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Increasing the patient’s voice in osteogenesis imperfecta research and care

October 19, 2021

The Osteogenesis Imperfecta Foundation Patient-Centered Outcomes Research Project brought patient voices into efforts to improve patient-centered outcomes research and education in osteogenesis imperfecta.

Rare bone diseases constitute about 5% of all known rare diseases. Osteogenesis imperfecta (OI) is a group of genetic disorders causing connective tissue dysfunction and bone fragility, affecting an estimated 25,000 to 50,000 people in the U.S. Many patients with rare diseases, including those with conditions like OI, suffer from delays in diagnosis and lack of access to the complex multidisciplinary care they require.

Children’s orthopaedic surgeon Laura Tosi, M.D., is the co-lead of a two-year program, Osteogenesis Imperfecta Foundation Patient-Centered Outcomes Research Project. The now completed program brought patient voices into efforts to improve patient-centered outcomes research and education in osteogenesis imperfecta.

Increasingly, the OI community has become more vocal about its need for information and options for evidence-based care. Research about this condition often lacks the patient’s voice. Collecting the patient’s perspective about natural history, clinical best practices, quality of life and research priorities is challenging because, like so many rare diseases, the affected population is relatively small and geographically dispersed.

“We were excited that so many members of the OI community (patients, caregivers, clinicians, and researchers) stepped up to help us with this work for the last two years,” said Dr. Tosi. “They served on committees, completed surveys, and attended training sessions to learn more about patient-centered outcomes research.”

The program accomplished many goals, including creating a community of stakeholders who are trained in patient-centered outcomes research, with specific attention to priority topics identified by the OI community.

“We believe that attention to the broad impact of OI on patients’ lives, from patients’ perspectives, is urgently needed to better inform assessment, care and comparative effectiveness recommendations across the life span,” said Dr. Tosi.

The program considered the patients’ perspective and encouraged a collaborative effort among Children’s National Bone Health Program staff, geneticists, endocrinologists and other specialists to achieve rapid, accurate diagnosis that facilitates individualized care.

“Advances in knowledge can and will happen faster when more people participate in research from the outset,” said Dr. Tosi. “This means not just shaping the questions but also gaining the ability to understand and interpret the impact of such investigations.”

The program also expanded the communications and education strategies related to patient-centered outcomes, even during COVID-19.

The pandemic positively influenced the program’s educational efforts, Dr. Tosi added. The difficulties that emerged in the early months of the pandemic helped capture the community’s attention as they discussed the importance of the program. Through a COVID-19 supplemental award, the program gained more resources to expand the scope of the original education efforts.

With the new challenges and the possible physical and mental health threats that the pandemic posed to people with OI, including isolation and social distancing, the team used engagement strategies to raise awareness of the COVID-19 hazards, disseminated best practices for responses, and enhanced communications between stakeholders. The researchers were able to:

Expand virtual meetings, which allowed them to reach a wider range of patients.
Create and disseminate COVID-19 content (e.g., prophylactic care, symptoms, diagnosis, treatment, outcomes).
Use their existing OI Registry to document and track evolving issues such as more difficult access to medical care (or other necessary services), “daily living” concerns or burdens, and options for safe “return to work” and American Disabilities Act “work accommodations.”
Gather information on therapeutic options (e.g., pros and cons of medicines, counseling, telemedicine) and their potential to mitigate the health problems that isolation and social distancing create.
Develop tools to prepare the community for telemedicine, with emphasis on educating health professionals about patients’ higher vulnerability to coronavirus.

While the outcomes of this initiative were overwhelmingly positive, the researchers are also considering some changes, such as implementing “hybrid” models of in-person and remote meetings in the future.

Dr. Tosi served as project co-lead alongside colleagues Tracy Hart, project lead, from the Osteogenesis Imperfecta Foundation (OIF) and Bryce Reeve, Ph.D., co-project lead, director of the Center for Health Measurement at Duke University.

$x-ray of a fracture$

Genetic disorders, including osteogenesis imperfecta, rarely mimic child abuse

June 24, 2021

$x-rays of fractures$

In suspected child abuse cases, pediatric specialists are often called for clinical consultations or subpoenaed to courtrooms to discuss unexplained fractures and hemorrhage. During routine clinical practice, Children’s National Hospital (CNH) geneticists, child abuse pediatricians, orthopedists and radiologists use a multidisciplinary, stepwise approach that differentiates genetic disorders from cases of suspected child abuse. These teams provide a clear process for when clinical and radiological review suffices versus cases when judicious use of genetic testing and biochemical testing should be considered.

Every year, approximately 675,000 children suffer abuse or neglect, and at least 1,700 die from abuse — one of the leading causes of childhood morbidity and mortality nationwide.

Ill-intended arguments regarding genetic disorders often reach the court. Out of the 7,000 known rare diseases, rare bone diseases constitute about 5% of the cases. When there are true genetic disorders like osteogenesis imperfecta (OI), a group of genetic disorders that cause fractures, orthopedic specialists help tremendously with diagnosis and treatment. The Children’s National Bone Health Program specializes in caring for healthy children, children with genetic bone conditions, and children whose bones have been damaged from illness or poor nutrition. Their team of experts enhances treatment to meet the needs of each child help us provide the best possible care for children with a broad range of bone health conditions When a rare condition that causes bone fragility is suspected, these teams work together to provide proper diagnosis and management.

“OI is a diagnosis that can be made clinically with the help of geneticists, radiologists and orthopedists,” said Tanya Hinds, M.D., a child abuse pediatrician at Children’s National. “Outside of the newborn period, multiple unexplained fractures in infants with radiologically normal bones is suspicious for child physical abuse, not OI.”

When these regional cases reach the courtroom, Children’s National pediatricians often serve as clinician-educators and expert witnesses. According to Children’s National experts, clinicians must share the best available medical practices in both the hospital and courtroom. Unfortunately, in some cases around the country, a handful of expert medical witnesses provide unique and unsubstantiated opinions, sometimes claiming the presence of a rare genetic disorder as a cause of fracture or hemorrhage, when this has not been diagnosed by mainstream genetics specialists.

“On the part of expert witnesses, scientifically sound explanations versus unfounded hypotheses can influence outcomes in civil proceedings, which determine a child’s placement and criminal proceedings, which determine judgment on the perpetrators,” said Natasha Shur, M.D., medical geneticist at Children’s National, and Nathaniel Robin, M.D., professor and clinical genetics director at the University of Alabama in an editorial published in Current Opinion in Pediatrics.

Dr. Hinds works on behalf of children to provide the best and most comprehensive work-up in cases of unexplained fractures or hemorrhage. As a board-certified child abuse pediatrician, she is responsible for implementing the evidence-based practice guidelines of the American Academy of Pediatrics and other similar societies. Dr. Hinds mentioned that it is possible to use medical history, physical examination and diagnostic testing to differentiate traumatic causes of fractures and subdural hematomas from genetic causes, a belief she states is held by the vast majority of child serving clinicians.

“In cases of suspected child abuse, a multidisciplinary group of clinicians at Children’s National routinely provide comprehensive and top-rate care and consider alternative explanations for fractures,” said Eglal Shalaby-Rana, M.D., a radiologist at Children’s National who has partnered with the hospital’s Child and Adolescent Protection Center team on these challenging cases since 1991. “A multidisciplinary team is crucial to the evaluation and often includes additional specialists such as pediatric radiology, trauma surgery, hematology and in some cases genetics.”

Further, these clinician-educators and researchers at Children’s National call for increased publication and use of consensus guidelines such as the consensus statement on abusive head trauma published in Pediatric Radiology in 2018. “Consensus guidelines synthesize the best available medical evidence and should be the basis for both clinical practice and education offered in the courtroom,” said Drs. Shur, Hinds and Shalaby-Rana.

Distinguishing child abuse from genetic disorders

Drs. Hinds, Shalaby-Rana and Shur have served as expert witnesses and in turn wanted to come together to help develop frameworks that share scientifically sound information with peers who might encounter spurious arguments in courtrooms regarding genetic disorders as an explanation for physical abuse and inflicted fractures. Their 2021 literature review, published in Current Opinion in Pediatrics, addresses some of these issues.

To help distinguish child physical abuse from a genetic disorder, Drs. Shur, Hinds and Shalaby-Rana worked as a multidisciplinary team to highlight best practices in six instances when genetic disorders were raised as explanations for inflicted fractures or hemorrhage, including Elhers-Danlos syndrome (EDS), osteogenesis imperfecta (OI), Menkes Disease and Glutaric Acidemia type I. In some cases, these explanations could be reasonable but should be diagnosed using routine clinical and radiological review, and when indicated, genetic and biochemical testing.

For instance, EDS is a diagnosis that is sometimes erroneously used to explain multiple fractures in cases of suspected physical abuse and can be misused in courtrooms. The most common EDS type is hypermobile EDS, often found in late adolescence or early adulthood. In some cases, babies erroneously receive hypermobility exams, or clinicians perform hypermobility assessments on parents of children with unexplained fractures — neither practice is indicated. Instead, the Children’s National team points out that children should receive a medical evaluation using the standard guidelines set by the American Academic of Pediatrics, American College of Radiology and other professional societies.

Dr. Shur also collaborated with radiologists at Boston Children’s Hospital in a related review published in Pediatric Radiology. There, George et al. addressed the clinical and molecular diagnosis criteria for EDS to help radiologists prevent misdiagnosis and support clinicians when seeing patients with multiple fractures.

“It is disturbing that the unsubstantiated EDS infant bone fragility hypothesis continues to be advanced in civil and criminal child abuse proceedings when fractures are not part of the diagnosis criteria for EDS,” said George et al.

The clinicians noted that the Beighton score, which helps diagnose hypermobile EDS, is not intended for children younger than 8 years old. Additionally, since the score provides insufficient data, other EDS features must be present, such as skin findings and connective tissue abnormalities.

OI, known as ‘‘brittle bone disease,’’ is a group of disorders that rarely present only with unexplained fractures. The researchers emphasize that infants and children with mild OI do not present exclusively with multiple fractures, which are specific to physical abuse such as multiple, bilateral rib fractures and classic metaphyseal lesions. Drs. Shur, Hinds and Shalaby-Rana share that pediatric specialists could overcome the diagnostic challenges between OI and child abuse through the inclusion of a genetic team in some cases, during the medical evaluation while also considering various criteria, such as family history, physical examination and laboratory findings. Molecular testing may be required in some instances, but it cannot substitute traditional clinical and radiology evaluations, according to these clinician-researchers.

Similarly, while Menkes disease can present with intracranial hemorrhage and fractures like child physical abuse, there are other distinguishing characteristics unique to Menkes disease, such as hair and facial dysmorphism. In a third related case-review published in Pediatric Radiology, Shur, Hinds and Shalaby-Rana et al. emphasize that diagnostic difficulties may arises when a multidisciplinary evaluation is omitted. They call upon all clinicians to provide ethical testimony in civil or criminal proceedings and to continue to utilize a multidisciplinary approach during daily clinical practice.

Irresponsible testimony and predatory journals

According to George et al., in collaboration with Dr. Shur, there are flawed publications on EDS associated with infant bone fragility that do not follow the gold standard of the scientific community. They believe this hypothesis must be rejected by experts in the field of pediatric imaging to safeguard the scientific integrity of the discipline. The lack of scientific design, peer review process and transparency causes negative consequences in the courtroom and threatens the proper adjudication of cases of suspected child physical abuse.

“Irresponsible testimony increasingly enters medico-legal proceedings dealing with allegations of child abuse, and so-called expert witnesses regularly cite these deeply flawed publications — in addition to misquoting the medical literature, loosely interpreting medical findings, presenting fictitious findings, and excluding salient and widely accepted facts from consideration,” said George et al.

In these pieces of literature, our Children’s National multidisciplinary team members reviewed the best available evidence and their collective decades of patient experience to highlight standard processes, which differentiate child physical abuse as a cause of fractures and hemorrhage from rare disorders. Rare does not mean mysterious, and with education and a multidisciplinary approach, every child can receive the best possible medical work-up and care, according to Drs. Shur, Hinds and Shalaby-Rana. They urge all physicians to share only mainstream clinical medicine in the courtroom to help ensure the best possible social outcomes for children and their families.

red flags for irresponsible testimony

Refining criteria for childhood skeletal fragility and osteoporosis

November 10, 2020

Orthopaedic surgeon Laura Tosi, M.D., presented information about bone fractures and skeletal fragility in children at this year’s POSNA Annual Meeting.

It’s true that broken bones are often a typical part of childhood, says international bone health expert Laura Tosi, M.D., an orthopaedic surgeon at Children’s National Hospital. But for some children, a single bone fracture under the right circumstances may be a signal that a child needs a closer look to rule out underlying skeletal fragility.

Dr. Tosi presented on this topic as part of the Pediatric Orthopaedic Society of North America’s (POSNA) 2020 Annual Meeting. The presentations were conducted virtually this year due to COVID-19.

“We know that between 27 and 40% of girls, and 42 to 51 percent of boys will have at least one fracture during childhood,” she says. “What we have also seen over time is that almost 40 percent of children who have one fracture will have more. How do we tell which children with a fracture may need our help to avoid future ones?”

During her session, Dr. Tosi discussed how adding more nuance to clinical evaluation criteria for childhood fractures can help identify which children should be evaluated for conditions affecting bone density.

To widen the scope and make sure an underlying bone density issue is detected and treated as early as possible, Dr. Tosi says there are some specific findings that should suggest the need for further exploration:

Does the child have an a priori risk for a fragility fracture due to a genetic bone disorder(such as osteogenesis imperfects (aka brittle bone disease) or immobility caused by a disorder such as spina bifida, cerebral palsy or muscular dystrophy?
Is there a mismatch between the fracture severity and level of trauma that led to the injury?
Does the child’s history include any of four factors known to be associated with increased fracture risk: early age at the time of the first fracture, intolerance to cow’s milk, low dietary calcium intake or high BMI values.
Does the child have a vertebral compression fracture?
Is there a family history of frequent fractures (which may indicate a previously unidentified genetic condition)

Dr. Tosi also laid out specific evaluation steps for a skeletal fragility condition when a child’s fracture meets criteria, including:

Family, nutrition and exercise histories
A detailed physical exam
Complete radiograph review, including previously existing films and bone densitometry
Rule out rickets and child abuse
A complete lab work up

“It can be extremely challenging to identify if a child’s first bone fracture is a result of typical childhood activity or something else,” says Dr. Tosi. “But the risks of waiting to evaluate a fracture that meets some of the criteria above may mean we are delaying a treatment that might improve bone density and prevent a future fracture altogether — which is always what we’d hope to do.”

In the past, bone health experts felt that the word “osteoporosis” should not be used in children and pushed for the term “low bone density for age.” That perspective has begun to change thanks to important advances in our understanding of the genetic basis of bone fragility, the important role of chronic conditions and how the use of bone-active medications can significantly reduce fracture risk and improve function in certain conditions.

She then spoke about the benefits of early detection for conditions causing skeletal fragility by presenting compelling evidence of the resiliency of a child’s bones when they are managed appropriately.

She noted that she’s seen significant bone remodeling in patients with serious bone degeneration due to osteogenesis imperfecta and leukemia, for example, thanks to early detection and treatment.

“Our knowledge of bone density and bone health is improving, but is still imperfect,” she concluded. “But as we learn more, and are able to appropriately identify and treat kids with skeletal fragility or osteoporosis earlier, we can continue to refine how we evaluate and care for all of them.”

Building patient-centered outcomes research in osteogenesis imperfecta

February 10, 2020

Children’s orthopaedic surgeon Laura Tosi, M.D., is the co-lead on a program to improve patient-centered outcomes research and education in osteogenesis imperfecta that recently received a Eugene Washington Engagement Award of $250,000 from the Patient-Centered Outcomes and Research Institute (PCORI).

Children’s orthopaedic surgeon Laura Tosi, M.D., is the co-lead on a program to improve patient-centered outcomes research and education in osteogenesis imperfecta (OI) that recently received a Eugene Washington Engagement Award of $250,000 from the Patient-Centered Outcomes and Research Institute (PCORI). Dr. Tosi serves as project co-lead alongside colleagues Tracy Hart, project lead, from the Osteogenesis Imperfecta Foundation (OIF) and Bryce Reeve, Ph.D., co-project lead, director of the Center for Health Measurement at Duke University.

The project, which will be housed at the Osteogenesis Imperfecta Foundation, will run for two years and seeks to:

Create a community of stakeholders (patients/caregivers/clinicians/researchers) who are trained or training in patient-centered outcomes research, with specific attention to priority topics identified by the OI community.
Expand communications and education strategies related to patient-centered outcomes research to enhance the care of the OI community.
Establish and extend the capacity among patients, caregivers, clinicians and researchers in OI to participate in both patient-centered outcomes research and comparative effectiveness activities.
Develop an OI-specific toolkit focused on disseminating evidence-based clinical care recommendations to stakeholders and care providers, based on sustainable input from the OI community.
Extended the reach of these activities to support other rate bone disease communities.

Osteogenesis imperfecta is a group of genetic disorders causing connective tissue dysfunction and bone fragility. It is the most common of nearly 450 rare skeletal disorders and affects an estimated 25,000 to 50,000 people in the U.S. Collecting the patient’s perspective about natural history, clinical best practices, quality of life and research priorities is challenging because, like so many rare diseases, the affected population is relatively small and geographically dispersed.

“We hope this project will give us the ability to develop a set of best practices for care and research based on research that incorporates the patient’s point-of-view,” says Dr. Tosi. “I’m excited to work with this team and begin to change how we think about and care for OI patients and their families.”

Giving voice to adult osteogenesis imperfecta patients

August 14, 2017

With the influx of increasingly effective technology at our fingertips, the landscape of patient care for complex diseases has changed for the better in recent years. Doctors and researchers can accelerate new discoveries and improvements in patient care by querying and utilizing patient data gathered from all over the world.

For Laura L. Tosi, M.D., director of the Bone Health Program at Children’s National Health System, these changes have galvanized years of research into patients with osteogenesis imperfecta (OI), a population that is particularly difficult to trace into adulthood.

OI is a rare genetic disorder characterized by excessively fragile bones with a high susceptibility to recurrent fractures. Commonly known as “brittle bone disease,” OI is mostly caused by mutations in type I collagen genes. The severity of the disease varies widely and a cure for OI still remains to be found. Currently, treatment methods include medications, physical and occupational therapy, as well as surgery – all of which aim to reduce risk of further fracture, help patients manage pain and promote a healthy lifestyle.

Two of the most critical challenges that accompany the treatment of rare diseases, however, are the paucity of data on the adult patient experience and the challenge of transitioning patients safely from the multispecialty clinics frequently available in childhood to adult care givers who may have never seen the disorder in their career.

Through her research, Dr. Tosi aims to fill these critical knowledge gaps, and has found the Patient-Reported Outcome Measurement Information System (PROMIS®), the patient-reported outcome platform funded by the National Institutes of Health, to be particularly advantageous.

PROMIS® harnesses a set of measurement tools that uses computer adaptive technology and person-centered measurements to evaluate and monitor physical, mental and social health in adults and children. These tools quickly tailor themselves to individual responses and, because of their user-friendly design, provide a level of convenience and easy accessibility that other platforms lack.

“I have a number of OI patients moving into adulthood who cannot get care in the adult world, because my colleagues who care for adults have less experience with the disease and because caring for OI adult patients is largely uncharted territory,” says Dr. Tosi. Realizing the importance of giving voice to adults with OI, Dr. Tosi has harnessed a diverse range of standardized PROMIS® tools to attempt to capture a more complete understanding of the patient experience, ranging from the quality of social participation and peer relationships to physical and emotional distress.

When her first PROMIS®-based mailing to patients received an overwhelming response of more than 1,100 respondents in just 90 days, Dr. Tosi knew that pushing this research forward and out into the community was imperative. The results from that first survey, published in 2015 in the Orphanet Journal of Rare Diseases, demonstrated that adults with OI generally reported lower physical health status and were more likely to struggle with auditory and musculoskeletal problems.

Continued research in this area will not only generate much-needed knowledge about long-term healthcare issues and needs for OI patients, but also help clinicians improve their current treatment methodologies to anticipate these concerns ahead of time, if possible.

“The number of responses to our first survey demonstrated that patients really want to be heard. When you give them tools and ask them to tell you about themselves in ways that they hope will change how you practice, they want to help,” says Dr. Tosi, “because everyone wants to grow old well.”

At the end of August, Dr. Tosi will present her research at the 13^th International Conference on Osteogenesis Imperfecta in Oslo, Norway. She also presented her research at the 8^th International Conference on Children’s Bone Health as well as at the 17^th Annual OI Foundation Scientific Meeting.

Now taking part in designing and executing a national natural history study of patients with OI, Dr. Tosi plans to lead the charge for incorporating and implementing PROMIS® tools into the study. “Once we improve our tools, we will have the ability to query individuals from Alaska to Timbuktu, and provide a far more comprehensive understanding of this very complex and multi-faceted disorder. Harnessing the power of the internet and engaging the patient in delineating their disorder as well as their response to treatment offer a giant step forward in caring for individuals with rare diseases,” she says.