Topic 10.2. Screening and management of osteoporosis in Friedreich ataxia
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
Topic Contents
10.2 Screening and management of osteoporosis in Friedreich ataxia
10.2.1 Effects of Friedreich ataxia on bone health
10.2.2 Screening bone health
10.2.3 Management of low vitamin D, calcium and bone mineral density
Disclaimer / Intended Use / Funding
Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.
These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.
The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.
Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.
These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.
Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.
10.2 Screening and management of osteoporosis in Friedreich ataxia
Andreas Eigentler, Jaclyn Tamaroff, Miriam Cnop, Shana E. McCormack and David R. Weber
10.2.1 Effects of Friedreich ataxia on bone health
Osteoporosis is a skeletal disorder characterized by impaired bone strength. Osteoporosis increases risk of fractures, and is an endemic disease mainly in the elderly (50). In adults, a diagnosis of osteoporosis can be made based upon deficits in bone density alone. By contrast, the diagnosis of osteoporosis in a child requires a history of clinically significant low-trauma fractures (commonly defined as a single vertebral fracture, two long bone fractures before age 10, or three long bone fractures by age 19), with or without a finding of low bone density for age (areal bone mineral density (aBMD) Z-score of -2 or lower for age and sex) (51). Diminished bone loading, due to neuromuscular weakness and/or the inability to tolerate weight bearing activity, is a common cause of impaired bone strength in children and young adults with chronic disease (52, 53). Although individuals with Friedreich ataxia (FRDA) are known to have increased risk for scoliosis and foot deformities, there have been few studies on bone density and risk of fractures in FRDA.
Data from the Friedreich Ataxia Clinical Outcome Measures (FA-COMS) registry showed that 2.1% (23/1104) of people with FRDA reported osteoporosis or osteopenia, and 9.7% (107/1104) reported a fracture, of which none were vertebral/spinal or femoral fractures (54). However, these numbers likely underestimate the prevalence of impaired bone health, since many patients may not have undergone appropriate screening procedures required to identify low bone mineral density.
In one pilot study, bone mineralization was examined systematically in a small study cohort of individuals with FRDA; the prevalence of low bone mineral density was nearly 20% (55). Furthermore, increased severity of ataxia was associated with decreased aBMD of both the femoral neck and lumbar spine, indicating perhaps that ataxia-related decreases in mobility could contribute to decreased bone density. In addition, GAA repeat length, an index of genetic disease severity, was also associated with low bone density, and it may be that the disease itself has adverse impacts on bone health. This study also showed that a majority of individuals with FRDA presented with low 25-OH vitamin D levels (55), which is associated with an increased risk of osteoporosis and fractures (56, 57).
10.2.2 Screening bone health
Adults with Friedreich ataxia
Screening for low aBMD, which characterizes osteopenia and osteoporosis, includes dual-energy X-ray absorptiometry (DXA) and a structured evaluation of fracture history. The mobility status of individuals with FRDA might impact bone mineral density, as demonstrated in a small cross-sectional study where there has been a significantly lower aBMD in the femoral neck (of the hip) in individuals with FRDA who use wheelchairs (55). Measurement of forearm aBMD and/or distal femur could complement traditional assessments in individuals who are mostly non-ambulatory, as these skeletal sites have yielded additional insights in related populations.
Though there is no direct evidence of screening benefit in FRDA, we recommend screening aBMD in adults with FRDA since there are available treatments if low aBMD is identified, and at least one study found a substantial burden of clinically relevant low aBMD in FRDA (55). Radiation exposure during a DXA scan is extremely low and therefore not considered a relevant risk of screening. The determination of low aBMD and consequently the initiation of an appropriate therapy/prophylaxis could potentially prevent fall-related fractures, and could thus maintain or improve quality of life and prolong capacity for ambulation. While FRDA-specific evidence should be collected, there is persuasive evidence in a range of other populations and conditions for the benefits of osteoporosis therapy, such that opportunities to treat in FRDA should not be missed. In adults with FRDA and osteoporosis, there are a range of approved therapies from which an individualized treatment regimen can be selected by a clinician with relevant expertise.
Children with Friedreich ataxia
No data regarding bone mineralization status or risk of low aBMD in children with FRDA are available. Recent consensus statements (58, 59) highlight the potential utility of DXA in other similar conditions where risk for secondary osteoporosis may be increased, and DXA results may influence treatment decisions. The most appropriate timing for initiation of universal screening is not clear. The utility of universal screening may be lower in individuals with FRDA who have a relatively low burden of comorbidities and minimal limits to ambulation, although there are not yet data to guide this decision. Most appropriate recommendations regarding screening may depend on the age and pubertal status of the child, related imaging results, integrated assessment of fall risk, as well as priorities of patients and families.
In general, risk factors that would support DXA screening in children with FRDA include a clinically significant fragility fracture (long bone or spine), and/or decline in functional status, in particular transition to being mainly non-ambulatory. The frequency of subsequent scans will be guided by degree of aBMD deficit on the initial scan and the clinical scenario (fracture history, ambulatory status, etc.). Per current ISCD guidelines (60), total body less head (TBLH) and lumbar spine (LS) are the standard DXA scan sites in children. In patients with lumbar scoliosis, LS scans will not be accurate and alternate sites should be considered. Hip should be considered in ambulatory adolescents where ongoing need for bone density monitoring into adulthood is expected. Lateral distal femur (if local expertise is available) should be considered in non-ambulatory patients who are anticipated to be at increased risk of distal femur fractures. Forearm scans can also be considered if unable to perform other sites due to factors including scoliosis, contractures, or indwelling hardware. Vertebral fracture assessment by lateral spine x-ray or DXA should be considered in patients with back pain localized to the vertebral column and/or a lumbar spine (aBMD Z-score of -2 or lower), or other suggestive features on DXA (e.g., a lack of expected increase in lumbar spine aBMD).
Screening for low vitamin D
Since vitamin D levels are dependent on several variables (time/season of year at assessment, degree of latitude, activity outdoors) screening might be more widely used in corresponding conditions (e.g., high latitude/low sun exposure, low activity outdoors). Since assessment of vitamin D is done through routine venipuncture and generally available (e.g., during routine laboratory assessments in FRDA, such as glucose, HbA1c) and vitamin D3 supplements (with or without calcium) are widely available, annual assessment of vitamin D (25-OHD) to determine the need for supplementation is warranted, ideally near the end of winter.
10.2.3 Management of low vitamin D, calcium and bone mineral density
Nutritional approaches are reasonable to optimize bone health in individuals with FRDA. Low 25-OH vitamin D levels were present in the majority of the study population in the pilot study described above (55). Since vitamin D deficiency has been associated with an increased risk for osteoporosis and fractures (56, 57), ensuring adequate intake of vitamin D3, along with calcium for bone mineralization, is appropriate.
With respect to pharmacologic treatment options, although there is no FRDA-specific evidence with respect to the benefit of anti-osteoporotic therapy, the pathophysiology and clinical course of FRDA-related bone disease is likely to be similar to what has been described in other forms of secondary osteoporosis arising from neuromuscular weakness and immobility. Therefore, it is reasonable to assume that evidence supporting the use of bisphosphonates to increase aBMD in children with osteoporosis secondary to conditions including cerebral palsy, spinal muscular atrophy and Rett syndrome may be relevant to the FRDA population (61-64). In addition, in adults with FRDA, the full and rapidly evolving armamentarium of approved pharmacologic therapies for osteoporosis, including anti-resorptive and anabolic agents, should be considered according to individualized assessments by a clinician with relevant expertise.
Screening bone mineral density in adults
QUESTION: Should universal screening assessment (DXA + DXA or other vertebral fracture assessment) versus risk-stratified screening assessment (DXA + DXA or other VF assessment) be used for adults with Friedreich ataxia?
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[/sg_popup]STRENGTH OF RECOMMENDATION: ↑↑
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RECOMMENDATION: We recommend universal screening assessment of bone mineral density (DXA scan, fracture history) over risk-stratified screening in adults with Friedreich ataxia, given the availability of anti-osteoporosis medications that have been shown to prevent pathological fractures due to low bone mineral density (osteopenia, osteoporosis) in related populations.
JUSTIFICATION: Although there are no randomized controlled trials, we recommend screening of bone mineral density in Friedreich ataxia since the prevalence of low aBMD might be underestimated and is at least 20% according to a small cross-sectional study (55). Radiation exposure during a DXA scan is extremely low and therefore considered trivial. Determining low aBMD and initiating a corresponding therapy/prophylaxis will potentially prevent fall-related fractures and could maintain or improve quality of life and prolong capacity for ambulation. The initial DXA scan could be ordered by a primary care physician or Friedreich ataxia specialist. If osteoporosis is diagnosed, adults with Friedreich ataxia should be managed by clinicians with relevant clinical experience, such as an endocrinologist.
SUBGROUP CONSIDERATION: This recommendation is for adults with Friedreich ataxia. The mobility status of individuals with Friedreich ataxia might be important in terms of bone mineral density, since in a small cross-sectional study there was a significantly lower aBMD in the femoral neck in individuals with Friedreich ataxia who use wheelchairs, probably related to immobility. Measurement of forearm aBMD and/or distal femur could complement routine assessments (spine and hip, as per ISCD 2019 (65)) in individuals who are mostly non-ambulatory as these skeletal sites have yielded additional insights in related populations.
Annual DXA assessment could be considered for individuals found to have low bone density for age on the initial DXA and/or in whom the DXA results would guide further management decisions. The frequency may be adjusted based upon trends in BMD and with input of a bone health specialist. For individuals found to have BMD within the expected range for age, consideration should be given to repeating DXA in 2-3 years, or sooner as indicated by a clinical change (such as change in mobility status, use of new medications that could impact bone health, new fracture history).
Evidence to Recommendation Table PDFScreening bone mineral density in children
QUESTION: Should universal screening (DXA + DXA or other VF assessment) versus risk-stratified screening assessment (DXA + DXA or other VF assessment) be used for children with Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION: ↑
[sg_popup id=”658″ event=”click”][/sg_popup]LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: Clinicians should consider universal screening of children with Friedreich ataxia for low bone density via DXA; at minimum, a risk-stratified approach is recommended.
JUSTIFICATION: Recent consensus statements (58, 59) highlight the potential utility of DXA in other similar conditions where risk for secondary osteoporosis may be increased, and DXA results may influence treatment decisions. The most appropriate timing for initiation of universal screening is not clear. The utility of universal screening may be lower in individuals with Friedreich ataxia who have a relatively low burden of comorbidities and minimal limits to ambulation, although there are not yet data to guide this decision. The initial DXA scan could be ordered by the primary care physician or Friedreich ataxia specialist. If low bone mineral density is diagnosed, children with Friedreich ataxia should be managed by a clinician with relevant clinical experience, such as a pediatric endocrinologist.
SUBGROUP CONSIDERATION: This recommendation is for children with Friedreich ataxia. The most appropriate screening strategy may depend on the age and pubertal status of the child; the longitudinal trajectory of aBMD Z-score and/or absolute aBMD or BMC, DXA and/or related imaging results; an integrated assessment of fall risk; as well as priorities of patients and families. Routine skeletal sites in pediatric DXA scans include the lumbar spine and total body less head (66). Additional sites could be evaluated based on age, clinical history, and local expertise.
Evidence to Recommendation Table PDFScreening for vitamin D deficiency
QUESTION: Should screening of vitamin D and bone specific markers versus no screening or risk-stratified screening be used for all individuals with Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION: ↑
[sg_popup id=”658″ event=”click”][/sg_popup]LEVEL OF EVIDENCE: ⨁⨁◯◯
RECOMMENDATION: We conditionally recommend annual screening for vitamin D deficiency over no screening or risk-stratified screening in individuals with Friedreich ataxia.
JUSTIFICATION: Since assessment of vitamin D is done through venipuncture and is generally available (e.g., during routine laboratory assessments in Friedreich ataxia such as glucose, HbA1c), along with the wide availability of supplementation with vitamin D, we conditionally recommend assessing vitamin D levels as a basis for supplementation if needed.
SUBGROUP CONSIDERATION: This recommendation is for all individuals with Friedreich ataxia. As vitamin D levels are dependent on several variables (time/season of year during assessment, degree of latitude, activity outdoor), screening might be more widely used in corresponding conditions (e.g., high latitude/low sun exposure, low activity outdoors). Additionally, in individuals found to meet age-specific criteria for osteoporosis, additional screening for markers of bone mineral metabolism could be considered as part of a dedicated bone health evaluation.
Evidence to Recommendation Table PDFRoutine calcium and vitamin D supplementation
QUESTION: Should routine calcium and vitamin D supplementation versus selective vitamin D and calcium supplementation be used for all patients with Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION: ↓
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RECOMMENDATION: We conditionally recommend against routine calcium and vitamin D supplementation for individuals with Friedreich ataxia, but vitamin D and calcium supplementation should be considered for those with identified nutritional and/or biochemical deficiencies in calcium and vitamin D intake as these are known risk factors for decreased bone health and may contribute to longer-term fracture risk.
JUSTIFICATION: Addressing identified nutritional deficiencies in calcium and vitamin D in individuals with low bone health is considered best practice in both adults (e.g., National Osteoporosis Foundation guidelines: https://www.bonesource.org/clinical-guidelines) and children (58). However, there may be risks (e.g., hypercalciuria) with universal supplementation. There are no data to suggest any additional benefit of calcium or vitamin D supplementation for bone health beyond the standard daily recommended intakes (DRIs).
SUBGROUP CONSIDERATION: This recommendation of for all individuals with Friedreich ataxia. Nutritional requirements vary by age, sex, and size, and so supplementation, when indicated, should be individualized. Vitamin D levels can also be used to guide treatment.
Evidence to Recommendation Table PDFAnti-resorptive therapy in children
QUESTION: Should anti-resorptive therapy versus watchful waiting be used for children (under 18 years) with Friedreich ataxia who may not yet meet osteoporosis criteria but have at least one fragility fracture?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION: ↑
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RECOMMENDATION: We conditionally recommend anti-resorptive (bisphosphonate) therapy for children with Friedreich ataxia who may not yet have an aBMD Z-score of -2.0 or lower, but have at least one clinically significant fragility fracture.
We recommend that treatment be undertaken by a clinician with relevant expertise, such as a pediatric endocrinologist.
JUSTIFICATION: Although there is no Friedreich ataxia-specific evidence with respect to the benefit of anti-resorptive therapy, Friedreich ataxia-related bone disease likely shares features of other forms of secondary osteoporosis for which there is some available evidence, including from cerebral palsy, Duchenne’s muscular dystrophy, and other disorders, particularly inflammatory and/or nutritional. Recent consensus statements (58, 59) emphasize the need for larger and longer-term studies, but recommend consideration of bisphosphonates for two or more long bone fractures and/or one vertebral fracture, the latter being the prototype of a fragility fracture. Additional recommendations are offered stratified by bone DXA Z-score.
This recommendation is based on the capacity of bisphosphonates to increase aBMD and improve vertebral morphology in other conditions (62). Effects on fracture rate may be present but are difficult to demonstrate. Since bisphosphonate therapy is off-label in pediatrics and has associated risks, both known and unknown, referral to an experienced center is appropriate.
SUBGROUP CONSIDERATION: This recommendation is for children with Friedreich ataxia who may not yet have aBMD Z-score of -2.0 or lower, but have at least one clinically significant fragility fracture, where “clinically significant” is defined as a low trauma (fall from standing height or less, at no more than walking speed) fracture of vertebral body, lower extremity long bone, or humerus. The most appropriate treatment recommendations may depend on the age and pubertal status of the child; the longitudinal trajectory of aBMD Z-score and/or absolute aBMD or BMC, DXA and/or related imaging results; an integrated assessment of fall risk; risk of complications from bisphosphonate-related adverse events; as well as priorities of patients and families.
Evidence to Recommendation Table PDFIndividuals with Friedreich ataxia and osteoporosis should be managed by clinicians with relevant experience.
Lay summary of clinical recommendations for osteoporosis in Friedreich ataxia
Osteoporosis (fragile bones) is a skeletal disorder characterized by impaired bone strength. Osteoporosis increases risk of fractures (broken bones). The density of bones can be measured by doing a DXA (dual energy x-ray absorptiometry) scan.
The clinical interpretation of DXA scans varies by age and gender.
● In children and adults under 50 years:
○ Osteoporosis is typically defined by both a low bone mineral density (BMD, Z-score = -2 or lower) and the presence of clinically relevant fragility fracture(s).
○ In the absence of a fragility fracture, a BMD Z-score of -2 or lower is interpreted as “below the expected range for age”, and may indicate risk of fracture in the future.
○ A BMD Z-score greater than -2 is interpreted as “within the expected range for age” but does not completely rule out fragility fracture risk.
● In post-menopausal women and men 50 years of age or older:
○ Osteoporosis is defined by a BMD T-score of -2.5 or lower.
○ A BMD T-score between -1 and -2.5 is defined as “low bone density” and may be associated with increased risk of fragility fracture.
Why these recommendations?
Although there is limited information about bone health specifically in Friedreich’s Ataxia, we are proposing recommendations based on what is known about risk for impaired bone health in the general population and in individuals with other chronic health conditions.
Screening
For adults with Friedreich ataxia, we recommend universal screening assessment of BMD (using a DXA scan and taking an individual’s history of fracture) over screening only those thought to be at higher risk of osteoporosis. This is because available anti-osteoporosis medications have been shown to prevent broken bones due to low bone mineral density in related populations. Therefore, the benefit of screening for low bone mineral density outweighs the very small radiation exposure from DXA scans.
We also suggest screening of children with Friedreich ataxia for low bone health using a DXA scan, or at least screening children thought to be at highest risk of osteoporosis.
The recommendation for bone mineral density screening in children is weaker than for adults because:
1) there are less data on bone disease in children with Friedreich ataxia
2) there are fewer high-quality studies showing the safety and benefits of anti-osteoporosis medications in children
3) using a DXA scan to predict the risk of having a fracture in the future is more complex in children, particularly around the time of puberty.
Vitamin D deficiency has been associated with an increased risk for osteoporosis and fractures. Therefore, universal screening for vitamin D deficiency may be a better option than either no screening or only screening those considered to be at higher risk.
Management of nutritional deficiencies
We suggest addressing low calcium and vitamin D intake from the diet in individuals with Friedreich ataxia, as these are known risk factors for worse bone health and may contribute to longer-term fracture risk.
Management of low bone health
In case of the presence of osteoporosis, treatment of adults with Friedreich ataxia should follow general clinical guidelines.
For children, we suggest that medications called anti-resorptive (bisphosphonate) therapy should be considered for those who have at least one serious fracture that occurred without major trauma.
If possible, treatment should be managed by a clinical team with the appropriate expertise, including an endocrinologist.
What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?
Your healthcare provider may take a thorough history about fractures, your mobility status, and your nutritional status. Since individuals with Friedreich ataxia may be at risk for osteoporosis (fragile bones), your healthcare provider might arrange further investigations, including a DXA scan, a blood test to assess vitamin D levels and possibly other indicators of bone health (for example, calcium levels).
Depending on the results of these tests, calcium and vitamin D supplements and/or a medication might be started, with regular follow-up investigations.
Who are these recommendations specifically for?
Screening recommendations are for all individuals with Friedreich ataxia.
Calcium and vitamin D supplements may be recommended for individuals with Friedreich ataxia who have low vitamin D levels and/or low nutritional intake.
The osteoporosis management recommendations are for those with a diagnosis of osteoporosis or for children with a serious fracture not related to major trauma.
Professor, Universite Libre de Bruxelles, Brussels, Belgium
Email: miriam.cnop@ulb.be
Andreas Eigentler, MD, PhD
Resident of Neurology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
Email: andreas.eigentler@i-med.ac.at
Shana E. McCormack, MD, MTR
Assistant Professor of Pediatrics, Attending Physician, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Email: mccormacks1@chop.edu
Jaclyn Tamaroff, MD
Instructor in Pediatrics, Division of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nasvhille, Tennessee, USA
Email: jaclyn.tamaroff@vumc.org
David R. Weber, MD, MSCE
Assistant Professor of Pediatrics – Endocrinology, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Email: weberd@chop.edu
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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.