Blue Sclerae Research Articles

Four patients with Sillence type I osteogenesis imperfecta and mild bone fragility, complicated by left ventricular cardiac valvular disease and cardiac tissue fragility caused by type I collagen mutations

Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular heart disease and associated with tissue fragility. The diagnosis of a type I collagen disorder was confirmed by abnormal COL1A1 or COL1A2 gene sequencing. One patient was investigated with electrophoresis of collagens from cultured skin fibroblasts, showing structurally abnormal collagen type I, skin biopsy showed unusual histology and abnormal collagen fibril ultra-structure at electron microscopy. The combined clinical, surgical, histological, ultra-structural, and molecular genetic data suggest the type I collagen defect as contributory to cardiac valvular disease. The degree of tissue fragility experienced at cardiac surgery in these individuals, also reported in a small number of similar case reports, suggests that patients with OI type I need careful pre-operative assessment and consideration of the risks and benefits of cardiac surgery.

Alendronate treatment for osteogenesis imperfecta type III in twin babies: a case report

Osteogenesis Imperfecta (OI) is a connective tissue disorders. There are several types of OI. OI can be autosomal dominant, some cases can be found in recessive by mosaicism in the parent. The main goal of treatment is to reduce the incidence of fractures, prevent deformities of bones and scoliosis, and improve the functional patient. This is a case of OI given alendronate as an alternative treatment. Twin boys babies born in Moewardi Hospital by sectio caesaria. Baby I and II seemed swollen on both of hand and leg. Both of the babies appeared to be less active and limitation of range of motion, with blue sclera. Result of x-rays, it appeared multiple fractures in extremities and costae. We diagnosed osteogenesis omperfecta type III, clinically. We gave alendronate 1 x 1 mg orally, because sodium pamidronate was not available at that time. Alendronate were given by thirty to forty five degree position. Orthopedic surgeon gave on conservative therapy by slap. During treatment in hospital, appeared new fractures in each baby. After giving alendronate therapy for 4 months, the baby I didn’t show new fractures, the baby II suffered three new fractures. There were no side effect of alendronate treatment on gastrointestinal. At the aged of 5th month, the patients were given intravenously sodium pamidronate for 3 days with a dose of 2 mg. Three months after pamidronate, the baby I didn't show new fractures, the baby II suffered one new fracture. Bone mineral density was not performed in these patients. We conclude that oral biphosphonate could be alternative treatment for OI if intravenous biphosphonate is unavailable. It still needs more reseach regarding to effectiveness of oral biphosphonate compare to intravenous biphosphonate.

Effect of osteogenesis imperfecta on children and their families

Osteogenesis Imperfecta (OI) is a heterogeneous genetic disorder, with features that include increased bone fragility, pathological fractures, blue sclera, dentinogenesis imperfecta and conductive or mixed hearing loss. Clinical variability is wide from children with few fractures and normal stature to children with multiple fractures, long bone deformity, scoliosis and extreme short stature. Although there is no curative treatment, there are several therapeutic tools capable of improving the course of the condition and patient quality of life. We aim to evaluate the effect of OI on the well being of children with the disorder and their families through a family-centered questionnaire. Sixty children with OI from the Vietnam National Hospital of Pediatrics and/or their parent(s), who attended the first annual family support group in 2011, completed a child and parent questionnaire. 60 patients participated, 26 female and 34 male. The median age was 6.0 years [interquartile range (IQR) 0.25 - 18 years]. Of these, 36 (60%) had dentinogenesis imperfect and 23 (38.3%) had a scoliosis. The median number of fractures was 6.0 (IQR 0 – 30) and median number of hospitalizations due to OI was 5.0 (IQR 0-30). Among patients of school age, 9 (15%) could not go to school due to OI. Almost all parents (93.7%) worried about school social communication of the patients. Among these parents, 100% fear of inferiority with friends and 98.3% fear of broken bones. Most parents (76.2%) were significantly concerned about their child's health. The parents’ themselves reported psychological concerns, with feelings of desperation (58.4%), anxiety (81.7%) and depression (56.7%). Osteogenesis imperfecta appeared to have a significant deleterious effects on the life of the patients and their families. These data provide a baseline from which to evaluate the effectiveness of interventions to improve the medical and psychological needs of this cohort and their families.

Osteogenesis Imperfecta—A Human Temporal Bone Case Study

Osteogenesis imperfecta (OI) is defined as one of the inherited connective tissue disorders that can result in fragile bones, blue sclera, and deafness. This genetic disease affects collagen type 1 (COL1), which leads to different manifestations depending on the mutation. There are four subtypes of OI, based on different defects in the collagen synthesis, types I, II, III, and IV. OI type I, previously known as OI tarda, is the most common and least severe subtype, is autosomal dominant, and results in blue sclera, increased risk of bone fracture and progressive hearing loss in 50% of patients. OI type II, previously known as OI congenital, is the most severe form, it usually leads to perinatal death and is autosomal recessive. OI Type III is the most severe type among children who survive the neonatal period. The degree of bone fragility and the fracture rate vary widely. OI Type IV diagnosis often occurs later in life and usually represents the patients that do not fit into subtypes I–III (1,2). Deafness is one of the main features of osteogenesis imperfecta and conductive hearing loss is the most common form, but mixed or pure sensorineural hearing losses are not uncommon (3). In the University of Minnesota temporal bone collection, we found one case that fits in the OI diagnosis.

Unilateral spinal anaesthesia in a patient with Osteogenesis Imperfecta with a lower leg fracture: a case report

Osteogenesis Imperfecta is a rare, genetically determined disease with several possible complications in anaesthesia. Anaesthesiologists therefore pay special attention to the treatment of patients suffering from Osteogenesis Imperfecta since they commonly suffer from a difficult airway and intraoperative positioning difficulties.We report here the case of unilateral spinal anaesthesia in a patient suffering from Osteogenesis Imperfecta type I. A 28-year-old patient diagnosed with Osteogenesis Imperfecta type I was admitted to the hospital due to lower leg fracture requiring surgical treatment. The patient had blue sclerae, triangular-shaped face, macroglossia, scoliosis of thoracic and lumbar parts of the spine, pectus carinatum and thrombocytopenia. Upon the correction of thrombocytopenia, unilateral spinal anaesthesia with hyperbaric levobupivacain was chosen in order to avoid possible complications typical for general anaesthesia. Consequently, unilateral spinal anaesthesia with a customized local anesthetic could be consdered as a safe anesthetic method for such patients.

Clinical and laboratory features of temporary brittle bone disease

Temporary brittle bone disease has been described since 1990. It is a syndrome characterised by multiple unexplained fractures in early childhood. There is growing evidence that it has natural causes and does not represent inflicted trauma. We report the clinical and laboratory features of 104 patients investigated personally between 1985 and 2000. These patients had in aggregate 976 fractures or fracture-like lesions. Our patients included disproportionate numbers of infants born preterm or as a result of multiple pregnancy. The fractures were mainly identified in the first 6 months of life and entirely within the first year of life. Most fractures were asymptomatic, particularly the many rib fractures and metaphyseal lesions. Few patients had evidence of bruising at presentation; none had clinical evidence of inflicted injury commensurate with the fractures found. In 22 patients the fractures were found in the course of investigation for unrelated symptoms. In several cases fractures took place while the children were in hospital. Unexplained bruising and sub-conjunctival haemorrhages also occurred in hospital, suggesting collagen defects. Hernias were recorded; in most these resolved spontaneously, again suggesting transient collagen defects. Among the unexplained symptoms of the patients was a history of vomiting, often projectile vomiting. Some patients had unusually blue or grey sclerae for the child's age. Many patients had abnormally large anterior fontanelles. Laboratory findings included anaemia, neutropenia and an exceptionally high serum alkaline phosphatase. Our findings reinforce the view that children with temporary brittle bone disease have a distinctive and identifiable syndrome which probably includes osteopathy of prematurity. These patients do not have osteogenesis imperfecta and are not the victims of non-accidental injury. While the causes of this syndrome remain uncertain, its distinctive features should now be more readily recognised.

Identification of a novel heterozygous mutation in exon 50 of the COL1A1 gene causing osteogenesis imperfecta

SummaryA 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI.Learning points OI is a rare but important genetic metabolic bone and connective tissue disorder that manifests a diverse clinical phenotype that includes recurrent low-impact fractures.Most mutations that underlie OI occur within exon 50 of the COL1A1 gene (coding for protein constituents of type 1 pro-collagen).The diagnosis of OI is easily missed in its mild form. Early diagnosis is important, and there is a need for improved awareness of OI among health care professionals.OI is a diagnosis of exclusion, although the key diagnostic criterion is through genetic testing for mutations within the COL1A1 gene.Effective management of OI should be instituted through a multidisciplinary team approach that includes a bone specialist (usually an endocrinologist or rheumatologist), a geneticist, an audiometrist and a genetic counsellor. Physiotherapy and orthopaedic surgery may also be required.

Osteogenesis imperfecta type V: Clinical and radiographic manifestations in mutation confirmed patients

Osteogenesis imperfecta (OI) type V is a specific OI phenotype with interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. The causative gene mutation for OI type V has been recently discovered. The purpose of this report is to review the clinical and radiographic characteristics of mutation confirmed OI type V in detail. Sixteen (nine familial and seven sporadic) patients were enrolled in the study. Blue sclera and dentinogenesis imperfecta were not evident in any patient. However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were additionally observed in 11 patients. Of the radiographic abnormalities, cortical thickening and bony excrescence of interosseous margin of the ulna was the most common finding, followed by overgrowth of the olecranon and/or coronoid process of the ulna. Slender ribs and sloping of the posterior ribs with or without fractures were also a consistent finding. Hyperplastic callus was detected in 75% of patients and was commonly encountered at the femur. Heterotopic ossification in the muscles and tendon insertion sites were noted in four patients, which resulted in bony ankylosis or contracture of joints. The current study confirms common clinical and radiographic findings of OI type V and reports additional phenotypic information. These observations provide clues to recognize OI type V more promptly and guide to direct targeted molecular study. © 2013 Wiley Periodicals, Inc.

Osteogenesis Imperfecta: An Uncommon Association with Non-Communicating Hydrocephalus

Osteogenesis imperfecta (OI) is a generalised disorder of connective tissue presenting with fragile bones, blue sclera and early deafness. Hydrocephalus is usually associated with type 2 OI. Here we present a rare case of noncommunicating hydrocephalus and patent foramen ovale in type 3 OI. DOI: http://dx.doi.org/10.3126/jnps.v33i1.6692 J Nepal Paediatr Soc. 2013;33(1):63-65

Brittle cornea syndrome: recognition, molecular diagnosis and management

Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.

ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components

Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype–phenotype study

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa–Kuroki) syndrome (MIM#147920). To further elucidate the genotype–phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2‐Kabuki score 0–10). Sequencing of the full coding region and intron–exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice‐site mutations, 34 of which were novel. In five additional patients, novel, i.e. non‐dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median ‘MLL2‐Kabuki score’ of 6) as compared to the patients without MLL2 mutations (median ‘MLL2‐Kabuki score’ of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Síndrome de escleras azules

Presentamos el caso de una mujer de 35 años de edad, quien tuvo múltiples fracturas óseas, talla corta, xifoescoliosis izquierda, escleras azules, limitación funcional de caderas, dentinogénesis imperfecta, osteoporosis severa e hipoacusia de conducción. Se revisa los tipos de osteogénesis imperfecta, cuadro clínico, diagnóstico diferencial, tratamiento y pronóstico.

Identification of a novel heterozygous mutation in exon 50 of the COL1A1 gene manifesting clinically as osteogenesis imperfecta

A 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI.

English

Introduction Osteogenesis imperfecta (OI) is a human genetic disorder of increased bone fragility and low bone mass. Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures. There is variable association of typical extra skeletal manifestations with the disorder, including blue sclera, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, hearing impairment and the presence of Wormian bones on skull radiography1. The most widely used classification of OI distinguished four clinical types2. The most relevant clinical characteristic of all OI t-ypes is bone fragility, the severity of which increases in the order type I < type IV < type III < type II. It is now w-idely recognized that there may be m-any more types of OI than those class-ified by Sillence et al. Some forms of congenital brittle bones have been considered OI and have been added as types V, VI and VII3–5. There is still no perfect consensus about the definition of OI. Plotkin recently proposed defining OI as syndromes resulting from mutations in either COL1A1 or COL1A2 genes, and to group all other syndromes with congenital brittle bones as ‘syndromes resembling OI (SROI)’, pending the identification of their causal mutations6. In the new Nosology and Classification of the Genetic Skeletal disorders7, OI is declined in several forms depending on the severity of the phenotype, whatever the mode of the transmission or the gene involved. We first review the genetic mutations implicated in the eight different types of OI, then, the craniofacial consequences of OI mutations are summarized. * Corresponding author Email: mgoldberg.goldberg004@gmail.com

Osteogenesis Imperfecta Type VI with Severe Bony Deformities Caused by Novel Compound Heterozygous Mutations in SERPINF1

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by bone fragility, frequent fractures, and low bone mass. Dominantly inherited COL1A1 or COL1A2 mutations appear to be causative in the majority of OI types, but rare recessively inherited genes have also been reported. Recently, SERPINF1 has been reported as another causative gene in OI type VI. To date, only eight SERPINF1 mutations have been reported and all are homozygous. Our patient showed no abnormalities at birth, frequent fractures, osteopenia, and poor response on pamidronate therapy. At the time of her most recent evaluation, she was 8 yr old, and could not walk independently due to frequent lower-extremity fractures, resulting in severe deformity. No clinical signs were seen of hearing impairment, blue sclera, or dentinogenesis imperfecta. In this study, we describe the clinical and radiological findings of one Korean patient with novel compound heterozygous mutations (c.77dupC and c.421dupC) of SERPINF1.

Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome

BackgroundWhereas mutations affecting the helical domain of type I procollagen classically cause Osteogenesis Imperfecta (OI), helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed OI/Ehlers-Danlos syndrome (EDS)-phenotype.MethodsWe performed biochemical and molecular analysis of type I (pro-) collagen in a cohort of seven patients referred with a clinical diagnosis of EDS and showing only subtle signs of OI. Transmission electron microscopy of the dermis was available for one patient.ResultsAll of these patients harboured a COL1A1 / COL1A2 mutation residing within the most N-terminal part of the type I collagen helix. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis. Importantly, patients with this type of mutation do not show a typical OI phenotype but mainly present as EDS patients displaying severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, easy bruising, and sometimes signs of arterial fragility. In addition, they show subtle signs of OI including blue sclerae, relatively short stature and osteopenia or fractures.ConclusionRecognition of this distinct phenotype is important for accurate genetic counselling, clinical management and surveillance, particularly in relation to the potential risk for vascular rupture associated with these mutations. Because these patients present clinical overlap with other EDS subtypes, biochemical collagen analysis is necessary to establish the correct diagnosis.

A Clinical Approach to a Family History of Sudden Death

Sir William Osler reportedly once said, “Varicose veins are the result of an improper selection of grandparents.” Indeed, our family history strongly influences many aspects of our cardiovascular system, with the magnitude of effect ranging from very strong for autosomal dominant genetic disorders to more subtle in the setting of complex multigenic diseases like coronary atherosclerosis and hypertension. Accordingly, the standard evaluation of any new patient who presents to a physician includes assessment of their family history. Unfortunately, the family history may sometimes be discounted as noncontributory without detailed review. This can be exacerbated by busy office schedules with declining amounts of time available for comprehensive evaluations. A few minutes saved might seem to justify the lack of focus on an aspect of history that is sometimes deemed not to be particularly useful. However, a thorough assessment of family history also may provide the key diagnostic information to determine the cause of an illness, to determine who else is at risk of disease within the family, to add useful prognostic information, and to help for family planning and reproductive decisions. A family history of sudden death should prompt consideration of a wide range of heritable cardiovascular conditions, including many monogenic disorders (Table). However, the terms used by the lay public to describe sudden death may not adequately explain the cause of death on initial consideration. For instance, the phrase “heart attack” may be used to describe sudden death of any etiology. Further questioning may help one to discern whether there was a history of heart failure, cardiomyopathy, coronary artery disease (or its risk factors), aortic aneurysm, or features of syndromic disorders that are associated with sudden death. View this table: Table. Monogenic Disorders Associated With Sudden Death A 40-year-old man presents to a physician for evaluation of palpitations. These occur briefly about once per …

Clinical, radiographic, diagnostic and cephalometric features of pycnodysostosis in comparison with Turkish cephalometric norms: A case report

Pycnodysostosis is a rare genetic disorder and was first described in 1962 by Maroteaux and Lamy. The incidence of this anomaly is estimated to be 1.7 per 1 million births. The principal characteristics of this disorder are short stature, prominent eyes with blue sclera, beaked nose, cranial dysplasia, exposed fontanelles and cranial sutures, clavicular dysplasia, total/partial dysplasia of the terminal phalanges, obtused mandibular gonial angle, and generally increased bone density. Some features of pycnodysostosis are similar to osteopetrosis and cleidocranial dysostosis. Therefore, it must be distinguished from osteopetrosis and cleidocranial dysostosis in order to diagnose it in individuals of a younger age.The aims of this case report were to show the clinical, radiographic, and diagnostic features, as well as the cephalometric characteristics of pycnodysostosis in comparison with Turkish cephalometric norms.

The influence of ibandronate treatment on bone density and biochemical bone markers in patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is characterized by different signs including increased bone fragility, short stature, blue sclera, abnormal tooth growth and often secondary immobility. No curative therapy has been found for this rare disease up to now, and different pharmacological substances have been tried as treatment for severe forms of OI. Promising results were seen with intravenous bisphosphonates in the treatment of patients with OI. The aim of present study was to show the effect of intravenous ibandronate therapy on bone density and bone metabolism markers. We analyzed the data of 27 patients with the diagnosis of OI who were treated off-label with intravenous ibandronate. Ibandronate was administered by intravenous infusion every three months at a dosage of 0.3–2 mg. Bone turnover markers and bone density were measured before starting therapy and every three months during treatment. Bone density was measured by using an ultrasound imaging system providing an accurate image of the calcaneus and by evaluating broadband ultrasound attenuation (BUA). Twenty-seven patients were treated with intravenous ibandronate during the observation period. 18 were female. The mean age of all patients was 23.9 years ± 19.6 (range 4–63). Seventeen patients were categorized to have OI Type I, 5 patients to have OI Type III and 5 patients to have OI Type IV. There was a statistically significant decrease in total alkaline phosphatase (P<0.0001). We detected also a statistically significant decrease in the ratio urinary deoxypyridinoline/urinary creatinine (P=0.0048) and the ratio urinary pyridinoline/urinary creatinine (P<0.0001) respectively. There was also a statistically significant increase in serum magnesium (P=0.034) and BUA (P=0.0071). No statistically significant changes were seen for total serum calcium (P=0.16), the ratio of urine calcium/urine creatinine (P=0.29), alkaline phosphatase (isoform bone) (P=0.3), procollagen-I-peptide (P=0.5), osteocalcin (P=0.9), serum phosphatase (P=0.71), parathormone (P=0.11) and the ratio urine phosphatase/urine creatinine (P=0.58) Therapy with ibandronate in patients with OI leads to a normalisation of bone turnover markers and increasing bone density. Therefore serum alkaline phosphatase and bone density are possible parameters to monitor bisphosphonate treatment in patients with OI.