Fatigue is often mentioned by individuals with OI during the clinical appointment. As the prevalence and experience of fatigue in patients with OI is largely unknown, we set out to perform a pilot study regarding occurrence and severity of fatigue in people with OI to determine whether this needs to be explored further. 99/151 patients filled in the FSS. We assessed the medical records for age, gender and type of OI. We did not analyze for any medical confounders such as recent fracture(s), cardiac or lung complications, initiated therapy, physical exertion, mobility and work. The mean and median FSS score of the individuals with OI was respectively 4.4 and 4.8.
FSS results compared to results in two control groups
The fatigue scores in our study cohort are significantly higher compared to the Dutch national control group(n = 113)  and the American control group (n = 20) . Merkies et al.  define a mean FSS score ≥ 5.1 as severe fatigue, and a score > 4 and < 5 equates “borderline fatique “. When analysing the FSS results of the OI cohort according to the definitions of Merkies et al. the OI cohort experiences borderline fatigue, influencing daily living, with regard to the mean FSS score.
Krupp et al.  defined a FSS score of > 4 as moderate to high fatigue level, influencing daily living. When analyzing the FSS results according the definition of Krupp et al.  it appears that 42.4% of the respondents (n = 42) had a mean FSS score of five or higher indicating severe fatigue. 23.1% (n = 23) had a score between four and five indicating borderline fatigue. When analysing the results with the definition of Merkies et al., it appears that 38.4% of the respondents (n = 38) had a mean FSS score of five or higher indicating severe fatigue. 27.3% (n = 27) had a score between 4 and 5.1, indicating borderline fatigue. These mean FSS scores are very high compared to the general population, with only 5% of the general population being severely fatigued . The presence and severity of fatigue is almost equal across all OI types, which could indicate that OI type and severity of OI is not influencing fatigue. This may demonstrate that although most people with OI type 1 will have reached a higher level of daily functioning than patients with OI type 3 and 4, they still experience comparable impact of fatigue on their daily functioning. The FSS scores in the OI cohort also exceed minimal clinically important difference (MCID) values determined for other patient groups, which are for example 0.4 for SLE and 0.7 for RA (rheumatoid arthritis) [17, 18]. Given the above, there appears to be sufficient evidence for the presence of increased occurrence and severity of fatigue in OI patients in the investigated cohort.
FSS results compared to one similar study involving OI patients
A comparable study was recently performed in Norway by Arponen et al. . It concerned a cross-sectional study of responses of OI patients matched with healthy controls from Norway to a questionnaire, designed to evaluate levels of experienced fatigue and body pain as well as presence or absence of symptoms related to sleep disturbance or sleep apnoea. Fatigue was evaluated with, among others, the FSS questionnaire which demonstrated a FSS mean score of 5 in patients with OI(n = 56). Interestingly, the Norwegian control group scored a mean FSS score of 4 (n = 56). Arponen et al. concluded that in comparison with age and gender matched controls, adults with OI do not differ in experienced fatigue .
The Dutch control group , has a lower mean FSS score (2.9, n = 113) than the control group in the Norwegian study of Arponen et al.(4.0, n = 56, 9]. Compared to the American original validation  who report a mean FSS of 2.3 ± 0.7 (n = 20) again the mean FSS score in the Norwegian control group is high.
However, there may be an explanation for the high score in the control group as a Norwegian national study investigating fatigue in the general population,  concluded that the high FSS scores in the general population of Norway can be due to difficulties in translation of the US-English version of the FSS into Norwegian because of lack of the concept of fatigue in Norwegian language . A valid comparison between Norway, the Netherlands and the US regarding the FSS may therefore not be possible. A validation of the FSS in a Swiss control group is comparable to the Dutch and American results with a mean FSS score of 3.00 ± 1.08, (n = 454) . As such, we can conclude that the mean FSS score of our Dutch control group is comparable with the American and Swiss control groups and that our earlier conclusion that the severity of fatigue is increased in the Dutch OI cohort still holds true.
Limitations of this study and further directions for research
There is a low response rate (151/221 gave consent and 99/151 filled in the FSS) when looked at the initially approached patients. It is difficult to speculate why this could be the case but an important factor may be that with regard to consent as well as with regard to filling in the FSS, patients were only approached once and were not sent reminder(s). Biases are difficult to avoid as it may be that the people who felt that fatigue was influencing there life significantly, were more inclined to participate but it is also possible that these patients were limited by fatigue to participate in the study. As mentioned before, there are many scales to measure the nature, severity and impact of fatigue in a range of clinical populations and a limitation of the FSS is that it is a general questionnaire, and as such not specially developed for OI. The FSS however explores the severity of fatigue and is therefore suitable for initial screening in different clinical populations and can be used for longitudinal measurements which is important in assessing whether fatigue can increase or decrease over time and exploring possible modifiers of fatigue. Another limitation of our study lies with the control populations as both the Dutch control group and the US control group date from respectively 1999 and 1989 and trends in fatigue may change in the population over time.
Lastly, we did not investigate any factors that influence fatigue in OI patients in our study, but this is an important direction for further research into fatigue in patients with OI as fatigue may influence QOL. Other factors have been reported as well . It is already known that the presence of pain, but also educational level and employment status influence the severity of fatigue. Bathmen et al. published on fatigue in Marfan syndrome, another hereditary connective tissue disorder. The authors concluded that occurrence of chronic pain and employment status influenced the severity of fatigue . Interestingly, a study in children with OI reported a decrease of the level of fatigue after a 12-week individual and supervised physical training program, and increase of the level of fatigue after the program had stopped [10, 23]. Studies in other patient groups, including people with Marfan syndrome reported good effects of physical activity on fatigue [24,25,26]. This is important knowledge since some OI patients or parents of OI patients tend to limit their physical activity when they become aware of the inherited bone fragility . Some age categories may benefit from an individual and supervised training program.