Czynniki wpływające na jakość życia indonezyjskich dzieci z osteogenesis imperfecta

Introduction

Osteogenesis imperfecta (OI) is a rare genetic disease characterised by decreased bone density, which leads to frequent fractures. The disease leads to problems in many aspects of daily life, including social life and school life, due to limitations in physical activities caused by bone deformities. Most patients with OI have normal developmental status during childhood without neurological complications. However, neurological complications of OI can affect intellectual function, which in turn affects academic performance. Children with OI may find themselves becoming entirely dependent on others, especially children with severe OI, in whom these problems are worse [1–6].

Classification of OI severity was proposed by Sillence in 1979, who classified OI into 4 types: OI type I is the mildest type (osseus fragility, adulthood hearing loss, blue sclerae); OI type II is characterised by extremely severe osseus fragility and is perinatally lethal; OI type III presents with moderate to severe osseus fragility, normal sclerae, severe deformity of long bones and spine; and OI type IV presents with osseous fragility, generally normal sclerae, and severe deformity of long bones and spine [4].

The Sillence classification has undergone developments over time. Some individuals diagnosed with OI type IV have shown distinct symptoms differing from the previously identified symptoms of OI type IV, such as the development of hypertrophic callus accompanying fractures; this condition is classified as OI type V. Other OI cases show histological changes when examined under polarised light, which are then classified as OI type VI. Genes responsible for OI continue to be discovered, leading to the classification of OI into 8 types. With advances in molecular biology technology, the classification of OI has expanded and varied to 16 types and continues to grow. However, these classification changes are confusing and overly complex, especially since some genetically different types have similar clinical symptoms. Therefore, in 2010, INCDS decided to simplify the classification into just 5 types. This latest classification retains the first 4 types from the Sillence classification but with the addition of type V. The determination of OI types is more emphasised based on the clinical severity of the disease. To facilitate clinical application, OI criteria are organised based on the severity of the disease: mild to moderate OI includes types I, IV, and V, while OI with severe deformities includes types II and III [4, 7–9].

In 2010, the International Nomenclature Group for Constitutional Disorders of the Skeleton (INCDS) categorised OI into 5 types. This updated classification maintains the first 4 types from the Sillence classification and includes OI type V, which exhibited similarities to OI type IV. Osteogenesis imperfecta type V is distinguished by specific traits such as calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation. The determination of OI types is now emphasised based on the clinical severity of the disease. To facilitate clinical application, OI criteria are organised according to the clinical severity level, with mild to moderate OI encompassing OI type I, OI type IV, and OI type V, while OI with severe deformities includes OI type II and type III OI [4].

Clinical severity of OI is directly associated with quality of life (QoL). Song et al. [11] reported that the QoL of children with type III and IV OI was significantly lower compared to normal controls in physical mobility, emotional and social functions, school performance, and total QoL assessed with the Paediatric Quality of Life Inventory (PedsQL) 4.0. A study by Suskaeur showed no differences in temperament and emotional qualities of children with OI compared to normal controls, but children with OI had lower physical activity scores [3].

Studies show that type III OI contributed most to the burden of developmental and mental problems in children, as well as family financial burdens, despite bisphosphonate therapy [10–13]. Osteogenesis imperfecta also has a significant impact on the patient’s family, and this impact is associated with clinical severity, bisphosphonate therapy, prior surgeries, access to hospitals, and an increase in total family expenses to manage the disease. Economic hurdles such as poverty can affect QoL; children living in poverty are reported to have worse physical development, as well as psychosocial disturbances, and thus lower QoL scores [12–15].

Bisphosphonate therapy has been the standard treatment for children with OI for over 15 years. The initial hypothesis for using bisphosphonates was to reduce osteoclastic activity or bone resorption to strengthen bones. However, while reducing osteoclastic activity does not improve bone quality, bones remain brittle despite increased mechanical strength due to increased bone volume. Bisphosphonates have become widely used for OI treatment and gained broader recognition following the publication of a series of case reports of children with OI treated with intravenous pamidronate in Montreal in 1998. Bisphosphonates can be administered both intravenously and orally. They are also effective in healing vertebral bone fractures due to compression. Additionally, bisphosphonates reduce bone pain and improve the QoL for children with OI undergoing treatment during their growth period [1, 4, 9]. Studies conducted in various health centres treating children with severe deformities, including in Indonesia, show that this therapy reduces fracture frequency, allows growth rates to reach nearly normal levels, increases bone mineral density, significantly reduces pain complaints, and enhances mobility. The effects of bisphosphonate therapy are particularly noticeable in moderate to severe OI, while in mild OI the effects can only be assessed clinically because the bone mineral density is often normal [4].

Quality of life is a multidimensional concept that is individual and time-dependent, combining physical, emotional, and social aspects. There are differences in the literature regarding which dimensions should be included in QoL assessment, but most agree that QoL evaluation is subjective and should be done through patient interviews. Assessing QoL is crucial in evaluating children with chronic conditions because it is important to measure how well children adapt to their disease and how they cope with disease-related problems and ongoing treatments. There is currently no specific QoL assessment for children with OI, but efforts are made to evaluate their QoL using various instruments that involve mobility, psychosocial components, and the recurrence of fracture frequency [9].

To assess QoL in children with OI, some experts use physical parameters. For example, Engelbert et al. evaluated disability in OI by examining joint movement range, muscle strength, and functional abilities. The correlation between short stature and other outcome differences indicates that short stature has a more significant impact on QoL outcomes compared to economic factors and education levels [9, 13].

The various limitations with which OI patients live and the different factors that influence their lives, including frequent hospital visits, recurring fractures, specific daily care practices, and procedures such as surgery, can all contribute to QoL, and assessment of QoL is essential for treatment evaluation and the patient’s well-being. Thus far, no Indonesian studies have investigated the factors that influence QoL in children with OI. Two published studies from Jakarta only evaluated mental-emotional and intellectual factors, thus a more comprehensive study is needed.

Aim of the study

To thoroughly assess how OI affects the patients’ QoL, we comprehensively investigated the factors that influence QoL including psychosocial, financial, and mental-emotional problems.

Material and methods

This was a cross-sectional study aiming to investigate the QoL of children with OI based on clinical severity and to assess the association of QoL with psychosocial problems, behavioural problems, and socioeconomic characteristics.

Due to the COVID-19 pandemic, recruitment and data collection were done online by consecutive sampling on OI patients at the Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia, and the Gatot Soebroto Army Central Hospital, Jakarta, Indonesia, from August to December 2020. We recruited children and adolescents with OI aged 4–18 years, and we excluded any participants who had secondary osteoporosis (e.g. from long-term glucocorticoid use), refused to provide consent for the study, and participants who could not be contacted online. Data collection was facilitated by the Indonesian OI Forum (Fosteo), in which all participants in the study were members, where basic data such as names, addresses, and phone numbers were thoroughly recorded. Additionally, patients’ weight and height were documented in their latest medical records during their hospital visits.

In this study, we adopted the OI classification proposed by the INCDS, which included the Mild-moderate OI category (type I, type IV, and type V), and the severe OI category (type II and type III). The use of this classification can facilitate the interpretation of the research, considering that genetic testing or bone biopsy cannot be performed in Indonesia. Generally, severe OI is characterised by significant clinical disabilities, and in the context of patients participating in this study, severe OI typically involves ambulatory impairment. This study also dichotomously divided the age groups into pre-teen and teenage according to Erik Erikson’s psychological theory to explore whether there is a difference between teenage OI patients in the identity phase and pre-teen patients in the phases of guilt, inferiority, and role confusion, given that QoL is also associated with psychological aspects [5]. Regarding the basic physical attributes of OI patients, those capable of exercising were categorised as active, those who could only perform daily activities or play were considered moderate, and those with ambulatory issues preventing physical activity were categorised as sedentary.

We utilised instruments to assess participants’ QoL and its association with psychosocial and mental-emotional problems using PEDS QL 4.0, Paediatric Symptom Checklist 17 (PSC-17), and the Strength and Difficulties Questionnaire (SDQ). The PedsQL is a concise, standardised, and generic evaluation tool designed to systematically assess how patients and their parents perceive the quality of life related to health in children dealing with chronic medical conditions. This instrument evaluates health-related QoL across physical, emotional, social, and school functioning domains. The PSC-17 is a screening survey intended for completion by parents to identify school-age children who may be experiencing a broad range of psychosocial and emotional problems, including internalisation, externalisation, and attention. Lastly, the SDQ measures psychological well-being by addressing emotional symptoms, conduct problems, hyperactivity/inattention, peer relationship issues, and prosocial behaviour [17–20].

PEDS QL 4.0 was used to evaluate QoL, which consists of 23 items divided into 4 domains: 8 items on physical wellbeing, 5 items on emotional wellbeing, 5 items on social functions, and 5 items on school life. The total scores were transferred to a 0–100 scale, on which better QoL was indicated by a higher PEDS QL score. To screen for psychosocial problems, PSC-17 was used, comprising 17 questions divided into 3 subscales: internalisation (5 questions), externalisation (7 questions), and attention (5 questions). Each question was answered with “never” (0 points), “sometimes” (1 point), or “always” (2 points), and behavioural, emotional, and psychosocial problems were suspected if the total score was ≥ 5 for the internalisation subscale, ≥ 7 for the externalisation subscale, and ≥ 7 for the attention subscale, or if the total score for all subscales was ≥ 15. The SDQ was used to screen for behavioural problems, which contains 25 items divided into 5 scales with 5 items each: emotional symptoms, conduct problems, hyperactivity/inattention, peer relationship problems, and prosocial behaviour. Interpretation of this questionnaire was performed according to the authors of the original SDQ.

Osteogenesis imperfecta patients who fit our inclusion criteria were interviewed using the PEDS QL 4.0, PSC-17, and SDQ questionnaires. Then, video calls were conducted to interview the patients on the financial burden, logistical problems, and family resiliency using the World Bank questionnaire. The outcomes analysed were the final scores of PEDS QL 4.0, PSC-17, SDQ, and World Bank questionnaires, which were compared with OI clinical severity to evaluate statistical significance.

A detailed analysis of physical problems and QoL among patients involved examining the relationship between stature and QoL. Anthropometric measurement (weight and height) was conducted by trained personnel (paediatric residents) confirmed by paediatricians under paediatric endocrinology fellowship training or paediatric endocrinologists. Stature was evaluated based on the only national average growth chart of Indonesian children (2018 Indonesian National Synthetic Growth Chart [INSGC]) by Pulungan et al. and the standardised growth charts for children with OI by Robinson et al. [20, 21]. The height-for-age Z-scores of –1, 0, and 1 represent normal stature, –2 stunted, and –3 severely stunted categories based on INSGC, while the height-for-age percentiles of 3, 50, and 95 represent normal, 2 stunted, and < 2 severely stunted categories based on the standardised growth chart for OI [20, 21].

Results

The sample was composed of 50 children and adolescents with OI who had received treatment from the 2 centres in Jakarta. Patient characteristics are summarised in Table I.

Twenty-six subjects were male, and the median age of the subjects was 8 years. Only 41 subjects completed the self-report PedsQL questionnaire because it was not available for subjects under 5 years old. Only one subject identified as physically active, while 30 subjects reported themselves as moderately active, and 19 were sedentary. Osteogenesis imperfecta type was divided into 2 categories: severe (type III) and mild-moderate (type I and IV). Thirty-five subjects (70%) had severe OI and 15 (30%) had mild-moderate OI. The majority (92%) of subjects had good compliance with bisphosphonate therapy protocols.

Based on parents’ reports of QoL, disease severity affected QoL; there was evidence that subjects with severe OI were around 3.5 times more likely to experience poor QoL compared to subjects with mild-moderate OI [PR (95% CI): 3.429 (0.898–13.091), p = 0.029] (Table II). On the other hand, based on subjects’ self-reports, QoL and disease severity did not have a statistically significant relationship [PR (95% CI): 3.018 (0.794–11.473), p = 0.084]; the number of subjects with severe disease who reported poor QoL (n = 13) and good QoL (n = 15) was similar (Table III).

As seen in Table IV, there was strong evidence that poor QoL reported by parents was associated with impairments in the physical and psychosocial domains of the PSC-17 questionnaire (p < 0.001). Subjects with poor QoL were 5 times more likely to report psychosocial impairments [PR (95% CI): 5 (2.690–9.293)]. Similarly, poor self-reported QoL was associated with impairments in the physical and psychosocial domains in the PSC-17 (p < 0.001), and compliance with bisphosphonate therapy was associated with good self-reported QoL (p = 0.043). Based on subjects’ self-reports, subjects with poor QoL were 4 times more likely to experience psychosocial problems [PR (95% CI): 4.125 (2.257–7.540)]. Compared to those with good compliance to bisphosphonate therapy, subjects who had poor compliance to bisphosphonate therapy reported 3 times poorer self-reported QoL. No evidence of association was found between OI disease severity and family income (Table V). The majority of subjects had middle-high income. Compared to those with normal stature, OI patients who were stunted or severely stunted based on the standardised growth charts for children with OI [17] were approximately 3 times more likely to self-report poor QoL [PR (95% CI): 3.36 (2.050–5.520), p = 0.014].

Discussion

According to previous studies, patients with OI can participate in school and several other activities in the same way as their healthy peers, albeit with some physical limitations, including finishing their studies, and working for a living [11, 12, 14]. Our study investigated how the QoL of children and adolescents with OI relates to disease severity, psychosocial and mental-emotional factors, parents’ economic and education status, patient’s age group, and compliance to bisphosphonate therapy (Table VI). We found poor QoL to be associated with OI severity; children with severe OI were 3 times more likely to experience decreasing parent-reported QoL compared to children with mild-moderate OI, but not in self-reported QoL. Our findings are supported by previous reports showing that OI severity is related to QoL [11, 14]. Song et al. [14] found that children with severe OI had poorer QoL in all aspects. Factors that influence QoL in children with severe OI include gross motor difficulties such as impaired walking, bone deformities, and recurrent fractures [14, 22, 23].

A study by Seikaly et al. [24] found that similar associations and differences in self-reported and parent-reported QoL can be present. The difference between self-reported and parent-reported QoL may reflect discrepancies in comprehension of the questionnaire; children may find reporting subjective complaints difficult but can report physical complaints such as pain, emotional changes, fatigue, or gastrointestinal symptoms. Self-reported QoL is preferable to assess changes in QoL because the child is the person experiencing the symptoms [22, 23].

We found that parent-reported psychosocial factors, mental-emotional factors, adolescence, education level, and bisphosphonate therapy did not have significant associations with OI patients’ QoL. Patient-reported compliance to bisphosphonate therapy had a significant association with QoL; non-compliant patients had a 4-fold increased risk of poor QoL.

The underlying mechanism of how OI severity influences emotional and psychosocial aspects still needs to be elucidated but is predicted to be associated with the duration of the disease and the patients’ adaptation and coping mechanism [3, 5]. A cohort study by Tsimicalis et al. [25] showed differences in patient-reported and parent-reported QoL in OI patients undergoing zoledronate therapy. Parent-reported QoL was generally lower than patient-reported QoL after 3 cycles of zoledronate, in contrast with our finding of only patient-reported QoL being significantly associated with QoL changes.

Suskaeur et al. [3] reported that patients with OI type III and IV had similar temperaments compared to their healthy peers. Szczepaniak-Kubat et al. [22] used the WHOQOL-BREF questionnaire to assess QoL in OI patients and found that OI did not affect the global QoL or general health of the respondents, nor did it affect the mental and physical health and social functioning. Another study on OI in Indonesia concluded that OI patients aged 4–12 years did not experience mental and emotional problems, but this study did not fulfil the required sample size [5].

A decrease in QoL observed by both the parent and the patient based on OI clinical severity was significantly related to impairment in the physical and psychosocial domains of the PEDS QL questionnaire (p < 0.001) and to psychosocial factors. In addition to parent reports, education level, adolescent age, and economic status were not associated with QoL in OI patients. Studies by Engelbert et al. [11], Vanz et al. [12], Song et al. [14], Szczepaniak-Kubat et al. [26], and Hill et al. [27] found that education level did not affect QoL in OI patients, and the factor with most influence was clinical severity.

In our study, clinical severity was not significantly related to the family’s socioeconomic status. Family financial burdens include the costs of hospital visits, bisphosphonate therapy, and general care-taking [13]. In Indonesia, bisphosphonate therapy and surgeries were covered by national health insurance; thus, no economic hardships were reported by the patients. The subjects of our study did not cite hospital visits as burdensome, probably due to them being long-term patients with a low number of fractures per year due to routine zoledronate therapy, which only required one to two hospital days. Although there were a lot of improvements in management and OI awareness, there are still disparities and inequalities in OI medication access in every region in Indonesia. Accurate understanding is needed in the health care system to maintain compliance with the treatment [28, 29]. Pulungan et al. reported that no registered OI patients who received bisphosphonate treatment showed serious adverse effects [28, 29].

The strength of our study lies in being the first to utilise multiple validated questionnaires, including PEDS QL, PSC-17, SDQ, and the World Bank tool, to assess the clinical severity and impact of OI. Additionally, the study analysed the relationship between anthropometric status and the QoL of OI patients using the only national average growth chart for Indonesian children and standardised growth charts of OI patients.

However, the cross-sectional method restricted our ability to establish causality, including examining the correlation between QoL and the ability of the patient to walk. The use of questionnaires, measured at a single time point, limited our capacity to discern temporal relationships. Additionally, we did not account for potential variations in how parents and children interpret the questionnaires, nor did we consider patients’ adaptive and coping mechanisms, factors that could influence psychosocial and mental-emotional aspects.

To comprehend the factors contributing to the reduced QoL in individuals with severe OI, more in-depth analyses are necessary, including examining the correlation between QoL and the ability of patients to walk independently. Considering that most physical activity data were obtained through interviews rather than direct physical examinations due to the impact of the COVID-19 pandemic, this approach is particularly important. Unfortunately, this aspect was not explored in the present study due to insufficient data, thereby introducing an essential limitation to the research.

Conclusions

QoL in OI was significantly linked to clinical severity, with a threefold higher likelihood of poor QoL in severe OI compared to mild-moderate cases. In our study, clinical severity was not significantly related to the family’s socioeconomic status.