Bone microarchitecture and strength assessment in adults with osteogenesis imperfecta using HR-pQCT: normative comparison and challenges.

Data on bone microarchitecture in osteogenesis imperfecta (OI) are scarce. The aim of this cross-sectional study was to assess bone microarchitecture and strength in a large cohort of adults with OI using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to evaluate challenges of using HR-pQCT in this cohort. Second-generation HR-pQCT scans were obtained at the distal radius and tibia in 118 men and women with Sillence OI type I, III, or IV using an extremity-length-dependent scan protocol. In total, 102 radius and 105 tibia scans of sufficient quality could be obtained, of which 11 radius scans (11%) and 14 tibia scans (13%) had a deviated axial scan angle as compared with axial angle data of 13 young women. In the scans without a deviated axial angle and compared with normative HR-pQCT data, Z-scores at the radius for trabecular bone mineral density (BMD), number, and separation were -1.6 ± 1.3, -2.5 ± 1.4, and -2.7 (IQR: 2.7), respectively. They were -1.4 ± 1.5 and -1.1 ± 1.2 for stiffness and failure load and between ±1 for trabecular thickness and cortical bone parameters. Z-scores were significantly lower for total and trabecular BMD, stiffness, failure load, and cortical area and thickness at the tibia. Additionally, local microarchitectural inhomogeneities were observed, most pronounced being trabecular void volumes. In the scans with a deviated axial angle, the proportion of Z-scores <-4 or >4 was significantly higher for trabecular BMD and separation (radius) or most total and trabecular bone parameters (tibia). To conclude, especially trabecular bone microarchitecture and bone strength were impaired in adults with OI. HR-pQCT may be used without challenges in most adults with OI, but approximately 12% of the scans may have a deviated axial angle in OI due to bone deformities or scan positioning limitations. Furthermore, standard HR-pQCT parameters may not always be reliable due to microarchitectural inhomogeneities nor fully reflect all inhomogeneities.

OI is a rare condition with large clinical heterogeneity. One of the major characteristics associated with OI is the increased fracture risk due to defects in bone structure and material. Data on the defects in bone structure at the micrometer level (i.e. bone microarchitecture) are scarce. Bone microarchitecture can be assessed noninvasively using HR-pQCT, but its use in OI has not extensively been described. Yet, potential challenges may arise related to among others the occurrence of short extremities and skeletal deformities in OI. We assessed bone microarchitecture and strength in 118 adults with OI types I, III, or IV using HR-pQCT with an extremity-length-dependent scan protocol. Additionally, we evaluated potential challenges of using HR-pQCT in this cohort. Our results demonstrated that predominantly trabecular microarchitecture­especially trabecular number and separation­and overall bone strength were impaired in adults with OI as compared with normative data. Furthermore, we observed various microarchitectural inhomogeneities, most pronounced being trabecular void volumes. Regarding applicability, HR-pQCT could be used without challenges in most adults with OI. However, deviations in scan region may potentially influence HR-pQCT parameters, and standard HR-pQCT analyses may not always give accurate results due to microarchitectural inhomogeneities nor fully reflect all microarchitectural inhomogeneities.

Vertebral fracture assessment (VFA) for monitoring vertebral reshaping in children and adolescents with osteogenesis imperfecta treated with intravenous neridronate.

PURPOSE: The study was aimed at monitoring vertebral bodies changes with the use of Vertebral Fracture Assessment (VFA) in children and adolescents affected by osteogenesis imperfecta (OI) during treatment with intravenous neridronate. METHODS: 60 children and adolescents (35 males and 25 females; age 1-16 years) with OI type I, III and IV were included in the study. Intravenous neridronate was administered at the dose of 2 mg/kg every 3 months in all patients. Lumbar spine (LS) bone mineral density (BMD) and VFA by dual X-ray absorptiometry (DXA) were assessed every 6 months up to 24 months during treatment. VFA with vertebral morphometry (MXA) was used to calculate the three indices of vertebral deformity: wedging, concavity and crushing. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], total alkaline phosphatase (ALP), bone alkaline phosphatase (BALP) and urinary C-terminal telopeptide of type 1 collagen (CTx) were measured at any time point. RESULTS: Mean LS BMD values significantly increased at 24 months compared to baseline (p < 0.0001); the corresponding Z-score values were -1.28 ± 1.23 at 24 months vs -2.46 ± 1.25 at baseline; corresponding mean Bone Mineral Apparent Density (BMAD) values were 0.335 ± 0.206 vs 0.464 ± 0.216. Mean serum levels of ALP, BALP and CTx significantly decreased from baseline to 24 months. By MXA, we observed a significant 19.1% reduction of the mean wedging index of vertebral reshaping at 12 months, and 38.4% at 24 months (p < 0.0001) and of the mean concavity index (16.3% at 12 months and 35.9% at 24 months; p < 0.0001). Vertebral reshaping was achieved for 66/88 (75%) wedge fractures and 59/70 (84%) concave fractures, but there were 4 incident mild fractures. Finally, VF rate was reduced at 24 months compared to baseline: 37/710 (5.2%) vs 158/710 (22.2%). CONCLUSION: Our study demonstrates the utility of VFA as a safe and alternative methodology in the follow-up of children and adolescents with OI.

Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles.

OBJECTIVE: Osteogenesis imperfecta (OI) is commonly associated with short stature, but it is unclear whether this is exclusively secondary to fractures and bone deformities or whether there is a primary defect in longitudinal bone growth. As metacarpal and phalangeal bones are rarely affected by fractures and deformities, any length deficits in these bones should reflect a direct disease effect on longitudinal growth. This study therefore assessed the relationship of hand bone length with clinical OI type and genotype. STUDY DESIGN: Prospective study. RESULTS: The length of all 19 tubular hand bones were measured in 144 individuals (age 6 to 57 years; 68 female) who had OI caused by COL1A1 or COL1A2 variants. Measurements of bone length were converted to z-scores using published reference data. Bone length was mostly normal in OI type I but was significantly decreased in OI types III and IV. Mean hand bone length z-score (i.e., the average length z-score of all 19 bones of a hand) was -0.2 for OI type I, -2.9 for OI type III and -1.2 for OI type IV. Mean hand bone length z-score was positively associated with height z-score (r2 = 0.65, P < 0.001). Regarding genotype-phenotype correlations, mean hand bone length z-score was close to 0 in individuals with COL1A1 mutations leading to haploinsufficiency but were significantly lower in the presence of mutations leading to triple-helical glycine substitutions in either the alpha 1 or alpha 2 chain of collagen type I. CONCLUSION: COL1A1 and COL1A2 mutations affect bone growth not only by inducing fractures and bone deformities, but also through longitudinal growth deficits in bones that do not fracture or deform.

Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know.

PURPOSE OF REVIEW: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. RECENT FINDINGS: The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.

Geometry reconstruction method for patient-specific finite element models for the assessment of tibia fracture risk in osteogenesis imperfecta.

Lower limb deformation in children with osteogenesis imperfecta (OI) impairs ambulation and may lead to fracture. Corrective surgery is based on empirical assessment criteria. The objective was to develop a reconstruction method of the tibia for OI patients that could be used as input of a comprehensive finite element model to assess fracture risks. Data were obtained from three children with OI and tibia deformities. Four pQCT scans were registered to biplanar radiographs, and a template mesh was deformed to fit the bone outline. Cortical bone thickness was computed. Sensitivity of the model to missing slices of pQCT was assessed by calculating maximal von Mises stress for a vertical hopping load case. Sensitivity of the model to ±5 % of cortical thickness measurements was assessed by calculating loads at fracture. Difference between the mesh contour and bone outline on the radiographs was below 1 mm. Removal of one pQCT slice increased maximal von Mises stress by up to 10 %. Simulated ±5 % variation of cortical bone thickness leads to variations of up to 4.1 % on predicted fracture loads. Using clinically available tibia imaging from children with OI, the developed reconstruction method allowed the building of patient-specific finite element models.

Reliability of vertebral fractures assessment (VFA) in children with osteogenesis imperfecta.

The aim of this study is to evaluate the diagnostic accuracy of vertebral fractures assessment (VFA) in comparison with conventional radiography in identifying vertebral fractures in children and adolescents affected by OI. On 58 patients (33 males, 25 females; age range 1-18 years; 41 children and 17 adolescents) with osteogenesis imperfecta (OI type I, n = 44, OI type III, n = 4; OI type IV, n = 10), lateral spine images by radiographs and by dual-energy X-ray absorptiometry (DXA) were acquired. For vertebral fracture diagnosis, plain radiographs were used as "gold standard" and VFA and morphometric X-ray absorptiometry (MXA) were performed. The visualized vertebrae were 738 (97.9%) by radiographs and 685 (90.9%) by DXA of a total of 754 vertebrae from T4 to L4. VFA and MXA identified, respectively, 129 (74%) and 116 (66%) of the 175 vertebral fractures detected by radiographs. Radiographs identified 36 patients with vertebral fractures, VFA 35 and MXA 41 (6 false positives). On a per vertebra basis, radiographs and VFA had elevated agreement (93.9%; k score 0.81, 95% CI 0.76-0.86), that resulted slightly lower for MXA (90.6%; k score 0.72, 95% CI 0.65-0.78). VFA and MXA demonstrated high sensitivity (95.6 and 94.1 %, respectively) while specificity was 100% for VFA and 90.6% for MXA on a per patient basis; the agreement was excellent for VFA (98.3%; k score 0.96, 95% CI 0.89-1.03) and good for MXA (87.9%; k score 0.73, 95% CI 0.55-0.91). The diagnostic performance parameters resulted better for VFA (sensitivity 95.6%; specificity 100%; PPV 100%; NPV 97.2%), than for MXA (sensitivity 94.1%; specificity 85.4%; PPV 72.7%; NPV 97.2%). The results of our study demonstrate the reliability of VFA for diagnosis of vertebral fractures in children with OI suggesting its use as a more safe and practical alternative to conventional radiography.

Introduction of a new standardized assessment score of spine morphology in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to multiple bone deformities and fractures. In the absence of causal therapy, a symptomatic approach is based on treatment with bisphosphonates and physiotherapy. The clinical and radiological manifestations vary. Therefore, standardization and quantification for an objective comparison, especially during therapy, are required. In this paper, radiological changes of the spine are quantified according to their clinical relevance to define a scoring system that transfers the morphological changes into a single value representing the severity of the disease. MATERIALS AND METHODS: 268 lateral spine X-rays of 95 patients with OI (median age 5.6 years) were assessed. The findings were classified based on their clinical relevance. RESULTS: The three criteria, vertebral compression, thoracolumbar kyphosis and deformity type, were quantified in a new grading system. Based on this, a "severity classification" (1 to 5) was defined with implications for diagnostics and treatment. A mathematical formula that takes into account the three criteria and their correlations to clinical relevance, resulting in a "severity score", was developed. CONCLUSION: "Severity classification" and "severity score" introduce a new concept for a standardized evaluation of spine X-rays in patients with OI. For both scientific and routine purposes, it provides the user with a simple and easy-to-handle tool for assessing and comparing different stages of severity prior to and during therapy with detailed accuracy.

Intravenous pamidronate treatment in children with moderate to severe osteogenesis imperfecta: assessment of indices of dual-energy X-ray absorptiometry and bone metabolic markers during the first year of therapy.

Bisphosphonates are now widely used to treat children with osteogenesis imperfecta (OI). However, there are few published data following the initial evolution of changes in bone mass with such treatment. The purpose of the present study was to assess indices of skeletal size and total and regional bone mass in children with OI during the first year of their pamidronate therapy. Twenty-six children [11 males, age median 10.6 (range 3.2-15.5) years] with type III (n=9) or type IV (n=17) OI received intravenous pamidronate 1.0 mg/kg/day on 3 consecutive days, 3-monthly over a 1-year period. Bone mass assessed by dual energy X-ray absorptiometry, serum alkaline phosphatase (ALP) and urine type I collagen N-terminal telopepetide (NTX) were measured at each cycle. Lumbar (L2 to L4) vertebral height increased by median (interquartile range) 4.5% (7.3), area by 11.3% (19.3), bone mineral content (BMC) by 73.7% (50.4), and bone mineral density (BMD) by 48.7% (34.7), P<0.0001 during the first year of therapy. Total body bone area increased by 26.7% (26.3), total body BMC by 41.4% (44.5), and total body BMD by 8.8% (8.3), P<0.0001. Head bone area remained constant whilst head BMC and BMD increased. Pre-infusion U-NTX and S-ALP levels decreased progressively during the follow-up indicating reducing bone turnover rate during pamidronate therapy. Increased bone area and mineral mass were observed during the first year of intravenous pamidronate therapy in children with OI. Increased head bone mass implies a direct effect of pamidronate on skeletal mass accretion, rather than an indirect effect mediated through increased physical activity.

Osteopenia in children: CT assessment.

PURPOSE: To assess the value of computed tomographic (CT) measurements of cortical bone in children with osteopenia. MATERIALS AND METHODS: The area and density of cortical bone in the midshaft of the femur were measured with CT in 37 children with osteopenia. Twenty had osteoporosis in one leg, nine had osteogenesis imperfecta (IO), and eight had vitamin D-resistant rickets. Comparisons were made between the CT measurements of the normal and abnormal extremities and between patients with OI or rickets and a group of 17 healthy, matched children. RESULTS: Sex, age, height, and weight did not influence cortical bone density; values were similar for the 17 control subjects. Children with osteoporosis and IO had reduced bone area but normal bone density. Compared with control subjects, patients with rickets had similar bone area but reduced bone density (869 mg/cm3 K2HPO4 +/- 79 [standard deviation] vs 1,132 mg/cm3 K2HPO4 +/- 41). CONCLUSION: CT measurements of area and density of cortical bone aided the differentiation of the various disorders that cause osteopenia in children.

Computed tomographic assessment of vertebral bone mineral in childhood.

Quantitative computed tomography (QCT) was used to assess trabecular bone mineral concentration in the vertebrae of 132 children, 45 with suspected disorder of bone mineralisation, 54 with thalassaemia and 37 controls. The range for bone mineral concentration in controls, expressed as equivalent K2HPO4 concentrations, was 90-190 mg cm-3. Abnormally low values were seen in all untreated children with idiopathic juvenile osteoporosis, 3/9 steroid recipients, and three patients with osteogenesis imperfecta. Abnormally high values were seen in 10/14 chronic renal failure patients. Comparison of the single and dual-energy methods showed that the single energy method, which has a lower radiation dose and is less prone to error from movement artifact, is satisfactory in most paediatric applications.