Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes.

Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH (Fgfr3ach mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in Fgfr3ach mice. Meclozine (2 mg/kg/d) was orally administered to Fgfr3ach mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female Fgfr3ach mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of Fgfr3ach mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in Fgfr3ach mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in Fgfr3ach mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of Fgfr3ach mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.

Quality of life in adult patients with developmental dysplasia of the hip who were treated for hip dislocation during childhood.

Developmental dysplasia of the hip (DDH) can lead to premature loss of hip function if not properly treated; however, few studies have focused on the long-term outcomes of DDH. We conducted a survey of health-related quality of life in adult patients with DDH who were treated for hip dislocation during childhood. We sent a questionnaire to 287 adult patients with DDH who were treated for hip dislocation during childhood in our institutions. We examined patient demographics, disease-specific medical history, and health-related quality of life using the short form-36. Physical component summary (PCS), mental component summary (MCS) and role/social component summary (RCS) were compared between the patients and Japanese standard values. Sixty-eight patients were evaluated after exclusion. The overall mean PCS, MCS and RCS scores of the patients were comparable to the standard values. The PCS was maintained until the age of 50, but it was significantly decreased in 10 patients over 50 years old. In addition, PCS was significantly lower in patients who underwent open reduction than in those who were conservatively reduced. The MCS and RCS of the patients did not differ from the standard values in each age and treatment group. Additionally, the PCS, MCS and RCS did not differ according to bilaterality, age at diagnosis, or requirement for additional surgeries. Physical quality of life was maintained until the age of 50 but rapidly declined thereafter in patients with DDH, especially in those who required open reduction during childhood.

Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia.

Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.

Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model.

BACKGROUND: Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice). METHODS: The OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine). RESULTS: BMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization. CONCLUSION: Upregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.

Meclozine ameliorates bone mineralization and growth plate structure in a mouse model of X­linked hypophosphatemia.

X-linked hypophosphatemic rickets (XLH) is characterized by hypo-mineralization of the bone due to hypophosphatemia. XLH is caused by abnormally high levels of fibroblast growth factor 23, which trigger renal phosphate wasting. Activated fibroblast growth factor receptor 3 (FGFR3) signaling is considered to be involved in XLH pathology. Our previous study revealed that meclozine attenuated FGFR3 signaling and promoted longitudinal bone growth in an achondroplasia mouse model. The present study aimed to examine whether meclozine affected the bone phenotype in a mouse model of XLH [X-linked hypophosphatemic (Hyp) mice]. Meclozine was administered orally to 7-day-old Hyp mice for 10 days, after which the mice were subjected to blood sampling and histological analyses of the first coccygeal vertebra, femur and tibia. Villanueva Goldner staining was used to assess bone mineralization, hematoxylin and eosin staining was used to determine the growth plate structure and tartrate-resistant acid phosphatase staining was used to measure osteoclast activity. The osteoid volume/bone volume of cortical bone was lower in meclozine-treated Hyp mice compared with untreated Hyp mice. Meclozine treatment improved the abnormally thick hypertrophic zone of the growth plate and ameliorated the downregulation of osteoclast surface/bone surface in Hyp mice. However, meclozine had only a marginal effect on mineralization in the trabecular bone and on calcium and phosphate plasma levels. A 10-day-tratment with meclozine partially ameliorated bone mineralization in Hyp mice; hence, meclozine could alleviate XLH symptoms.

Guided growth for coronal lower limb deformities in skeletal dysplasia.

Coronal angular deformities of the lower limbs are common in young children with skeletal dysplasia . The guided growth technique has been applied to correct deformities in children, but there are few comprehensive reports on the effectiveness of the procedure in skeletal dysplasia. We reviewed 44 limbs of 22 patients with various types of skeletal dysplasias who underwent guided growth surgery. Fifteen varus and 29 valgus limbs were treated with 102 epiphysiodesis. The average age at surgery, at implant removal, and at the latest examination was 10.4 ± 3.6 years, 11.8 ± 3.7 years and 14.1 ± 4.4 years, respectively. The mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (mMPTA), lateral distal tibial angle (mLDTA) and mechanical axis deviation (MAD) were measured from standing anteroposterior radiographs of both lower limbs. The mLDTA, mMPTA and MAD were successfully improved after surgery. Moderate or severe deformities were observed in 100% of the varus and 83% of the valgus limbs preoperatively, whereas only 14% of the varus and 20% of the valgus limbs had residual deformities at the latest examination. Correction of deformities was limited in some older children. Fifteen limbs (34%) required repeated implantations due to recurrence or inverted deformity. The guided growth surgery is effective in correcting coronal angular deformities in children with skeletal dysplasia with a limited risk of complications. The timing of surgery and implant removal is critical in obtaining satisfactory correction and preventing recurrence or inverted deformities.

Efficacy of soluble lansoprazole-impregnated beta-tricalcium phosphate for bone regeneration.

The proton pump inhibitor lansoprazole has been previously identified to upregulate the expression and transcriptional activity of runt-related transcription factor 2 (Runx2) that promotes lineage commitment and differentiation of osteoprogenitor cells. We could not elicit the expected efficacy of insoluble lansoprazole in enhancing osteogenesis when combined with beta-tricalcium phosphate (ß-TCP) bone substitutes. This study aimed to evaluate the effects of soluble lansoprazole on in vitro osteoblastogenesis and new bone formation in vivo. Commercially available human mesenchymal stem cells or patient-derived bone marrow-derived stromal cells were treated with 20 µM of soluble lansoprazole at the beginning of osteogenic induction. Soluble lansoprazole-impregnated ß-TCP materials were embedded in the cortical bone defect model of rabbits. Rabbits were sacrificed four weeks postoperatively and undecalcified bone specimens were prepared for evaluation of intra-material new bone formation. Only a 1-day treatment with soluble lansoprazole facilitated osteoblastic differentiation and matrix calcium deposition when added to undifferentiated human mesenchymal stromal cells at the beginning of the osteogenic differentiation. Soluble lansoprazole dose-dependently accelerated intra-material new bone formation when being impregnated with porous ß-TCP artificial bones. Local use of soluble lansoprazole can be applicable for fracture and bone defect repair when combined with porous ß-TCP scaffolds.

Two children with hypophosphatasia with a heterozygous c.1559delT variant in the ALPL gene, the most common variant in Japanese populations.

Hypophosphatasia (HPP), a genetic disorder characterized by decreased tissue-nonspecific alkaline phosphatase (TNSALP) activity, is caused by loss-of-function mutations in the ALPL gene, which encodes TNSALP. The most frequent pathogenic variant in Japanese patients with HPP is a frameshift mutation in the ALPL gene, c.1559delT, and its carrier frequency is reported to be one in 480 in the Japanese population. We report the cases of two Japanese children with HPP who had a heterozygous c.1559delT variant in the ALPL gene. One case (involving a neonate) exhibited respiratory insufficiency associated with vitamin B6 dependent convulsions, significant defective mineralization similar to the severe form of HPP, and extremely low ALP activity. Enzyme replacement therapy (ERT) using asfotase alfa promptly improved her respiratory insufficiency, bone mineralization, and maintained her motor development during infancy. The second case involved a 10-year-old boy who demonstrated diffuse musculoskeletal pain and weakness that progressively disturbed mobility. Although he showed no bony lesions, the clinical symptoms and biochemical abnormalities were compatible with childhood HPP. ERT successfully relieved the severe generalized pain and significantly improved motor function.

Gain-of-Function of FGFR3 Accelerates Bone Repair Following Ischemic Osteonecrosis in Juvenile Mice.

Bone collapse, bone deformity, and a long treatment period are major clinical problems associated with juvenile ischemic osteonecrosis (JIO). Accelerating the process of bone repair in JIO is expected to shorten the treatment duration and better maintain morphology. We previously indicated that both bone formation and resorption were accelerated following distraction osteogenesis-mediated limb lengthening in genetically engineered mutant mice with a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) gene (i.e., Fgfr3 mice). The purpose of this study was to investigate the role of FGFR3 in the bone repair process following surgically induced ischemic osteonecrosis in the mutant mice. Epiphyseal deformity was less in the Fgfr3 mice compared to the wild-type mice at 6 weeks following ischemic osteonecrosis in skeletally immature age. Assessment of the morphology by micro-computed tomography (CT) revealed that the trabecular bone volume was increased in the Fgfr3 mice. Dynamic bone histomorphometry revealed increased rates of bone formation and mineral apposition in the Fgfr3 mice at 4 weeks post-surgery. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells rapidly increased, and the numbers of TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells rapidly decreased in the Fgfr3 mice. Vascular endothelial growth factor (VEGF) expression was increased at the earlier phase post-surgery in the Fgfr3 mice. The activation of FGFR3 signaling shortens the time needed for bone repair after ischemic osteonecrosis by accelerating revascularization, bone resorption, and new bone formation. Our findings are clinically relevant as a new potential strategy for the treatment of JIO.

Prognostic factors for mobility in children with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility. Although the disease severity is known to influence the ability to walk, little is known about how children with severe OI can achieve practical ambulation (PA). This study aimed to determine the early predictors of future mobility in children with OI. Thirty OI patients with an average age of 12.1 years were classified into the PA group (22 patients) and nonambulator group (NA group: 8 patients) on the basis of the Hoffer classification. Various clinical parameters related to mobility were compared between the PA and NA groups. Therapeutic interventions were also compared between the 2 groups. The mean age at diagnosis and initial fracture were significantly lower in the NA group than in the PA group. The height was significantly smaller in the NA group than in the PA group at all ages examined (at birth, 3 years, and 6 years). The number of patients with respiratory failure was significantly higher in the NA group than in the PA group. The age at initial corrective osteotomy of the lower extremities in the PA group was significantly lower than that in the NA group, although there was no significant difference in the disease severity in infancy between the groups. Height during infancy, age at initial fracture, and neonatal respiratory status could be prognostic factors for mobility in OI. Surgical interventions at an early age may influence walking ability in children with moderate OI.

Appropriate Surgical Timing of Salter Innominate Osteotomy for Residual Acetabular Dysplasia in Children.

BACKGROUND: Salter innominate osteotomy (SIO) provides favorable results for treating residual acetabular dysplasia in young children. In this study, we examined the midterm results of SIO according to the age at surgery to determine the optimal timing of this procedure. METHODS: We retrospectively examined 50 hips of 42 patients (8 boys and 34 girls) with acetabular dysplasia who underwent SIO and were followed up until skeletal maturity. The center-edge angle (CEA) was measured based on the anteroposterior radiographs of the hip obtained before surgery, 5 weeks after surgery, and at the latest follow-up. Severin classification was evaluated at the latest follow-up. Patients were categorized into 3 groups according to age at surgery: younger than 7 years of age (group A), 7 to 8 years of age (group B), and 9 years of age or older (group C). RESULTS: The mean preoperative CEA level of 0.9 degrees improved to 17.1 degrees postoperatively, which was increased to 28.1 degrees at the latest examination. Overall, 45 hips (90%) were classified as Severin I or II, with 96% in group A, 94% in group B, and 57% in group C. In group C, postoperative acetabular coverage was similar to that in the other groups (16.6 degrees in group A, 14.8 degrees in group B, and 18.1 degrees in group C), although the final outcome was unsatisfactory. The average improvement in CEA from postoperative to skeletal maturity was significantly smaller in group C than in the other groups (12.7 degrees in group A, 11.3 degrees in group B, and 3.0 degrees in group C). CONCLUSIONS: SIO showed favorable outcomes with satisfactory acetabular coverage at skeletal maturity. However, satisfactory acetabular coverage could not be obtained in some older patients because of limited postoperative remodeling capacity and smaller secondary improvement of CEA. We recommend that SIO should be performed in patients aged 8 years or younger. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Predictive ability of inflammatory markers and laboratory parameters in Legg-Calvé-Perthes disease: A single-center retrospective comparative study.

ABSTRACT: Legg-Calvé-Perthes disease (LCPD) presents with chronic nature of inflammation, characterized by prolonged synovitis. So far, no single blood marker has been identified to guide clinicians in estimating the severity and prognosis. Blood neutrophil to lymphocyte ratio (NLR) or systemic immune inflammation index (SII) is a simple indicator of subclinical inflammation. This study aims to examine the predictive ability of NLR, SII, and common laboratory parameters for estimating the severity of LCPD. The pre-operative laboratory findings at the time of osteotomy and implant removal in patients with unilateral LCPD who had been treated with the Salter innominate osteotomy and followed up until skeletal maturity as well as those of age-matched control patients with idiopathic noninflammatory conditions were analyzed. The datasets of 26 or 38 LCPD patients at the time of osteotomy or implant removal, respectively, and those of 20 control patients were available for analysis. At the time of osteotomy, compared to the control group, a significantly higher mean NLR or SII and a significantly lower mean alkaline phosphatase value were observed in the LCPD group. The alkaline phosphatase levels of patients with the modified lateral pillar (LP) group-A hips were significantly lower than those with the non-LP-A hips, whereas no significant differences were observed in any of the parameters between patients with favorable LP-A or -B hips and those with unfavorable LP-B|C border or -C hips. In agreement with the conventional opinion, it may be difficult to predict a meaningful prognosis of LCPD with the use of inflammatory markers or common laboratory parameters obtained in the initial stage of the disease.

Bypass of Epiphyseal Fragmentation Following Early Salter Innominate Osteotomy and Its Clinical Relevance in Legg-Calvé-Perthes Disease.

BACKGROUND: It has been demonstrated that early femoral varus osteotomy (FVO) produces a greater probability of skipping or interruption of epiphyseal fragmentation, thereby shortening the length of fragmentation stage for hips in the active stage of Legg-Calvé-Perthes disease. This "bypassing phenomenon" is thought to effect less disease severity or outcome, whereas it remains to be elucidated whether this phenomenon is specific to early FVO. We sought to investigate the presence and characteristics of the "bypassing phenomenon" following pelvic osteotomy performed in the avascular necrosis or early fragmentation stage as well as its correlation with disease severity and radiographic outcomes. METHODS: A retrospective review of data was conducted for 79 patients with unilateral Legg-Calvé-Perthes disease who had been diagnosed from 1987 to 2015, undergone the Salter innominate osteotomy (SIO) during the stage of avascular necrosis or in the early part of the fragmentation stage between 6.0 and 12.0 years of age, and followed up until skeletal maturity. Epiphyseal fragmentation was classified into 4 patterns according to a previous study. We compared lateral pillar groups and Stulberg grades between patients with and without bypass of the fragmentation stage. RESULTS: The mean age at surgery and follow-up period was 8.1 and 7.9 years, respectively. Sixty hips were in the Waldenström stage I and 19 hips in stage IIa at the surgery. In hips receiving SIO during stage I, the mean duration of the fragmentation stage was 276 days. The fragmentation pattern was typical for 40 hips, abortive for 17 hips, and atypical with horizontal fissure for 3 hips. Patients whose fragmentation was aborted experienced significantly less severe lateral pillar involvement and more favorable Stulberg outcomes at skeletal maturity. CONCLUSIONS: Incomplete bypass of epiphyseal fragmentation was observed in 28% of patients following early SIO performed in the avascular necrosis stage. In contrast to FVO, no patient bypassed fragmentation completely. Patients with incomplete bypass had a significantly higher proportion of less severe hips and a significantly greater probability of being associated with favorable radiographic outcomes compared with those without bypass. LEVEL OF EVIDENCE: Level IV-therapeutic study.

Disease-specific complications and multidisciplinary interventions in achondroplasia.

Achondroplasia (ACH) is the most common skeletal dysplasia and characterized by a disproportionate short stature, macrocephaly with frontal bossing, exaggerated lumbar lordosis, and trident hands. It is induced by activated mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In addition to short stature, patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. Several investigational drugs that modulate abnormal FGFR3 signaling have recently emerged, vosoritide being the most developed. This review presents the different disease-specific complications of ACH occurring in neonates, infants, childhood, adolescent, and adults and reports the current multidisciplinary interventions for these various complications. Moreover, we propose treatment strategies for children with ACH from the perspective of quality of life in adulthood.

Inconvenience and adaptation in Japanese adult achondroplasia and hypochondroplasia: A cross-sectional study.

The health-related quality of life is reduced in patients with achondroplasia (ACH) and hypochondroplasia (HCH); however, the detailed inconveniences in the daily living and individual adaptations have not been elucidated. This study aimed to evaluate the inconvenience and adaptation in patients with ACH/HCH. A cross-sectional study was conducted in patients with ACH/HCH aged 20 yr or older. Questionnaires were sent to 567 patients (described 86) with a medical history at the co-authors' institutions or who were registered at the patients' association with ACH in Japan. The questionnaire included a free description format for the inconveniences and adaptations in daily living; a content analysis was performed. The recorded inconveniences included 148 physical, 84 mental, and 52 social problems. Patients who underwent spine surgery had significantly more recorded physical problems than those who did not (p < 0.05). Pain and numbness were significantly higher in patients aged ≥ 50 yr (p < 0.05). The 160 and 1 adaptations were for physical and social problems, respectively. No patient adaptation was found for mental health problems. Individual adaptations by ACH/HCH patients can improve only some aspects of physical and social problems. Multilateral social support is needed to resolve patients' issues.

A cross-sectional nationwide survey of osteosclerotic skeletal dysplasias in Japan.

BACKGROUND: The osteosclerotic skeletal dysplasias (OSSDs) are a heterogeneous group of disorders characterized by systemic bone sclerosis. Little is known about OSSDs because of their rarity. We conducted a cross-sectional nationwide survey of OSSDs and examined the incidence, epidemiology, and therapeutic interventions on these disorders. METHODS: This study consisted of a two-step survey. The number of patients with OSSDs who had visited medical institutions between April 2017 and March 2018 was reported from a total of 341 facilities (1364 departments from pediatrics, orthopaedic surgery, neurosurgery, and otolaryngology in each facility) by the first questionnaire. In the secondary survey, their clinical features were assessed by collecting demographic data, diagnostic details, current status, family histories, therapeutic interventions, histories of bone fracture and osteomyelitis, severity assessed by the modified Rankin Scale (mRS) and recent lifestyle conditions of the patient by the EQ-5D. RESULTS: In the first survey, 51 facilities (56 departments) reported one or more OSSDs patients, including 50 patients with osteopetrosis and 57 patients of other OSSDs. Among 87 patients eligible for inclusion in the analysis in the secondary survey, we investigated detailed information on the 42 patients with osteopetrosis. The number of initial visits of osteopetrosis patients during the surveillance period was five per year, indicating that the estimated incidence of osteopetrosis seemed to be 0.6 per 100,000 live births. Eighty-six bone fractures were reported in 22 patients (52%), and interventions of pseudarthrosis were conducted in five patients. Nine patients (23%) showed significant disabilities with the mRS of grade 3 or higher. Neurological complications and severe anemia were the factors that deteriorate patients' quality of life. CONCLUSIONS: This is the first study to examine the detailed epidemiology of OSSDs in Japan. We demonstrated that the incidence of OSSDs is extremely rare. Bone fragility and delayed fracture healing seem to be important orthopaedic problems for patients with osteopetrosis.

Health-related Quality of Life in Adult Patients with Multiple Epiphyseal Dysplasia and Spondyloepiphyseal Dysplasia.

OBJECTIVES: Multiple epiphyseal dysplasia (MED) and spondyloepiphyseal dysplasia (SED) are skeletal dysplasias associated with premature osteoarthritis and short stature. Patients with SED often have spinal and ocular problems. Few reports have focused on the health-related quality of life (HRQoL) of patients with skeletal dysplasias associated with premature osteoarthritis. The purpose of this study was to evaluate the HRQoL of adult patients with MED and SED. METHODS: Questionnaires covering demographics, medical history (cataract, retinal detachment, and osteoarthritis), surgical history (osteotomy and arthroplasty), and the Short Form-36 (SF-36) health survey were sent to all patients with MED and SED with medical records at the investigators' institutions. Among the 27 patients who completed the questionnaire, patients aged 20 years or older were included in this cohort. RESULTS: The subjects were 18 affected individuals. The physical component summary score (PCS) was significantly lower in the MED and SED groups than in the normal population and tended to deteriorate with age. Conversely, there was a positive correlation between the mental component summary score and age. The role/social component summary score was not correlated with age. MED patients with osteoarthritis had a low PCS. PCS was particularly low in two SED patients with a medical history of cataract, whereas there was no association with a history of retinal detachment or osteoarthritis. CONCLUSIONS: The physical domain of HRQoL in MED and SED patients significantly deteriorated at a young age. Appropriate medical management of these skeletal dysplasias is required not only for orthopedic functions but also for ocular problems.

Asfotase alfa has a limited effect in improving the bowed limbs in perinatal benign hypophosphatasia: A case report.

Hypophosphatasia (HPP) is a rare skeletal dysplasia characterized by impaired bone mineralization, caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Enzyme replacement therapy (ERT) by administration of asfotase alfa was reported to improve the survival rate, bone mineralization, and short stature in the severe form of HPP. However, the effect of asfotase alfa in improving the skeletal phenotypes for the mild form of HPP has not been elucidated. We report a case with perinatal benign HPP who had compound heterozygous mutations of p.F327L and p.R30X in the TNSALP gene. No hypomineralization was seen in the radiographs from the neonatal period, but bowing of the femurs and ulnares bilaterally was persistent. ERT was administered during the age of 7.8 to 10.8 yr, although there was an interruption in the treatment for one year. The bowed femurs and ulnares were not improved by the treatment with asfotase alfa at the age of 10.8 yr. Bone mineral density of the lumbar spine was between -0.5 and -1.0 of the z-score, and the patient's height was about -2.0 SD during the treatment. Asfotase alfa might have a limited effect in improving the bowed limbs in perinatal benign hypophosphatasia.

Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish.

Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones.