Effects of intermittent corticosteroids on scoliosis, bone density, and vertebral fractures in duchenne muscular dystrophy

Abstract

Introduction

Spinal involvement is common in Duchenne muscular dystrophy (DMD), specifically scoliosis and vertebral fractures. Treatment with corticosteroids (CS) delays scoliosis onset, but also induces low bone mineral density, increasing fracture risk.

Objective

Assess long-term effects of intermittent CS on scoliosis development, bone mineral density and vertebral fractures in DMD.

Method

We retrospectively analysed real-world data from a single national reference center in the Netherlands. Spinal imaging was obtained by yearly anteroposterior radiographs. Scoliosis was defined as lateral spinal curvature with a Cobb angle of >10°. Yearly lumbar spine bone mineral density (LSBMD) Z-scores were measured with dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine. Vertebral fractures were evaluated using yearly vertebral fractures assessments (VFA).

Results

We included 86 individuals with DMD who visited the outpatient clinic between 2002 and 2022, aged 4-18 years. Seventy-five patients (87.2%) developed scoliosis (median age 11.0 years), mostly after loss of ambulation. Scoliosis progressed to >20° in 40 (46.5%) and to >30° in 29 (33.7%) of all patients. Spinal fusion was performed in 20 (23.3%) of all patients (median age 18.5 years). Cobb angles significantly increased after loss of ambulation (LoA) (p<0.001).

Mean height SDS was -0.8. LSBMD Z-score declined below -2.0 in 27 (31.4%) patients and was significantly lower after LoA (p<0.001). Of 86 patients, 64 underwent VFAs, with 16 (25%) developing vertebral fractures during follow-up, mostly asymptomatic (87.5%).

Conclusion

Individuals with DMD on intermittent CS experience a higher incidence of scoliosis, fewer vertebral fractures, and generally maintain higher LSBMD Z-scores compared to published data on patients receiving daily CS.

Introduction

Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked recessive disorder caused by mutations in the DMD gene, resulting in an absence of functional dystrophin. ¹ This leads to progressive muscle wasting and cardiorespiratory insufficiency. If untreated, most patients will lose ambulation by the age of 10 years. ² Spinal involvement is common in DMD, scoliosis is reported in 90% of untreated patients, which can rapidly progress in the non-ambulant phase.^3–5 Furthermore, vertebral fractures are frequently observed in individuals with DMD, associated with low and declining bone mineral density. ⁶

DMD is currently treated with long-term corticosteroids (CS), generally started at age 4-5 years, and recommended for life-long use. Worldwide, various drugs and regimens are used, including daily or intermittent prednisone and deflazacort schemes. The 10-days-off-10-days-on (10/10) regimen and weekend dosing are the most common of the intermittent schemes. Previous studies have shown that CS treatment leads to a delay in loss of ambulation. Furthermore, CS delay the onset and progression of scoliosis, with fewer patients requiring spinal surgery.^7–9 However, long-term usage of CS comes with significant side-effects, including decreased bone mineral density and increased risk of fractures.^6,8 Previous studies have described the development of scoliosis, bone mineral density and vertebral fractures in individuals with DMD treated with daily deflazacort or prednisone regimens.^10–18 However, little is known regarding these effects of intermittent regimens. Some papers have reported on vertebral fracture occurrence in the intermittent regimen, but these are mostly focused on patients in the ambulant phase of the disease and with limited follow-up beyond LoA.^13–15 Furthermore, research on scoliosis development in patients with intermittent CS regimens is lacking.

In the Netherlands, DMD is commonly treated with 10/10 prednisone. In the event of side effects, mainly behavioral difficulties, this can be switched to 10/10 deflazacort. As part of the standard of care, all patients are seen once a year at the outpatient clinic of a specialized hospital, starting around the age of 5 years. From this age, all patients undergo lateral dual-energy X-ray absorptiometry (DXA) scans for evaluation of bone mineral density. Evaluation for vertebral fractures is done by way of vertebral fracture assessment (VFA) using the DXA scan. Spinal assessment further includes anteroposterior (AP) radiographs for evaluation of scoliosis, which is generally started at the age of 6 to 7 years according to common clinical practice in the Netherlands. All spinal assessments continue until either the age of 18 years, or earlier in case of spinal fusion surgery.

In this paper, we describe long-term effects of the intermittent CS regimen on lumbar bone mineral density, vertebral fractures and scoliosis by providing real-world data from a single center.

Methods

For this retrospective longitudinal cohort study, we included pediatric individuals with DMD treated with intermittent CS, defined as either a 10/10 prednisone regimen, a 10/10 deflazacort regimen, or those who switched from 10/10 prednisone to 10/10 deflazacort, with a treatment duration of ≥1 year. All patients were seen annually at the outpatient clinic of Leiden University Medical Center (LUMC) between January 2002 and December 2022. Data were collected from the Dutch Dystrophinopathy Database (DDD) ¹⁹ and included demographics, scoliosis as measured by Cobb angles, age of onset of scoliosis, age at scoliosis surgery, bone mineral density Z-scores of the lumbar spine, vertebral fractures, back pain, age at loss of ambulation (LoA), 25-hydroxyvitamin D (25OHD) concentrations, height, weight, and steroid usage.

Height was measured annually and expressed in standard deviation scores (SDS) according to Dutch reference data for age and sex. ²⁰ It was measured standing in ambulant patients and estimated based on ulnar length in non-ambulant patients. ²¹ LoA was defined as the patient reported inability to walk 5 meters unaided at home or as the clinician assessed inability to complete the 10 meter run test within 45 seconds if patient reported LoA was unavailable.

Scoliosis was assessed by annual AP spinal radiographs in supine and sitting positions (after LOA). Scoliosis was defined as a lateral spinal curvature with Cobb angle >10°. Scoliosis was further categorized into Cobb angle >20° and Cobb angle >30°. All available AP spinal radiographs were reassessed by two trained clinicians (LB and PBW) and evaluated by consensus.

Bone mineral density of the lumbar spine (LSBMD), from lumbar vertebra 1 to 4, was assessed using DXA scans (Hologic Discovery until 2019 and Hologic Horizon since 2019; Hologic Inc., Bedford, MA, USA) and expressed in Z-scores, with height corrections made to account for size-related influences (normal range -2 ≤ Z-score ≤ 2). ²² DXA scans were performed annually at the outpatient clinic visit or upon indication if patients experienced back pain suspected to be caused by vertebral fractures. Vertebral fractures were analyzed using yearly DXA-based VFA of the thoracic and lumbar spine, involving thoracic vertebra 4 to lumbar vertebra 4. VFA were also performed in case of back pain and clinical suspicion of vertebral fractures. All VFA were evaluated by expert readers. Fractures were graded using the Genant score based on the percentage reduction in height, as grade 0 (normal), grade 1 (20-25%), grade 2 (26-40%), or grade 3 (>40%), and classified as symptomatic or asymptomatic. ²³ The spinal deformity index (SDI) was calculated as the sum of Genant grades across all assessable vertebrae and scaled to the total number of vertebrae scanned. ²⁴ All DXA scans and VFAs were analyzed by a trained technician (PDS). Any images of insufficient quality to reliably determine the presence or absence of fractures were excluded from the analysis.

Statistical analysis was conducted using R version 4.3.1 (R foundation for statistical computing, Vienna, Austria). Results were presented as means (SD) for normally distributed data, or medians (interquartile range (IQR)). Kaplan-Meier analysis was used to describe age at LoA, first vertebral fracture and the age at which patients developed a Cobb angle >10°, >20°, >30°, or underwent spinal fusion surgery. Data are presented as median time to event and IQR. Subanalysis was performed to assess median age at which Cobb angle exceeded 10°, 20°, and 30°, with patients categorized according to height SDS.

Linear mixed effects models (LMEM) were used to model the effect of LoA on progression of scoliosis and LSBMD, respectively. Two way ANOVA was used to test for differences between the modelled ambulant and non-ambulant progression. Serum 25OHD levels expressed in nanomoles per liter (nmol/L), measured at each visit, were added as a time-varying covariate to the LSBMD LMEM. Cox proportional hazards regression with age as the underlying time scale was used to assess the association between longitudinal LSBMD Z-scores and the risk of a first vertebral fracture.

Results

Demographics

Data from 638 visits in 86 patients aged 4-18 years were included (table 1). All patients were treated with intermittent CS, either with 10/10 deflazacort, 10/10 prednisone, or had switched between these two. LoA occurred at a median age of 11.2 years. Chronic vitamin D supplementation was started at 400 IU daily dosing at the same age as CS treatment in all patients. Dosing was increased during yearly follow-up if 25-hydroxyvitamin D levels dropped below 50 nmol/L.

Table 1.

Cohort characteristics.

​	N=86
CS usage, n (%)
10/10 prednisone	44 (51.2)
10/10 deflazacort	4 (4.7)
Switched from 10/10 prednisone to 10/10 deflazacort	38 (44.2)
Age at start CS, mean (sd), years	6.1 (±2.0)
Age at first radiograph, mean (sd), years	8.5 (±2.7)
Radiographic follow up duration, mean (sd), years	5.1 (±2.9)
Height SDS, mean (sd)	-0.8 (±0.8)
Age at first DXA scan, mean (sd), years	8.1 (±3.1)
DXA scan follow up duration, mean (sd), years	5.5 (±3.4)
Ambulatory at first radiograph, n (%)	68 (79.1)
Ambulatory at first DXA scan, n (%)	68 (79.1)
Age at LoA, median (IQR), years	11.2 (9.4 – 12.5)
25OHD concentration, mean (sd), nmol/L*	52.3 (±17.6)

CS = corticosteroids; 10/10 =10 days on/10 days off; DXA = dual-energy X-ray absorptiometry; BMI = body mass index; 25OHD = 25-hydroxyvitamin D; LoA = loss of ambulation.

*reference value 25OHD: 50-250nmol/L.

Scoliosis

After reassessment of 563 AP spinal radiographs, 18 were excluded due to poor quality leading to a final dataset that included 545 radiographs from 86 patients. During follow-up, 75 out of 86 patients (87.2%) developed scoliosis at a median age of 11.0 years. 40 out of 86 patients (46.5%) progressed to a Cobb angle of >20° at a median age of 15.3 years. Finally, 29 out of 86 patients (33.7%) developed a Cobb angle of >30° at a median age of 16.3 years. All patients with a Cobb angle of >30° were referred for spinal fusion surgery, according to the standard of care guidelines, and 20 out of 86 patients (23.3%) underwent the procedure at a median age of 18.5 years (Figure 1, Table 2). Out of the 75 patients who developed scoliosis, 15 (20%) did not lose ambulation within the studied time period, while 26 out of 75 (34.7%) lost ambulation before the onset of scoliosis. All 40 patients who developed a Cobb angle >20° lost ambulation within the studied time period. Among these, the majority (93%) reached a Cobb angle >20° after LoA. Only three patients progressed to >20° before LoA, including one who progressed to a Cobb angle of >30° while still ambulant. Figure 2 depicts modelled Cobb angle progression both after loss of ambulation at the median age of 11.2 years and in case patients remained ambulant. Loss of ambulation was found to negatively impact scoliosis progression (p<0.001). There was no difference in median age at Cobb angle >10°, >20° or >30° between patients when stratified by height SDS (p=0.2, p=0.4, p=0.3).

Figure 1.

Kaplan Meier analysis of age of onset of degree of scoliosis (>10°, >20°, >30°), or spinal fusion surgery for all 86 patients. Patients who developed scoliosis >30° were also included in the >10° and >20° analysis, and those who developed >20° were also included in the >10° analysis.

Table 2.

Results.

​	N=86
Age at scoliosis Cobb angle >10°, median (IQR), years	11.0 (8.2 – 13.8)
Age at scoliosis Cobb angle >20°, median (IQR), years	15.3 (13.8 – 17.2)
Age at scoliosis Cobb angle >30°, median (IQR), years	16.3 (15.0 – 18.3)
Age at spinal fusion surgery, median (IQR), years	18.5 (16.8 – 18.7)
Time from LoA to scoliosis Cobb angle >10°, mean (SD), years	0.8 (3.3)
Time from LoA to scoliosis Cobb angle >20°, mean (SD), years	3.3 (2.2)
Time from LoA to scoliosis Cobb angle >30°, mean (SD), years	4.3 (2.0)
LSBMD Z-score in ambulant individuals, mean (SD)	-0.8 (±0.9)
LSBMD Z-score in individuals with vertebral fractures, mean (SD)	-1.0 (±0.8)
LSBMD Z-score in individuals without vertebral fractures, mean (SD)	-0.6 (±1.1)
LSBMD Z-score in non-ambulant individuals, mean (SD)	-1.5 (±1.2)
LSBMD Z-score in individuals with vertebral fractures, mean (SD)	-1.4 (±1.1)
LSBMD Z-score in individuals without vertebral fractures, mean (SD)	-1.6 (±1.2)
Age at first vertebral fracture, median (IQR), years	18.6 (15.0 – NAa)
Scaled SDI, median (IQR)	0.0 (0.0 – 0.0)
Scaled SDI in individuals with vertebral fractures, median (IQR)	1.9 (1.2 – 2.4)

LoA = loss of ambulation; LSBMD = lumbar spine bone mineral density; SDI = spinal deformity index

^a75th quantile was not reached due to small number of events

Figure 2.

LMEM showing modelled Cobb angle trajectories in degrees for ambulant (red) and non-ambulant (blue) patients with loss of ambulation at age 11.2 years.

Bone mineral density

Data from 516 DXA scans in 84 patients were included. The majority of LSBMD Z-scores were within the normal range (-2 ≤ Z-score ≤ 2), with 90 out of 516 (17.4%) Z-scores falling below -2 in 27 out of 84 (32.1%) patients. Of these 27 patients, 6 were still ambulant (Figure 3). Figure 4 shows the modelled Z-scores for patients with loss of ambulation at 11.2 years and for patients who remained ambulant. Z-scores significantly decreased after loss of ambulation (p<0.001) (Table 2). In a subgroup analysis of patients with available VFA, 87 DXA scans from 40 ambulant individuals and 167 scans from 52 non-ambulant individuals were included. Within these groups, LSBMD Z-scores did not differ significantly between patients with and without vertebral fractures (ambulant: p = 0.156; non-ambulant: p = 0.626). The mean 25OHD concentration was above 50 nmol/L, however 38 (44.2%) patients had a concentration <50 nmol/L at one or more measurements (Table 1). LSBMD was not significantly affected by 25OHD concentrations (p=0.7).

Figure 3.

Boxplot showing lumbar spine bone mineral density (LSBMD) Z-scores per age category, grouped by ambulation status.

Figure 4.

LMEM showing modelled lumbar spine bone mineral density (LSBMD) Z-score trajectories for ambulant (red) and non-ambulant (blue) patients with loss of ambulation at age 11.2 years.

Vertebral fractures

Data from 254 VFAs in 64 patients were included. In 187 out of 254 VFAs (72.0%), one or more vertebrae were un-assessable, resulting in 889 out of 3302 vertebrae (26.9%, median 4.0, range 0-12) that could not be evaluated, mostly involving the thoracic spine. In total, 16 out of 64 patients (25.0%) experienced 36 vertebral fractures (range: 1-8 fractures per patient). Median SDI for these 16 individuals with fractures was 1.9 (1.2 – 2.4, range 1 – 28) (Table 2).

At initial diagnosis, 22 fractures in 13 patients were classified as grade 1. During follow-up, one fracture remained grade 1, and 4 fractures progressed to grade 2. Three fractures were no longer visible during follow-up, and the remaining 14 fractures (in 10 patients) had no follow-up due to age, spinal fusion surgery, or insufficient quality of subsequent VFAs. Thirteen fractures (in 5 patients) were grade 2 at first diagnosis. Of these, 2 were intermittently classified as grade 1 or 2 during follow-up, 2 were no longer present on later assessments and 9 fractures had no further follow-up. One fracture was classified as grade 3 at first diagnosis. As this patient died shortly after, no further follow-up was available.

When considering the highest measured grade for each fracture, out of the 36 fractures, 18 (50.0%) were classified as grade 1, 17 (47.2%) as grade 2, and 1 (2.8%) as grade 3. Only 2 patients (12.5%) reported symptoms of back pain. All others were asymptomatic, and these fractures were diagnosed during routine assessments as part of the standard of care. Intravenous bisphosphonate treatment was initiated in 2 patients, both with progressive vertebral fractures and long bone fractures, 1 of whom experienced symptoms of back pain. LSBMD Z-scores were comparable between patients with and without vertebral fractures (p=0.8) (Figure 5).

Figure 5.

Spaghetti plot showing lumbar spine bone mineral density (LSBMD) Z-scores in patients with vertebral fractures (orange) and those without vertebral fractures (blue). Orange triangles indicate the moment vertebral fractures were diagnosed.

Discussion

In this retrospective single center study, we have shown long-term outcomes of intermittent CS treatment in DMD on scoliosis, LSBMD and vertebral fractures. We found a high prevalence of scoliosis, relatively normal range of LSBMD Z-scores and few and mostly asymptomatic vertebral fractures.

Scoliosis is common in DMD, affecting up to 90% of steroid naïve patients, mostly in the non-ambulant phase.^10,25 In our cohort, 87.2% of patients on intermittent CS developed scoliosis with a Cobb angle >10°, which is significantly higher than reported in those on daily CS (31%), as diagnosed by yearly radiographs. ¹⁰ Furthermore, scoliosis progressed to a Cobb angle of >20° in 46.5% of patients at median age of 15.3 years. This is higher than reported in those in daily CS (20%) using twice yearly radiographs. ¹¹ It is also higher and earlier than reported in those on deflazacort (7.9%, median age of onset >20° not reached) and prednisone (17.9%, median age 18.6 years) irrespective of regimen. ¹⁶ In contrast, our findings were in line with those of a recent study, ²⁶ which reported scoliosis with a Cobb angle >20° in 41% of patients on low dose (<20mg/day) and 47% on standard of care dose (>20mg/day) daily prednisone or deflazacort. However, in both of these studies diagnosis of scoliosis was based on clinical examination whereas the Cobb angle was only assessed by spinal radiograph when scoliosis was suspected. These numbers might therefore be less precise than when follow up is done by yearly radiographs. In our cohort, 33.8% of patients developed a Cobb angle >30°, which is lower than reported in steroid naïve patients (75-90%). ²⁵ Finally, 23.3% of patients in our cohort underwent spinal fusion surgery, which is again higher than reported in those on daily CS (15%). ¹⁰

This difference in scoliosis occurrence in our cohort on intermittent CS compared to daily CS likely reflects the overall effect of steroid treatment on disease progression. Both regimens slow motor decline, however, daily treatment has a more pronounced effect, delaying motor milestones such as loss of ambulation (median 14.5 years) and hand-to-mouth function. In contrast, LoA occurs earlier in patients on intermittent treatment (median 11.2 years in our cohort).^15,27 While the exact cause of scoliosis in DMD is not fully known, it is thought that declining mobility and progressive muscle weakness lead to changes in the trunk and ultimately to scoliosis. ⁵ This explains the more rapid progression of scoliosis in the older and non-ambulant population. ²⁵ We also hypothesized that the less severe height reduction seen in patients on intermittent CS might contribute to a higher incidence of scoliosis, as increased height is associated with an increased risk of spinal deformities in healthy adolescents. ²⁸ However, we found no differences in scoliosis occurrence when grouping patients by height SDS. While spinal fusion surgery prevalence in our cohort did not differ substantially from those in daily CS (23% vs. 15%), this could also be due to differences in referral for spinal fusion surgery, with some centers referring at a Cobb angle ≥20°, while in the Netherlands patients are referred once they reach a Cobb angle >30°.^5,11

Osteoporosis is a well-known side effect of prolonged CS usage, with increasing muscle weakness and loss of weight-bearing mobility also contributing to progressive loss of bone mineral density.^6,29 Furthermore, loss of ambulation significantly decreases LSBMD, both in CS naïve individuals with DMD and those treated with daily CS. ³⁰ Other factors including, but not limited to, hormonal imbalances and systemic inflammation have also been found to contribute to poor bone health in DMD. ³¹ Our analysis shows that 86.9% of individuals with DMD have LSBMD Z-scores within the normal range in the ambulant phase, which declines to 58.6% after loss of ambulation. Mean LSBMD Z-scores found before and after loss of ambulation were similar to those reported in steroid naïve patients (before LoA: -0.8; after LoA: -1.7)³⁰. In a more recent paper, LSBMD in daily versus intermittent CS was compared, using bone mineral apparent density as an outcome, which corrects for short stature. No differences in LSBMD between daily and intermittent treatment were observed, though the follow-up period was only 2 years. ¹⁴ While 25OHD levels in our cohort were in the low-normal range, possibly reflecting non-adherence, they did not significantly affect LSBMD Z-scores.

With regard to vertebral fractures, our study showed that 25% of patients developed vertebral fractures during follow-up, as diagnosed with yearly screening with VFA. This is less than reported in daily (40%) and more than previously reported in intermittent (8%) using routine VFAs. ¹⁴ However, in this previous study, patients were younger (mean 8.3 years) and follow-up was 2 years, while in our cohort, median age at first fracture was 18.6 years. Using lateral spinal radiographs, a higher fracture frequency of 53% in patients on daily deflazacort ¹⁷ and slightly higher frequency of 32% in patients on a mixture of daily deflazacort and prednisone ¹⁰ have been reported. Overall, our fracture frequency of 25% on intermittent CS is lower than reported for daily CS. Median SDI for individuals with fractures was comparable to previous reports (1.9 in our cohort vs. 1.9 and 2.0 in daily cohorts).^32,33 Most of the fractures in our study were asymptomatic, and mean age of occurrence was during teenage years. However, 72% of our VFAs had one or more vertebrae that could not be evaluated sufficiently due to inadequate imaging quality. Therefore, the actual number of vertebral fractures could potentially be higher. As previous research has mentioned the limitations of both lateral radiographs and VFA by DXA in diagnosing grade 1 vertebral fractures, it should be noted that the number of vertebral fractures could potentially have been underestimated in our research as well as in published papers. ³⁴

Because previous research reporting exact LSBMD Z-scores in both ambulant and non-ambulant individuals with DMD is limited, direct comparison of LSBMD between intermittent and daily CS remains challenging. In our cohort, LSBMD Z-scores during the ambulatory phase were mostly within the normal range. A recent review reporting patients on daily corticosteroids (most data between ages 8–11) found lower LSBMD Z-scores than observed in our cohort. ³⁵ These differences may relate to higher cumulative steroid exposure on daily CS. While loss of ambulation in itself also decreases bone mineral density, we hypothesize that this effect is less than that of continued daily steroid exposure, as is reflected in the lower rate of vertebral fractures experienced in our cohort. While others ³³ have reported significantly lower LSBMD Z-scores in patients with vertebral fractures, we could not replicate those findings in our study, possibly due to the small number of events. Vertebral fractures can artificially increase LSBMD measurements, which may mask true deficits. In our subgroup analysis, LSBMD Z-scores did not differ significantly between patients with and without fractures, but the limited number of events may have reduced our ability to detect subtle effects. It is important to note that LSBMD Z-score decline had not stabilized at the end of follow-up. Given the lifelong indication for CS and the expanded life expectancy, it can be expected that LSBMD Z-scores will decline further with advancing age. Likewise, vertebral fractures may also occur at later ages, beyond the scope of this pediatric study.

Our research had several limitations. Given the retrospective nature and the usage of real-world data, there were a number of missing assessments which can be seen in the declining number of available DXA scans and VFAs. This has multiple reasons. First, the studied time period covers 20 years in which the standard of care has changed significantly, with more DXA scans and VFAs having been performed in the last decade. Second, after loss of ambulation, DXA scans (and therefore VFAs) become more difficult for patients to endure, which lessens patient compliance. Finally, 20 (23.3%) individuals with DMD underwent spinal fusion surgery, after which DXA scans and VFAs of the lumbar spine are no longer reliable. The use of VFA for vertebral fracture assessment is another limitation. As noted, 26.9% of scanned vertebrae were of insufficient quality to reliably determine the presence or absence of vertebral fractures. Furthermore, some fractures were no longer visible during subsequent analyses. This may reflect remodeling of mild deformities, growth-related reshaping of vertebral bodies, or variability in patient positioning. Additionally, the semiquantitative nature of fracture grading may lead to different interpretations over time, especially for borderline cases. Although VFA by DXA is an acceptable method for evaluating vertebral fractures, its use in children has historically been considered inferior to lateral spinal radiographs. ³⁶ However, recent advancements in DXA technology have enhanced image resolution, and VFA by DXA is now considered non-inferior to lateral radiographs for detecting fractures in children.^34,37 Vertebral fractures were classified as symptomatic based on the presence of back pain, which was assessed through clinical notes in the electronic patient files. It is important to note that, as with all retrospective studies, the accuracy of this classification is inherently limited by the availability and quality of the clinical documentation. Data on pubertal status were not available. As pubertal maturation is associated with increases in bone mineral density, differences in pubertal timing or progression may have influenced individual LSBMD Z-scores.

A large proportion of our population switched from 10/10 prednisone to 10/10 deflazacort, due to experienced side effects. This switch in treatment occurred at different timepoints for each patient, both before and after loss of ambulation, and we therefore did not further specify any treatment subgroups in our analysis. Finally, a proportion of patients participated in a clinical trial during the studied time period, in addition to using 10/10 CS. Although these drugs all targeted muscle tissue and mainly involved ambulant patients, an additional effect on LSBMD, vertebral fracture risk, or both cannot be excluded from our analysis.

Consideration for clinical practice should be given to the optimal timing of spinal screening. In the Netherlands, scoliosis screening by AP spinal radiographs begins in the ambulant phase, typically around 6 to 7 years of age. This timing was established through a nationwide initiative involving clinical experts from the Dutch university medical centers to implement the 2018 international guidelines. Our reported median age of scoliosis, even when using a Cobb angle of >10°, was 11.0 years, and later for more clinically significant scoliosis (>20° and >30°). We also found that the majority of patients experienced scoliosis after LoA. While this paper highlights the high incidence of scoliosis in 10/10 CS, initiating screening after loss of ambulation, when scoliosis becomes more clinically relevant, will lead to a reduction in radiation exposure, patient burden, time and costs.

Similarly, although often asymptomatic, the high number of vertebral fractures underlines the need to continue with screening. The 2018 care considerations for DMD recommend bisphosphonate therapy for symptomatic grade 1 vertebral fractures, as well as for grade 2 and 3, regardless of symptoms. ³⁸ While a recent review concluded that there was insufficient evidence available to definitely determine the ability of bisphosphonates to decrease fracture risk, it confirmed a positive effect on bone mineral density. ³⁹ Continued screening enables early identification of patients, particularly those with progressive or multiple fractures combined with low LSBMD, who may benefit from treatment, even as the indication for therapy remains the subject of ongoing debate.

In our cohort, LSBMD Z-scores were mostly within the normal range in the ambulant phase, and most vertebral fractures occurred after loss of ambulation. This suggests that routine lumbar spine DXA screening in early ambulatory patients may have limited yield and that the timing of routine DXA could be reconsidered to coincide with declining ambulatory function. Furthermore, while the quality of VFA has increased over the years, lateral spinal radiographs remain an accessible method to assess vertebral fractures. While this does come at the cost of radiation exposure, it could very well be a good alternative for centers in possession of an older DXA scanner and for those patients who are less able to endure a DXA scan with VFA.

Conclusion

In summary, individuals with DMD on 10/10 corticosteroids experience a higher incidence of scoliosis, fewer vertebral fractures, and higher LSBMD Z-scores than reported for individuals receiving daily corticosteroids. The high prevalence of scoliosis supports continued screening, started upon loss of ambulation, offering an optimal balance between clinical benefit and reducing unnecessary interventions. Since LSBMD Z-scores remain mostly within the normal range in the ambulant phase, it may be reasonable to reconsider the timing of screening to coincide with declining ambulatory function. Although vertebral fractures were few compared to daily corticosteroids, most were asymptomatic, supporting the need for ongoing fracture assessment. Together, combined bone mineral density and vertebral fracture screening are important to identify patients who may benefit from osteoporosis treatment.

ORCID iDs

Nadine A. Ikelaar https://orcid.org/0000-0002-0609-4752

Louise S. M. Blok https://orcid.org/0009-0006-9392-8167

Mees H. P. Stoop https://orcid.org/0009-0006-2202-5227

Petra Dibbets-Schneider https://orcid.org/0000-0003-0538-8270

Erik H. Niks https://orcid.org/0000-0001-5892-5143

Ethical considerations

This study adhered to the principles outlined in the Declaration of Helsinki. The medical ethical committee of Leiden-Den Haag-Delft declared that the Dutch dystrophinopathy database (DDD) which was used to acquire data for this research, is not subject to the Medical Research Involving Human Subjects Act (WMO). Local feasibility was declared by the medical ethical committees of Radboudumc and Kempenhaeghe-MUMC. Patient registration and data collection procedures in the DDD were conducted in accordance with the latest EU General Data Protection Regulation (GDPR).

Consent to participate

All registrants provided written informed consent, complying with Dutch legislation, allowing the storage of their contact details and relevant diagnostic information.

Data Availability Statement

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.*