male and 

123 (68.3%) were female. Fatigue was reported by 8 (4.4%) 

of the patients, myalgia by 5 (2.8%) and low back pain by 

45 (25%) of the patients. Four (2.2%) of the patients were 

diagnosed with inflammatory low back pain by the physical 

therapy and rehabilitation specialist; and 41 (22.8%) were 

had sacroiliitis. All the side effects that were examined were found to be independent of age, gender, 
isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness.

Conclusions: The side effects are not as common as feared; thus, patients and physicians should not 
hesitate to use systemic isotretinoin in indicated cases.



Original Article | Dermatol Pract Concept. 2023;13(2):e2023121 3

diagnosed with mechanical low back pain. The mean isotreti-

noin treatment duration was 9.6 weeks with a standard devi-

ation of 6.7 weeks; the mean isotretinoin dosage was 0.582 

mg/kg/day with a standard deviation of 0.18 mg/kg/day; and 

144 (80%) of the patients were isotretinoin-naïve, whereas 

36 (20%) were using isotretinoin for the second time. Patient 

characteristics and side effects are summarized in Table 1.

Relationship of Side Effects to Patient 
Characteristics

Fatigue, myalgia and low back pain were the side effects 

that were examined in this study. All of the side effects that 

were examined were found to be independent of age, gen-

der, isotretinoin dosage (mg/kg/day), treatment duration and 

isotretinoin-naiveness. The relationships of side effects to the 

patient characteristics are summarized in Table 2.

Character of the Low Back Pain

The patients with low back pain were further examined for 

the character of low back pain by the physical therapy and 

rehabilitation specialist. Within the patients with low back 

pain, only 4 (8.9%) had inflammatory low back pain. There 

was no statistically significant relationship between the age 

of the patient, gender of the patient, isotretinoin dosage 

(mg/kg/day), treatment duration (weeks) and isotretinoin- 

naiveness of the patient; and the character of low back pain. 

Table 3 summarizes the relationship of the character of low 

back pain to the patient characteristics.

Table 1. Patient characteristics and side effects.

Patient characteristics N=180
Age

Mean ± SD
Median (IQR)

20.3 ± 5
20 (17 – 22)

Gender, N (%)

Male
Female

57 (31.7)
123 (68.3)

Side Effects, N (%)

Fatigue
Myalgia
Low Back Pain

8 (4.4)
5 (2.8)
45 (25)

Character of Low Back Pain, N (%)

Inflammatory
Mechanical

4 (2.2)
41 (22.8)

Treatment Duration (Weeks)

Mean ± SD
Median (IQR)

9.6 ± 6,7
8 (4 – 12)

Isotretinoin Naiveness, n (%)

Naive
Not Naive

144 (80)
36 (20)

Isotretinoin dosage (mg/kg/day)

Mean ± SD
Median (IQR)

0.582 ± 0.18
0.565 (0.5 – 0.695)

IQR = interquartile range; SD = standard deviation.

Table 2. Relationship of side effects to patient characteristics.

FATIGUE MYALGIA LOW BACK PAIN

Present Absent Present Absent Present Absent

Mean Age ±,SD
Median (Range) in years

19.8 ± 2
20 (18 -21)

20.3 ± 5.1
20 (17 – 22)

21.6 ± 2
21 (20 – 23,5)

20.3 ± 5.1
20 (17 – 22)

19.3 ± 4.2
19 (16 – 21)

20.6 ± 5.3
20 (17 – 22)

P 0.906a 0.162 a 0.1 a

Gender

Male
Female

2 (25)
6 (75)

55 (32)
117 (68)

0 (0)
5 (100)

57 (32.6)
118 (67.4)

14 (31.1)
31 (68.9)

43 (31.9)
92 (68.1)

P 0.678 b 0.181 c 0.926 b

Isotretinoin dosage (mg/
kg/day)

0.625 ± 0.2
0.58

(0.46 – 0.73)

0.58 ± 0.2
0.57

(0.5 – 0.68)

0.582 ± 0.2
0.6

 (0.4 – 0.76)

0.582 ± 0.2
0.56

(0.5 – 0.68)

0.599 ± 0.2
0.6

(0.5 – 0.69)

0.576 ± 0.2
0.5

(0.44 – 0.7)

P 0.608 a 0.951 a 0.23 a

Treatment duration (weeks) 9.9 ±8.7
4 (4 – 19)

9.6 ± 6.7
8 (4 – 12)

13.6 ± 9.2
16 (4 – 22)

9.5 ± 6.7
8 (4 – 12)

8.9 ± 6.7
8 (4 – 12)

9.8 ± 6.8
8 (4 – 12)

P 0.583 a 0.324 a 0.391 a

Isotretinoin-naiveness
Naive
Not Naive

7 (87.5)
1 (12.5)

137 (79.7)
35 (20.3)

5 (100)
0 (0)

139 (79.4)
36 (20.6)

38 (84.4)
7 (15.6)

106 (78.5)
29 (21.5)

P 1 c 0,585 c 0,389 b

a Mann Whitney U test; 2Pearson chi-squared test; c Fisher exact test.

Conclusions

Systemic isotretinoin therapy is known to have side effects in 

many organ systems, including the musculoskeletal system 



4 Original Article | Dermatol Pract Concept. 2023;13(2):e2023121

average doses prescribed in the literature: 0.6 mg/kg/day, 

0.55 mg/kg/day and 0.53 mg/kg/day[4,11,12]. There was no 

relationship between the daily dose of systemic isotretinoin 

treatment and the prevalence of the side effects. In alignment 

with this result, Karaosmanoğlu and Mülkoğlu also con-

cluded that there is no correlation between the cumulative 

dosage of isotretinoin and the severity of low back pain [8].

Previously in the literature, Acar et al reported that low 

back pain was more common in male patients and pain 

severity increased with increasing age [4]. In contrast, this 

study revealed that the side effects of systemic isotretinoin 

treatment are independent of age and gender. Our study also 

revealed that side effects of systemic isotretinoin are inde-

pendent of the treatment duration and isotretinoin naiveness 

of the patient.

Although systemic isotretinoin treatment is the most ef-

fective treatment modality for acne vulgaris, both patients 

and prescribing physicians express fear about the side ef-

fects [13]. Compared to the previous literature, we report a 

lower prevalence of fatigue and musculoskeletal side effects 

(namely myalgia and low back pain) and no case of sacro-

iliitis in our patient population, which supports the use of 

systemic isotretinoin in indicated cases of acne vulgaris. Fur-

thermore, we also report that side effects of isotretinoin treat-

ment are independent of age, gender, daily isotretinoin dose, 

treatment duration and isotretinoin naiveness of the patient.

Fatigue, myalgia and low back pain can be observed 

during systemic isotretinoin treatment. These side effects 

are independent of the patient age, gender, daily systemic 

isotretinoin dosage, treatment duration and isotretinoin-na-

iveness of the patient. The side effects are not that common; 

thus, patients and physicians should not hesitate to use sys-

temic isotretinoin in indicated cases.

[6,7]. Low back pain has been reported to be a common 

side effect of systemic isotretinoin therapy in the literature 

[5,8]. Low back pain can be categorized into two groups: 

inflammatory, and mechanical low back pain [9]. Approxi-

mately 16 percent of the patients receiving systemic isotreti-

noin therapy develop musculoskeletal side effects including 

myalgia, arthralgia and low back pain. Although rare, sac-

roiliitis can also be observed in patients receiving systemic 

isotretinoin therapy, which can be classified as a cause of 

inflammatory low back pain [10].

In this study, 45 patients (25%) have reported low back 

pain; of which 4 (2.2%) have been diagnosed with inflam-

matory low back pain and 41 (22.8%) have been diagnosed 

with mechanical low back pain by the physical therapy and 

rehabilitation specialist. None of the patients were diag-

nosed with sacroiliitis. Previous studies on this subject have 

reported a prevalence of low back pain, among patients re-

ceiving systemic isotretinoin treatment, of 78.7%, 46.9%, 

49.3% and 10.4% [4,5,11,12]. Among the patients with 

low back pain, 60.3%, 54.7% and 44%1 had inflamma-

tory low back pain [4,11,12]. We report a lower prevalence 

of low back pain and inflammatory low back pain due to 

systemic isotretinoin use compared to most of the studies in 

the literature.

In our patient population, the prevalence of fatigue 

was 4.4% and of myalgia was 2.8%. In the literature, fa-

tigue has been reported to have a prevalence of 54% and of 

50.7% [11,12]; myalgia has been reported to have a preva-

lence of 46.9% and 42.5% [11,12] Again, we report a lower 

prevalence of fatigue and myalgia due to systemic isotreti-

noin therapy compared to the literature.

The average daily dose of systemic isotretinoin pre-

scribed in our study (0.582 mg/kg/day) is similar to the 

Table 3. Relationship of the character of low back pain to patient characteristics.

Character of low back pain

PInflammatory (N = 4) Mechanical (N = 41)

Age 22.8 ± 9.7
19 (16.3 – 33)

19 ± 3.4
19 (16 – 21)

0.631a

Gender

Male
Female

3 (21.4)
1 (3.2)

11 (78.6)
30 (96.8)

0.082 b

Isotretinoin dose (mg/kg/day) 0.593 ± 0.1
0.585 (0.5 – 0.693)

0.599 ± 0.2
0.6 (0.5 – 0.695)

0.967 a

Treatment Duration (weeks) 6.3 ± 6.7
4 (1.75 – 13)

9.2 ± 6.7
8 (4 – 12)

0.234 a

Isotretinoin Naiveness

Naive
Not naive

3 (7.9)
1 (14.3)

35 (92.1)
6 (85.7)

0.505 b

a Mann Whitney U test; b Fisher exact test.



Original Article | Dermatol Pract Concept. 2023;13(2):e2023121 5

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