| 1. |
- Costa, Adriana, et al.
(författare)
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PLS3 Mutations in X-Linked Osteoporosis : Clinical and Genetic Features in Five New Families
- 2023
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Ingår i: Calcified Tissue International. - : Springer. - 0171-967X .- 1432-0827. ; 114, s. 157-170
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Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.
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| 2. |
- Cronin, O., et al.
(författare)
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Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis
- 2022
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 110:3, s. 273-284
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Tidskriftsartikel (refereegranskat)abstract
- The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health. It is therefore closely aligned with many of the recognised modifiable factors that influence bone mass accrual in the young, and bone maintenance and skeletal decline in older populations. While understanding of the relationship between micro-organisms and bone health is still in its infancy, two decades of broader microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and pathogenesis of osteoporosis as well as its prevention and treatment. Pre-clinical research has demonstrated biological interactions between the microbiome and bone metabolism. Furthermore, observational studies and randomized clinical trials have indicated that therapeutic manipulation of the microbiota by oral administration of probiotics may influence bone turnover and prevent bone loss in humans. In this paper, we summarize the content, discussion and conclusions of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in October, 2020. We provide a detailed review of the literature examining the relationship between the microbiota and bone health in animal models and in humans, as well as formulating the agenda for key research priorities required to advance this field. We also underscore the potential pitfalls in this research field that should be avoided and provide methodological recommendations to facilitate bridging the gap from promising concept to a potential cause and intervention target for osteoporosis.
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| 3. |
- Ivaska, Kaisa K., et al.
(författare)
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Bone Turnover Marker Profiling and Fracture Risk in Older Women : Fracture Risk from Age 75 to 90
- 2022
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 111:3, s. 288-299
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A major challenge in osteoporosis is to identify individuals at high fracture risk. We investigated six bone turnover markers (BTMs) to determine association with specific fracture types; the time-frame for risk prediction and whether these are influenced by age at assessment. Methods: Population-based OPRA cohort (n = 1044) was assessed at ages 75, 80, 85 and fractures documented for up to 15 years. Six BTMs were analyzed at each time-point (N-terminal propeptide of type I collagen, PINP; total osteocalcin, OC; bone-specific alkaline phosphatase, BALP; C-terminal telopeptide of type I collagen, CTX; tartrate-resistant acid phosphatase 5b, TRAcP5b; urinary osteocalcin). Hazard ratios (HR) for any, major osteoporotic, vertebral and hip fractures were calculated as short (1, 2, 3 years) and long-term risk (5, 10, 15 years). Results: At 75 year, high CTX levels were associated with an increased risk of all fractures, including major osteoporotic fractures, across most time-frames (HRs ranging: 1.28 to 2.28). PINP was not consistently associated. Urinary osteocalcin was consistently associated with elevated short-term risk (HRs ranging: 1.83–2.72). Other BTMs were directionally in accordance, though not all statistically significant. BTMs were not predictive for hip fractures. Association of all BTMs attenuated over time; at 80 year none were associated with an increased fracture risk. Conclusion: CTX, urinary OC and TRAcP5b are predictive for fracture in a 1 to 3 year, perspective, whereas in the long-term or above age 80 years, BTMs appear less valuable. Resorption markers, particularly CTX, were more consistently associated with fracture risk than formation markers in the very elderly.
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| 4. |
- Johansson, Peter, et al.
(författare)
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Increased Risk of Hip Fracture in Patients with Lymphoma, a Swedish Population Study of 37,236 Lymphoma Patients.
- 2020
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 106, s. 591-598
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Tidskriftsartikel (refereegranskat)abstract
- Increased bone loss has been noted in lymphoma patients; however, the incidence of hip fracture is not known. The aim of our study was to explore the risk for hip fracture in patients with lymphoma compared with the entire Swedish population. The risk of hip fracture was determined in a retrospective population cohort study of adult Swedish lymphoma patients (n=37,236), diagnosed 1995-2015 and compared with the entire Swedish population during the same period. The incidence of hip fracture in lymphoma patients was higher in women than in men, increased by age, and decreased by calendar year as also demonstrated in the total population. 2.2% of the men and 4.7% of women with lymphoma sustained a hip fracture. For the total group of females, the hazard ratio (HR) was 1.19 (95% CI 1.11-1.28) and for men, the hazard ratio was 1.06 (95% CI 0.97-1.17) compared with the Swedish population. The HR for hip fracture (2016) was 2.80 (95% CI 1.20-6.53), 2.04 (95% CI 1.30-3.20), 1.56 (95% CI 1.21-2.01), 1.08 (95% CI 0.89-1.30), and 1.07 (95% CI 0.92-1.25) in females aged 40, 50, 60, 70, and 80years, respectively. Corresponding figures for men were not significant in 2016. Unmarried men with lymphoma had a two times higher risk for hip fracture (HR 2.02 95% CI 1.63-2.50) compared with married men. Patients with lymphoma had an increased risk of hip fracture, especially younger women and unmarried men. The incidence of hip fracture is decreased by calendar year in the lymphoma patients and the entire Swedish population.
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| 5. |
- Makitie, RE, et al.
(författare)
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A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report
- 2021
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 109:6, s. 626-632
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Tidskriftsartikel (refereegranskat)abstract
- Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.
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| 6. |
- Malmgren, B, et al.
(författare)
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Abnormalities in Tooth Formation after Early Bisphosphonate Treatment in Children with Osteogenesis Imperfecta
- 2021
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 109:2, s. 121-131
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with intravenous bisphosphonate (BP) in children and adolescents with osteogenesis imperfecta (OI) started in Sweden in 1991. No human studies on the role of BP therapy in development of disturbances in tooth mineralization or tooth morphology have been published. The study cohort comprised 219 individuals who were divided into four groups: group 1, BP treatment onset before 2 years of age (n = 22); group 2, BP treatment onset between 2 and 6 years of age (n = 20); group 3, BP treatment onset between 6 and 10 years of age (n = 13); and a control group of patients with OI who had not received BP therapy (n = 164). The chi-square test was used in between-group comparisons of the prevalence of tooth agenesis. The prevalence of tooth agenesis was significantly higher in children who began BP treatment before the age of 2 years (group 1; 59%,) compared to the controls (10%; p < 0.001) and to children who had begun BP therapy between ages 2 and 6 years (group 2; 10%; p = 0.009) or between ages 6 and 10 years (group 3; 8%; p = 0.003). Different types of disturbances in the enamel formation were seen in 52 premolars, where 51 were seen in those who began BP treatment before the age of 2 years. To conclude, starting BP treatment before the age of 2 years increases the risk of abnormalities in tooth formation manifesting as morphological aberrations, tooth agenesis, and enamel defects.
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| 7. |
- Malmgren, B, et al.
(författare)
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Bisphosphonate Therapy and Tooth Development in Children and Adolescents with Osteogenesis Imperfecta
- 2020
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 107:2, s. 143-150
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Tidskriftsartikel (refereegranskat)abstract
- Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by repeated fractures and skeletal disorders. At present, bisphosphonate (BP) therapy is the gold standard for OI treatment. The present retrospective study evaluated the effect of BP therapy on tooth development and eruption of permanent teeth in a cohort of children receiving pamidronate. Three groups were studied: patients with OI who were treated with BPs (n = 45), patients with OI who were not treated with BPs (n = 117), and age- and gender-matched healthy controls (n = 121). Dental age, dental maturity, and tooth eruption were assessed on panoramic radiographs using the methods of Demirjian et al. (Hum Biol 45(2):211–227, 1973) and Haavikko (Suom Hammaslaak Toim 66(3):103–170, 1970) and were evaluated using the t-test, Chi-square test, and the Mann–Whitney U test. Dental age in the study group was significantly (p < 0.05) lower than chronological age compared with both control groups. Dental maturity and the eruption of permanent teeth were also significantly (p < 0.05) delayed in the study group in relation to the two control groups. The dental age was significantly lower (p < 0.001) in patients with OI type III treated with BPs compared with healthy controls and the dental maturation was significantly delayed in patients with OI type IV treated with BPs compared with those not treated. In conclusion, BP therapy in OI patients seems to lower the dental age, delay the dental maturity, and tooth eruption. BP administration before 2 years of age might be a contributing factor.
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| 8. |
- Matthews, BG, et al.
(författare)
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αSMA Osteoprogenitor Cells Contribute to the Increase in Osteoblast Numbers in Response to Mechanical Loading
- 2020
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 106:2, s. 208-217
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Tidskriftsartikel (refereegranskat)abstract
- Bone is a dynamic tissue that site-specifically adapts to the load that it experiences. In response to increasing load, the cortical bone area is increased, mainly through enhanced periosteal bone formation. This increase in area is associated with an increase in the number of bone-forming osteoblasts; however, the origin of the cells involved remains unclear. Alpha-smooth muscle actin (αSMA) is a marker of early osteoprogenitor cells in the periosteum, and we hypothesized that the new osteoblasts that are activated by loading could originate from αSMA-expressing cells. Therefore, we used an in vivo fate-mapping approach in an established axial loading model to investigate the role of αSMA-expressing cells in the load-induced increase in osteoblasts. Histomorphometric analysis was applied to measure the number of cells of different origin on the periosteal surface in the most load-responsive region of the mouse tibia. A single loading session failed to increase the number of periosteal αSMA-expressing cells and osteoblasts. However, in response to multiple episodes of loading, the caudal, but not the cranial, periosteal surface was lined with an increased number of osteoblasts originating from αSMA-expressing cells 5 days after the initial loading session. The proportion of osteoblasts derived from αSMA-labeled progenitors increased by 70% (p < 0.05), and the proportion of αSMA-labeled cells that had differentiated into osteoblasts was doubled. We conclude that αSMA-expressing osteoprogenitors can differentiate and contribute to the increase in periosteal osteoblasts induced by mechanical loading in a site-specific manner.
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| 9. |
- Maurotti, Samantha, et al.
(författare)
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Effects of C-Peptide Replacement Therapy on Bone Microarchitecture Parameters in Streptozotocin-Diabetic Rats.
- 2020
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 107, s. 266-280
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Tidskriftsartikel (refereegranskat)abstract
- C-peptide therapy protects against diabetic micro- and macrovascular damages and neuropatic complications. However, to date, the role of C-peptide in preventing diabetes-related bone loss has not been investigated. Our aim was to evaluate if C-peptide infusion improves bone quality in diabetic rats. Twenty-three male Wistar rats were randomly divided into three groups: normal control group; sham diabetic control group; diabetic plus C-peptide group. Diabetes was induced by streptozotocin injection and C-peptide was delivered subcutaneously for 6weeks. We performed micro-CT and histological testing to assess several trabecular microarchitectural parameters. At the end, diabetic plus C-peptide rats had a higher serum C-peptide (p=0.02) and calcium (p=0.04) levels and tibia weight (p=0.02) than the diabetic control group. The diabetic plus C-peptide group showed a higher trabecular thickness and cross-sectional thickness than the diabetic control group (p=0.01 and p=0.03). Both the normal control and diabetic plus C-peptide groups had more Runx-2 and PLIN1 positive cells in comparison with the diabetic control group (p=0.045 and p=0.034). Diabetic rats receiving C-peptidehad higher quality of trabecular bone than diabetic rats not receiving this treatment. If confirmed, C-peptide could have a role in improving bone quality in diabetes.
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| 10. |
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