Abstract
Background:
Prior studies have linked bone marrow density (BMD) with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, the risk of BMD loss and associated factors in relapsing remitting MS (RRMS) and NMOSD patients remains insufficiently evaluated. The objective of this study was to assess the risk of osteopenia and osteoporosis and identify associated factors in RRMS and NMOSD.
Methods:
This matched case-control study was conducted in Isfahan, Iran, between November 2022 and November 2023. Patients diagnosed with RRMS and NMOSD, along with healthy controls (HCs), underwent densitometry of the femoral neck and lumbar spine regions. Osteopenia and osteoporosis were defined according to the WHO criteria, and associated risk factors were identified through logistic and linear regression analyses.
Results:
The 30 RRMS and 30 NMOSD patients, as well as 35 age- and sex-matched healthy controls (HCs), were included. The odds of osteopenia or osteoporosis did not significantly differ between RRMS patients and HCs (odds ratio (OR) =1.7, P = 0.34). In contrast, NMOSD patients had a higher probability of developing these conditions than HCs (OR = 3.3, P = 0.02). BMD loss in RRMS was associated significantly with alkaline phosphatase (ALP) levels (OR = 1.1, P = 0.013), while in NMOSD, significant relationships were found with age (OR = 1.3, P = 0.013), EDSS (OR = 3.4, P = 0.02), physical activity (OR = 0.2, P = 0.02), ALP (OR = 1.2, P = 0.02), 25-hydroxy Vitamin D (vitamin D3) (OR = 0.9, P = 0.034), and phosphorus levels (OR = 0, P = 0.004).
Conclusions:
Although no association was found between RRMS and BMD loss, NMOSD increased the risk of BMD loss threefold compared with HCs. Clinicians are advised to routinely evaluate these patients and their risk factors for BMD loss and implement preventive measures accordingly.
Keywords: Bone mineral density, multiple sclerosis, neuromyelitis optica spectrum disorder, osteopenia, osteoporosis
Introduction
Multiple sclerosis (MS) is a chronic neurological disorder characterized by neuroinflammation and neurodegeneration, which affects a global population exceeding 2.8 million individuals.[1] People with MS (PwMS) exhibit diverse clinical presentations, and various demographic, clinical, and paraclinical risk factors have been linked to unfavorable long-term prognoses.[2] The majority of PwMS are first diagnosed with the relapsing-remitting subtype (RRMS), which is marked by episodes of acute neurological deterioration (relapse) followed by either full or partial recovery.[1] In MS, pathological demyelination, inflammation, and axonal injury impair neuronal conduction, leading to muscle weakness, sensory disturbances, and visual and balance deficits.[3] PwMS exhibit an elevated risk of osteoporosis and decreased bone mineral density, which, in combination with disease-related functional impairments, significantly increases their susceptibility to fractures.[4]
Osteoporosis, a progressive bone disorder, is particularly common in PwMS, largely due to sustained disability and reduced mechanical bone loading.[5,6] Both men and women diagnosed with MS exhibit a greater susceptibility to osteoporosis.[7,8] According to a meta-analysis, the overall prevalence of osteoporosis and osteopenia in PwMS was shown to be 14% and 41%, respectively.[9] The progression of osteoporosis in PwMS can be attributed primarily to the cumulative effects of diverse factors.[4] Osteoporosis in PwMS can be attributed mainly to physical inactivity, vitamin D3 deficiency, a chronic inflammatory process, glucocorticoids, anticonvulsants, and other medications.[10,11,12,13] Dual-energy X-ray absorptiometry (DEXA) is the established diagnostic method for osteoporosis. This method evaluates bone density in proportion to bone area and presents findings using T- and Z-scores. Osteoporosis is characterized by a T-score of -2.5 standard deviations or less, while osteopenia falls within the range of T-scores between -1 and -2.5.[8]
Neuromyelitis optica spectrum disorder (NMOSD) represents inflammatory disorders of the central nervous system (CNS), primarily impacting the optic nerves and spinal cord, with occasional brainstem involvement. These disorders precipitate acute episodes of optic neuritis, myelitis, and brainstem encephalitis.[14] NMOSD is commonly associated with pathogenic immunoglobulin-G (IgG) antibodies directed against aquaporin-4 (AQP4), the principal water channel in the CNS.[15,16,17] Moreover, NMOSD-IgG results serve to differentiate NMOSD from MS.[17] NMOSD-AQP4 patients may encounter mobility problems, reduced engagement in weight-bearing activities, heightened susceptibility to falls, and prolonged steroid therapy, all recognized as contributing factors to decreased bone mineral density (BMD).[18,19]
Comparing bone health in RRMS and NMOSD is particularly important because, despite similar demographic features, they involve distinct inflammatory mechanisms. Unlike progressive MS, where bone loss is mostly a result of long-term disability, RRMS and NMOSD provide a chance to explore how inflammation alone may contribute to early bone loss before major mobility issues develop.
The risk of osteopenia and osteoporosis and associated contributors in RRMS and NMOSD patients have not been thoroughly evaluated yet. Hence, the objective of the study was to explore the risk of osteopenia and osteoporosis among RRMS and NMOSD patients as well as to determine the relationship between multiple demographic and clinical features of RRMS and NMOSD patients and osteopenia and osteoporosis in comparison to healthy controls (HCs).
Methods and Materials
Participants
This study comprised an age- and sex-matched case-control design conducted at the MS clinic of Kashani Hospital, Isfahan, Iran, between November 2022 and November 2023. In this study, 30 PwMS, 30 NMOSD patients, and 35 HCs were recruited. Participants were selected based on the following inclusion criteria: 1) fulfilling the diagnostic criteria outlined in the 2017 McDonald criteria[20] for PwMS and confirming the course of RRMS,[21] and the International Consensus diagnostic criteria for NMOSD patients,[22] 2) having an Expanded Disability Status Scale (EDSS)[23] score of less than 7, and 3) aged 18 to 50 years. A group of HCs, aged 18 to 50, was recruited from clinic visitors undergoing routine screenings and clinic staff members who did not have chronic conditions such as neurological, autoimmune, cardiovascular diseases, cancers, debilitating disorders, medications, or any disorder that can affect bone mineral density (BMD). Controls were individually matched with each case, ensuring similarity in age (within ± 5 years) and gender.
Subjects fulfilling the following conditions were excluded: 1) people with acute relapse in a recent year; 2) participants with corticosteroids administrating in a recent year; 3) those with a medical history encompassing acute or chronic disease, including autoimmune disorders, neurological disorders, metabolic disorders, and endocrine disorders; 4) individuals with congenital bone and skeletal abnormalities; and 5) participants experiencing menopause.
Data collection
Sociodemographic and clinical characteristics
A structured face-to-face interview was conducted with each case and their respective matched control, employing a structured questionnaire to gather data on the following: 1) Sociodemographic details, encompassing age, gender, body mass index (BMI), physical activity (using Persian version of Baecke Habitual Physical Activity Questionnaire[24]), and smoking habits; 2) disease-related inquiries, including disease duration, initial and current EDSS scores[23] (which was confirmed by a neurologist), MS subtype, and utilization of disease-modifying therapies (DMTs), as well as any dietary supplements administered; and 3) comorbidity conditions such as osteopenia, osteoporosis, hypothyroidism, and sleep disorders were also documented.
Bone mineral densitometry
BMD was assessed using dual-energy X-ray absorptiometry (DEXA) with a Hologic Discovery Wi device (Hologic Inc., Bedford, MA, USA). Prior to data collection, the system underwent daily calibration according to the manufacturer’s protocol, and all scans were performed under the supervision of a board-certified radiologist with extensive experience in densitometry. A trained technician with certification in bone densitometry conducted the scans, following the International Society for Clinical Densitometry (ISCD) guidelines.
Measurements were obtained at three anatomical sites: total hip, femoral neck, and lumbar spine (L2–L4). The results were reported as absolute BMD values (g/cm²), T-scores, and Z-scores. In line with World Health Organization (WHO) criteria, osteoporosis was defined as a T-score ≤ –2.5, and osteopenia as a T-score between –1.0 and –2.5. T-scores compare the patient’s BMD to the peak bone mass of a young healthy reference population, while Z-scores reflect deviations from the mean BMD of an age- and sex-matched population.
To enhance the assessment of bone microarchitecture, the trabecular bone score (TBS) was also analyzed using TBS iNsight software (version 3.0.2.0; Medimaps, Merignac, France). Quality assurance and control protocols were strictly followed throughout the study, with oversight by a qualified medical physicist to ensure the reliability and reproducibility of the measurements. Potential confounders such as age and sex were carefully considered during the interpretation of T- and Z-scores. Z-scores, in particular, allowed us to account for physiological BMD variations related to these demographic factors, and statistical analyses were adjusted accordingly to minimize bias.
Laboratory analysis
Upon the patient’s arrival at the clinic, a comprehensive array of blood tests from the cubital blood sample, including assessments for total 25-hydroxy vitamin D (25(OH) D or vitamin D3), parathyroid hormone (PTH) levels, and bone turnover markers (alkaline phosphatase (ALP), calcium, and phosphorus), was conducted. Fasting serum samples obtained between 7:00 AM and 8:00 AM from participants were used for biochemical analyses. Within 30 minutes of collection, the samples underwent centrifugation, followed by freezing and storage at -80°C until markers were analyzed.
The serum levels of calcium, phosphorus, ALP, and PTH were evaluated using the spectrophotometry method by Olympus AU480 (Beckman Coulter, Inc.). Furthermore, serum levels of vitamin D3 were assessed using enzyme-linked immunosorbent assay (ELISA) by a commercial kit (Pars Peyvand Co, Iran). Reference values of vitamin D3 included a normal level (>30 ng/ml; >75 nmol/l), insufficiency (20-30 ng/ml; 50-75 nmol/l), and vitamin D3 deficiency.
Statistical analysis
To ensure adequate statistical power, we calculated the sample size using G*Power software version 3.1.9.7 for Windows, informed by prior related studies.[25,26] The normality of the data distribution was evaluated through the Shapiro–Wilk test, Q-Q plot, and P-P plot. Categorical variables were represented as frequency (%), while continuous variables were depicted as mean ± SD. Regarding comparing data of groups, one-way analysis of variance (ANOVA) was utlized for normally distributed data, while Kruskal–Wallis and Chi-square tests were utilized for non-normally distributed data.
Subsequently, unadjusted univariate logistic regression analyses were executed for each group to explore potential factors associated with osteopenia or osteoporosis. All data analyses were executed using IBM SPSS for Windows (Version 26, Statistical Package for Social Sciences). The level of significance was established at P < 0.05.
Result
Study populations
A total of 30 RRMS patients, 30 NMOSD patients, and 35 age- and sex-matched HCs were included in this study. The median (interquartile range (IQR)) ages of RRMS (86.7% female), NMOSD (76.7%) patients, and HCs (77.1% female) were 37 (33, 41), 36 (33.5, 42.3), and 34 (30, 47), respectively. The median (IQR) EDSS of RRMS patients was 0 (0-2) at the time of BMD assessment, while it was 1.5 (1-2.5) in NMOSD patients. The mean disease duration of RRMS and NMOSD patients was nearly 6.5 and 10 years, respectively. There was no significant difference in the physical activity of RRMS (F = 0.1, P value = 0.79) and NMOSD (F = 0.2, P value = 0.67) patients with HCs. RRMS and NMOSD patients administrated more vitamin D3 supplements than HCs (Chi2 = 8, P value = 0.007 and Chi2 = 6.2, P value = 0.017, respectively). 11 (36.6%) of NMOSD patients were aquaporin-4-IgG-positive. Table 1 presents further details on the demographic and clinical characteristics of participants.
Table 1.
Demographic and clinical characteristics of participants (n=95)
| Characteristics | Participants | Test Statistics (P) | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| RRMS (n=30) | NMOSD (n=30) | HCs (n=35) | RRMS vs. NMOSD | RRMS vs. HCs | NMOSD vs. HCs | |
| Sex, n (%) | ||||||
| Female | 26 (86.7) | 23 (76.7) | 27 (77.1) | Chi2=1 (0.506) | Chi2=1 (0.359) | Chi2=0 (1) |
| Age (y), median (IQR) | 37 (33, 41) | 36 (33.5, 42.3) | 34 (30, 47) | K-W H=0.4 (0.836) | K-W H=0.6 (0.437) | K-W H=0.3 (0.584) |
| Disease duration (years), mean (SD) | 10.3 (5.9) | 6.7 (4.4) | - | F=7.1 (0.124) | - | - |
| EDSS at Diagnosis, median (IQR) | 2 (1, 2) | 2 (2, 2.5) | - | K-W H=8.4 (0.004) | - | - |
| EDSS, median (IQR) | 1 (1, 3) | 2.5 (2, 3.5) | - | K-W H=6.7 (0.009) | - | - |
| BMI (kg/m2), median (IQR) | 23.8 (22.2, 26.5) | 22.7 (21.1, 23.6) | 25.8 (22.9, 28.1) | K-W H=4.3 (0.038) | K-W H=2.3 (0.129) | K-W H=11 (0.001) |
| Physical activity level, mean (SD) | 6.7 (1.2) | 6.6 (0.8) | 6.6 (0.6) | F=0.3 (0.601) | F=0.1 (0.792) | F=0.2 (0.67) |
| Disease modifying therapies | ||||||
| Interferon | 15 (50) | 0 (0) | - | - | - | - |
| Rituximab | 11 (36.6) | 26 (86.7) | - | - | - | - |
| Teriflunomide | 2 (6.7) | 0 (0) | - | - | - | - |
| Dimethyl fumarate | 2 (6.7) | 0 (0) | - | - | - | - |
| Azathioprine | 0 (0) | 4 (13.3) | - | - | - | - |
| Vitamin D3 Supplement Administration, n (%) | 26 (86.7) | 25 (83.3) | 19 (54.3) | Chi2=0.1 (1) | Chi2=8 (0.007) | Chi2=6.2 (0.017) |
| Comorbidities | ||||||
| Hypothyroidism, n (%) | 4 (13.3) | 8 (26.7) | 7 (20) | Chi2=1.7 (0.333) | Chi2=0.5 (0.526) | Chi2=0.4 (0.567) |
| Sleep disorder, n (%) | 8 (26.7) | 7 (23.3) | 10 (28.6) | Chi2=0.1 (1) | Chi2=0 (1) | Chi2=0.2 (0.779) |
| Smoking, n (%) | 6 (20) | 3 (10) | 7 (20) | Chi2=1.2 (0.472) | Chi2=0 (1) | Chi2=1.2 (0.319) |
Significant P-values are in bold. BMI: Body mass index, EDSS: Expanded disability status scale, HCs: Healthy controls, IQR: Interquartile range, K-W H: Kruskal-Wallis H, NMOSD: Neuromyelitis optica spectrum disorder, RRMS: Relapsing-remitting multiple sclerosis, SD: Standard deviation
Laboratory findings
Laboratory tests analysis revealed that RRMS patients had higher serum levels of PTH (Kruskal-Wallis H = 4.4, P value = 0.036) and vitamin D3 (Kruskal-Wallis H = 5.2, P value = 0.022) than HCs. On the other hand, NMOSD patients had higher ALP levels (F = 6.7, P value = 0.012) and lower phosphorus (F = 8.2, P value = 0.006) than HCs. It is noteworthy that calcium was not significantly different between RRMS patients and HCs (Kruskal-Wallis H = 0.2, P value = 0.64) and NMOSD patients and HCs (Kruskal-Wallis H = 0, P value = 0.94). Further laboratory findings are presented in Table 2.
Table 2.
Laboratory data of participants (n=95)
| Characteristics | Participants | Test Statistics (P) | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| RRMS (n=30) | NMOSD (n=30) | HCs (n=35) | RRMS vs. NMOSD | RRMS vs. HCs | NMOSD vs. HCs | |
| Calcium (mg/dl), median (IQR) | 9.1 (8.9, 9.2) | 9.1 (8.9, 9.3) | 9.2 (8.7, 9.4) | K-W H=0.3 (0.607) | K-W H=0.2 (0.639) | K-W H=0 (0.937) |
| Phosphorus (mg/dl), mean (SD) | 3.4 (0.4) | 3.3 (0.4) | 3.6 (0.4) | F=2.5 (0.118) | F=1.3 (0.26) | F=8.2 (0.006) |
| ALP (IU/L), mean (SD) | 148.7 (41.3) | 163.3 (42.4) | 139 (33.7) | F=1.8 (0.181) | F=1.1 (0.3) | F=6.7 (0.012) |
| PTH (pg/ml), median (IQR) | 42 (36, 58) | 39.5 (35.8, 50.1) | 37 (34, 45) | K-W H=1.1 (0.304) | K-W H=4.4 (0.036) | K-W H=1.8 (0.183) |
| Vitamin D3 (ng/ml), median (IQR) | 38.7 (31.8, 54) | 36.8 (25.5, 45.6) | 34 (26, 38) | K-W H=1.2 (0.28) | K-W H=5.2 (0.022) | K-W H=1.4 (0.236) |
| Vitamin D3, n (%) | ||||||
| Normal | 23 (76.7) | 19 (63.3) | 22 (62.9) | Chi2=1.3 (0.527) | Chi2=3.6 (0.168) | Chi2=2.5 (0.284) |
| Insufficient | 3 (10) | 5 (16.7) | 10 (28.9) | |||
| Deficiency | 4 (13.3) | 6 (20) | 3 (8.2) | |||
Significant P-values are in bold. ALP: Alkaline phosphatase, HCs: Healthy controls, IQR: Interquartile range, K-W H: Kruskal-Wallis H, NMOSD: Neuromyelitis optica spectrum disorder, PTH: Parathyroid hormone, RRMS: Relapsing-remitting multiple sclerosis, SD: Standard deviation
Bone marrow densitometry
There were no significant differences in the rates of osteopenia or osteoporosis between patients with RRMS patients and HCs (Chi2 = 0.9, P value = 0.42). In contrast, NMOSD patients exhibited higher rates of osteopenia or osteoporosis compared to HCs (Chi2 = 5.2, P value = 0.04). The only significant difference in BMD measurements was found in the lumbar spine Z-score, revealing lower values in NMOSD patients than HCs (F = 5.5, P value = 0.022). The other Z- and T-scores in the femoral neck and lumbar regions showed no significant differences among the groups (P value > 0.05 for all). The overview of bone marrow densitometry is shown in Table 3.
Table 3.
Characteristics of bone marrow densitometry of participants (n=95)
| Characteristics | Participants | Test Statistics (P) | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| RRMS (n=30) | NMOSD (n=30) | HCs (n=35) | RRMS vs. NMOSD | RRMS vs. HCs | NMOSD vs. HCs | |
| BMD, n (%) | ||||||
| Normal | 19 (63.3) | 14 (46.7) | 26 (74.3) | Chi2=2.1 (0.341) | Chi2=1.6 (0.455) | Chi2=5.2 (0.073) |
| Osteopenia | 10 (33.3) | 13 (43.3) | 7 (20) | |||
| Osteoporosis | 1 (3.4) | 3 (10) | 2 (5.7) | |||
| BMD, n (%) | ||||||
| Normal | 19 (63.3) | 14 (46.7) | 26 (74.3) | Chi2=1.7 (0.299) | Chi2=0.9 (0.422) | Chi2=5.2 (0.04) |
| Osteopenia or Osteoporosis | 11 (36.7) | 16 (53.3) | 9 (25.7) | |||
| Left Femoral Neck T-score, mean (SD) | -0.2 (0.8) | -0.3 (1.1) | -0.3 (1.2) | F=0.4 (0.527) | F=0.2 (0.648) | F=0 (0.878) |
| Left Femoral Neck Z-score, median (IQR) | -0.2 (-0.5, 0.4) | -0.6 (-1, 0.8) | 0.3 (-0.5, 1) | K-W H=1.1 (0.287) | K-W H=1.4 (0.236) | K-W H=3.1 (0.076) |
| Lumbar Spine T-score, mean (SD) | -0.3 (1) | -0.6 (1.2) | -0.3 (1.4) | F=1.1 (0.294) | F=0 (0.967) | F=1 (0.333) |
| Lumbar Spine Z-score, mean (SD) | -0.1 (0.9) | -0.5 (1.1) | -0.3 (1.4) | F=1.8 (0.188) | F=1.7 (0.195) | F=5.5 (0.022) |
Significant P-values are in bold. BMD: Bone marrow density, HCs: Healthy controls, IQRL Interquartile range, K-W H: Kruskal-Wallis H, NMOSD: Neuromyelitis optica spectrum disorder, RRMS: Relapsing-remitting multiple sclerosis, SD: Standard deviation
Risk of BMD loss in RRMS and NMOSD patients
According to the univariable logistic regression model, there was no significant difference in the chance of osteopenia or osteoporosis between RRMS patients and HCs (odds ratio (OR) =1.7, 95% CI: 0.6 to 4.8, P value = 0.34). At the same time, NMOSD patients exhibited increased odds of developing osteopenia or osteoporosis compared to HCs (OR = 3.3, 95% CI: 1.2 to 9.4, P value = 0.02). Furthermore, no significant difference was found in the likelihood of osteopenia or osteoporosis between RRMS and NMOSD patients (OR = 2, 95% CI: 0.7 to 5.5, P value = 0.3).
Factors affecting bone mineral density in RRMS and NMOSD
Based on univariable regression analyses, higher serum levels of ALP were associated with the odds of BMD loss in RRMS patients (OR = 1.1, 95% CI: 1 to 1.2, P value = 0.013). The probability of BMD loss exhibited marginally significant relationships with disease duration (OR = 1.1, 95% CI: 1 to 1.3, P value = 0.075), serum level of calcium (OR = 0.1, 95% CI: 0 to 1.4, P value = 0.085) and phosphorus (OR = 0.1, 95% CI: 0 to 1.2, P value = 0.072), vitamin D3 (OR = 1, 95% CI: 0.9 to 1, P value = 0.088), and sleep disorders (OR = 4.4, 95% CI: 0.8 to 4.6, P value = 0.088) in RRMS.
The univariable logistic regression model showed that patients with older ages (OR = 1.3, 95% CI: 1.1 to 1.5, P value = 0.013) and higher EDSS (OR = 3.4, 95% CI: 1.1 to 9.5, P value = 0.02) were at a higher chance of BMD loss in NMOSD. On the other side, some factors were significantly associated with reduced odds of osteopenia or osteoporosis, such as higher levels of phosphorus (OR = 0, 95% CI: 0 to 0.2, P value = 0.004), higher physical activity (OR = 0.2, 95% CI: 0.1 to 0.8, P value = 0.02), and higher serum level of vitamin D3 (OR = 0.9, 95% CI: 0.9 to 1, P value = 0.034) in NMOSD patients. The comprehensive results of the univariate logistic regression analyses are detailed in Table 4.
Table 4.
Characteristics of participants associated with osteopenia or osteoporosis in univariate logistic regression
| Characteristics | RRMS (n=30) | NMOSD (n=30) | HCs (n=35) | |||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| OR (95% CI) | P | OR (95%CI) | P | OR (95%CI) | P | |
| Sex (Ref: Female) | 1.9 (0.2-5.7) | 0.557 | 2.7 (0.4-17) | 0.283 | 0.3 (0-3.2) | 0.347 |
| Age | 1.1 (1-1.2) | 0.169 | 1.3 (1.1-1.5) | 0.013 | 601 (0-∞) | 0.994 |
| Disease duration | 1.1 (1-1.3) | 0.075 | 1 (0.8-1.1) | 0.598 | - | |
| EDSS at Onset | 4.5 (0.8-6.3) | 0.092 | 2.6 (0.611.4) | 0.201 | - | |
| EDSS | 1.6 (0.8-3.2) | 0.185 | 3.4 (1.1-9.5) | 0.02 | - | |
| BMI | 0.8 (0.6-1.1) | 0.126 | 0.7 (0.5-1) | 0.085 | 0.7 (0.5-0.9) | 0.015 |
| Physical activity level | 0.6 (0.3-1.4) | 0.244 | 0.2 (0.1-0.8) | 0.02 | 0.1 (0-0.4) | 0.01 |
| Vitamin D3 Supplement Administration (Ref: No) | 0 | 0.999 | 0.7 (0.1-5.1) | 0.744 | 0.3 (0.1-1.5) | 0.153 |
| Calcium | 0.1 (0-1.4) | 0.085 | 0.2 (0-1.9) | 0.148 | 0.1 (0-0.5) | 0.009 |
| Phosphorus | 0.1 (0-1.2) | 0.072 | 0 (0-0.2) | 0.004 | 0 (0-0.1) | 0.008 |
| ALP | 1.1 (1-1.2) | 0.013 | 1.2 (1-1.4) | 0.02 | 1.1 (1-1.2) | 0.005 |
| PTH | 1 (1-1.1) | 0.332 | 1 | 0.592 | 1 (1-1.2) | 0.412 |
| Vitamin D3 | 1 (0.9-1) | 0.088 | 0.9 (0.9-1) | 0.034 | 0.8 (0.7-1) | 0.011 |
| Comorbidities | ||||||
| Hypothyroidism (Ref: No) | 0.5 (0.1-5.9) | 0.607 | 1.7 (0.3-8.7) | 0.546 | 2.8 (0.5-15.8) | 0.257 |
| Sleep disorder (Ref: No) | 4.4 (0.8- 4.6) | 0.088 | 1.2 (0.2-6.7) | 0.818 | 5.3 (1-27) | 0.047 |
| Smoking (Ref: No) | 4.9 (0.7-32.9) | 0.105 | 1 | 0.15 | 2.8 (0.5-15.8) | 0.257 |
Significant P-values are in bold. ALP: Alkaline phosphatase, BMI: Body mass index, EDSS: Expanded disability status scale, HCs: Healthy controls, IQR: Interquartile range, NMOSD: Neuromyelitis optica spectrum disorder, OR: Odds ratio, PTH: Parathyroid hormone, RRMS: Relapsing-remitting multiple sclerosis, SD: Standard deviation
Discussion
In the current study, while MS did not exhibit a noteworthy association with BMD loss, NMSOD demonstrated heightened odds of osteopenia and osteoporosis. Several factors associated with BMD loss in MS and NMOSD patients were identified. In MS, serum levels of ALP showed significant associations with BMD loss. Additionally, trends suggest potential roles for EDSS, vitamin D3 and calcium serum level, disease duration, physical activity, and BMI. For NMOSD patients, age, EDSS, physical activity, ALP, vitamin D3, and phosphorus levels exhibited significant relationships, while BMI showed a possible trend.
Bone mineral density in RRMS
The complexity of bone metabolism in MS is considerable.[26] We found no significant relationship between MS and BMD loss among RRMS patients. Consistent with us, a large-scale study conducted by Yao et al.[27] found no significant causal relationship between MS and the risk of BMD loss. A case-control study based on population data revealed that PwMS exhibit lower BMD levels and a higher prevalence of osteoporosis than those without MS, even after considering various potential confounding factors.[25] In our study, RRMS patients did not demonstrate a significant disparity compared to HCs in the Z-score for the femoral neck and lumbar region. Aligned with our findings, a study by Moghaddasi et al.,[28] which encompassed RRMS patients, reported no statistically significant difference in BMD between PwMS and HCs. A meta-analysis comprising seven studies found that PwMS have notably lower BMD at the femoral neck compared to HCs.[29] Moreover, they showed that PwMS exhibit a diminished Z-score within the lumbar region compared to HCs, whereas there exists a generally insignificant variance in the Z-score at the femoral neck between PwMS and HCs.[29] The greater impact on the femoral neck compared to the lumbar region aligns with reduced mobility in MS and prolonged sitting or wheelchair use, exerting mechanical stress on the lumbar spine.[25,30] A meta-analysis indicated that PwMS exhibited decreased overall BMD in comparison to HCs. However, the studies included in this meta-analysis encompassed various types of MS rather than specifically focusing on RRMS.[31]
Factors associated with the risk of BMD loss in RRMS
Different factors have been proposed to correlate with osteoporosis, low BMD, or substantial bone loss in PwMS. Our study identified elevated ALP as a risk factor for reduced BMD, while disease duration, serum calcium levels, and vitamin D3 exhibited trends linked to the risk of bone loss in MS.
ALP, one of the bone turnover markers, exhibited a direct relationship with BMD in PwMS. In line with our study, a study by Zinganell et al.[32] revealed that patients with PwMS and osteoporosis exhibited elevated bone turnover markers, similar to the general population. These markers, like ALP, reflected increased bone resorption due to age-related or postmenopausal hormonal changes, as seen in individuals without osteoporosis. Tüzün et al.[33] found a relationship between femoral BMD and bone ALP in women with MS, where most PwMS had EDSS scores below 6. A direct trend association between the level of ALP and lumbar BMD in premenopausal women with MS was marginally significant.[12] Controversy exists regarding the disparity in ALP levels between PwMS and HCs. Our study, consistent with previous studies,[28,34,35] found no significant difference, while Terzi et al.[12] reported a significant distinction. This association may reflect the role of ALP as a key enzyme involved in bone turnover, particularly in osteoblastic activity, which can signal increased bone remodeling. Future studies could further investigate the interplay of ALP with other bone metabolism markers in RRMS and NMOSD.
The present study identified no significant relationship between physical activity and BMD loss in PwMS. In contrast to our findings, prior research has reported a notable decrease in physical activity among PwMS, along with a significant correlation with BMD.[26,36,37] This disparity may stem from the utilization of different methodologies for assessing physical activity. A population-based study also indicated that physical activity during bone growth periods, rather than solely the current ambulatory status, impacted BMD in PwMS.[38] A study revealed a correlation between physical activity and BMD in MS; however, no significant association was identified between physical activity and trabecular bone score.[39] This underscores the significance of incorporating physical activity and bone density assessments when examining these associations. Given potential variances in activity thresholds between individuals with MS and those without,[40] it has been proposed that an increment of 29,000 accelerometer counts daily correlates with a 0.01 g/cm2 augmentation in femoral neck BMD in MS.[26] Moreover, the absence of a significant association between physical activity and the risk of BMD loss in our study might be attributed to RRMS patients having the same physical activity levels as HCs.
No significant association between the status of disability and risk of BMD loss was found in PwMS. Prior studies have demonstrated associations between ambulatory status, heightened disability, or a severe progression of MS and occurrences of bone loss, low BMD, osteopenia, or osteoporosis.[32,41,42,43] The contrast may be explained by the fact that all PwMS in our study had RRMS and a median EDSS score of 0, which differs from the established cutoffs indicating clinically relevant risk for osteoporosis, such as an EDSS score >4.5[32] or ≥5.5.[7] Huang et al.,[31] in a meta-analysis, indicated that EDSS scores exceeding three were linked to diminished BMD in the lumbar spine and femoral neck among PwMS. In female PwMS, lumbar spine and femoral neck BMDs were 1–2 SDs lower than in age-matched HCs, with the lowest values seen in those with the most severe disease.[44]
Laboratory findings of our study unveiled diminished levels of vitamin D3 among PwMS compared to HCs. However, our study did not establish an association between low vitamin D3 levels and osteoporosis. Although lower levels of vitamin D3 have been associated with decreased BMD and heightened bone loss in certain studies,[12,45] divergent findings exist in other investigations, consistent with our findings, which reveal no discernible correlation between BMD and vitamin D3 levels in MS.[32,37,41,43,46,47] Moreover, randomized trials demonstrated that high doses of vitamin D3 intake do not impact BMD or biochemical indicators of bone formation in PwMS.[48,49]
A trend relationship between sleep disorders and BMD among PwMS was indicated in our findings. A few efforts have been dedicated to clarifying the precise relationship between sleep and BMD, and unfortunately, their participants were not PwMS conclusively. Previous studies have demonstrated a substantial link between sleep duration and decreased BMD in PwMS.[50,51] Fu et al.[52] showed a significant correlation between reduced sleep duration and lower BMD, potentially attributable to hormonal factors associated with sleep deprivation. Yamaura et al.[53] found no relationship between insomnia and BMD. Further studies concentrating on PwMS are warranted to elucidate the relationship between sleep status and BMD in MS.
Bone mineral density in NMOSD
Our study demonstrated that NMOSD can increase the probability of osteopenia or osteoporosis. Moreover, we identified decreased BMD in NMOSD patients compared to healthy controls. Our findings are in accordance with previous studies, which demonstrated diminished BMD in NMOSD patients compared to HCs.[19] A large-scale study conducted by Jung et al.[54] revealed that NMOSD patients faced a higher risk of fractures, possibly attributable to the diminished bone mineral density observed in these patients.
Factors associated with the risk of BMD loss in NMOSD
Our study identified that older age, greater disability, and increased bone turnover markers, such as ALP, were directly associated with BMD loss in NMOSD, whereas higher levels of physical activity and serum vitamin D3 were found to have an inverse relationship with BMD in those. In spinal cord diseases such as MS, bone loss predominantly affects the hip, with chronic hip immobilization considered the primary cause of this occurrence.[55,56] In NMOSD patients, low BMD tends to be more pronounced in younger individuals and is linked to steroid use.[54] Implementing prophylactic calcium supplements may offer partial prevention against this occurrence.[54] Moreover, inflammation, among other underlying mechanisms linked to NMOSD-AQP4, could negatively impact bone metabolism.[57] In chronic autoimmune inflammatory conditions, it has been suggested that inflammatory cytokines may lead to an overactive state of osteoclasts.[58] It has been postulated that NMOSD-AQP4 patients may manifest an elevated degree of bone resorption compared to bone formation.[54,59] Notably, there is a paucity of evidence concerning the evaluation of BMD and its associated factors in NMOSD. Thus, our study may serve as an initial impetus, prompting further well-designed investigations to delineate various dimensions of this area.
Some limitations inherent to this study necessitate a cautious interpretation of the findings. Limited sample sizes for MS and NMOSD patients in this study precluded covariate adjustment in the multivariate regression analyses. Hence, our findings may serve as a hypothesis for prospective studies with larger sample sizes, which can also account for the influence of potential covariates. Additionally, no data were collected regarding the fracture history of participants. PwMS with recent fractures may be at increased risk for osteoporosis.[8] Future studies are warranted to explore the role of fracture history as a potential contributor to the risk of osteoporosis in MS. Furthermore, our analyses did not account for hormonal factors known to influence bone health, such as menarche and lactation. In addition, incorporating inflammatory biomarkers in future studies may help elucidate the underlying mechanisms of BMD loss in these populations.
This study specifically investigated BMD in RRMS patients, the most common type of MS, due to limited prior research in this population. Moreover, given the limited research on BMD in NMOSD, our comprehensive evaluation identified distinct risk factors, which may inform the design of future studies in this underinvestigated population.
Conclusion
In conclusion, RRMS showed no significant relationship with BMD decline, while NMOSD increased the risk of BMD loss. Additionally, serum levels of bone turnover markers (ALP, phosphorus, calcium), vitamin D3, disease duration, and sleep disorders were predominant factors that have relationships with BMD in RRMS. Moreover, age, disability, physical activity, serum level of bone turnover markers (ALP and phosphorus), vitamin D3, and BMI were identified as considerable contributors to BMD in NMOSD. These findings highlight the necessity of assessing bone health and management strategies in routine care plans for RRMS and NMOSD patients and highlight the importance of considering various demographic and clinical characteristics when evaluating BMD risk in these patients. More longitudinal studies with large sample sizes are required to validate these findings and elucidate the underlying mechanisms. Clinicians should routinely assess BMD in NMOSD and RRMS patients, even at early disease stages. Future studies should focus on fracture risk, bone turnover dynamics, and the long-term skeletal effects of disease-modifying therapies.
Contributors
Elham Sadat Azimi: Data curation. Aysa Shaygannejad: Data curation. Saeed Vaheb: Data curation, Investigation. Mohammad Yazdan Panah: Conceptualization, Investigation, Visualization, Writing – original draft, Writing – review and editing. Mohammad Mohammadi: Formal analysis. Mohammad Hossein Mokhtari Jazi: Data curation. Fereshteh Ashtari: Conceptualization, Investigation. Vahid Shaygannejad: Conceptualization, Investigation, Validation, Writing – review and editing. Omid Mirmosayyeb: Conceptualization, Methodology, Investigation, Supervision, Validation, Project administration, Writing – review and editing.
Ethics approval
The study protocol received approval from the Ethics Committee of MUI (IR.MUI.MED.REC.1401.203), and informed consent was obtained from all subjects before their enrollment. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Availability of data and materials
The data supporting the findings of this study is available from the corresponding author upon reasonable request.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
Not applicable.
Funding Statement
Nil.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data supporting the findings of this study is available from the corresponding author upon reasonable request.