Mortality and morbidity in patients with osteogenesis imperfecta in Denmark.

Ostegenesis 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.

Mortality and Causes of Death in Patients With Osteogenesis Imperfecta: A Register-Based Nationwide Cohort Study.

Osteogenesis imperfecta (OI) is a hereditary connective tissue disease that causes frequent fractures. Little is known about causes of death and length of survival in OI. The objective of this work was to calculate the risk and cause of death, and the median survival time in patients with OI. This study was a Danish nationwide, population-based and register-based cohort study. We used National Patient Register data from 1977 until 2013 with complete long-term follow-up. Participants comprised all patients registered with the diagnosis of OI from 1977 until 2013, and a reference population matched five to one to the OI cohort. We calculated hazard ratios for all-cause mortality and subhazard ratios for cause-specific mortality in a comparison of the OI cohort and the reference population. We also calculated all-cause mortality hazard ratios for males, females, and age groups (0 to 17.99 years, 18.00 to 34.99 years, 35.00 to 54.99 years, 55.00 to 74.99 years, and >75 years). We identified 687 cases of OI (379 women) and included 3435 reference persons (1895 women). A total of 112 patients with OI and 257 persons in the reference population died during the observation period. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for males with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for females 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. We were limited by the lack of clinical information about phenotype and genotype of the included patients. Patients with OI had a higher mortality rate throughout their life compared to the general population. © 2016 American Society for Bone and Mineral Research.

Femoral non-elongating rodding in osteogenesis imperfecta - the importance of purchasing epiphyseal plate.

BACKGROUND: Corrective osteotomy and intramedullary rodding are widely used in children with osteogenesis imperfecta (OI), but revision rodding is often required. This study aims to investigate the effect of purchasing distal femoral epiphysis on the longevity of fixation using non-elongating rod. METHODS: We investigated children with Sillence type III or IV OI who received antegrade femoral Rush rod fixations at age between 4 and 10 years in our institution. The fixations were classified into group A in which the rod reached distal femoral epiphysis and group B in which the rod stopped at femoral metaphysis. Failure of fixation is defined as rod cutting out of the cortex or when revision surgery was performed. Calculation of longevity of each rod fixation and Kaplan-Meier survival analysis were performed and compared between the two groups. RESULTS: Eighteen children had the first femoral rodding at a mean age of 6.9 years and received a total of 61 femoral roddings with a mean follow-up of 11.4 years. Group A included 38 roddings performed at a mean age of 7.1 years and group B included 23 roddings performed at a mean age of 6.6 years. Group A had less revision rate (58% vs. 87%), more chance of survival > 3 years (74% vs. 43%), and longer median survival time (80 months vs. 33 months) than group B. CONCLUSIONS: Less revision rate and better 3-year and 5-year survival rate were proved in the roddings that purchased epiphysis. We emphasize on using the precise implant length to purchase distal femoral epiphysis when non-elongating rod is the only available implant for fixation in children with OI.

What type of valve is most appropriate for osteogenesis imperfecta patients?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was in osteogenesis imperfecta (OI) patients with valve disease undergoing valve replacement which type of valve (bioprosthetic or mechanical) is most appropriate in terms of safety, complications and survival. Altogether more than 77 papers were found as a result of the reported search, of which 43 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Previous review articles have presented case reports up to 2009. As all published data are based on case reports, we conducted a more detailed analysis that included the aforementioned series, reports that were missed prior to 2009 and all published data from 2009 to October 2013. Our analysis identified 43 OI patients. Mechanical valves were used in the majority of cases (31 patients), bioprosthetic valves in 10 patients and homografts in 2 patients. We conclude that based on the best available evidence, it appears that bioprosthetic valves have had better outcomes (mortality rate 10%) and a lower valve-related complication rate (0%) compared with mechanical valves (mortality rate 16.1%, complication rate 16.1%), even though differences were not statistically significant. Although the existing evidence is solely based on case reports of a relatively small number, we would suggest the use of bioprosthetic valves in OI patients with valve disease, as they appear to be safer according to our analysis. Moreover, considering the surgical difficulties related to the friability and weakness of the tissues in terms of suture lines and implantation of the valve as well as the high risk of perioperative bleeding which can be related to tissue friability, capillary fragility and platelet dysfunction followed by the risk of major traumatic fractures and a possible risk of aortic dissection in the future, the bioprosthetic valves seem to be safer taking into account the avoidance of lifelong anticoagulation and its secondary bleeding complications.

Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes.

Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.

Free energy simulation to investigate the effect of amino acid sequence environment on the severity of osteogenesis imperfecta by glycine mutations in collagen.

Molecular dynamics simulations were carried out to calculate the free energy change difference of two collagen-like peptide models for Gly --> Ser mutations causing two different osteogenesis imperfecta phenotypes. These simulations were performed to investigate the impact of local amino acid sequence environment adjacent to a mutation site on the stability of the collagen. The average free energy differences for a Gly --> Ser mutant relative to a wild type are 3.4 kcal/mol and 8.2 kcal/mol for a nonlethal site and a lethal site, respectively. The free energy change differences of mutant containing two Ser residues relative to the wild type at the nonlethal and lethal mutation sites are 4.6 and 9.8 kcal/mol, respectively. Although electrostatic interactions stabilize mutants containing one or two Ser residues at both mutation sites, van der Waals interactions are of sufficient magnitude to cause a net destabilization. The presence of Gln and Arg near the mutation site, which contain large and polar side chains, provide more destabilization than amino acids containing small and nonpolar side chains.

Osteogénesis imperfecta tipo II: estudio de dos casos / Osteogenesis imperfecta type II: report of two cases

Se presentan dos casos clínicos de fetos con osteogénesis imperfecta tipo II, productos de partos vaginales de pretérmino, de sexo femenino, ambos sin signos vitales y con malformaciones congénitas evidentes desde el punto de vista esquelético. En ambos fetos se evidencia al estudio macroscópico cráneo blando y aplastado, colapso de la región tóracoabdominal, acortamiento de las extremidades y genitales externos femeninos. En la disección se aprecia hipoplasia pulmonar y malrotación intestinal. El estudio radiológico evidencia ausencia total de osificación para el primer feto y solo puntos rudimentarios para la base del cráneo, omóplato, húmero, un hueso del antebrazo, el ilíaco, el fémur y un hueso de la pierna, para el segundo feto. El tratamiento actual del que se dispone está muy lejos de ser exitoso y se restringe a terapia ortopédica y administración de bifosfonatos. El trasplante de células mesenquimáticas y su transformación a células osteogénicas, abre nuevas perspectivas en el manejo de la enfermedad

We present two clinical cases of fetuses with osteogenesis imperfecta type II, products of preterm vaginal deliveries, both females, without vital signs and congenital malformations evident in the skeletal system. Macroscopical study shows in both fetuses soft and crushed skull, collapse of the thoracoabdominal region, shortening of the limbs and external female genitalia. Pulmonary hypoplasia and intestinal malrotation are evident at the dissection. Radiological screening shows total absence of ossification for the first fetus and only rudimentary points for the base of the skull, scapula, humerus, a forearm bone, the ilium, femur and leg bon for the second fetus. Current treatment available is far from being successful and is limited to orthopedic therapy and administration of bisphosphonates. Transplantation of mesenchymal cells and their transformation into osteogenic cells, opens new perspectives on the management of the disease

The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study.

The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type II (four children) and achondroplasia (two children). Eleven other diagnoses each occurred once in the 12 year period. The minimum prevalence range, per live births, of each of the common skeletal dysplasias in Northern Ireland has been calculated; thanatophoric dysplasia 0.80/10,000, osteogenesis imperfecta type II 0.15/10,000 and achondroplasia 0.07/10,000. The prevalence range for thanatophoric dysplasia is much higher than reported in previous studies. We discuss reasons for the prevalence figures obtained.

Osteogenesis imperfecta: determining the demographics and the predictors of death from an inpatient population.

Osteogenesis imperfecta is a heritable disease that may result in bone fragility, increased joint laxity, decreased muscle tone, thinning of the skin, a bluish appearance of the sclerae, and scoliosis in as many as 60% of cases. The purpose of this study was to examine the impact of patient and hospital characteristics on mortality rate during inpatient stays. Data was collected retrospectively from the Healthcare Cost and Utilization Project Kids' Inpatient Database, a resource designed to analyze pediatric hospital usage. Data were collected from 1793 patients in the 27 states. Overall, 3% of this population died during hospitalization. Self-pay patients, patients in hospitals with small bed sizes, patients in non pediatric hospitals, and younger patients all had higher mortality rates than did their counterparts. In addition, black patients were 3.7 times more likely to die than did patients of any other race, and women were more likely to die than did men, although more than half of the number of patients were classified as white and 52% were men. Although these trends suggest that the mortality of younger patients may be reduced by admittance to children's hospitals, the children who are hospitalized younger tend to have more severe forms of the disease and are therefore more deformed and more difficult to treat. Overall, the results of this study indicate that children with osteogenesis imperfecta who need hospitalization may benefit from being referred to a large children's hospital, and that there is further research needed into the significant differences in the mortality of black patients and female patients.

[Updates in osteogenesis imperfecta].

Osteogenesis Imperfecta, a heterogenous group of inherited disorders, is characterized by both bone fragility and low bone mass. Since the Sillence classification of the disease, significant progress has been made in understanding the molecular, histological and genetical pathogenesis of the disease, and it led to expanded nosology. The multidisciplinary approach including rehabilitation, medications and surgery, may significantly improve the quality of life and prolong life expectancy.

Double valve replacement in a patient with osteogenesis imperfecta.

Valvular heart disease (predominantly aortic and mitral valve disease) has been well documented in patients with osteogenesis imperfecta. Twenty-two prior reports of valve replacement and/or repair have been published. Mortality from cardiac surgery in these patients has been high, particularly in those receiving double valve prostheses. Here, a patient is described with advanced cardiovascular disease who underwent successful aortic and mitral valve replacement. This represents the second reported survival of double valve replacement in osteogenesis imperfecta and a reduced mortality rate for this procedure.

Mortality in various types of osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a group of closely related inherited diseases characterized by abnormal bone fragility. The current clinical classification system delineates 6 types, one of which (type II) is so severe that mortality is 100%, either intrauterine or perinatal. The types are differentiated by clinical groups, by severity, and by the presence or absence of other features such as blue sclerae or dentinogenesis imperfecta. There are no known previous studies of mortality in OI. RESULTS: From a registry created in association with the Brittle Bone Society, 743 patients with OI in England and Wales were observed in the period 1980-1993. These were classified into 3 groups (type IA, type III, and types IB, IVA, and IVB combined). Average annual mortality rates were determined in each group by sex and attained age. These rates were compared with 1981 rates in the population of England and Wales, matched by sex and age. Results are given in terms of exposures, observed and expected deaths, and 2 indices of excess mortality: mortality ratios and excess death rates per 1000 person-years. CONCLUSION: In type IA, 51.5% of the OI cases overall, there was no significant excess mortality (mortality ratio 108%, based on 15 deaths). In type III, on the other hand, excess mortality was very high in children and still significantly high at ages 15-34 years. In the combined group of types IB, IVA, and IVB, the mortality ratio was 157% in patients aged 45 and up (not significant at the 95% confidence level), but higher ratios at younger ages were significant, even though based on a total of only 5 deaths.

Four new cases of lethal osteogenesis imperfecta due to glycine substitutions in COL1A1 and genes. Mutations in brief no. 152. Online.

Perinatal lethal osteogenesis imperfecta is the result of heterozygous mutations of the COL1A1 and COL1A2 genes. Here we describe the molecular defects responsible for four case of lethal OI. Two glycine substitutions within the COL1A1 gene (G478S, G994D) and two glycine substitutions within the COLIA2 gene (G319V, G697C) were identified. The mutation sites were localized in proalpha2(I) and proalpha2(I)mRNA molecules, respectively, by chemical cleavage of mismatch in hereteroduplex nucleic acids. Subsequent reverse transcription PCR amplification, cloning and sequencing, led to mutation identification. The aminoacid substitutions were due to two G-->A transitions in COL1A1(cases 1,2), to a G-->T transversion in COL1A2 (case 3), and to two contiguous point mutations in COL1A2 (case 4). All five nucleotide changes appeared to be fresh mutations. COLIA1(accession number Z74615) and COL1A2(accession number Z74616) wild type coding sequences (cDNA) were deduced from the EMBL DNA sequence database. The mutations described here can also be found in the human type I collagen mutation database at the web site:http://www.le.ac.uk/genetics/collagen.

Causes of death in osteogenesis imperfecta.

AIMS: To determine the causes of death in patients with osteogenesis imperfecta, excluding infants with the perinatal lethal form (type II). METHODS: Seventy nine patients with known osteogenesis imperfecta were identified, 37 of whom had been seen clinically in life. Causes of death were identified from death certificates, postmortem reports, medical records, hospital consultants, relatives, and the Brittle Bone Society's records. RESULTS: Patients with the milder types of osteogenesis imperfecta, I and IV, often had a normal lifespan and died of unrelated illnesses such as myocardial infarction and malignancy. In some of these patients and in many patients with the more severe type III disease, it was clear that osteogenesis imperfecta contributed significantly to death, almost certainly to many of the respiratory deaths and to deaths from cardiac failure due to kyphoscoliosis. Osteogenesis imperfecta also caused six deaths, directly or indirectly, due to basilar invagination of the skull. Osteogenesis imperfecta may have contributed to deaths from intracranial bleeding. Apparently minor traumatic incidents may have disastrous consequences in patients with this disorder. CONCLUSIONS: Prompt care for respiratory infections and prevention of trauma in patients with osteogenesis imperfecta is essential.

Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta.

A study was carried out in the United Kingdom of patients with severe osteogenesis imperfecta (OI), born with fractures to normal parents, in order to determine recurrence risks. A total of 105 cases from 98 families survived the perinatal period and 60 cases from 57 families were stillborn or died during the first week of life. The majority of the perinatal survivors correspond to the overlapping group of Sillence type III and sporadic type IV OI. In 40 of these, the radiograph at birth was available and in 37 it showed a characteristic appearance similar to that described previously for type III OI. The other three cases had radiological type IIB OI at birth and died before 26 months of age. The patients with perinatally lethal OI were subdivided on radiological appearance into Sillence type IIA (30 cases, described in the previous paper), type IIB (12 cases from 11 families), and type IIC (three cases from three families), and in five cases from three families the radiological appearance was the same as that of the 37 perinatal survivors described above. Ten cases from 10 families were not classified because their radiographs were unavailable. To analyse the empirical recurrence risks, patients were grouped according to radiological appearance at birth. Those with a type III-like pattern numbered 42 cases and they were grouped with the other cases of severe deforming OI who survived the perinatal period, for whom no x ray at birth was available, making a total of 107 cases. Taking one affected child per family as the proband, there were 98 probands. They had 146 sibs, of whom 10 were affected, giving an empirical recurrence risk of 6.9%. This is consistent with the disease arising as a new dominant mutation in about three quarters of families and as a recessive in about one quarter in this heterogeneous group. It is reasonable to give a recurrence risk of up to 25% in cases with parental consanguinity and a risk of 4.4% in cases with unrelated parents. Fifteen patients (14 probands) with Sillence type IIB OI had 13 sibs, one affected, giving an empirical recurrence risk of 7.7%. The parents were consanguineous in three families and the evidence for autosomal recessive inheritance for the majority in this group is probably stronger. The three patients with type IIC OI had three healthy sibs and the 10 unclassifiable perinatally lethal cases had 22 sibs, all normal. The radiological appearance at birth predicts prognosis to some extent; essentially, the better the bone morphology and mineralisation the longer the survival.

Consequences of an osteogenesis imperfecta diagnosis for survival and ambulation.

In osteogenesis imperfecta, time of initial fracture and radiographic appearance of long bones and ribs at time of initial fracture provide good prognostic indicators concerning survival and ambulation. Osteogenesis imperfecta congenita (OIC) comprises those patients with intrauterine and/or birth fractures. Radiographs of newborns with OIC-A show short, broad, and crumpled femurs and ribs, whereas initial radiographs of patients with OIC-B demonstrate bones with normal contours in spite of fractures. Osteogenesis imperfecta tarda (OIT) comprises those patients who fracture initially after birth. Patients with OIT-A fracture initially before walking begins, and patients with OIT-B after walking has begun. In OIC-A, 15 of 16 (94%) died; one survived but was wheelchair bound. In OIC-B, only two of 27 (8%) died, with 59% in wheelchairs and 33% ambulatory. No patients with OIT died. In OIT-A, 33% were in wheelchairs and 67% were ambulatory. In OIT-B, 100% were ambulatory.