Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis

Pathophysiology and therapeutic options in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is the most common hereditary disease causing an increased bone fragility. The wide variability of the phenotype can not be explained by the genotype. Most forms are caused by mutations in genes influencing synthesis and posttranslational modification of collagen. Most patients are affected by mutations in the genes COL1A1/A2. The increased knowledge about underlying genetic alteration and pathophysiology in some rare recessive forms has led to new therapeutic strategies. OI VI is caused by mutations in SERPINF1 leading to an increased activity of osteoclasts via the OPG/RANKL-pathway. In these patients a medical treatment with denosumab has been proven to be more effective as antiresorptive treatment compared to the former therapy with bisphosphonates. In patients affected by mutations in WNT1 an osteoanabolic treatment might be more suitable than an antiresorptive therapy. Pharmacological treatment has to be included in an interdisciplinary therapeutic concept in combination with physiotherapy and surgical treatment

Dynamics of Skeletal Status under Optimized Management during Subsequent Pregnancy in Three Women with a History of Pregnancy‐ and Lactation‐Associated Osteoporosis Carrying pathogenic Variants in WNT1 and LRP5

Abstract Pregnancy‐ and lactation‐associated osteoporosis (PLO) is a rare but clinically highly relevant condition, characterized by reduced bone mineral density (BMD) and acute onset of severe pain due to symptomatic bone marrow edema of the hip or vertebral and/or insufficiency fractures, among others. Previous reports showed a high frequency of hereditary bone disorders unmasked by PLO, predisposing for more severe forms. To date, no data on the risk for additional fractures during subsequent pregnancy in women with PLO and genetic bone disorder have been available. To address this question, we retrospectively analyzed the clinical, biochemical, and densitometric course of three women with a history of PLO and detected variants in WNT1 or LRP5 and subsequent pregnancies. Calcium homeostasis and bone turnover were optimized by basic treatment, and timely initiation of weaning was recommended. Teriparatide treatment for 12 months under strict contraception was initiated in one woman after the diagnosis of PLO. In none of the women did additional fractures or symptomatic bone marrow edemas occur, and BMD by dual‐energy X‐ray absorptiometry as bone microarchitecture by high‐resolution peripheral quantitative computed tomography remained stable. In conclusion, this report expands the understanding of this rare but severe condition and helps to improve clinical counseling and management. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

Current structure of care and treatment options for patients with rare bone diseases at University Hospitals in Germany

Medical care for patients with Rare Bone and Mineral conditions (RBMC) require lifelong, multidisciplinary efforts including different subspecialties such as endocrinology, nephrology, orthopaedics, rheumatology, radiology, cardiology, neurology, internal medicine, paediatrics and clinical genetics. National networking and local organization and management of care in RBMC is of central importance and was assessed by means of a national survey. The aim of the study was to identify and characterize the services, organisation and existing expertise concerning RBMC at University Hospitals in Germany. All 32 Centers for Rare Diseases (ZSE) at German University Hospitals were contacted with a questionnaire in 2018. Of those, 15 centers took part in the survey, resulting in a response rate of 47%. The responses revealed differences most pronounced in the level of equipment and diagnostic capabilities. While most centers had implemented tools for patient empowerment, only few centers were involved in research activities in RBMC or offered structured training programs for physicians and medical students. The results of the survey can be helpful to initiate concrete action plans to improve healthcare for patients with RBMC in Germany

Bone mineral density and microarchitecture change during skeletal growth in harbor seals (Phoca vitulina) from the German coast

Abstract Across species, the skeletal system shares mutual functions, including the protection of inner organs, structural basis for locomotion, and acting as an endocrine organ, thus being of pivotal importance for survival. However, insights into skeletal characteristics of marine mammals are limited, especially in the growing skeleton. Harbor seals (Phoca vitulina) are common marine mammals in the North and Baltic Seas and are suitable indicators of the condition of their ecosystem. Here, we analyzed whole-body areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and lumbar vertebrae by high-resolution peripheral quantitative computed tomography (HR-pQCT) in neonate, juvenile, and adult harbor seals. Along skeletal growth, an increase in two-dimensional aBMD by DXA was paralleled by three-dimensional volumetric BMD by HR-pQCT, which could be attributed to an increasing trabecular thickness while trabecular number remained constant. Strong associations were observed between body dimensions (weight and length) and aBMD and trabecular microarchitecture (R2 = 0.71–0.92, all p < 0.001). To validate the results of the DXA measurement (i.e., the standard method used worldwide to diagnose osteoporosis in humans), we performed linear regression analyses with the three-dimensional measurements from the HR-pQCT method, which revealed strong associations between the two imaging techniques (e.g., aBMD and Tb.Th: R2 = 0.96, p < 0.0001). Taken together, our findings highlight the importance of systematic skeletal investigations in marine mammals during growth, illustrating the high accuracy of DXA in this context. Regardless of the limited sample size, the observed trabecular thickening is likely to represent a distinct pattern of vertebral bone maturation. As differences in nutritional status, among other factors, are likely to affect skeletal health, it appears essential to routinely perform skeletal assessments in marine mammals. Placing the results in the context of environmental exposures may allow effective measures to protect their populations

Intra-articular osteoid osteoma accompanied by extensive bone marrow edema. A clinical and micro-morphological analysis

Osteoid osteoma (OO) is a benign bone tumor producing non-mineralized bone matrix (i.e., osteoid). While peritumoral edema is commonly found in OO, extensive bone marrow edema has been reported less frequently. Furthermore, the micro-morphological characteristics of the nidus and its central calcification remain unclear. In this study, a consecutive series of four patients suffering from extensive bone marrow edema triggered by intra-articular osteoid osteoma underwent clinical examination, magnetic resonance imaging (MRI) and computed tomography (CT) as well as dual-energy X-ray absorptiometry (DXA) and laboratory bone turnover analyses. The obtained resection specimens were processed by undecalcified histology and were subsequently analyzed by light microscopy and quantitative backscattered electron imaging (qBEI). We report an entity of intra-articular osteoid osteoma in the knee and foot, in which an extensive and persistent bone marrow edema syndrome masked the correct diagnosis. While metabolic bone diseases were excluded in all cases, the reassessment of the patients' clinical history including pain characteristics (nocturnal, aspirin sensitivity) led us to perform additional CT, where the tumor was diagnosed. The micro-morphological analysis of the OO biopsies revealed that the nidus was surrounded by hyperosteoidosis, while central mineralization was detected in all cases. This mineralized area showed a significantly higher mineralization heterogeneity than the surrounding trabecular bone and more disorganized collagen fibers detected by qBEI and polarized light microscopy, respectively. Taken together, our results indicate that osteoid osteoma should be considered when persistent and extensive, periarticular bone marrow edema is diagnosed. The central calcification that is found inside the nidus in conventional imaging was mirrored by bone matrix with a heterogeneous mineralization pattern

Variation in skull bone mineral density of ringed seals (Phoca hispida) from the Gulf of Bothnia and West Greenland between 1829 and 2019

Bone is remodelled constantly through a balance of bone formation and resorption. This process can be affectedby various factors such as hormones, vitamins, nutrients and environmental factors, which can create an imbalanceresulting in systemic or local bone alteration. The aim of the present study was to analyse the changes in bone mineral density (BMD) over time in skulls of ringed seals (Pusa hispida) from the Baltic and Greenland using museum samples. Overall, 303 skulls (102 Male, 89 Female, 112 unknown) were used for bone investigationsand were divided into three periods according to collection year: before 1958 (n = 167), between 1958 and 1989 (n=40) and after 1994 up to 2019 (n=96). All skulls were examined by dual-energy X-ray absorptiometryto obtain the BMD. Skull BMD of the Baltic seals was positively correlated with the historical polychlorinatedbiphenyls (PCB) contamination having potential effects on the constitution of bones. BMD fluctuated between the three study periods (LM: p-value &lt; 0.001, F-value = 47.5) with the lowest BMD found between 1897 and 1957, in the Gulf of Bothnia, where the highest peak of contaminant concentration was in the second period. BMD levels increased with increasing PCB concentration (LM: p &lt; 0.001). The Greenland population showed significant lower BMD levels in the pollution and post-pollution period than the Baltic population (LM:p &lt; 0.001). It also revealed a higher BMD in males than in females (LM: p=0.03). In conclusion, the variations between 1829 and 2019 in the Baltic Sea and Greenland may to a certain extent reflect normal fluctuations; however, this study revealed several factors affecting BMD, including sex and PCB levels

Bilateral Looser zones or pseudofractures in the anteromedial tibia as a component of medial tibial stress syndrome in athletes

Purpose!#!Medial tibial stress syndrome (MTSS) represents a common diagnosis in individuals exposed to repetitive high-stress loads affecting the lower limb, e.g., high-performance athletes. However, the diagnostic approach and therapeutic regimens are not well established.!##!Methods!#!Nine patients, diagnosed as MTSS, were analyzed by a comprehensive skeletal analysis including laboratory bone turnover parameters, dual-energy X-Ray absorptiometry (DXA), and high-resolution peripheral quantitative computed tomography (HR-pQCT).!##!Results!#!In 4/9 patients, bilateral pseudofractures were detected in the mid-shaft tibia. These patients had significantly lower levels of 25-hydroxycholecalciferol compared to patients with MTSS but similar levels of bone turnover parameters. Interestingly, the skeletal assessment revealed significantly higher bone mineral density (BMD) Z-scores at the hip (1.3 ± 0.6 vs. - 0.7 ± 0.5, p = 0.013) in patients with pseudofractures and a trend towards higher bone microarchitecture parameters measured by HR-pQCT at the distal tibia. Vitamin D supplementation restored the calcium-homeostasis in all patients. Combined with weight-bearing as tolerated, pseudofractures healed in all patients and return to competition was achieved.!##!Conclusion!#!In conclusion, deficient vitamin D levels may lead to pseudofractures due to localized deterioration of mineralization, representing a pivotal component of MTSS in athletes with increased repetitive mechanical loading of the lower limbs. Moreover, the manifestation of pseudofractures is not a consequence of an altered BMD nor microarchitecture but appears in patients with exercise-induced BMD increase in combination with reduced 25-OH-D levels. The screening of MTSS patients for pseudofractures is crucial for the initiation of an appropriate treatment such as vitamin D supplementation to prevent a prolonged course of healing or recurrence.!##!Level of evidence!#!III

Gnathodiaphyseal dysplasia is not recapitulated in a respective mouse model carrying a mutation of the Ano5 gene

Mutations in the gene ANO5, encoding for the transmembrane protein Anoctamin 5 (Ano5), have been identified to cause gnathodiaphyseal dysplasia (GDD) in humans, a skeletal disorder characterized by sclerosis of tubular bones, increased fracture risk and fibro-osseous lesions of the jawbones. To better understand the pathomechanism of GDD we have generated via Crispr/CAS9 gene editing a mouse model harboring the murine equivalent (Ano5 p.T491F) of a GDD-causing ANO5 mutation identified in a previously reported patient. Skeletal phenotyping by contact radiography, μCT and undecalcified histomorphometry was performed in male mice, heterozygous and homozygous for the mutation, at the ages of 12 and 24 weeks. These mice did not display alterations of skeletal microarchitecture or mandible morphology. The results were confirmed in female mice and animals derived from a second, independent clone. Finally, no skeletal phenotype was observed in mice lacking ~40% of their Ano5 gene due to a frameshift mutation. Therefore, our results indicate that Ano5 is dispensable for bone homeostasis in mice, at least under unchallenged conditions, and that these animals may not present the most adequate model to study the physiological role of Anoctamin 5.ISSN:2352-187