The evaluation of bone status has become an important part of SMA management due to the availability of the intrathecal treatment, nusinersen, and the clinical development of other systemic approaches. However, in mainland Chinese patients with SMA, the BMD value remains unknown. This was the first evaluation of bone health in Chinese children with SMA based on DXA scanning in 40 patients with SMA type 2 or 3. We obtained baseline data on BMD and analyzed its related factors in this population, which could help to improve bone health management, select appropriate interventions to prevent low-trauma fractures, and evaluate the effects of treatment drugs.
Patients with SMA have an increased probability of pathological low bone mineral content due to muscle atrophy, limited development of gross motor functions, long-term low activity, insufficient vitamin D intake, and osteoporosis, which increases the risk of fragility fractures, severely affecting the quality of life. Skeletal system complications have been previously reported in children with SMA types 1–3. In 1986, Burke et al.  presented three cases of children with SMA type 1 with multiple perinatal fractures. Poruk et al.  reported that the mean values of whole-body BMD and LS BMD of 47 patients with SMA type 1 were both much lower than those of age-matched healthy controls. In recent years, an increasing number of BMD studies have included children with SMA type 2 or 3. Vai et al.  confirmed that LS bone mineral apparent density Z-score significantly decreased below − 1.5 in 50% of children with SMA type 2 or 3, and fractures occurred in 36.7% of patients including four patients with peripheral fractures and seven with vertebral fractures. Wasserman et al.  reported a BMD Z-score below − 2.0 in 85% of 62 patients with SMA types 1–3, and osteoporosis was diagnosed in 12.9% of these patients. Furthermore, fractures and osteoporosis could occur even in younger patients aged 3–4 years. In our cohort including patients with SMA type 2 or 3, 67.5% of patients had BMD Z-scores ≤ -2.0, consistent with the results of these previous studies. We suggested that low BMD is also frequently encountered in mainland Chinese patients with SMA, and it is necessary to regularly test and evaluate the bone status of children with SMA.
Our study found that the phenotype was mainly associated with the TBLH BMD and LS BMD Z-scores. Both the TBLH BMD and LS BMD Z-scores of children with SMA type 2 were significantly lower than those of the children with type 3. Wasserman et al.  also reported that patients with SMA type 1 had significantly lower BMD Z-scores at all skeletal sites compared to those with SMA type 2 or 3. This study showed that the more severe the phenotype, the lower the BMD Z-score. The effect of the severity of the phenotype on BMD may be related to numerous factors. Low BMD is related to the degree of muscle atrophy and motor function. The more severe the phenotype, the more obvious the muscle atrophy and the lower the motor function scores. Behringer et al.  revealed that ASM atrophy in SMA type 2 was more obvious than that in SMA type 3, while weight-bearing activities and traction of muscle could directly affect the increase of BMD. Conversely, the survival motor neuron (SMN) protein may directly influence BMD. Khatri et al.  revealed that the reduction of BMD in pediatric patients with SMA tends to be more pronounced than that in patients with other neuromuscular diseases. A previous study confirmed that the SMN protein plays an important role in bone remodeling and affects bone metabolism by regulating the expression of osteoclast stimulating factor by osteoclasts . It has been reported that in patients with SMA, the more severe the phenotype, the lower the amount of the SMN protein. Therefore, a high incidence of low BMD and fractures in patients with SMA may not be simply attributed to muscle weakness and lack of exercise but is one of the primary symptoms of the disease itself [22, 23].
Multiple studies have reported high fracture prevalence in children with SMA, while in our study, only 5% (2/40) of children with SMA children had fractures, which was significantly lower than the fracture rate of 36–46% reported by other studies [17, 24, 25]. The low rate of fractures in our patients may be related to their decreased participation in outdoor activities and rehabilitation. In our cohort, the patients with SMA were over-protected by their parents and seldom went outdoors to avoid possible injury, and only 30% (12/40) of the children visited a formal rehabilitation department for regular physical treatment for 1–3 years. The fractures in our patients occurred in children with regular long-term rehabilitation training and activities. One study has reported that fractures in patients with SMA and osteoporosis may occur in the regular rehabilitation process . With the development of multidisciplinary management and intrathecal administration of nusinersen in China, patients will inevitably face more rehabilitation training and a return to social life, and the proportion of fractures in Chinese patients may increase. Due to the high prevalence of low BMD in this population, we recommend the regular monitoring of BMD for Chinese patients with SMA in the future, and the appropriate exercise and rehabilitation methods must be well arranged according to their BMD data.
A low 25-OH-D level was found in 37.5% of our patients with SMA type 2 or 3, consistent with the findings of studies in other countries . Our study also showed that the serum PTH level was correlated with TBLH BMD in the linear regression model. Since PTH can promote bone resorption, elevated PTH levels can lead to bone density reduction. It is known that there is a negative relationship between vitamin D and PTH levels. Hence, vitamin D deficiency must be corrected to avoid an abnormal increase in bone resorption due to increased PTH secretion. Notably, vitamin D is a steroid hormone that can promote the absorption of Ca and P by small intestinal mucosa cells, thereby increasing blood Ca and P concentrations, which are beneficial to new bone formation and calcification, thus playing an important biological role in bone health. In 2018, international SMA management consensus  experts recommended that vitamin D levels and intake should be monitored annually, and supplements should be administered in the presence of low vitamin D levels or osteoporosis. However, in our study, none of the patients used vitamin D and Ca supplements regularly. This indicated that Chinese clinicians should pay more attention to this aspect to promote the bone health status of patients with SMA.
Although our study was the first to report a comprehensive view of BMD and fracture history across pediatric SMA types 2 and 3 in China, there were still several limitations. First, children with SMA type 1 were not included in our study. Second, the small sample size limited any detailed statistical analysis on differences among subtypes. Finally, our report cross-sectionally examined bone mineral density, lacking long-term monitoring and follow-up.
We conclude that low BMD was commonly observed in mainland Chinese patients with SMA and more than one-third of our patients also had vitamin D insufficiency or deficiency. BMD Z-scores at all skeletal sites of patients with SMA type 2 were substantially lower than those of patients with SMA type 3. The SMA phenotype and serum PTH level were the factors associated with the BMD of the patients. Therefore, the regular monitoring of BMD and serum vitamin D levels and timely intervention are of great importance in children with SMA. In a more thorough future investigation, the sample size must be expanded to minimize the bias of BMD data for better multidisciplinary management and individual treatment of patients with SMA.