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Melorheostosis is a rare bone disease characterized by abundant bone formation with a characteristic radiographic appearance that resembles "dripping candle wax." Recent data have shown that the majority of cases are due to somatic activating mutations in bone. Melorheostosis has several clinical and radiographic presentations, which are now known to be caused by different somatic mutations such as MAP2K1 , SMAD3 , KRAS , and LEMD3. This review provides a comprehensive look at the clinical features, diagnostic approaches, and current treatment options for melorheostosis, alongside future research directions aimed at improving patient outcomes. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-β antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade. [ABSTRACT FROM AUTHOR]

Rare bone diseases (RBD) cause physical and sensory disability that affects quality of life. Mobility challenges are common for people with RBDs, and travelling to gait analysis labs can be very complex. Smartphone sensors could provide remote monitoring. This study aimed to search for and identify variables that can be used to discriminate between people with RBD and healthy people by using built-in smartphone sensors in a real-world setting. In total, 18 participants (healthy: n=9; RBD: n=9), controlled by age and sex, were included in this cross-sectional study. A freely available App (Phyphox) was used to gather data from built-in smartphone sensors (accelerometer & gyroscope) at 60 Hz during a 15-min walk on a level surface without turns or stops. Temporal gait parameters like cadence, mean stride time and, coefficient variance (CoVSt) and nonlinear analyses, as the largest Lyapunov exponent (LLE) & sample entropy (SE) in the three accelerometer axes were used to distinguish between the groups and describe gait patterns. The LLE (p=0.04) and the SE of the z-axis (p=0.01), which are correlated with balance control during walking and regularity of the gait, are sufficiently sensitive to distinguish between RBD and controls. The use of smartphone sensors to monitor gait in people with RBD allows for the identification of subtle changes in gait patterns, which can be used to inform assessment and management strategies in larger cohorts. • Smartphone-based metrics can be used to distinguish gait changes in individuals with RBD. • Smartphone sensors could enable remote monitoring by individuals with RBD. • Remote gait monitoring could facilitate the assessment and management of larger cohorts. [ABSTRACT FROM AUTHOR]

Background: A balanced diet rich in calcium and protein is recommended for bone-healthy people and osteoporosis patients, but it may also be important for rare bone disease (RBD). Little data is available on RBD and diet. Therefore, the aim of this study was to evaluate the nutritional behavior of patients with RBD. Methods: This single-center, cross-sectional, questionnaire-based study assessed the nutritional behavior of RBD patients (X-linked hypophosphatemia (XLH), osteogenesis imperfecta (OI), hypophosphatasia (HPP)), osteoporosis (OPO) patients and healthy controls (CTRL). The nutritional questionnaire comprised 25 questions from seven nutritional areas. The associations between socioeconomic factors and BMI were assessed by age-adjusted univariate analysis of covariance (ANCOVA). Results: Fifty patients with RBD (17 OI, 17 HPP, 16 XLH; mean age of 48.8 ± 15.9, 26.0% male, mean BMI 26.2 ± 5.6), 51 with OPO (mean age 66.6 ± 10.0, 9.8% male, mean BMI 24.2 ± 3.9) and 52 CTRL (mean age 50.8 ± 16.3, 26.9% male, mean BMI 26.4 ± 4.7) participated. Twenty-six (52.0%) RBD, 17 (33.4%) OPO and 24 (46.1%) CTRL were overweight or obese according to BMI. Only a minority of RBD, OPO and CTRL had a daily intake of at least three portions of milk or milk products (17.3% RBD, 15.6% OPO, 11.6% CTRL, p = 0.453). In general, similar nutritional behavior was observed between the three subgroups. However, significant differences were found in caffeine consumption (p = 0.016), fruit/vegetable juice consumption (p = 0.034), portions of fish per week (p = 0.044), high-fat meals per week (p = 0.015) and consumption of salty snacks (p = 0.001). Conclusion: Nutritional counseling, controlling BMI and ensuring sufficient calcium and protein intake are crucial in patients with osteoporosis as well as in rare bone diseases. Vitamin D does not appear to be sufficiently supplied by the diet, and therefore supplementation should be considered in patients with bone diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. Methods The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. Results A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P

Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (n  = 103, 89.2%); median age at first symptoms 45 years (range 20-73). The diagnosis was excluded in the remaining 51 "non-CNO" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (P  < 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages. [ABSTRACT FROM AUTHOR]

(1) Background: The use of complementary and alternative medicine (CAM) has seen a notable increase in popularity. However, there is an absence of data regarding the prevalence of CAM use in patients with rare bone diseases (RBDs). (2) Methods: This monocentric, cross-sectional study was carried out in a reference hospital for RBDs. RBD patients included individuals with osteogenesis imperfecta, hypophosphatasia and X-linked hypophosphatemia, and their data were compared with those of patients with osteoporosis (OPO) and of healthy controls (CON). This study utilized the German version (I-CAM-G) of the I-CAM questionnaire. (3) Results: This study comprised 50 RBD patients [mean age (SD) of 48.8 (±15.9), 26% male], 51 OPO patients [66.6 (±10.0), 9.8% male] and 52 controls [50.8 (±16.3), 26.9% male]. Treatments by naturopaths/healers were more prevalent in the RBD group (11.4%) compared with OPO (0%) and CON (5.8%) (p = 0.06). More than half of the OPO (60.8%) and CON (63.5%) patients and 46% of the RBD patients reported vitamin/mineral intake within the past 12 months (p = 0.16). Individuals with tertiary education had a significantly higher odds ratio of 2.64 (95% CI: 1.04–6.70, p = 0.04) for visiting any CAM provider. Further, OPO patients were significantly less likely to use self-help techniques compared with the CON group (OR = 0.42, 95% CI: 0.19–0.95; p = 0.04). (4) Conclusions: Herbal medicine, vitamin and mineral supplements, and self-help techniques were the most common forms of CAM reported by patients with RBDs. However, the use of CAM was generally low. [ABSTRACT FROM AUTHOR]

Background: Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. Methods: The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. Results: A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P < 0.001), higher total charges ($85,180.97 ± 1,239.47 vs. $49,884.26 ± 20.99, P < 0.001), suffering more procedure, diagnosis and transferring records in comparison to patients with common conditions. GSD patients had a significantly higher 30-day all-cause readmission rate based on Nationwide Readmissions Database. Conclusions: The heavy health-care utilization and economic burden emphasized the urgency for policy leaders, scientific and pharmaceutical researchers, health care providers and employers to identify innovative ways and take effective measurements immediately, and eventually to help improve the care, management, and treatment of these devastating diseases. [ABSTRACT FROM AUTHOR]

In the US, rare diseases are defined as disorders affecting fewer than 200,000 US residents or disorders for which there is no reasonable expectation that drug development costs will be recoverable by US sales. Almost 800 of the approximately 10,000 defined rare diseases are bone disorders. Until recently, their rarity and heterogeneity have unfortunately hindered their exploration at both clinical and scientific levels. However, wider availability of genetic testing, development of new surgical and pharmaceutical treatment options, and patient advocacy have motivated efforts to study, diagnose, and treat these disorders. Thus, care of the patient with a rare skeletal disorder is now evolving rapidly. This report presents a brief summary of important developments in skeletal disorders impacting bone quality and frequently co-managed by pediatric orthopaedic surgeons. Key Concepts: (1) Although a “cure” is not yet available for most rare bone disease patients, new agents are frequently being advanced as new genes and their products are identified as molecules to target. (2) Medical therapies, often combined with surgical interventions and physical therapy, are reducing pain and increasing function in many pediatric orthopaedic patients with rare bone disorders. (3) New tools for physician education and patient management are increasingly available to assist the pediatric orthopaedic surgery community.

Abstract Background Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires

Introduction: Rare bone diseases (RBDs) are a heterogenous group of disorders that are poorly understood and challenging to treat. This creates a plethora of unmet needs for people with RBDs as well as their families and care providers, including diagnostic delays, limited access to expert care, and a lack of specialized treatments. The RBD Summit, which took place across 2 days in November 2021, was a virtual meeting of 65 RBD experts from clinical, academic, and patient communities as well as the pharmaceutical industry. The first meeting of its kind, the RBD Summit aimed to facilitate dialog and information exchange between delegates to advance knowledge and awareness of RBDs and improve patient outcomes. Methods: Key challenges were discussed, and actions for overcoming them were proposed, including how obstacles to diagnosis can be overcome by (a) improving awareness of RBDs, (b) the implementation of a person-centered care pathway, and (c) how to narrow the communication gap between patients and healthcare professionals. Results: Agreed actions were categorized as short term and long term, and priorities determined. Conclusion: In this position paper, we provide an overview of key discussions from the RBD Summit, summarize the subsequent action plan, and discuss the next steps in this continued collaboration. [ABSTRACT FROM AUTHOR]

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms, which can give rise to a multifaceted syndrome, otherwise called tumor-induced osteomalacia (TIO). Localizing these tumors is crucial to obtain a cure for the phosphate metabolism derangement, which is often the main cause leading the patient to seek medical help, because of invalidating physical and neuromuscular symptoms. A proportion of these tumors is completely silent and may grow unnoticed, unless they become large enough to produce pain or discomfort. FGF-23 can be produced by several benign or malignant PMTs. The phosphate metabolism, radiology and histology of these rare tumors must be collectively assessed by a multidisciplinary team aimed at curing the disease locally and improving patients' quality of life. This narrative review, authored by multiple specialists of a tertiary care hospital center, will describe endocrine, radiological and histological features of these tumors, as well as present surgical and interventional strategies to manage PMTs. [ABSTRACT FROM AUTHOR]

Context: Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials. Objective: This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. Methods: A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists. Conclusion: Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction. [ABSTRACT FROM AUTHOR]

Purpose of Review: This study aims to review diagnosis, potential complications, and clinical management in craniofacial fibrous dysplasia. Recent Findings: Fibrous dysplasia (FD) is a rare mosaic disorder in which normal bone and marrow are replaced with expansile fibro-osseous lesions. Disease presents along a broad spectrum and may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). The craniofacial skeleton is one of the most commonly impacted areas in FD, and its functional and anatomical complexities create unique challenges for diagnosis and management. Summary: This review summarizes current approaches to diagnosis and management in FD/MAS, with emphasis on the clinical and therapeutic implications for the craniofacial skeleton. [ABSTRACT FROM AUTHOR]

Background: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care. Results: 92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1–Q3 36–56). Skeletal burden correlated with baseline Physical Function (rs = − 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function (mean 67 ± SD24 to 74 ± 21, effect size (ES) 0.31, p = 0.020), Role Physical (39 ± 41 to 53 ± 43, ES 0.35, p = 0.066), Social Functioning (64 ± 24 to 76 ± 23, ES 0.49, p = 0.054), and Health Change (39 ± 19 to 53 ± 24, ES 0.76, p = 0.016), chronic patients in Physical Function (52 ± 46 to 66 ± 43, ES 0.31, p = 0.023) and Emotional Wellbeing (54 ± 27 to 70 ± 15, ES 0.59, p < 0.001). New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated (rs = − 0.472, p < 0.001). Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function. Conclusions: All FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers. [ABSTRACT FROM AUTHOR]

Abstract Background Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements. Methods In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded. Results In total, 8.46% of the measurements of a total of 6.918.126 values showed a value

Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients. [ABSTRACT FROM AUTHOR]

Abstract Background Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase. It is characterized by defective bone mineralization associated with low alkaline phosphatase activity. Clinical features of pediatric HPP are highly variable, and can include premature loss of teeth, musculoskeletal problems, and impaired mobility. The effects of pediatric HPP on sleep, mood, regulation of attention and behavior, and other aspects of behavioral health have not been comprehensively studied. Methods Parents of 30 children with HPP (14 females, 16 males) between the ages of 3 and 16 years (mean age = 8.0 years) enrolled in this cross-sectional survey-based study. Molecular genetic and biochemical testing as well as clinical records were reviewed to verify diagnosis of HPP. The cohort included 15 patients with a more clinically severe presentation of HPP who had received treatment with enzyme replacement therapy (asfotase alfa) and 15 children with less severe HPP who were treatment-naïve. Parents provided information regarding psychopathological comorbidity, emotional and behavioral well-being, and quality of life. Results Clinically significant behavioral health challenges were evident in 67% of children with HPP. The most common behavioral findings included sleep disturbance and symptoms of attention deficit hyperactivity disorder (ADHD), each of which were observed ≥ 50% of individuals. Sleep disturbance, pain interference, poor behavioral regulation, and mood/anxiety symptoms were associated with reduced physical and psychosocial quality of life. Behavioral concerns were evident among children with HPP receiving asfotase alfa treatment as well as among children with clinically less severe disease who had not initiated therapy. Although most children in the cohort (77%) had age-typical development of adaptive skills, emotional and behavioral challenges were associated with weaker adaptive function. Conclusions Children with HPP are at increased risk for ADHD symptoms and other behavioral health challenges. There is likely an under-recognition of these findings in clinical practice.

Abstract Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children’s Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.

This case report describes the rare occurrence of idiopathic juvenile osteoporosis (IJO) in an 11-year-old boy with bone fragility and fractures, particularly in the thoracic and lumbar vertebrae. After excluding discernible underlying causes, the diagnosis was confirmed using clinical and radiological assessments. Treatment commenced with oral bisphosphonates, leading to notable bone mineral density (BMD) improvements and the absence of subsequent fractures. IJO presents diagnostic challenges owing to its multifaceted nature, necessitating the exclusion of other common causes of pediatric osteoporosis. Although the pathophysiology of IJO remains poorly understood, this case underscores the potential efficacy of bisphosphonate therapy in managing the condition and improving patient outcomes. Notably, the patient's symptoms ameliorated as puberty commenced, aligning with the typical IJO patterns reported in the literature. Although the long-term impact of bisphosphonate treatment in pediatric IJO cases warrants further investigation, this case exemplifies the potential to enhance the quality of life of affected individuals., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shimazaki et al.)

Background: Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements.Methods: In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded.Results: In total, 8.46% of the measurements of a total of 6.918.126 values showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Here, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% (1:194) of subjects show laboratory signs of HPP.Conclusion: These data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended. [ABSTRACT FROM AUTHOR]

Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

BACKGROUND This report describes a new strategy for the care of patients with osteogenesis imperfecta, based on an interdisciplinary team working. Thereby, we aim at fulfilling three main goals: offering thorough coordinated management for all, and improving physical activity and quality of life of the patients. AIM With rare diseases such as osteogenesis imperfecta (OI), patients and their family often suffer from inadequate recognition of their disease, poor care coordination and incomplete information. A coordinated interdisciplinary approach is one possible solution for providing both comprehensive and cost-effective care, with benefits for patient satisfaction. Poor physical activity and impaired quality of life represent a considerable burden for these patients. To better address these issues, in 2012 we created an interdisciplinary team for the management of OI patients in our University Hospital Centre (CHUV, Lausanne University Hospital,). In this article we describe the implementation of this interdisciplinary care strategy for patients suffering from OI, and its impact on their physical activity and quality of life. METHODS All patients from the French part of Switzerland were invited to join us. We proposed two complementary evaluations: the initial interdisciplinary evaluation and a yearly follow-up during a special day – the “OI day”. This day features specialised medical appointments adapted to each patient’s needs, as well as lectures and/or workshops dedicated to patients’ and families’ education. Our first aim was to propose for each patient the same management, from diagnosis to the bone health evaluation and physical therapy advice. Our second aim was to evaluate the evolution of physical activity, quality of life (measured by EQ-5D, SF-36 and a dedicated questionnaire) and satisfaction of patients and their families. Here we report both the initial and the long-term results. RESULTS Since 2012, 50 patients from the French part of Switzerland received the personalised medical evaluation. All of the patients included in this study had the same initial evaluation and at least one participation in an OI Day. All patients had an adaptation of their bone acting drugs. Over a 7-year period, 62% of inactive patients started some physical activity, and 44% of patients who were not involved in any athletic activity started participating in sports. The mean EQ-5D increased from 0.73 to 0.75 (p = 0.59). The mean physical SF36 (musculoskeletal function) score was 59.09 ± 22.72 and improved to 65.79 ± 21.51 (p = 0.08), whereas it was 68.06 ± 20.05 for the mental SF36 without alteration during follow-up. The OI day was revealed to be useful, it contributed to improvement in continuity of care and helped families to better understand the OI patients’ health. CONCLUSIONS Our interdisciplinary approach aimed at offering the same thorough management for all patients from the French part of Switzerland, and at improving both the physical activity and the satisfaction of the patients and their family. This report is a basis for future work focusing on the effect of bone fragility and the impact of OI on patients’ social relations.

Abstract Background Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from dysfunction of the tissue non-specific alkaline phosphatase enzyme. Its manifestations are extremely variable, ranging from early lethality to disease limited to the dentition. The disease is life-threatening when manifesting within the first six months of life, excepting the extremely rare benign perinatal hypophosphatasia. Childhood hypophosphatasia, defined as onset of symptoms between six months and eighteen years, can manifest as rickets, pain, decreased mobility, deficits of growth, and fractures. Historical treatment has generally involved a combination of dietary and rehabilitative interventions. Main document Asfotase alfa (Strensiq™), is a first-in-class bone-targeted recombinant tissue nonspecific alkaline phosphatase which has shown significant improvements in morbidity and mortality in patients with perinatal and infantile hypophosphatasia. Subsequent research has also shown improvements in morbidity for patients with childhood hypophosphatasia as measured by improvement in rickets, growth, strength, mobility, and quality of life. This enzyme replacement therapy has generally been well-tolerated, with most adverse reactions being mild-to-moderate in nature. The author shares their approach to decisions on commencement of ERT based from experience of managing approximately fifteen patients across the age spectrum. This approach focuses on assessing the severity of five key manifestations of childhood HPP: decreased mobility, pain, rickets, deficits of growth, and fractures.

Background: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase. It is characterized by defective bone mineralization associated with low alkaline phosphatase activity. Clinical features of pediatric HPP are highly variable, and can include premature loss of teeth, musculoskeletal problems, and impaired mobility. The effects of pediatric HPP on sleep, mood, regulation of attention and behavior, and other aspects of behavioral health have not been comprehensively studied.Methods: Parents of 30 children with HPP (14 females, 16 males) between the ages of 3 and 16 years (mean age = 8.0 years) enrolled in this cross-sectional survey-based study. Molecular genetic and biochemical testing as well as clinical records were reviewed to verify diagnosis of HPP. The cohort included 15 patients with a more clinically severe presentation of HPP who had received treatment with enzyme replacement therapy (asfotase alfa) and 15 children with less severe HPP who were treatment-naïve. Parents provided information regarding psychopathological comorbidity, emotional and behavioral well-being, and quality of life.Results: Clinically significant behavioral health challenges were evident in 67% of children with HPP. The most common behavioral findings included sleep disturbance and symptoms of attention deficit hyperactivity disorder (ADHD), each of which were observed ≥ 50% of individuals. Sleep disturbance, pain interference, poor behavioral regulation, and mood/anxiety symptoms were associated with reduced physical and psychosocial quality of life. Behavioral concerns were evident among children with HPP receiving asfotase alfa treatment as well as among children with clinically less severe disease who had not initiated therapy. Although most children in the cohort (77%) had age-typical development of adaptive skills, emotional and behavioral challenges were associated with weaker adaptive function.Conclusions: Children with HPP are at increased risk for ADHD symptoms and other behavioral health challenges. There is likely an under-recognition of these findings in clinical practice. [ABSTRACT FROM AUTHOR]

Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases. [ABSTRACT FROM AUTHOR]

A 24-year old man was referred to the Erasmus MC Bone Center because of an asymptomatic increasing skull defect of the left parietal bone. The defect was first noticed at the age of six, and gradually increased over the years. His medical history was unremarkable, without any known trauma and a negative family history for bone diseases. Laboratory tests showed a low vitamin D level without other abnormalities. Particularly, there was no increase in markers of inflammation or bone turnover. CT-scans of the skull showed an osteolytic region of the parietal skull bone, with a two-centimeter increase in diameter over 9 years. Contrast enhanced MRI showed lymphangiogenic invasion, which was compatible with our suspicion of Gorham-Stout disease. The patient was referred to the neurosurgeon for treatment with a bone graft while considering additional drug treatment. Gorham-Stout or vanishing bone disease is a rare entity characterized by progressive osteolysis with lymphangiogenic bone invasion. Although already reported in 1838, currently the diagnosis and treatment of Gorham-Stout disease is still challenging. The underlying pathophysiology is not clarified yet and several theories exist. The disease usually affects persons younger than 40 years and the majority present with bone disease of the maxillofacial region, the upper extremities or the torso. The clinical presentation includes most frequently pain, swelling, and functional impairment of the affected region, but the disease can also be asymptomatic. Laboratory investigations are usually normal, and diagnosis is based upon imaging and sometimes pathology examination of affected bone tissue. Treatment is experimental and there is no general consensus about the best option due to lack of randomized controlled trials. Case reports showed patients treated with bisphosphonates, interferon-alpha, anti-VEGF therapy, mTOR inhibitors, and radiotherapy. There are some reports of surgery with prosthetic or bone grafts but no long-term follow-up data exist. This paper describes a unique case of Gorham-Stout disease of the parietal skull bone and discusses the current state of knowledge about this rare bone disease.

Abstract Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility. Using data from a large cohort of individuals with OI from the Osteogenesis Imperfecta Foundation's linked clinical research centers, we examined the association between exposure to bisphosphonate (BPN) treatment (past or present) and lumbar spine (LS) areal bone mineral density (aBMD), fractures, scoliosis, and mobility. From 466 individuals, we obtained 1394 participant‐age LS aBMD data points. Though all OI subtypes were examined, primary analyses were restricted to type I OI (OI‐1). Using linear regression, we constructed expected OI‐1 LS aBMD‐for‐age curves from the data from individuals who had never received BPN. LS aBMD in those who had been exposed to BPN was then compared with the computed expected aBMD. BPN exposure in preadolescent years (age 2 years correlated with LS aBMD in preadolescent individuals. BPN exposure also had a significant association with non‐aBMD clinical outcome variables. Logistic regression modeling predicted that with BPN exposure, a 1‐year increase in age would be associated with an 8.2% decrease in fracture probability for preadolescent individuals with OI‐1, compared with no decrease in individuals who had never received any BPN (p

A 24-year old man was referred to the Erasmus MC Bone Center because of an asymptomatic increasing skull defect of the left parietal bone. The defect was first noticed at the age of six, and gradually increased over the years. His medical history was unremarkable, without any known trauma and a negative family history for bone diseases. Laboratory tests showed a low vitamin D level without other abnormalities. Particularly, there was no increase in markers of inflammation or bone turnover. CT-scans of the skull showed an osteolytic region of the parietal skull bone, with a two-centimeter increase in diameter over 9 years. Contrast enhanced MRI showed lymphangiogenic invasion, which was compatible with our suspicion of Gorham-Stout disease. The patient was referred to the neurosurgeon for treatment with a bone graft while considering additional drug treatment. Gorham-Stout or vanishing bone disease is a rare entity characterized by progressive osteolysis with lymphangiogenic bone invasion. Although already reported in 1838, currently the diagnosis and treatment of Gorham-Stout disease is still challenging. The underlying pathophysiology is not clarified yet and several theories exist. The disease usually affects persons younger than 40 years and the majority present with bone disease of the maxillofacial region, the upper extremities or the torso. The clinical presentation includes most frequently pain, swelling, and functional impairment of the affected region, but the disease can also be asymptomatic. Laboratory investigations are usually normal, and diagnosis is based upon imaging and sometimes pathology examination of affected bone tissue. Treatment is experimental and there is no general consensus about the best option due to lack of randomized controlled trials. Case reports showed patients treated with bisphosphonates, interferon-alpha, anti-VEGF therapy, mTOR inhibitors, and radiotherapy. There are some reports of surgery with prosthetic or bone grafts but no long-term follow-up data exist. This paper describes a unique case of Gorham-Stout disease of the parietal skull bone and discusses the current state of knowledge about this rare bone disease. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a hereditary musculoskeletal disorder characterized by low serum alkaline phosphatase (ALP) activity leading to poor bone mineralization. On a micro-morphological level, this may not only be reflected by an enrichment of osteoid but also a degradation of bone quality. Asfotase alfa is an enzyme replacement therapy that was recently demonstrated to improve bone mineralization as well as clinical status (e.g. growth, muscle strength and quality of life). However, the underlying changes of bone quality parameters on asfotase alfa treatment are currently not known. In the present study, we report a 24-year-old woman with genetically confirmed infantile-onset HPP and recurrent fractures. While the initiated asfotase alfa treatment was followed by rapid clinical improvements (i.e., disappearance of bone marrow edema, increase of muscle strength), the BMD assessed by DXA at the hip and spine increased moderately at two years follow-up. A detailed skeletal assessment using high-resolution peripheral quantitative computed tomography (HR-pQCT) and a high-resolution analysis of two consecutive iliac crest bone biopsies revealed only minor improvements of bone microarchitecture but a remarkable reduction of osteoid parameters. Furthermore, the high mineralization heterogeneity at baseline assessed by quantitative backscattered electron imaging (qBEI) decreased after 2 year of asfotase alfa treatment. Finally, we found an increase in mineral maturation reflected by higher mineral-to-matrix and carbonate-to-phosphate ratios using Fourier transform infrared spectroscopy (FTIR) imaging as well as increased local mechanical properties using reference point indentation (RPI). Taken together, our findings provide evidence for an improvement of bone quality indices beyond the mere reduction of osteoid indices and thereby contribute to the understanding of fracture risk reduction in HPP patients on asfotase alfa treatment. • Asfotase alfa treatment resulted in rapid reduction of bone marrow edema in an adult HPP patient • A high-resolution assessment of bone quality in consecutive iliac crest biopsies before and during treatment was performed • Strong osteoid reduction (histology) but only minor improvements in bone microstructure (HR-pQCT) were observed • qBEI, FTIR and RPI revealed increase of matrix mineralization, other bone quality parameters and local mechanical properties [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a genetic disorder that is usually caused by disturbed production of collagen type I. Depending on its severity in the patient, this disorder may create difficulties and challenges for the dental practitioner. The goal of this article is to provide guidelines based on scientific evidence found in the current literature for practitioners who are or will be involved in the care of these patients. A prudent approach is recommended, as individuals affected by OI present with specific dentoalveolar problems that may prove very difficult to address. Recommended treatments for damaged/decayed teeth in the primary dentition are full-coverage restorations, including stainless steel crowns or zirconia crowns. Full-coverage restorations are also recommended in the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can also be performed, but not immediately before or after intravenous bisphosphonate infusions. Clear aligners are a promising option for orthodontic treatment. In severe OI types, such as III or IV, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present. Given the great variations in the severity of OI and the limited quantity of information available, the best treatment option relies heavily on the practitioner’s preliminary examination and judgment. A multidisciplinary team approach is encouraged and favored in more severe cases, in order to optimize diagnosis and treatment.

Background: Proteus syndrome is a rare developmental disorder of unknown aetiology. It is a disorder characterized by postnatal overgrowth affecting multiple tissues. Proteus syndrome is most frequently manifested in skeletal changes. As manifestations of Proteus syndrome are highly variable, and many are found in other overgrowth syndromes, and due to inconsistent application of diagnostic criteria, the literature has more reports of patients misdiagnosed than correctly diagnosed. The purpose of this study is to report the clinical and radiographic patterns of affection of the musculoskeletal system in Proteus syndrome in the light of the proposed diagnostic criteria and cases reported in the literature. Methods: The clinical and radiographic musculoskeletal characteristics of a child with Proteus syndrome are illustrated along with a literature update. The orthopaedic manifestations in our patient are correlated to cases and proposed diagnostic criteria reported in the literature. Results: The study of the presented case and review of available literature show that there tends to be a highly characteristic pattern of skeletal abnormalities in Proteus syndrome. Conclusion: The rarity of Proteus syndrome and the variability of signs make the diagnosis challenging. Clinical and radiographic examinations are important contributors to the diagnosis. The clinical utility of the reported cases is significantly dependent on consistent application of diagnostic criteria that augment diagnostic accuracy. The present case reinforces the need for supplementary musculoskeletal imaging modalities to be implemented in the diagnosis of Proteus syndrome.

Paget's disease of bone (PDB) is a focal disorder of skeletal remodeling leading to alteration of bony structures and properties, uncommonly reported in people under the age of 40 years, particularly in the Southeast Asia region. In the literature, PDB has been well reported in regions of Europe, in contrast to Asia where there has been limited records of prevalence of PDM especially in the younger age population. Here, we report a 21-year-old male patient presenting with an advanced disease with complaints of auditory impairment, bone pain, and neurological signs due to compression of the interverbal disc developed progressively over two months, having an elevated serum alkaline phosphatase level of 601 IU/L. The patient was administered zoledronic acid that brought significant improvement in his health. We aim to signify the advanced presentation of PDB in our region to create awareness about the condition among physicians and aid in the prompt diagnosis and prevention of the most dreaded complications of the disease, such as osteosarcoma, secondary osteoarthritis, and fractures., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Rizvi et al.)

The article offers a study that examine the health concerns with osteogenesis imperfecta (OI). Topics discussed include OI is rare genetic disorder that affects collagen protein leading to brittle bones, mentions the role of OI International Conference in Oslo that focuses on the Brittle Bone Disease Consortium (BBDC), and information on the primary concerns like breathing, hearing, and the effects of aging.

Purpose of Review: The goal of this review is to highlight some of the considerations involved in creating animal models to study rare bone diseases and then to compare and contrast approaches to creating such models, focusing on the advantages and novel opportunities offered by the CRISPR-Cas system.Recent Findings: Gene editing after creation of double-stranded breaks in chromosomal DNA is increasingly being used to modify animal genomes. Multiple tools can be used to create such breaks, with the newest ones being based on the bacterial adaptive immune system known as CRISPR/Cas.Summary: Advances in gene editing have increased the ease and speed, while reducing the cost, of creating novel animal models of disease. Gene editing has also expanded the number of animal species in which genetic modification can be performed. These changes have significantly increased the options for investigators seeking to model rare bone diseases in animals. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a genetic disorder that is usually caused by disturbed production of collagen type I. Depending on its severity in the patient, this disorder may create difficulties and challenges for the dental practitioner. The goal of this article is to provide guidelines based on scientific evidence found in the current literature for practitioners who are or will be involved in the care of these patients. A prudent approach is recommended, as individuals affected by OI present with specific dentoalveolar problems that may prove very difficult to address. Recommended treatments for damaged/decayed teeth in the primary dentition are full-coverage restorations, including stainless steel crowns or zirconia crowns. Full-coverage restorations are also recommended in the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can also be performed, but not immediately before or after intravenous bisphosphonate infusions. Clear aligners are a promising option for orthodontic treatment. In severe OI types, such as III or IV, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present. Given the great variations in the severity of OI and the limited quantity of information available, the best treatment option relies heavily on the practitioner's preliminary examination and judgment. A multidisciplinary team approach is encouraged and favored in more severe cases, in order to optimize diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Reference Centers and Rare Disease Health Networks aim to improve the management of patients with rare diseases. The French reference center for Fibrous Dysplasia was certified in 2006. The objective of our study was to assess the effectiveness of our reference center since its constitution. In a retrospective cohort study, we compared the activity of our center, including the time elapsed between access to the center and the diagnostic delay of patients with Fibrous Dysplasia between two periods, 1994–2006 (before certification) and 2007–2019 (after certification). Data were extracted from patients' records (Easily®). Wilcoxon and Fisher tests were performed, using R®. Our cohort included 527 patients with Fibrous Dysplasia/Mc Cune Albright syndrome. The activity of the Fibrous Dysplasia center increased from 139 patients in the first period (1994–2006) to an additional 388 patients for the second period (2007–2019). Mean time elapsed to diagnosis of Fibrous Dysplasia was 1.5 years before 2007 and 1.9 years after 2007 (p = 0.12). Diagnosis was made before referral in over 80% of patients. There was a non-significant decrease in the number of patients with delayed diagnosis: 37 patients (44%) in the first period had a diagnostic delay and 94 patients (33%) in the second period (p = 0.07). Patients were referred to our center on average 6.8 years (before 2007) and 7.9 years (after 2007) after their diagnosis (p = 0.77). Healthcare organization with reference centers significantly impacted the management of patients with Fibrous Dysplasia/Mc Cune Albright syndrome, with a substantial increase in the activity of our center, that roughly tripled since certification. This healthcare organization was also associated with a trend toward decreasing diagnostic delay. However, diagnostic delay affected more than a third of patients and the time to access to the center remained extended (≈7–8 years after diagnosis). The current challenge lies in informing primary care providers and patients about education to rare diseases and existence of reference centers for earlier and more effective specialized management. • Reference Centers aim to improve the management of patients with rare diseases, but we do not know their impact on care. • This study assessed the value of the French reference center for Fibrous Dysplasia. • This study highlighted the key role of GP in diagnosis and referral to reference centers. • This study highlighted the delay in referral as a critical barrier to improved care. [ABSTRACT FROM AUTHOR]

Summary: Camurati-Engelmann (CE) is a very rare disease affecting one in every million persons worldwide. It is characterized by an enlargement of long bones. We aimed to assess bone characteristics in three siblings with different tools. Even if there was an excess of bone density, quality seemed to be deteriorated. Introduction: CE disease is a rare monogenic disorder affecting approximately one in every million persons worldwide. It is mainly characterized by a progressive hyperostosis of the periosteum and endosteum of the diaphysis of long bones. Limited data are available about bone characteristics in these patients. In three siblings with CE disease, we aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) by dual-energy X-ray absorptiometry (DXA) and material characteristics at tissue level using bone impact reference point indentation. Methods: Clinical data were collected and a general laboratory workup was performed. At the lumbar spine and hip, BMD and TBS were measured using DXA imaging. Bone material strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Results: All three cases had densitometric values consistent with high bone mass (sum of Z-score at the lumbar spine and hip > 4). Hip BMD was extremely high in all three siblings at both total hip and femoral neck, while at the lumbar spine, two of them had normal values but the third again had very high BMD. TBS values were in the normal range. In contrast, BMSi measurements were at low or very low levels, compared with normal controls. Conclusion: Despite strikingly increased BMD and normal microarchitecture, BMSi is affected in patients with CE. Microindentation could be an appropriate tool for assessing bone fragility in these patients. Bone disease in this group of patients requires further study to better understand the underlying regulatory mechanisms and their alterations. [ABSTRACT FROM AUTHOR]

A working group on rare bone diseases was held in Atlanta, Georgia as part of the 2016 annual meeting of the American Society for Bone and Mineral Research. The meeting was organized by Matthew Drake. Given recent advances in our understanding of fibrodysplasia ossificans progressiva (FOP), the initial portion of the program was devoted to basic, translational, and clinical aspects of FOP. The remainder of the program was divided into updates on an array of rare bone diseases as detailed below. In total, there were more than 120 scientists from academia and industry in attendance. [ABSTRACT FROM AUTHOR]

The medical treatment of osteopetrosis is an ongoing clinical problem. There are no effective and safer therapeutic approaches for all its forms. However, recent discoveries concerning the etiology and the pathogenesis of osteopetrosis, the development of dedicated cellular and animal models, and the advent of new technologies are paving the way for the development of targeted and safer therapies for both lethal and milder osteopetrosis. This review summarizes the huge effort and successes made by researchers to identify and develop new experimental approaches with this objective, such as the use of non-genotoxic myeloablation, gene correction of inducible Pluripotent Stem Cells (iPSCs), lentiviral-based gene therapy, protein replacement, prenatal treatment, osteoclast precursors transplantation and RNA Interference. • The medical treatment of osteopetrosis is an ongoing clinical problem • There are no effective and safer therapeutic approaches for all osteopetrosis forms • We reviewed the most promising experimental therapies for osteopetrosis [ABSTRACT FROM AUTHOR]