Osteogenesis imperfecta (OI) is a genetic connective-tissue disorder characterized by bone fragility and susceptibility to fracture because of minimal trauma or no trauma at all.1–6 The incidence of OI varies among populations worldwide; the condition affects about 1 in 10 000 to 20 000 newborns.6–8
In addition to bone fragility and multiple fractures, other clinical features that may be associated with OI include joint hypermobility, blue sclera, dentinogenesis imperfecta, deafness, short stature, and the presence of Wormian bones in the skull.6,7,9 In most cases, inheritance is autosomal dominant and the condition is caused by mutations in the COL1A1 or COL1A2 genes, which code for collagen type I. However, in recent studies, autosomal recessive inheritance linked to mutations in other genes has been found to play a role in the biosynthesis of collagen.9–11
Osteogenesis imperfecta shows great clinical variability, ranging from mild forms associated with few fractures and normal growth to severe forms associated with intrauterine fractures and perinatal death. In 1979, Sillence et al12 first proposed the classification of OI into 4 types (I-IV) on the basis of clinical and radiological criteria. Other types of OI have recently been described, but the Sillence et al classification continues to be used most frequently in the clinical management of this condition.11,13
Because of the high prevalence of fractures and other clinical features, the treatment of OI is complex. A multidisciplinary approach and specific continuous monitoring are required to ensure a better overall prognosis and maximum level of functional independence.5,7,14–17 Rehabilitation, physiotherapy, and orthopedic surgery are the main components of OI treatment.7,18,19 In the last decade, the use of bisphosphonates has improved bone mass in patients with OI, achieving a consequent decrease in the number of fractures, subjective reduction of chronic bone pain, greater mobility, and increased muscle strength, all of which facilitate the execution of physical tasks and improve patients’ quality of life.2,5,7,16,20–26 A few studies have reported functional characteristics in OI; however, no studies had been published that associate the age of acquisition of gait or bone deformity with the degree of muscle strength or joint range of motion (ROM). This information is essential for a better understanding of the complications of the disease, helping plan short and long-term therapeutic interventions. Given that OI leads to functional limitations that compromise patients’ independence, gait, and quality of life, this study aimed at describing the clinical and functional features such as muscle strength, joint ROM, and gait of pediatric patients with OI.
This study was approved under number 09-501 by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre, and all parents or guardians of patients provided written informed consent.
This cross-sectional study was performed between April and December 2011 and included children and adolescents with clinical and radiological diagnoses of OI, according to Sillence criteria,12 at the Hospital de Clínicas de Porto Alegre's Reference Center for Treatment of Osteogenesis Imperfecta, Rio Grande do Sul, Brazil. Participants of both sexes aged 0 to 18 years were included. We excluded participants with hemodynamic instability, severe neurological deficits, and unstable fractures.
Clinical features evaluated included fracture history, intramedullary rod use, and the use of bisphosphonate therapy. Bone mineral density was measured by dual-energy x-ray absorptiometry (HOLOGIC QDR-4500, ver. 8 26 A:3, Waltham, Massachusetts). A Z-score for bone mass exceeding 2 standard deviations below the expected range for the patient's chronological age was defined as low bone mineral density, following the 2006 official consensus of the Brazilian Society for Clinical Densitometry.27
Body Structure and Function and Activity Assessment
A single trained observer performed all the following assessments using the following parameters:
- Joint hypermobility was assessed using the criteria of Carter and Wilkinson,28 modified by Beighton and Horan.29 This scale evaluates flexion of the thumb on the arm; hyperextension of the fingers, elbows, and knees; and flexion of the spine. The total possible score is 9, and a score of 5 or greater was considered joint hypermobility.
- Bone deformity was assessed by inspection, palpation, and bone images and confirmed according to the criteria of Sillence et al12 when at least 1 long bone was found to be out of appropriate biomechanical alignment.
- Gait acquisition and level of ambulation were evaluated. The age of gait acquisition and any delay in gait acquisition were assessed according to the criteria of Bayley,30 adapted by Tecklin.31 The normal age of gait acquisition was defined as an average of 11.7 (range, 9-17) months, and acquisition of more than 18 months of age was considered to be delayed. The level of ambulation was assessed according to the criteria of Bleck,32 modified by Land et al33: 0, not walking; 1, therapeutic walking; 2, household walking with or without assistance; 3, neighborhood or community walking with or without assistance; and 4, independently walking.
- Muscular strength was assessed using the manual muscle test (MMT),34 based on the index of the Medical Research Council,35 in the upper limbs (10 bilateral movements) and lower limbs (8 bilateral movements). This MMT scores muscle strength on a scale ranging from 0 to 5, with a higher score indicating greater strength. The total index score is 100.
- Joint ROM was assessed in 10 joints with a goniometer using the Pediatric Escola Paulista de Medicina (pediatric EPM-ROM) scale.36 This scale is used to evaluate 10 joint movements of the cervical spine and bilateral upper and lower limbs. Movements are classified as follows: (0) normal ROM, (1) mild limitation of ROM, (2) moderate limitation of ROM, and (3) severe limitation of ROM. The final score is based on the sum divided by the number of movements.
Statistical analyses were performed with SPSS software (ver. 18.0; SPSS Inc, Chicago, Illinois). The chi-square test was used to evaluate associations among categorical variables. In case of statistical significance, adjusted residuals tests were applied. Quantitative and qualitative variables were portrayed using mean ± standard deviation or median (25th-75th percentile). Qualitative variables are additionally described by absolute and relative frequencies. The Spearman correlation test was applied to asymmetrical quantitative and ordinal qualitative variables. Poisson regression was used to control the age effect when comparing the number of fractures between OI types. Groups of MMT scores were compared using the Student t test or 1-way analysis of variance with a post hoc Tukey test. Groups of pediatric EPM-ROM scores were compared using the Mann-Whitney or Kruskal-Wallis test. The level of significance was set at 5% (α ≤ .05).
A total of 62 patients (32 females and 30 males) from 2 months to 18 years old with a median (25th-75th percentile) age of 8 (2-14) years were evaluated. Table 1 shows the OI type and clinical features of patients. According to the Sillence et al12 classification, 31 (50%) patients had type I OI, 9 (14.5%) had type III, and 22 (35.5%) had type IV.
We observed significant differences in the presence of fractures at birth, age at first fracture, fractures of the lower limbs, intramedullary rod use, low bone mineral density, and use of bisphosphonates according to OI type. Patients with types III and IV OI showed a significantly higher incidence (χ2 = 22.6; P = .01) of fractures in the first 6 months of life, and the first fracture occurred at birth in 89% of patients with type III OI and 41% of patients with type IV OI(χ2 = 14.7; P = .001). For moderate to severe forms of OI, the age at first fracture was directly associated with the age of pamidronate treatment initiation (rs = 0.552; P < .001) showing a precocious diagnosis. The age at first fracture was inversely associated with the total number of fractures (rs = −0.528; P < .001). After adjusting for age, the occurrence of 10 or more fractures was 2.6 times more prevalent in patients with type III OI than in those with type I OI (95% CI, 1.28-5.37). The number of fractures did not differ significantly between patients with type I and type IV OI (PR = 1.09; 95% CI = 0.53-2.26; P = .806).
Body Structure and Function and Activity Findings
Table 2 presents body structure and function and activity findings according to OI type. We observed significant differences in the age of gait onset (χ2 = 18.7; P = .005), delayed gait acquisition (χ2 = 13.5; P = .001), level of ambulation (χ2 = 31.8; P < .001), and presence of bone deformities (χ2 = 26.3; P = .001) according to OI type. Joint hypermobility was found in 69.4% of patients, but its incidence did not differ among OI types (χ2 = 5.95; P = .051). The presence of bone deformities was directly associated with the total number of fractures (≤10 vs >10, χ2 = 5.4; P = .02) and age of gait onset (χ2 = 11.3; P = .01). Muscle strength in the upper and lower limbs was correlated with the level of ambulation (rs = 0,678, P < .001, and rs = 0.406, P = .001, respectively) and inversely associated with the presence of bone deformities (95 ± 9.7 vs 100 ± 0.0, t = 3.26; P = .026).
Table 3 shows pediatric EPM-ROM and MMT scores according to OI type. ROM results showed differences between OI types according to joint sites. Range of motion overall scores were more compromised in OI types III and IV than in OI type I (Kruskal-Wallis test; χ2 = 20.6; P = <.001). This difference was also found for ROM in the spine (Kruskal-Wallis test; χ2 = 6.97; P = 0.03) and lower limbs (Kruskal-Wallis test; χ2 = 19.2; P = <.001). For the upper limbs, a difference was found when OI type III was compared with types I and IV (Kruskal-Wallis test; χ2 = 19.9; P = <.001). The overall pediatric EPM-ROM score was inversely associated with the level of ambulation (rs = −0.464; P = .001) and directly associated with age of gait onset (rs = 0.330; P = .014), total number of fractures (rs = 0.480; P = .001), and presence of bone deformities (Mann-Whitney test; z = −4.81; P < .001). Manual muscle testing showed differences for the upper limbs when comparing OI type III with types I and IV (F = 13.1; P ≤ .001) and for the lower limbs when comparing OI type I with types III and IV (F = 13.3; P ≤ .001).
This study was the first Brazilian study that reported body structure and function and activity characteristics of pediatric OI patients. Our data showed the clinical variability in OI. The observed association between a greater number of fractures and lower age at first fracture corroborates the findings of previous studies, which have shown that children with more severe OI tend to have their first fracture at birth (intrauterine) and to sustain a high number of fractures during growth.2,7,37,38 In patients with type III OI, severe bone fragility leads to progressive skeletal deformity and multiple fractures. In OI type IV, great variability in the frequency and number of fractures has been observed, most of which occur early in life.2,38,39 Phenotype-genotype correlation studies have shown that mutations in the COL1A1 and COL1A2 genes lead to a quantitative reduction in collagen production, which is responsible for mild forms of OI; in contrast, a qualitative impairment in collagen production leads to moderate to severe forms of OI.4,10,11
In our study sample, the majority of fractures occurred in the lower limbs, and fractures occurred more frequently in patients with types III and IV OI than in those with type I OI. Previous studies have reported a high prevalence of fractures, especially in the lower limbs, in patients with OI.16,17,40 Children with moderate to severe OI are susceptible to a greater number of fractures than seen in the mild type. A fracture at the site of a bone deformity can exacerbate the deformation because of muscle contraction, generating a repetitive cycle of fractures and progressive deformity. Thus, children with significant long-bone curvature are highly susceptible to eventual fracture as they learn to stand, which limits neuromotor development.8,41
The main clinical feature of OI is reduced bone mass, which causes bone fragility leading to repetitive fracture. In patients with OI, the mineralized bone may be stiff, but it breaks more readily when subjected to external loads.2,6,7,38,42 The risk of fracture in childhood is associated with bone size and mass. Low total body bone mineral density and small bone area for height are the best predictive parameters for fracture risk.43
We observed that most patients with types III and IV OI receive bisphosphonate therapy, which Glorieux7 found to be associated with improved quality of life. Several studies have demonstrated that improved mobility and gait are associated with earlier treatment in participants with OI.4,16,25 Several treatment centers for children with OI have reported a marked increase in levels of functionality and gait associated with the use of bisphosphonates, including in children with severe OI.4,26,41,44,45 Bisphosphonate use in the first 2 years of life has shown promising results, considering that its effect on the skeleton is dependent on bone growth.7
Almost all children in our sample with type I OI acquired unsupported gait by the age of 18 months, whereas gait acquisition was within the normal age range in only 55% of those with type IV OI. Delayed gait acquisition was observed in 45% of children with type IV, 100% of those with type III, and only 16.1% of those with type I OI. Among the patients with type I OI who showed delayed gait acquisition, the delay was secondary to the occurrence of fractures in the lower limbs and/or orthopedic surgery. These data are in accord with a previous study that showed in the majority of patients with type I OI the first fractures are associated with the initial phase of gait acquisition because of greater time in the orthostatic position and consequently greater weight-bearing on the lower limbs.7 All children with type I OI and the majority of those with type IV OI, but only 1 of 9 patients with type III OI, were able to walk independently. These findings are in accord with the presence of fractures at birth or before 6 months of age, the higher number of fractures leading to bone deformities and joint limitation in OI type III.
Previous research has established that anthropometric changes influence the acquisition of basic milestones in motor development. Changes in body composition and proportion (the legs become longer than the trunk, the cephalic dimensions decrease in relation to the child's body, and changes in the musculoskeletal system including extensibility, stiffness, and strength) during the initial phase of gait acquisition affect locomotion because of instability.46,47 In patients with OI, the severity of the condition (type) is the primary clinical indicator of final gait capacity.48 The presence of bone deformities, especially in the lower limbs, can lead to abnormal mechanical tension on the bones, making them more vulnerable to fracture.4 Delays in gross motor development are common in children with OI because of significant joint hypermobility and bone deformities, but this situation may improve with age.5
Fourteen patients (22.6%) in our sample, 10 (45.5%) of whom had type IV OI, had intramedullary rods. Fractures in patients with OI are generally treated conservatively because the main postoperative complication is reduced bone mass because of a long period of immobility. Fracture stabilization with an intramedullary rod is strongly recommended in patients with OI, except for very young children.49 Surgical treatment aims to provide maximum functionality and the maintenance of upright posture and bone alignment and is suitable for fractures and the correction of bone deformities.15,17,50 Many patients with severe OI are able to walk only after the surgical correction of femoral and/or tibial deformities to provide appropriate biomechanical alignment and improve limb functionality.2,16 The placement of intramedullary rods in the lower limbs has been shown to improve the gait in patients with moderate to severe OI.48,51 The surgical treatment of OI achieves long-term reduction of the number of refractures and fractures in the long bones of the lower limbs, without subsequent functional limitations or gait compensation.49
Gait impairment may be associated with several factors, such as coxa vara, associated deformities, kyphoscoliosis, excessive upper limb angulation preventing the use of an auxiliary device, leg axis deviation, limb discrepancy, the first appearance of fractures, and the severity of bone fragility.5,52 Aarabi et al53 observed coxa vara in 10.2% of 283 children with OI. Oliveira et al51 found 55% of children with type III OI had coxa vara and a Trendelenburg gait.
We observed a high frequency of joint hypermobility in our patients, but no significant difference in the incidence of this parameter according to OI type. These findings differ from those of most previous studies, because joint hypermobility is one of the most commonly used features to distinguish OI types. The method of diagnosing joint hypermobility described by Beighton and Horan54 is used most frequently, but this method omits the evaluation of many joints, including the neck, shoulders, hips, and ankles, which can generate a significant number of false-negative results.55–58 The frequency of hypermobility varies according to the scoring system chosen59; scales employing 4 or more points are associated with greater positivity (65.9%) than those with 5 or more points and 3 or more criteria.60,61 Our results may have been affected by these factors. There is no hypermobility score specific for OI in the literature, and generic hypermobility scores have been used in pediatric physiotherapy.62
In patients with all OI types, we found that muscle strength was related directly to the level of ambulation and inversely to the age of gait acquisition and presence of bone deformities. Long-bone deformities in patients with OI are caused by muscle traction during bone growth, resulting in a pattern that can be identified in virtually all children with this condition, including nonambulatory cases.17,39 Muscle weakness and reduced long-bone growth, which are intrinsic to the disease, clearly influence physical performance and may restrict a child's activities, affecting motor function.5,7,63
We observed bone deformities in all patients with type III OI, 45.5% of those with type IV OI, and 9.7% of those with type I OI. Individuals with bone deformities had less muscle strength in the upper and lower limbs, greater impairment of joint motion, and acquired gait at a later age. Engelbert et al64 found skeletal disproportions in children with type III OI because of the reduction and change in long-bone and spinal growth caused by frequent fractures, which affected children's height but not body weight, leading to relative overweight.
Articular limitation affects the level of ambulation and is influenced by the total number of fractures and the presence of bone deformities. The main features of OI, namely bone fragility, musculoskeletal impairment, and repetitive fractures, affect growth and development to a disabling extent.48 The clinical features of OI involve functional impairment, limitation, and disability.18,48,64 In our sample, joint ROM and lower-limb muscle strength did not differ between patients with OI types III and IV but did differ between these patients and those with type I OI; these findings are consistent with the classification of the clinical severity of this pathology.
The pediatric EPM-ROM scale was developed as a low-cost, easily administered tool for the evaluation of articular ROM in patients with juvenile rheumatoid arthritis. The pediatric EPM-ROM does not include the quantification of joint movements more affected in OI secondary to deformities and bone fractures, such as shoulder abduction and adduction, elbow flexion and extension, radioulnar pronation and supination, and hip flexion and extension. Although we were able to relate the presence of bone deformities to the quantification of joint ROM, we found no published validated instrument that provides for adequate gradation of angles of long-bone curvature or pseudarthrosis secondary to fractures, especially in this specific population.
This study has limitations. The participants presented a broad age range and an unequal number of OI types. This different number of participants could account for the statistical results. The Sillence et al classification (I-IV) is the most frequently used classification in clinical practice; however, a new score recently proposed by Aglan et al65 on the basis of a quantitative level of disease severity may be a useful tool for future studies. Because this was a cross-sectional study, we could not evaluate the functional benefit of biphosphonate treatment.
The findings of our study are in accord with the disablement process in OI,18 whereby greater disease severity results in greater clinical and functional impairment and, consequently, less independence. Our data demonstrate that the clinical and functional findings of OI are variable. Individuals with type I OI showed slight impairment, and those with types III and IV OI exhibited the most severe clinical and functional effects, including compromised physical and neuromotor development. The identification and classification of clinical, body structure and function, and activity features are essential for the development of treatment and rehabilitation strategies, with the objective of minimizing the development of early complications secondary to the pathology.
The authors thank the children and adolescents for their generous participation and their families for their commitment; without them this work would not have been possible.
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