Abstract
Many neuromuscular diseases (NMD) result in muscle weakness, immobility and greater fracture risk. The objective of this study is to determine the fracture risk of adult patients at a multidisciplinary NMD clinic. Fracture risk was calculated using the Fracture Risk Assessment Tool, the presence of osteoporosis was quantified using bone densitometry and contributing co-morbidities were screened through serum markers. Of the 36 patients studied, 47% were found to be of moderate and high fracture risk. Two thirds of these patients had not been previously screened or treated for osteoporosis. These findings suggest that NMD patients warrant routine screening for osteoporosis and early treatment to reduce fragility fracture.
INTRODUCTION
A wide range of neuromuscular diseases affect the motor system. Examples include amyotrophic lateral sclerosis, neuromuscular junction disorders, and myopathies such as muscular dystrophy. Despite the heterogeneity of these disorders, they all have the potential to cause muscle atrophy and weakness, resulting in disuse, immobility, and nutritional deficiencies. These factors can lead to decreased bone mass and increased falls risk [1]. Evidence also shows that genetics may play a role in terms of bone density; for example, the survival motor neuron gene expressed in spinal muscular atrophy results in differential splicing in bone-resorbing osteoclasts [2].
Importantly, fractures in patients with neuromuscular disease have been linked to long term functional deficits that can be devastating because their baseline function may already be compromised. Despite the consequences, there are currently no guidelines to help clinicians decide whether these patients warrant screening or intervention for reduced bone density. Existing studies regarding fracture risk amongst patients with neuromuscular diseases are limited to patients with Duchenne muscular dystrophy with glucocorticoid exposure and patients with amyotrophic lateral sclerosis [3].
Clinical guidelines exist for the screening and treatment of osteoporosis for a variety of neurological diseases where patients are deemed at increased risk including stroke and spinal cord injury. However, neuromuscular disease has not yet been included because supporting data is sparse. Therefore, the purpose of this study is to test the hypothesis that patients across the spectrum of neuromuscular disease are at increased risk of osteoporosis and fragility fractures.
MATERIALS AND METHODS
Study design and recruitment
This single center, cross-sectional study involves all patients being actively followed at a regional multidisciplinary neuromuscular clinic, serving patients from central and northern Alberta. The study was approved by the human research ethics board at the University of Alberta. Over a period of 6 months, 84 adults (ages >18 years) were approached for recruitment. After informed consent and a functional assessment were obtained, each participant was given bloodwork and imaging requisitions to complete within 3 months. To maximize the response rate, subjects were telephoned at 3 months following recruitment to assess progress, and information packages were re-mailed a maximum of 2 times as a reminder. The only exclusion criterion was a known additional cause for secondary osteoporosis for which treatment was already ongoing.
Assessment and investigations
In addition to demographic information, a medical history (including exposure to glucocorticoids, estrogen exposure, previous fragility fractures, treatment for osteoporosis and fall history in the past 12 months) was collected. Patient ambulatory status was evaluated using the Vignos Ambulatory Scale (VAS) that has previously been validated amongst the neuromuscular population (Appendix A).
Investigations included bloodwork for possible serologic correlates to osteoporosis including levels of ionized calcium, 25-hydroxyvitamin D, albumin, magnesium, parathyroid hormone (PTH), thyroid stimulating hormone (TSH), alkaline phosphatase (ALP), testosterone, creatinine, and a serum protein electrophoresis (SPEP).
Bone density scan was done using a Hologic scanner calculating the z-score and t-scores at the femoral neck and spine. Lateral x-rays of the thoracic and lumbar vertebrae were obtained to investigate for vertebral compression fractures. The x-rays were interpreted by a single radiologist and vertebral fractures were reported as either present or absent.
Statistical analysis
Descriptive statistics were performed on patient demographics including age, sex, health characteristics such as body mass index (BMI), history of fragility fractures and previous or current treatment of osteoporosis. Individuals at moderate and high risk of fragility fractures were identified by inputting relevant clinical risk factors into the Fracture Risk Assessment Tool (FRAX, see Appendix B). It has been shown to be predictive of fracture risks not just in the femur, but also in the spine and wrist [4, 5]. Since the lowest age the FRAX tool accommodates is 40 years old, individuals younger than 40 were assigned this age.
Patients at moderate and high risk of fragility fractures were compared to those at low or no risk. Independent 2-sided t-tests were performed on variables including age, gender, BMI, smoking, alcohol use, history of fragility fractures, current treatment for osteoporosis, cumulative estrogen exposure, VAS score and vitamin D levels. Bonferroni correction was made for multiple comparisons. Statistical significance was set at p < 0.005.
RESULTS
Of all the 84 patients seen in the clinic over a 6-month period, 70 patients consented to the study. Following a series of follow-up efforts, 36 patients fully completed all components of the study, representing a response rate of 51%. These consisted of 18 males (out of 41) and 18 females (out of 29). Demographics and clinical characteristics of the 36 respondents are detailed in Table 1. Of note, 24 patients (67%) had never been screened for osteoporosis. Only 12 patients (33%) were on vitamin D and calcium supplementation. Of those, 3 (8.3%) were known to have a history of osteoporosis and were on bisphosphonates. There were no significant differences between respondents and non-respondents, as per descriptive statistics and analysis shown in Table 2. The range of neuromuscular disease was similar.
Descriptive statistics of the total sample (n = 36)
Abbreviations Used: LGMD: Limb Girdle Muscular Dystrophy; DMD: Duchenne Muscular Dystrophy; CPEO: Chronic Progressive External Ophthalmoplegia; FSHD: Fascioscapulohumeral Dystrophy; MELAS: Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes.
Comparison of responders versus non-responders in the study population (n = 70)
Abbreviations Used: LGMD: Limb Girdle Muscular Dystrophy; DMD: Duchenne Muscular Dystrophy; FTDM: Fiber Type Disproportionate Myopathy; CPEO: Chronic Progressive External Ophthalmoplegia; FSHD: Fascioscapulohumeral Dystrophy; EDMD: Emery-Dreyfuss Muscular Dystrophy; MELAS: Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes.
The average VAS score was 4.33, indicating difficulty transferring from a chair and going up and down stairs. For the 16 patients that had previous fragility fractures, their average VAS score was 0.88 points higher.
Although all patients had normal calcium levels, 10 patients (27.8%) had low vitamin D levels. One incidence (in different individuals, 2.8%) of low magnesium, TSH and testosterone and high ALP and PTH levels was found. All patients had normal SPEP, creatinine levels and glomerular filtration rates, consistent with no known history of renal disease.
Through imaging, 5 patients (13.9%) were found to have moderate to severe vertebral compression fractures on lateral spine x-rays. Fourteen patients (66.7%) had a bone density scan t-score at the femoral neck between –1.0 and –2.5 indicating osteopenia and 10 patients (27.8%) had a t-score below –2.5 indicating osteoporosis. Upon calculating FRAX scores to determine 10-year fragility fracture risk, 5 patients (13.9%) were found to be at moderate risk and 12 patients (33.3%) at high risk totalling 17 patients (47.2%) at a 10-year moderate and high risk. Four patients (11.1%) reported a history of greater than 3 months glucocorticoid exposure, and were all at moderate and high risk. Of the 36 patients, 16 (44%) also reported non-vertebral fractures. These included the wrist, femur, patella and foot. There was no significant correlation between previous fractures and age, gender or BMI.
All participants were stratified into no/low risk or moderate/high risk groups for further statistical analysis. Comparisons between these 2 groups were performed to determine factors contributing to increased fragility fracture risk. Two-sided t-tests revealed advanced age was a significant factor in the moderate and risk group. Although there was a trend that decreased ambulatory status was a possible risk factor in the moderate and high risk group (p = 0.14), it did not reach statistical significance which is likely due to the small sample size (Table 3). The decline in ambulatory status is not age dependent as the two are not significantly correlated (r = 0.14; p = 0.64). However, bone density was significantly correlated with ambulatory status (r = –0.37; p < 0.001). Analysis of BMI, history of fragility fractures, total estrogen exposure, vitamin D and calcium levels, smoking history, and alcohol consumption resulted in non-significant differences between the 2 groups.
Moderate and high versus low fragility fracture risk in the study population and significance of contributing factors (n = 36)
* = statistically significant (p < 0.005).
DISCUSSION
Based on the results, osteoporosis and fragility fracture risk are currently underdiagnosed and undertreated in the neuromuscular population. Despite results indicating decreased bone mass and osteopenia amongst 2/3 of participants, and a history of fragility fractures in nearly half, 2/3 of participants had never been screened for osteoporosis and very few were actually being treated. Furthermore, half of the patients were at a moderate and high 10-year risk of fragility fractures with major determinants being advanced age and reduced ambulatory status. Together, this information highlights the need to address the deficiency in guidelines for osteoporosis screening and interventions, a major gap in healthcare for patients with neuromuscular diseases.
The response rate of 51% represents a study limitation. There were several factors in the neuromuscular disease population that posed challenges to retention including intellectual and physical deficits amongst patients. For example, some patients were cognitively compromised and could not recall any conversation with them to participate and did not follow through with investigations. Motor deficits were also hindering as many patients were unable to organize transportation, or assistance with transfers and ambulation, outside of their normal activities.
Patients referred to multidisciplinary neuromuscular clinics are often more chronic and at a higher level of disability and severity. They may be at a higher fracture risk than the general population of patients with neuromuscular diseases, who may be earlier on with less risk of systemic complications, and thus less need for screening and intervention. This point is well illustrated by a study done by Chagarlamudi et al. (2017) on 94 patients with facioscapulohumeral muscular dystrophy (FSHD), the vast majority of them (89) were still ambulatory [6]. That group of patients did not have decreased BMD or increased fracture risk. In contrast, in the current study, despite the heterogeneity of the neuromuscular disease spectrum represented, they all share common features of being chronic conditions, immobility, muscle weakness, and disuse atrophy.
While the FRAX tool is the most comprehensive model available to stratify patients based on fragility fracture risk, it has limitations. The tool does not account for patients younger than 40 years old which likely resulted in several participants not being properly assessed according to their age. In addition, the tool incorporates t-scores at the femoral neck based on the epidemiological data of middle-aged Caucasian women. This leads to the challenge of age- and sex-matched controls in a more diverse population. Because the FRAX tool is based only on information extrapolated from its original cohort, factors not present in that cohort were not able to be taken into account. For example, although it is known that dose-responses exist for many clinical risk factors including smoking, glucocorticoids, and alcohol [7], these were not included in the FRAX assessment. Additionally, the FRAX tool does not take into account the number of previous fractures which is an important omission as a higher number likely carries a greater risk of subsequent fracture. Also, diet that may play a role in osteoporosis is not assessed.
It is now thought that high values for indices of bone turnover are associated with a fracture risk independent from bone mass density [8]. However, thus far there is no consensus on a reference analyte and how this would be incorporated into fragility fracture risk assessment, which is still a matter of clinical opinion. Therefore, it was not included in this study’s investigations.
In summary, many patients with neuromuscular disease presenting to a tertiary care multidisciplinary clinic are at significant risk of osteoporosis and fragility fractures. These patients warrant screening and intervention in order to prevent morbidity and mortality.
DECLARATIONS
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
The authors have no conflict of interest to report.
Footnotes
Appendix A
The Vignos Ambulatory Scale, a 10-point scale of increasing severity for assessing level of ambulation
| Grade | Description |
| 1 | Walks and climbs stairs without assistance |
| 2 | Walks and climbs stairs with aid of railing |
| 3 | Walks and climbs stairs slowly with aid of railing (over 25 seconds for eight standard steps) |
| 4 | Walks unassisted and rises from chair but cannot climb stairs |
| 5 | Walks unassisted but cannot rise from chair or climb stairs |
| 6 | Walks only with assistance or walks independently with long leg braces |
| 7 | Walks in long leg braces but requires assistance for balance |
| 8 | Stands in long leg braces but unable to walk even with assistance |
| 9 | Is in a wheelchair |
| 10 | Is confined to a bed |
Appendix B
Please answer the questions below to calculate the ten year probability of fracture with BMD. Age (between 40 and 90 years) or Date of Birth Sex Weight (kg) Height (cm) Previous Fracture (yes/no) Parent Fractured Hip (yes/no) Current Smoking (yes/no) Glucocorticoids (yes/no) Rheumatoid Arthritis (yes/no) Secondary Osteoporosis (yes/no) Alcohol 3 or more units/day (yes/no) Femoral neck BMD (g/cm2)
ACKNOWLEDGMENTS
We thank individuals including Aimee Soloway, Zaeem Siddiqi, Janice Richmond-Eisenstat at the neuromuscular multidisciplinary clinic at the Kaye Edmonton Clinic, University of Alberta for efforts in helping to coordinate this project. Stephanie Plamondon from the University of Calgary also provided valuable inputs.