Assessment of bone health and bone mineral density in patients with mucopolysaccharidosis receiving enzyme replacement therapy

Abstract

Background

Most patients with mucopolysaccharidosis (MPS) experience skeletal involvement due to impaired bone remodeling, glycosaminoglycan (GAG) accumulation, reduced mobility, and nutritional deficiencies. These factors may predispose to low bone mass and increased fracture risk. This study assessed bone mineral density (BMD) using height-adjusted dual-energy X-ray absorptiometry (DXA) in pediatric MPS patients receiving enzyme replacement therapy (ERT) and examined its associations with clinical, functional, and biochemical parameters.

Methods

This cross-sectional study included 29 children with biochemically and/or genetically confirmed MPS receiving ERT at Tanta University Hospital. Children under 5 years and ERT-naïve patients were excluded. BMD was measured at the lumbar spine (L1–L4) and femoral neck using DXA and adjusted for height-for-age z-score (HAZ). Clinical data, Katz Activities of Daily Living (ADL) score, anthropometry, and biochemical markers of bone metabolism were recorded. Statistical analyses included the Shapiro–Wilk test, Pearson correlation, and two-tailed t-test (p < 0.05).

Results

The cohort included 29 patients (19 males, 10 females; mean age 9.79 ± 3.85 years): 13 with MPS IVA, 11 with MPS I, 3 with MPS II, and 2 with MPS VI. Mean HAZ-adjusted BMD z-scores were − 1.84 ± 1.38 (right femur), − 2.07 ± 1.22 (left femur), and − 3.00 ± 1.49 (lumbar spine). Low bone mass for age (HAZ-adjusted z ≤ − 2) was present in 20/29 (68.9%) patients, predominantly affecting the spine. Vitamin D insufficiency/deficiency was observed in 75.9% of patients. Katz ADL score correlated strongly with BMD at all sites, particularly the lumbar spine (r = 0.88, p < 0.001). Total calcium and vitamin D levels showed positive correlations with BMD. Patients with cardiac involvement had significantly lower BMI than those without cardiac disease (p < 0.001).

Conclusions

Pediatric patients with MPS receiving ERT show a high prevalence of low bone mass for age, driven by a multifactorial interaction between impaired mobility, nutritional deficiencies, and intrinsic skeletal pathology. Routine height-adjusted DXA monitoring, early physiotherapy, and proactive vitamin D and calcium supplementation should be integrated into comprehensive MPS care.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-026-06870-y.

Background

Mucopolysaccharidoses (MPS) are inherited storage disorders resulting from lysosomal enzyme deficiencies, which lead to the accumulation of glycosaminoglycans (GAGs) in tissues. There are seven major types, most of which are autosomal recessive, except for MPS type II, which is X-linked [1].

Skeletal involvement is a common presentation, particularly with MPS type IVA, leading to significant deformities, short stature, and detectable dysostosis multiplex on X-ray. Patients may experience stiff joints, contractures, reduced mobility, and possibly joint hyperlaxity. The accumulation of GAGs affects chondrocytes and surrounding tissues, contributing to these manifestations [2].

Additionally, patients are at risk of osteopenia/osteoporosis due to dysfunctional bone remodelling and interactions between GAGs, bone morphogenetic proteins (BMP), and fibroblast growth factors (FGF). Later-stage immobility and malnutrition can act as exacerbating factors [3, 4].

Studies evaluating bone mineral density (BMD) in patients with MPS remain scarce. The present study describes BMD findings in a cohort of MPS patients who were already receiving enzyme replacement therapy (ERT) at the time of assessment, rather than evaluating the effect of ERT on bone health by dual-energy X-ray absorptiometry (DXA) scans and related clinical and laboratory bone health parameters [5].

Patients and methods

Study type and duration

It is an observational cross-sectional study with 29 MPS patients diagnosed by enzyme assay and/or genetic testing from 2018 to 2023.

Inclusion and exclusion criteria

The research included patients above five years of age receiving enzyme replacement therapy at the Department of Pediatrics, Tanta University Hospital. ERT-naive patients were excluded because baseline DXA scans before treatment initiation were unavailable; therefore, the study was designed to describe bone health in an ERT-treated cohort rather than to assess treatment effects.

Ethical approval and consent

Parents or caregivers provided written informed consent, and ethical clearance was granted by the Research Ethics Committee, Faculty of Medicine, Tanta University, Egypt (approval code: 362664PR25/3/2023). The research was conducted in accordance with the Declaration of Helsinki.

Methodology

Clinical assessment

Data extracted from patients’ medical records included sex, diagnosis, time of diagnosis, commencement date of enzyme replacement therapy (ERT), length of ERT exposure, and Katz score evaluation for Activities of Daily Living (ADL) [6].

A comprehensive physical examination was conducted, emphasizing musculoskeletal evaluation to assess mobility and identify deformities. Body measurements were recorded, including stature, weight, head circumference, and body mass index (BMI). The BMI was determined by dividing weight in kilograms by the square of height in meters. All measurements were calculated as standard deviation scores and interpreted using age- and sex-specific growth references provided by the Centers for Disease Control and Prevention (CDC) 2000 growth charts [7].

A formal dietary assessment of protein and caloric intake was not performed, as detailed nutritional analysis was beyond the scope of this study.

Laboratory assessment

The following laboratory parameters were collected: Total calcium, serum ionized calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone levels, and Vitamin D.

Radiological assessment

Dual-energy X-ray absorptiometry (DXA) scan:

Bone mineral density (BMD) was assessed via dual-energy X-ray absorptiometry (DXA). A Norland densitometer (XR-46, USA) with software version Rev. 3.9.6/2.3.1 was employed. Each examination took approximately 20 min to complete. Patients were measured while barefoot and wearing light clothing.

Bone mineral density (BMD) for each participant was reported in g/cm², measured at the lumbar spine (L1–L4) and femoral neck regions. Values were converted to age- and sex-specific z-scores using normative reference data for Egyptian children [8]. Given that short stature is common in patients with MPS, BMD was adjusted for height-for-age z-scores (HAZ) to account for body size differences. HAZ-adjusted BMD provides a standardized assessment of bone density independent of linear growth, in line with pediatric ISCD 2019 guidelines [9].

Osteopenia was classified as a height-for-age–adjusted BMD z-score ranging from − 2 to − 1 (inclusive), whereas low bone mass was defined as a HAZ-adjusted BMD z-score below − 2 [8].

All measurements were expressed as z-scores, determined by subtracting the population mean from an individual’s observed value and dividing the result by the population standard deviation.

Statistical analysis

Data were entered into Microsoft Excel and analyzed using JASP (version 0.14.1.0). Continuous variables were summarized as mean ± standard deviation (SD), median, minimum, and maximum, while categorical variables were presented as frequencies and percentages. The Shapiro–Wilk test was applied to assess normality. Pearson’s correlation coefficient (r) was used to examine relationships between continuous variables. Group comparisons were performed using a two-tailed Student’s t-test, with statistical significance defined as p < 0.05.

Given the exploratory nature of the study and the limited sample size, adjustments for multiple comparisons were not applied; therefore, statistically significant correlations should be interpreted with caution.

Results

Clinical and anthropometric characteristics

The study cohort included 29 patients (10 females, 19 males) with genetically or biochemically confirmed mucopolysaccharidosis: 13 with type IVA, 11 with type I, 3 with type II, and 2 with type VI (Table 1); see Suppl. table S1 for enzyme assay and molecular results. Functional assessment using the Katz ADL scale showed variable levels of dependence, with a mean score of 3.9 ± 1.1 (Table 1). Across the cohort, growth parameters were markedly affected (Table 1).

Table 1.

Clinical and anthropometric characteristics of the study cohort (n = 29)

Parameter	Mean ± SD	Range (Min–Max)	Abnormal findings (%)
Age at enrollment (years)	9.79 ± 3.85	5–18	—
Age at diagnosis (years)	4.90 ± 2.99	0.1–11	—
Age at ERT initiation (years)	5.70 ± 3.44	0.3–12	—
Duration of ERT (years)	4.09 ± 1.83	1–8	—
Katz ADL score (0–6)	3.9 ± 1.13	2–6	4/29 fully independent; 12/29 moderate impairment; 13/29 severe impairment
Weight (z-score)	−1.65 ± 1.79	−4.6–1.48	18/29 (62.1%) underweight
Height (z-score)	−3.72 ± 2.99	−9.9–0.73	19/29 (65.5%) short stature
Head circumference (cm)	54.9 ± 1.65	51–58	All: macrocephaly
BMI (kg/m²)	18.4 ± 3.45	14–25.5	18/29 underweight; 3/29 overweight
Cardiac involvement			13/29 (44.8% ); 8 (AR + MR), 3 (Cardiomyopathy),1 (AR + MR+PH), 1 (dilated right ventricle + PH)

Values are presented as mean ± SD and ranges unless otherwise specified. Percentages refer to the proportion of patients with abnormal findings. AR  Aortic regurgitation, MR Mitral regurgitation, PH Pulmonary hypertension

Cardiac involvement was present in 13/29 (44.8%) patients (Table 1). Mean BMI was significantly lower in patients with cardiac disease compared with those without cardiac involvement (15.9 ± 1.4 vs. 20.5 ± 3.3 kg/m²; Welch t = − 5.05, p < 0.001).

Biochemical characteristics

To further evaluate skeletal risk factors, laboratory parameters of mineral metabolism were analyzed. Overall, abnormalities were most frequent for vitamin D and phosphorus levels, and calcium, while magnesium, alkaline phosphatase, and parathyroid hormone were largely within reference ranges (Table 2).

Table 2.

Biochemical characteristics of the study cohort (n = 29)

Parameter	Mean ± SD	Reference range	Abnormal findings (%)
Total calcium (mg/dl)	9.39 ± 0.40	8.5–10.2	—
Ionized calcium (mmol/l)	1.17 ± 0.09	1.16–1.31	Hypocalcemia: 51.7%
Magnesium (mg/dl)	2.07 ± 0.14	1.8–2.6	—
Phosphorus (mg/dl)	4.92 ± 0.56	4.0–5.5	Hypophosphatemia: 55.1%
Alkaline phosphatase (IU/L)	212.7 ± 99.1	143–362	—
Parathyroid hormone (pg/l)	38.2 ± 25.1	15–65	—
Vitamin D (ng/ml)	23.1 ± 9.2	> 30 optimal	Deficiency/insufficiency: 75.9%

Percentages represent the proportion of patients with values outside the reference range

DXA scan results

Overall, most patients demonstrated reduced HAZ-adjusted BMD, predominantly affecting the lumbar spine (Table 3).

Table 3.

DXA scan results of the study cohort (n = 29)

Site	Mean z-score ± SD*	Range (Min–Max)
Right femur	−1.84 ± 1.38	−4.0–1.7
Left femur	−2.07 ± 1.22	−4.1–0.7
Lumbar spine	−3.00 ± 1.49	−5.3–0.8

Bone status (based on z-scores adjusted for HAZ)*:

- Normal BMD: 2/29 (6.9%)

- Osteopenia (spine only): 2/29 (6.9%)

- Osteopenia (spine + femoral neck): 5/29 (17.2%)

- Low bone mass (spine + femoral neck): 8/29 (27.5%)

- Low bone mass (spine only): 12/29 (41.4%), including 2 with concurrent femoral osteopenia

*BMD values are presented as height-for-age z-score–adjusted means (HAZ-BMD). Adjustment for HAZ accounts for growth impairment in MPS patients and allows more accurate comparison between groups of differing stature

Fracture history

None of the patients with HAZ-adjusted BMD z-scores ≤ − 2 had a history of low-trauma or fragility fractures.

Correlation results: laboratory parameters

Correlations between HAZ-adjusted BMD and biochemical parameters are presented in Table 4. Notably, total serum calcium and 25-hydroxyvitamin D showed consistent positive associations with BMD, whereas alkaline phosphatase correlated negatively.

Table 4.

Correlation between DXA z-scores and laboratory parameters

Variable	Right femur (r, p)	Left femur (r, p)	Spine (r, p)
Ionized calcium	0.04 (0.84)	0.06 (0.76)	0.15 (0.45)
Magnesium	0.15 (0.45)	0.03 (0.86)	0.30 (0.12)
Phosphorus	0.00 (0.99)	0.03 (0.90)	0.16 (0.41)
Alkaline phosphatase	−0.39 (0.04)*	−0.37 (0.04)*	−0.54 (0.002)*
Parathyroid hormone	−0.33 (0.08)	−0.38 (0.05)	−0.28 (0.14)
25-hydroxyvitamin D	0.36 (0.04)*	0.42 (0.02)*	0.59 (< 0.001)*
Total calcium	0.60 (< 0.001)*	0.59 (< 0.001)*	0.88 (< 0.001)*

* p < 0.05 considered statistically significant

Correlation results: katz score

The Katz ADL score correlated strongly with BMD across all sites, with the strongest association at the lumbar spine (Table 5).

Table 5.

Correlation between DXA z-scores and Katz ADL score

Site	r	p-value
Right femur	0.71	< 0.001*
Left femur	0.65	< 0.001*
Lumbar spine	0.88	< 0.001*

* p < 0.05 considered statistically significant

Stratification based on MPS subtype and vitamin D status

When stratified by MPS subtype, mean lumbar spine Z-scores were lowest in MPS II (− 4.87) and MPS VI (− 3.75), compared with MPS I (− 2.47) and MPS IVA (− 2.91). Because of small numbers in some subgroups (particularly MPS II and MPS VI), these findings are presented descriptively only (Table 6).

Table 6.

Bone mineral density, vitamin D, and functional status by MPS subtype

MPS type	n	Mean Spine Z-score	Mean Femur Z-score*	Mean Vitamin D (ng/ml)	Mean Katz ADL score
MPS I (Hurler)	11	−2.47	−1.60	27.56	4.09
MPS II (Hunter)	3	−4.87	−1.60	14.47	3.00
MPS IVA (Morquio)	13	−2.91	−2.19	22.12	4.15
MPS VI (Maroteaux–Lamy)	2	−3.75	−2.90	18.15	3.00

Because of small numbers in some subgroups (MPS II and MPS VI), comparisons between MPS types are descriptive only

*Mean femur Z-score = average of right and left femur

Moreover, when stratified by vitamin D status, patients with sufficient vitamin D levels (> 30 ng/ml) had higher mean spine (− 2.06) and femur (− 1.38) Z-scores than those with vitamin D insufficiency/deficiency (− 3.30 and − 2.14, respectively). However, low bone mass remained common even among vitamin D–sufficient patients (Table 7).

Table 7.

Bone mineral density according to vitamin D status

Vitamin D status	n	Mean Spine Z-score	Mean Femur Z-score*
Sufficient (> 30 ng/ml)	7	−2.06	−1.38
Insufficient/Deficient (≤ 30 ng/ml)	22	−3.30	−2.14

*Mean femur Z-score = average of right and left femur

Management of low BMI and supportive therapies:

Patients with low BMI received nutritional counseling emphasizing high-calorie, protein-enriched diets. Oral caloric supplements were prescribed when dietary intake was insufficient. Vitamin D and calcium supplementation were administered according to pediatric guidelines in patients with documented deficiency or insufficiency. Those with significant functional impairment were enrolled in physiotherapy programs focusing on mobility, weight-bearing activities, and joint range of motion. Patients with cardiac involvement were managed in collaboration with pediatric cardiology, and medical treatment was optimized to reduce metabolic stress and improve exercise tolerance.

Discussion

This cross-sectional study evaluated BMD in 29 Egyptian patients with MPS receiving ERT. Our findings support a multifactorial model of bone loss in MPS, driven by the combined effects of impaired mobility, widespread nutritional deficiencies (particularly vitamin D and calcium), and possible intrinsic disease-related skeletal pathology [2, 3, 4].

Biochemical correlates of bone health

Serum total calcium levels in our cohort were largely within the normal range, consistent with findings in Egyptian children with MPS [10] and in the general Egyptian pediatric population [11]. However, mild hypocalcemia was detected in over half of the patients when ionized calcium was considered. Ionized calcium is a more reliable indicator of biologically active calcium status when total calcium is borderline or equivocal [12].

Vitamin D deficiency was widespread in our cohort, affecting over three-quarters of patients, consistent with previous MPS studies and national data from Egypt [13, 14, 11]. This likely reflects both the high baseline prevalence of vitamin D deficiency among Egyptian children and disease-specific factors such as limited outdoor activity, reduced dietary intake, and immobility.

We observed significant positive correlations between vitamin D and BMD at all sites [15]. In contrast, ionized calcium showed no significant correlation with BMD, clarifying that long-term calcium availability rather than momentary ionized levels may be more closely linked to bone mineral status in this cohort.

Vitamin D is essential for bone health because it promotes intestinal absorption of calcium and phosphate, which are required for hydroxyapatite formation and proper mineralization of the osteoid matrix. Deficiency in vitamin D reduces calcium availability, triggers secondary hyperparathyroidism, increases bone resorption, and impairs bone strength. Inadequate dietary calcium further limits the substrate for bone formation, compounding the effects of vitamin D insufficiency [16].

Alkaline phosphatase (ALP) showed a significant negative correlation with BMD, consistent with studies linking higher bone turnover with lower BMD in pediatric and adult populations [17, 18].

Importance of HAZ-adjusted DXA interpretation

Interpretation of pediatric DXA is strongly influenced by body size because areal BMD depends on bone surface area rather than true volumetric density. Children with marked short stature—such as many patients with MPS—may therefore appear to have spuriously low BMD despite normal volumetric bone density [19, 20].

In accordance with ISCD 2019 recommendations, we adjusted BMD Z-scores for height-for-age (HAZ) to mitigate this bias and improve clinical interpretability [9, 19]. This adjustment reduces the risk of overdiagnosing “low bone mass” in growth-impaired children.

Even after HAZ adjustment, nearly 70% of our cohort met criteria for low bone mass for age, predominantly affecting the lumbar spine, confirming that reduced BMD in MPS is not merely an artifact of short stature [5, 10, 21].

Functional status and bone health

A key clinical finding was the strong positive correlation between Katz ADL scores and HAZ-adjusted BMD at all sites, most notably at the lumbar spine (r = 0.88, p < 0.001). This highlights the central role of mechanical loading and functional mobility in maintaining bone mass [6].

Clinically, this supports the early integration of structured physiotherapy, mobility optimization, and individualized rehabilitation programs alongside ERT and nutritional supplementation to preserve skeletal health.

Intrinsic disease-related skeletal pathology

Beyond nutritional and mobility factors, intrinsic MPS-related mechanisms likely contribute to bone fragility. Accumulation of glycosaminoglycans within bone and cartilage can disrupt osteoblast–osteoclast signaling and extracellular matrix integrity. Experimental evidence shows that cartilage-resident chondroitin sulfates can modulate Cathepsin K activity, potentially enhancing osteoclastic bone resorption [22].

MPS subtype and vitamin D stratification

Descriptive stratification by MPS subtype suggested lower mean spine Z-scores in MPS II and VI compared with MPS I and IVA; however, small subgroup sizes preclude statistical comparison. Similarly, patients with sufficient vitamin D levels demonstrated higher mean BMD, yet low bone mass remained common even in this group [13, 11].

This indicates that children with MPS are vulnerable to low bone mass due to a combination of disease-related skeletal abnormalities, limited mobility, and nutritional deficiencies.

Cardiac disease, BMI, and bone health

Patients with cardiac involvement had significantly lower BMI than those without cardiac disease, suggesting that chronic cardiac pathology may adversely affect nutritional status through increased metabolic demand, reduced exercise tolerance, and overall disease burden.

ERT and bone health

Because this study is cross-sectional and lacks baseline pre-ERT DXA data, we cannot determine whether ERT improves, worsens, or has no effect on BMD. Any potential interaction between ERT and bone health should therefore be considered hypothesis-generating rather than causal. Previous longitudinal observations suggest that BMD may transiently decline during periods of accelerated growth on ERT [5].

Conclusion

Children with MPS demonstrate a high burden of low bone mass for age, largely influenced by impaired mobility, nutritional deficiencies, and disease-related skeletal pathology. Routine height-adjusted DXA monitoring, early physiotherapy, and proactive vitamin D and calcium supplementation should be integrated into comprehensive care for pediatric MPS patients to mitigate long-term skeletal complications.

Study limitations

The study is limited by its small sample size, which reduces generalizability. The lack of baseline DXA scans before enzyme replacement therapy (ERT) prevents assessment of treatment effects on bone mineral density. Although height adjustments were applied, DXA provides areal rather than volumetric measurements, potentially underestimating bone mass in children with growth impairment. The cross-sectional design precludes evaluation of longitudinal changes, and the absence of a formal dietary assessment limits analysis of nutritional influences. Additionally, multiple correlations were explored without adjustment for multiple testing, introducing the possibility of type I error. Consequently, all findings should be considered exploratory and hypothesis-generating, requiring validation in larger, longitudinal studies.

Abbreviations

ADL

Activities of Daily Living

BMI

Body Mass Index

BMD

Bone mineral density

BMP

Bone morphogenetic proteins

CDC

Centers for Disease Control

DXA

Dual-energy X-ray absorptiometry

ERT

Enzyme Replacement Therapy

ECM

Extracellular matrix

FGF

Fibroblast growth factors

Gags

Glycosaminoglycans

HAZ

Height-for-age z-scores

MPS

Mucopolysaccharidoses

SD

Standard Deviation

Authors' contributions

NF: data collection and drafting of the initial manuscript.AM: conception and design of the study, supervision, data review, and statistical analysis. YA: data collection and contribution to manuscript drafting. All authors critically revised the manuscript, approved the final version, and agree to be accountable for all aspects of the work.

Funding

This study was not funded.

Data availability

The datasets generated and/or analyzed during this study can be obtained from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Parents or caregivers provided written informed consent, and ethical clearance was granted by the Research Ethics Committee, Faculty of Medicine, Tanta University, Egypt (approval code: 362664PR25/3/2023).

Consent for publication

Parents or caregivers provided consent for publication.

Competing interests

The authors declare no competing interests.