Introduction
Osteogenesis imperfecta (OI) is a rare, heritable connective tissue disorder with variable manifestations and numerous symptoms affecting 1–5 in 10,000 individuals [
1‐
3]. Most often the condition is caused by alterations in the type 1 collagen genes (e.g. COL1A1 and COL1A2), but mutations in other genes that are linked to the collagen synthesis are also associated with OI [
1]. OI affects multiple systems and organs in the body, resulting in an array of possible symptoms including fractures, skeletal deformities, pain, joint hypermobility and occasionally blue sclerae, hearing loss, dental abnormalities, basilar invagination, cardiovascular and pulmonary abnormalities [
1].
Currently there are no curative therapies for OI, and treatment primarily aims to manage and decrease fractures, pain, and bone deformities, and promote mobility and independence. To manage the spectrum of OI symptoms multi-disciplinary care is required [
4,
5]. Most therapeutic agents used in OI care were initially developed to target the bone metabolism in conditions such as osteoporosis and are used off-label [
4]. Bisphosphonates are most widely used; additionally human monoclonal antibodies (e.g., denosumab) and parathyroid hormone (e.g., teriparatide) are available [
4,
5].
Considering the lack of curative treatment and the condition’s effect on multiple systems and organs in the body, living with OI has a significant impact on the physical, social, and emotional wellbeing of individuals as well as their families and caregivers [
6‐
8]. However, due to its rarity and variability, research into OI is challenging, and there are few comprehensive, self-reported patient outcome studies in this field [
6,
9].
While some aspects of OI and their impact on health-related quality of life (HRQoL) are well-understood (e.g., mobility challenges and fractures) others, such as women’s health, characteristics of pain, treatment-related adverse events, pulmonological conditions, and gastrointestinal-, sleep-, and skin-related conditions are less well studied [
9]. Similarly, the impact on some caregivers of individuals with OI is incompletely understood, particularly fathers and siblings [
9]. In addition, as most HRQoL studies are cross-sectional and use small samples, our understanding of the HRQoL of individuals with OI at different life stages is limited [
7,
9]
OI may also be associated with a considerable economic burden on individuals and their families, even in socialised healthcare systems [
10,
11], and an increased use of healthcare and social service resources [
12‐
17]. However, studies focus on the societal and healthcare resource use associated with OI, while out of pocket spending is rarely described [
10,
11].
To better understand the humanistic, clinical and economic impact of OI on individuals with OI, their families, caregivers and wider society we conducted the IMPACT Survey (Living with osteogenesis imperfecta: understanding experiences based on community insight & evidence) aimed at individuals with OI, their caregivers and relatives. Here we present the study’s design, methodology and first findings, including demographics, clinical characteristics and clinical signs, symptoms and events and their impact.
Discussion
The IMPACT Survey has compiled the largest known patient-reported dataset on the experience of individuals with OI (n = 2312 individuals across self- and proxy reports), and their caregivers (n = 560) to date. This was achieved through an ambitious and self-driven collaboration between the clinical and OI communities, aided by third-party funding from a pharmaceutical manufacturer. Past research on the impact of OI on individuals and their caregivers has been limited by small sample sizes and did not cover the breadth of topics included in IMPACT [
6,
7,
9,
18,
19]. Therefore, IMPACT was designed as an online survey to maximise accessibility across geographies and included questions covering a breadth of topics exploring the clinical, humanistic, and economic impact of OI that may be insufficiently documented in the existing literature.
While in this survey sample self-reported OI severity correlated well with other characteristics like height, mobility and clinical OI type, OI types were split across multiple OI severities. This finding mirrors previous research and suggests that “severity” is a holistic, patient-centric view of individuals’ health, that is not entirely captured by the clinical OI type which is determined based on clinical and molecular patient characteristics [
20,
21]. Additionally, while general predictions about the clinical OI type can be made based on the causative gene, mutation type and location, genetic variation alone does not account for all phenotypic variation [
22‐
24].
Some characteristics of this sample reflect the nature of the study. While OI is equally prevalent in men and women, most direct respondents to the survey were female. This is in line with past patient-reported outcomes research in OI, where an increased participation of women with OI and female caregivers is common [
9]. Most direct respondents were from Europe and European respondents made up > 50% of participants. This strong representation of European individuals is unsurprising as survey languages and recruitment efforts focussed on this region, although the survey was open to participants from any geography. OI type 1, which is commonly associated with mild OI, was the most commonly reported type across direct and proxy respondents. This is a somewhat lower prevalence of type 1 than reported in past population-based studies, but in line with other large surveys among individuals with OI [
1,
20,
25]. Past research has shown that in samples selected primarily based on individuals’ availability and willingness to participate, more engaged individuals (e.g., those who participate more in a computer game or are more involved with an organisation) who may also be more severely affected by a given health concern are overrepresented [
26,
27]. Moreso, past patient-reported outcomes research similarly underrepresented individuals with OI type 1 [
9,
28].
The survey includes adults (both self- and proxy reported), adolescents (self- and proxy reported), caregivers (with and without OI) of individuals with OI, children (proxy-reported), and relatives of individuals with OI. Caregivers also provided information on the OI-related QoL of any siblings to individuals with OI in their care. For some of these populations few data are available elsewhere: comparatively few studies, which commonly have small samples, provide information on the wellbeing of caregivers and siblings [
29,
30] and few studies include self-reporting adolescents [
9].
This study found that, irrespective of age, individuals with OI experience numerous signs, symptoms and events that affect their HRQoL. Pain was highly prevalent and impactful on the HRQoL of individuals with OI, as reported in past research [
20,
31‐
33]. Notably, fatigue, which has rarely been explored in children, was prevalent in children in this sample, but much less so than adults or adolescents. Past research also found that fatigue was prevalent in adults but not children [
20,
34]. Furthermore, our data suggest that fatigue may be underreported in caregiver-based studies: in our dataset, fatigue was reported by much higher proportions of self-reporting compared with proxy-reported individuals. This discrepancy has also been detected for numerous other clinical events, signs and symptoms including, in adolescents compared with proxy adolescents, gynaecological and menstruation problems, mental health problems, sleep disturbance and stomach and bowel problems. Similarly, differences were also common among reports of adults compared with proxy adults, for example in the proportion of individuals experiencing hearing problems, fatigue, sleep disturbance, stomach and bowel problems and mental health problems. While the survey does not include self-reported paediatric data, this suggests that differences in self- and proxy report may be an issue in the paediatric population as well. Past literature largely reports that parents underreport pain and some other not directly observable health conditions, however some reports found relatively high agreement between self- and proxy report [
35‐
42]. Nonetheless, underreporting may contribute to suboptimal health outcomes due to lack of attention focused on understanding a health issue; while there are few reports on bowel problems in the OI population, past research lists diseases of the digestive system as a common cause of death [
43,
44]. Among adults and adolescents, our survey has found a high prevalence of bowel and stomach issues.
Our survey has also detected a high prevalence of mental health problems in adults, adolescents and, to a lesser extent, children. Past literature on the mental health impact of OI is conflicting: while some reports found higher prevalence of mental health issues in adults and children, others have reported that the mental health of individuals with OI is preserved which in part may be due to the adaptation process experienced by individuals with chronic conditions [
8,
19,
20,
31,
34,
45‐
47]. More detailed exploration of the mental health impact of OI and affected areas of life will be the subject of additional analyses of the IMPACT dataset.
A mental health impact of OI may be aligned with participants’ responses on the effect of signs, symptoms and events on their life. Pain and fatigue were commonly perceived as negatively impactful across survey populations and these conditions have indeed been associated with a negative impact on mental health in past reports [
48‐
50]. Additionally, the negative impact of OI may increase with age: larger proportions of adults described signs, symptoms and events they experienced as moderately-severely impactful compared with adolescents. This may be due to an overall increasing burden of health events and/or a progressively decreasing resilience to health events.
Similarly sleep disturbance was commonly reported among all age groups. This finding is aligned with past literature [
20,
34,
51,
52] and may be correlated with the findings of a high prevalence of mental health issues and fatigue in the OI population [
53‐
55]
It remains to be explored whether the changes in prevalence and impact of clinical symptoms are caused by underlying differences in respondent demographics, differences in awareness and perception of symptoms by individuals with OI and their caregivers, or changes in symptom intensity or resilience.
Further analysis of the survey responses may fill current data gaps in our understanding of the lived experience of the OI community, to improve treatment and care, and to evaluate potential differences across diverse geographical or cultural settings.
Strengths and limitations
The IMPACT survey was developed in collaboration with researchers and OI community members to ensure that the survey design is relevant and inclusive. To this end, questions were adjusted to fit multiple demographics, including individuals who are underrepresented in existing research. The design was also adapted to cover a wide range of geographies, include relevant and culturally appropriate answer options, and was translated into 8 languages to include as many members of the community as possible. However, though IMPACT did not include any validated patient-reported outcome tools, questions were validated by members of the OI community and academic researchers. Our study does not include a control population which limits the generalisability of our findings; comparison with past population-based research can provide insights into the significance of our findings but may not be able to fully mitigate this shortcoming. Questions about ethnicity were omitted due to the breadth of potential fielding geographies and the resulting multitude of possible responses and respondent attitudes on questions about this topic.
During its 3-month fielding period the survey generated a large sample that includes a wide range of community members including demographics for which few data are available, e.g., adolescents and caregivers (with or without OI) of multiple individuals with OI. Despite our best efforts to recruit men, most survey respondents were female. As the survey includes a convenience sample of individuals recruited by patient organisations, the survey population includes those who were able to respond to a survey online and are engaged with PAOs.
Lastly, any self-reported data are limited by the respondents’ accuracy and recall bias. As the survey was fielded in 2021 under the extraordinary circumstances of the Coronavirus Disease Pandemic 2019 (COVID-19) pandemic in 2021 this bias may be exacerbated, and the generalisability of some survey outcomes may be affected. To mitigate this limitation and contextualise survey findings, the survey included questions about behavioural changes among individuals with OI and caregivers due to the COVID-19 pandemic.
Declarations
Competing interests
SP and MR are employees of Wickenstones Ltd, Abingdon, United Kingdom. Wickenstones. MB and CR have received payments for their contributions to the present manuscript. MB has received grants and from Ultragenyx Pharmaceuticals Inc, Novato, USA. and the Osteogenesis Imperfecta Foundation. TH serves as the Chief Executive Officer of the Osteogenesis Imperfecta Foundation and has received unrestricted educational grants from Mereo BioPharma Group London, United Kingdom and Ultragenyx Pharmaceuticals Inc, Novato, USA. OS has participated in a national advisory board for Mereo BioPharma Group London, United Kingdom. FR has received study contracts for experimental preclinical studies with Precithera Inc, Quebec, Canada, Mesentech Inc, Vancouver, Canada and Catabasis Pharmaceuticals Inc, Cambridge, USA. He has participated in advisory boards for Ultragenyx Pharmaceuticals Inc, Novato, USA, Sanofi S.A. Paris, France, Novartis International AG, Basel, Switzerland and Mereo BioPharma Group, London, United Kingdom. FR has received a speaker fee from Ultragenyx Pharmaceuticals Inc, Novato, USA for a lecture and received a donation of experimental drugs for a preclinical study from Acceleron Pharma Inc, Cambridge, USA. CR received an institutional grant from and has been a speaker for BioMarin Pharmaceuticals Inc, Novato, California, has participated in advisory boards for Ultragenyx Pharmaceuticals Inc, Novato, USA. She has received an institutional grant from and is a consultant for Nextcure, Beltville, MD, USA. CR sits on the board of directors of the Osteogenesis Imperfecta Foundation. CR has also participated in an advisory board for Mereo BioPharma Group, London, United Kingdom. TW and IW hold leadership positions in the Osteogenesis Imperfecta Federation Europe, which has received grants from Mereo BioPharma Group, London, United Kingdom (unrestricted), Ultragenyx Pharmaceuticals Inc, Novato, USA (restricted grant for a conference), Quince Therapeutics Inc, San Francisco, CA, USA (donation for a conference), UCB (restricted grant to conference), Angitia Biopharmaceuticals Inc., Woodland Hills, CA, USA (donation to conference), Azafaros BV, Naarden, the Netherlands (donation to conference), Alexion Inc. Boston, MA, USA, (sponsorship of conference); Pega Medical Inc, Laval, Quebec, Canada (donation), Sanofi S.A. Paris, France (payment to IW for engagement in steering committee; donated to OIFE). IW has also received payment as a panellist from Takeda, Tokyo, Japan.
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