• Lars Folkestad.
• lfolkestad@health.sdu.dk.
• Dan Med J. 2018 Apr 1; 65 (4).

AbstractOstegenesis imperfecta (OI) is a hereditary disease of the connective tissue caused by mutations to, mainly, the genes that are involved in the biosynthesis of collagen type 1. Patients are grouped according to clinical severity and mode of inheritance according to Sillence's classification (originally 1979, updated 2014). According to our data, the population prevalence of OI in Denmark was 10.3 per 100,000, with 575 patients registered with an OI diagnosis in the National Patient Register and alive at the end of 2012 out of a total population of 5,602,628 persons. Hallmarks of the disease are multiple fractures, blue sclera and varying degrees of bone deformities. Collagen type 1 is the most abundant collagen in the body and is an important part of the structure and function of the heart and lungs, the skeleton and many other organs. We hypothesize that patients with OI will have increased prevalence and risk of fractures throughout life, lower bone mineral density (BMD), impaired bone microstructure and bone geometry and increased risk of cardiovascular diseasesthus increased risk of all cause mortality compared to the general population. 
This thesis is a systematic search and narrative review covering the four main areas of interest of the PhD scholarship (risk and causes of death, fracture rates, bone mineral density, -geometry and -microstructure and cardiovascular diseases in OI). In addition to the review the thesis include the following four studies:
 1) Study 1 aimed to investigate the main causes of death and the risk of premature death in patients with OI in Denmark. We used a nationwide, registry-based, cohort study design, and included all patients registered in the National Patient Register with an OI diagnosis and a matched reference population randomly selected from the Danish Civil Service Register (matched 5:1, on gender and month and year of birth for each OI patient). We identified 687 patients with OI (25,615 person years at risk) and a reference population of 3,435 (132,131 person years at risk). One hundred and twelve patients with OI and 257 persons in the reference population died during the observation period from 1977 to 2013. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for men with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for women with OI was 77.4 years, compared to 84.5 years in the reference population. Patients with OI had a higher risk of death from respiratory diseases, gastrointestinal diseases and trauma.
 Conclusion: The all-cause hazard ratio for premature death in OI was 2.9 compared to the reference population. There was an increased risk of death due to respiratory diseases, gastrointestinal diseases and death following trauma. 
2) Study 2 aimed to compare the fracture rates across the lifespan of patients with OI with that of the general population. Using a nationwide, registry-based, cohort study design, we counted all fractures registered from 1995 in the National Patient Register. The study included the same population as in study 1, but patients who died before 1995 were excluded. We identified 644 patients
 
(55.6% females) in the OI cohort through the Danish National Patient Register and 3,361 persons (55.2% females), randomly selected from the Civil Registry System. A total of 416 patients with OI experienced a total of 1,566 fractures during the observation period of median 17.9 years (IQ-range: 12.4-18.0), adding up to 10,137 person years. In comparison, 709 persons in the reference population experienced a total of 1,018 fractures during follow-up. Both male and female patients with OI had an increased fracture rate throughout their life. The fracture rate ratio for participants aged 0-19 years was 10.7, for participants aged 20-54 years 17.2, and for participants aged 55 years and over 4.1 when compared to the reference population. The highest fracture rate was seen in males with OI aged 0-19 years (257 fractures per 1,000 person years). The fractures appear to follow the same pattern as in the general population, with a peak during the toddler and adolescent years (IR (incidence rates) 233.9 per 1,000 person years), fewer fractures during adulthood (IR 84.5 per 1000 person years), and increased fracture rate in older women (IR 111.9 per 1,000 person years).
 Conclusion: Patients with OI have increased risk of fractures throughout life compared to the general population. The relative risk of fractures generally declines with age, however, increases in older women. 
3) Study 3 aimed to evaluate the bone mineral density (BMD) and bone geometry and -microarchitecture in patients with OI type I using a cross-sectional study design and evaluating the participants using HRpQCT. The study included 39 patients with OI type I, and 39 healthy age and gender matched non-OI individuals. The patients were shorter than the reference group (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In patients with OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with the reference group. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in patients with OI compared with the reference group. At radius, total bone area was 5% lower in OI patients than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in patients with OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the reference group (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI patients in both tibia and radius (p < 0.001 at both sites) when compared with reference group.
 Conclusion: Patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched individuals. 
4) Study 4 aimed to evaluate the risk of valvulopathies, atrial arrhythmias, heart failure and vascular dissections in patients with OI using a nationwide, registry-based, cohort study design. The study included the same population as in study 1. As patients with OI have increased risk of premature death, the risk of cardiovascular diseases is biased by the competing risk of death. We corrected for this increased risk by using a competing risk regression model. We found that the OI population had increased relative risk of mitral valve regurgitation (sub hazard ratio (SHR) 6.3), aortic valve regurgitation (SHR 4.5), atrial fibrillation/flutters (SHR 1.7) and heart failure (SHR 2.3) compared to the reference population. There was no difference in the risk of arterial aneurisms or arterial dissections.
 Conclusion: Patients with OI have increased risk of valvulopathies, atrial arrhythmias and heart failure when compared to the reference population, even after adjusting for risk factors for these car-diovascular diseases - indicating that the quantitative or qualitative defects of collagen type 1 synthesis seen in OI influence the risk of these cardiovascular diseases in patients with OI.Articles published in the Danish Medical Journal are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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