Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation. Consequently, defective TMEM53 accelerates osteogenesis. Herein, an American boy is compound heterozygous for a novel deletion and a novel missense mutation within TMEM53. His vision and sensorineural hearing became impaired. Radiographic survey revealed diploic thickening of his skull, broad calvarial and facial bones, skeletal modeling errors, vertebral body flattening, wide ribs, and osteopenia of expanded bones. DXA areal bone density (gm/cm2) Z-scores were low. His optic, auditory, and spinal canals were narrow. Mineral metabolism was intact. Serum alkaline phosphatase and osteocalcin levels were normal yet CTX was high. Iliac crest histomorphometry documented accelerated bone formation. His acute vision loss briefly improved following prednisone administration, optic canal decompression, and optic nerve sheath fenestration, but then progressed despite further surgeries and zoledronate treatment aimed to suppress bone turnover. Next generation sequencing of genes associated with elevated skeletal mass, including from high bone turnover, did not suggest an etiology. Whole genome sequencing then revealed within TMEM53: i) a paternally transmitted 54-base deletion, which included the mRNA splice acceptor site for exon 2 as well as 31 bases of exonic sequence (c. 62-23_92del), and ii) a maternally transmitted missense variant (c.650C > T, p.Ser217Leu: NM_024587.4/NP_078863.2) which is extremely rare in gnomAD (frequency = 0.000036), replaces Ser217 highly conserved across species, and is scored as damaging by SIFT and Mutation Taster. We call this new osteopathy TMEM53 craniotubular dysplasia.

Background In the contemporary era, where science and technology know no boundaries, this in vivo study explores the impact of growth modulation therapy using Twin Block, Forsus Fatigue Resistant, and Clear Block appliances on alkaline phosphatase (ALP) levels in gingival crevicular fluid (GCF). Bone physiology involves modeling and remodeling, with orthodontics applying forces to teeth, influencing tissue reactivity and bone modeling. ALP, a marker of osteoblast function, plays a crucial role in bone growth. GCF reflects immunological and inflammatory responses during orthodontic force application, making it a valuable medium for studying ongoing metabolic processes related to bone turnover. Aim The study aims to comparatively analyze ALP levels in GCF during growth modulation therapy, assessing the efficacy of Twin Block, Forsus Fatigue Resistant, and Clear Block appliances. The research involves 30 experimental samples divided into three study groups and a control group. The samples are collected at various time intervals, and ALP levels are analyzed using a spectrophotometer. Statistical analysis includes paired and unpaired t-tests, one-way analysis of variance (ANOVA), and multiple comparisons. Results Results demonstrate a significant increase in ALP levels during the growth modulation therapy, indicating a positive correlation with bone remodeling. Twin Block appears to be the most effective appliance, exhibiting higher ALP activity compared to Clear Block and Forsus groups. Conclusion In conclusion, this study provides valuable insights into the biochemical responses during growth modulation therapy, emphasizing the potential of GCF analysis in understanding orthodontic treatment effects.

The impact of milk on bone health in rural preschoolers is under-researched. This study, through a clinical trial and a meta-analysis, finds that milk supplementation enhances forearm and calcaneus bone acquisition in children, supporting the benefits of daily milk consumption.
OBJECTIVE: This study evaluated the impact of dairy supplementation on bone acquisition in children\'s limbs through a cluster-randomized controlled trial and a meta-analysis.
METHODS: The trial involved 315 children (4-6 year) from Northwest China, randomized to receive either 390 ml of milk daily (n = 215) or 20-30 g of bread (n = 100) over 12 months. We primarily assessed bone mineral density (BMD) and content (BMC) changes at the limbs, alongside bone-related biomarkers, measured at baseline, the 6th and 12th months. The meta-analysis aggregated BMD or BMC changes in the forearm/legs/calcaneus from published randomized trials involving children aged 3-18 years supplemented with dairy foods (vs. control group).
RESULTS: Of 278 completed the trial, intention-to-treat analysis revealed significant increases in BMD (4.05% and 7.31%) and BMC (4.69% and 7.34%) in the left forearm at the 6th and 12th months in the milk group compared to controls (P < 0.001). The calcaneus showed notable improvements in BMD (2.01%) and BMC (1.87%) at 6 months but not at 12 months. Additionally, milk supplementation was associated with beneficial changes in bone resorption markers, parathyroid hormone (- 12.70%), insulin-like growth factor 1 (6.69%), and the calcium-to-phosphorus ratio (2.22%) (all P < 0.05). The meta-analysis, encompassing 894 children, indicated that dairy supplementation significantly increased BMD (SMD, 0.629; 95%CI: 0.275, 0.983) and BMC (SMD, 0.616; 95%CI: 0.380, 0.851) (P < 0.05) in the arms, but not in the legs (P > 0.05).
CONCLUSIONS: Milk supplementation significantly improves bone health in children\'s forearms, underscoring its potential as a strategic dietary intervention for bone development. Trial registration NCT05074836.

UNASSIGNED: Prolonged phenytoin (PHD) therapy in epileptics predisposes patients to deleterious effects on bone health causing osteoporosis; however, despite its known effect on wound healing, collagen and fibroblast proliferation, and osteogenic differentiation, its impact on fracture healing remains poorly researched, we, report two cases of early exuberant callus formation in long bone fractures in patients undergoing long-term PHD therapy.
UNASSIGNED: Two female patients with known seizure disorder on long-term PHD therapy experienced proximal humerus fractures after trivial trauma. Metabolic work-up revealed low serum calcium and Vitamin D3 levels with elevated ALP, serum osteocalcin, and iPTH. Despite planned surgery, both patients showed early exuberant callus formation post-trauma, leading to conservative management with successful outcomes.
UNASSIGNED: Regular bone health monitoring is crucial for patients on long-term antiepileptic therapy, especially PHD users, to enhance treatment outcomes and address potential complications. Although the influence of PHD on fracture healing is uncertain, the cases presented hint at a potential beneficial correlation, indicating a need for more research in this domain.

Patients with phenylketonuria (PKU) present signs of impaired executive functioning and bone health in adolescence and adulthood, depending in part on the success of therapy in childhood. Therefore, nine children with well-treated PKU (4-7 years old, 22.2% ♀, seven with a full set of data, two included into partial analysis) and 18 age-, gender- and season-matched controls were analyzed for differences in executive functioning and bone parameters in plasma. Plasma was analyzed with commercially available kits. Cognitive performance in tonic alertness, visuo-spatial working memory, inhibitory control and task switching was assessed by a task battery presented on a touch screen. Regarding cognition, only the performance in incongruent conditions in inhibitory control was significantly better in children with PKU than in controls. No further differences in cognitive tests were detected. Furthermore, no significant difference in the bone turnover markers osteocalcin, undercarboxylated osteocalcin and CTX were detected between children with PKU and controls, while children with PKU had a significantly higher vitamin D concentration (69.44 ± 12.83 nmol/L vs. 41.87 ± 15.99 nmol/L, p < 0.001) and trended towards lower parathyroid hormone concentrations than controls (48.27 ± 15.16 pg/mL vs. 70.61 ± 30.53 pg/mL, p = 0.066). In this small group of well-treated preschoolers with PKU, no impairments in cognitive performance and bone turnover were observed, while vitamin D supplementation of amino acid supplements seems to be sufficient to achieve good vitamin D status.

This study aimed to histologically evaluate the effects of XPEED® and SLA surface on the mineral apposition rate (MAR) at 3 and 5 weeks in titanium dental implants placed in human bone. In total, 17 titanium dental implants with XPEED® surface (n = 9) used as test and SLA surface (n = 8) used as control were included in this study. Each patient received four doses of tetracycline 500 mg at 12 h intervals 2 weeks prior to biopsy retrieval. Implant retrieval was performed, and retrieved biopsies were carefully treated for histomorphometric evaluation under epifluorescence microscopy. At 3 and 5 weeks, newly formed bone appeared in direct contact with both types of tested surfaces. At 3 weeks, the MAR value was, respectively, 2.0 (±0.18) μm/day for XPEED® implants and 1.5 (±0.10) μm/day for SLA implants (p = 0.017). At 5 weeks, lower MAR values for both XPEED® and SLA implants were noted, with 1.2 (±0.10) μm/day and 1.1 (±0.10) μm/day, respectively (p = 0.046). The overall evaluation by linear regression analysis for both time and implant surfaces showed a decreased osteoblast activity at 5 weeks compared to 3 weeks (p < 0.005). The results of the present study show that the bone apposition rate occurs faster around implants with XPEED® surface at 3 weeks and 5 weeks of healing. MAR values may support the use of implants with XPEED® surfaces in early loading protocols.

Lead (Pb) is a global contaminant associated with multiple adverse health effects. Humans are especially vulnerable during critical developmental stages. During pregnancy, exposure to Pb can occur through diet and release from maternal bones. Apolipoprotein E gene (APOE) variants (ɛ2, ɛ3, ɛ4 alleles) may influence sex steroid hormones, bone metabolism, and Pb kinetics. We examined the interplay among maternal APOE (mAPOE) genotypes, fetal sex, parity, and Pb in maternal and cord blood (mB-Pb, CB-Pb) using linear regression models. Our study involved 817 pregnant women and 772 newborns with measured adequate levels of zinc and selenium. We compared carriers of the ε2 and ε4 alleles to those with the ε3/ε3 genotype. The geometric means (range) of mB-Pb and CB-Pb were 11.1 (3.58-87.6) and 9.31 (1.82-47.0) ng/g, respectively. In cases with female fetuses, the maternal mAPOE ε2 allele was associated with higher, while the mAPOE ε4 allele was associated with lower mB-Pb and CB-Pb levels. Nulliparity increased the strength of the observed associations. These findings highlight the significance of mAPOE genetics, fetal sex, and parity in prenatal Pb kinetics. Notably, the maternal ε2 allele may increase the risk of Pb exposure.

OBJECTIVE: To evaluate comprehensive bone health among young Indian women, including bone mass, microarchitecture, and turnover, in relation to their non-alcoholic fatty liver disease (NAFLD) status.
METHODS: This cross-sectional study (May 2018-November 2019) recruited women with a history of gestational diabetes mellitus (GDM) and normoglycemia in their index pregnancy, who were at least 6 months postpartum. All participants underwent abdominal ultrasonography for determination of NAFLD status (grades 2 and 3: severe NAFLD) and transient elastography (FibroScan) for hepatic fibrosis (LSM >6 kPa). Bone mass was assessed by DXA, bone microarchitecture with trabecular bone score {TBS} (low TBS ≤ 1.310) and bone turnover with markers of bone formation (osteocalcin and P1NP), and resorption (CTX).
RESULTS: Bone mineral density (BMD) at femoral neck (p = 0.026) and total hip (p = 0.007) was significantly higher among women with NAFLD (n = 170) compared to those without (n = 124). There was no significant difference in bone turnover markers between the two groups. The presence of NAFLD [adjusted OR: 1.82 (1.07, 3.11)] was associated with low TBS, with a greater strength of association among women with severe NAFLD [adjusted OR: 2.97 (1.12, 7.88)]. However, these associations were attenuated and no longer significant after additionally adjusting for BMI. Women with NAFLD and hepatic fibrosis manifested significantly higher BMD at lumbar spine, femoral neck, and total hip (p < 0.001 for all) and significantly lower bone turnover markers (osteocalcin, p = 0.009 and CTX, p = 0.029), however, the association with low TBS was not observed.
CONCLUSIONS: Among young Indian women, NAFLD is associated with increased bone mass and impaired bone microarchitecture, and hepatic fibrosis with increased bone mass and reduced bone turnover.

Postmenopausal osteoporosis, marked by estrogen deficiency, is a major contributor to osteoporotic fractures, yet early prediction of fractures in this population remains challenging. Our goal was to explore the temporal changes in bone-specific inflammation, oxidative stress, bone turnover, and bone-matrix water, and their relationship with estrogen deficiency-induced modifications in bone structure and mechanical properties. Additionally, we sought to determine if emerging clinically translatable imaging techniques could capture early bone modifications prior to standard clinical imaging. Two-month-old female Sprague Dawley rats (n = 48) underwent ovariectomy (OVX, n = 24) or sham operations (n = 24). A subgroup of n = 8 rats per group was sacrificed at 2-, 5-, and 10-weeks post-surgery to assess the temporal relationships of inflammation, oxidative stress, bone turnover, bone matrix water, mechanics, and imaging outcomes. OVX rats exhibited higher body weight compared to sham rats at all time points. By 5-weeks, OVX animals showed elevated markers of inflammation and oxidative stress in cortical bone, which persisted throughout the study, while cortical bone formation rate did not differ from sham until 10-weeks. DXA outcomes did not reveal differences between OVX and sham at any time point. Bound water, assessed using ultrashort echo time magnetic resonance imaging (UTE MRI), was lower in OVX at the earliest time point (2-weeks) and reduced again at 10-weeks with no difference at 5-weeks. These data demonstrate that bound water assessment using novel UTE MRI technology was lower at the earliest time point following OVX. However, no temporal relationship with bone turnover, inflammation, or oxidative stress was observed at the time points assessed in this study. These findings underscore both the increased need to understand bone hydration changes and highlight the usefulness of UTE MRI for non-invasive bone hydration measurements.

Transforming growth factor beta (TGF-β) is ubiquitously found in bone and plays a key role in bone turnover. Mice expressing constitutively active TGF-β receptor type I (Mx1;TβRICA mice) are osteopenic. Here, we identified the candidate genes involved in bone turnover in Mx1;TβRICA mice using RNA sequencing analysis. A total of 285 genes, including 87 upregulated and 198 downregulated genes, were differentially expressed. According to the KEGG analysis, some genes were involved in osteoclast differentiation (Fcgr4, Lilrb4a), B cell receptor signaling (Cd72, Lilrb4a), and neutrophil extracellular trap formation (Hdac7, Padi4). Lilrb4 is related to osteoclast inhibition protein, whereas Hdac7 is a Runx2 corepressor that regulates osteoblast differentiation. Silencing Lilrb4 increased the number of osteoclasts and osteoclast marker genes. The knocking down of Hdac7 increased alkaline phosphatase activity, mineralization, and osteoblast marker genes. Therefore, our present study may provide an innovative idea for potential therapeutic targets and pathways in TβRI-associated bone loss.