Cerebellum. 2014 Oct;13(5):549-57.
Low bone mineral density in Friedreich ataxia.
Eigentler A, Nachbauer W, Donnemiller E, Poewe W, Gasser RW, Boesch S.
Department of Neurology, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria.
Friedreich ataxia (FRDA) is the most common inherited neurodegenerative ataxia. Apart from predominant neurological features an involvement of the skeletal system in terms of scoliosis and foot deformities is frequent. Disease-related falls, mobility restrictions and wheelchair-dependency in later disease stages might additionally compromise bone structure in FRDA. The aim of this pilot study was to systematically evaluate the bone status in a representative FRDA cohort.
28 FRDA patients became enrolled in this cross-sectional study. Neurological assessment, a questionnaire comprising the history of fractures and osteoporosis as well as osteodensitometric measurements complemented with general and bone-specific laboratory parameters were performed. The WHO Fracture Risk Assessment tool (FRAX®) was applied, calculating the 10 year risk of suffering an osteoporotic fracture.
Six patients (21.4%) presented with a bone mineral density below the expected range for age in at least one of the examined sites (femoral neck, lumbar spine and forearm) irrespective of their gender. Corresponding Z-scores were significantly lower compared to normative values for the femoral neck and lumbar spine. Vitamin D status was insufficient in 11 and deficient in 8 FRDA patients. There was a strong negative correlation between ataxia severity, GAA repeat expansion and bone density in the femoral neck of FRDA patients.
This is the first report of an increased rate of low bone mineral density in FRDA. Given the increased risk of falls, this data rectifies routine bone mineral density measurements in FRDA which may help to initiate therapeutic interventions to prevent this condition.
Friedreich Ataxia (FRDA), although a rare disease with a prevalence of only 2-4 per 100,000 in the Caucasian population, is the most common hereditary ataxia. Besides key neurological symptoms comprising progressive ataxia of gait and limbs, dysarthria, muscle weakness, scoliosis, bladder dysfunction, and loss of position and vibration sense, other non-neurological symptoms can be observed. Involvement of the skeletal system in terms of scoliosis and foot deformities are frequently encountered in FRDA patients already when first neurological symptoms become manifest and further contribute to burden of disease.
Former reports of an increased risk for developing osteoporosis in more common neurological diseases like Parkinson’s disease or multiple sclerosis (1,2) as well as a young FRDA index patient who had suffered from a hip fracture turned our attention to investigating the bone mineral density (BMD) in our FRDA cohort. In this pilot study we found that Z-scores were significantly lower compared to normative values for the femoral neck and lumbar spine in about 20% of the study population.
A clear pathophysiological understanding for the basis of the observed bone mineralization impairment in FRDA is currently lacking. In accordance with FRDA specific pathological background, one might propose an early mitochondrial energy supply failure in osteoblasts. As a corollary, reduced ATP levels due to frataxin deficiency could exhibit an effect on osteogenesis and mineralization and therefore account for an early involvement of bone development (3). Another possible explanation refers to the putative iron misdistribution hypothesis in FRDA which results in cellular iron misdistribution with mitochondrial iron accumulation (4,5). As mitochondrial iron accumulation is known to preponderate in later disease stages, one cannot exclude a secondary pathophysiological role of iron in the skeletal involvement in FRDA, especially in maintaining bone mineralization. This notion has to be confirmed by histopathological examinations of the skeletal system in FRDA which is currently lacking.
In order to enlighten the question whether disease inherent traits or environmental factors can predict bone mineral density status in FRDA patients, we performed linear regression analyses. We were able to demonstrate an independent effect of the disease status, represented by the ‘Scale for the Assessment and Rating of Ataxia’ (SARA) score, on the BMD of the femoral neck and lumbar spine. A similar approach using the shorter GAA repeat length further emphasized a disease inherent influence on bone quantity and quality in FRDA.
Based on our findings and the fact that FRDA patients are at high risk of suffering falls due to ataxia we initiated a treatment with vitamin D and calcium as agreed with an endocrinologist to further prevent deterioration of bone mineral density. Follow-up investigations are ongoing.
(1) Smith ÉM, Comiskey CM, Carroll M. A Study of Bone Mineral Density in Adults With Disability. Archives of Physical Medicine and Rehabilitation 2009 Jul;90:1127-1135.
(2) van den Bos F, Speelman AD, van NM, et al. Bone mineral density and vitamin D status in Parkinson’s disease patients. J Neurol 2013 Mar;260:754-760.
(3) Miyazaki T, Iwasawa M, Nakashima T, et al. Intracellular and Extracellular ATP Coordinately Regulate the Inverse Correlation between Osteoclast Survival and Bone Resorption. Journal of Biological Chemistry 2012 Nov 2;287:37808-37823.
(4) Li K, Besse EK, Ha D, Kovtunovych G, Rouault TA. Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia. Human Molecular Genetics 2008 Aug 1;17:2265-2273.
(5) Richardson DR, Huang ML, Whitnall M, Becker EM, Ponka P, Suryo RY. The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich’s ataxia. J Mol Med (Berl) 2010 Apr;88:323-329.