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We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA_1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA_1c was used to classify patients into "adequately-" (ACD; n = 17 078; HbA_1c < 7.0%/53 mmol/mol) and "inadequately-" (ICD; n = 10 682; HbA_1c ≥ 7.0%/53 mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11 mmol/mol) increase in HbA_1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA_1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA_1c. Fracture risk between the T2D ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA_1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA_1c and eBMD. We obtained evidence that lower HbA_1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA_1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.

[This corrects the article DOI: 10.1093/jbmrpl/ziae093.].

At present, a lack of consensus exists regarding the clinical impact of osteoporosis on alveolar bone metabolism during implant osseointegration. While limited preclinical and clinical evidence demonstrates a negative influence of osteoporosis on dental extraction socket healing, no preclinical studies offer data on the results of implant placement in 6-mo-old, ovariectomized (OVX) Sprague-Dawley rats. This study aimed to investigate the outcomes of dental tooth extraction socket healing and implant placement in a rodent model of osteoporosis following daily vehicle (VEH) or abaloparatide (ABL) administration. Micro-CT and histologic analysis demonstrated signs of delayed wound healing, consistent with alveolar osteitis in extraction sockets following 42 d of healing in both the VEH and ABL groups. In a semiquantitative histological analysis, the OVX-ABL group demonstrated a tendency for improved socket regeneration with a 3-fold greater rate for moderate socket healing when compared to the OVX-VEH group (43% vs 14%), however, this finding was not statistically significant (p=.11). No significant differences were observed between vehicle and test groups in terms of implant outcomes (BMD and bone volume/total volume) at 14- and 21-d post-implant placement. Abaloparatide (ABL) significantly increased BMD of the femoral shaft and intact maxillary alveolar bone sites in OVX animals, demonstrating the therapeutic potential for oral hard tissue regeneration. The present model involving estrogen-deficiency-induced bone loss demonstrated an impaired healing response to dental extraction and implant installation.

Eagle syndrome is a bone disease where elongation of the styloid process leads to throat and neck pain, and in severe cases neurovascular symptoms such as syncope and neuralgia. The pathophysiology of Eagle syndrome is poorly understood with various theories having been proposed how this elongation is caused. To better understand the pathophysiology, we performed a work-up in 6 patients presenting with Eagle syndrome. Patients mainly presented with pain on turning the neck (100%), foreign body sensation (67%), tension in the neck (67%), and dysphagia (50%). The typical length of the styloid process ranges from 25 to 30 mm; however, [¹⁸F]NaF (sodium fluoride) PET/CT showed elongated styloid processes with an average length of 52.1 ± 15.6 mm (mean ± SD) with increased turnover at the base of one of the styloid processes. The removed styloid processes were further examined by histology, micro-CT, quantitative backscatter electron imaging (qBEI), Fourier transform infrared spectroscopy (FTIR), and circularly polarized light imaging. Histology revealed one case of a fractured styloid process healing through callus formation and one case of pseudarthrosis. Bone mineral density and mineralization was similar in the styloid processes when compared to cortical bone samples derived from the mandibular bone of different patients. Circular polarized light microscopy showed a collagen orientation in the styloid process comparable to the cortical bone samples with a distinct separation of collagen structure between the mineralized structure and the surrounding soft tissue with FTIR analysis demonstrating a typical composition of bone. This altogether suggests that the elongated styloid processes in Eagle syndrome are mature bone, capable of endochondral repair, possibly growing from the base of the process through endochondral ossification, rather than being a form of secondary calcification of the stylohyoid ligament as previously postulated.

High-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as a powerful imaging technique for characterizing bone microarchitecture in the human peripheral skeleton. The second-generation HR-pQCT scanner provides improved spatial resolution and a shorter scan time. However, the transition from the first-generation (XCTI) to second-generation HR-pQCT scanners (XCTII) poses challenges for longitudinal studies, multi-center trials, and comparison to historical data. Cross-calibration, an established approach for determining relationships between measurements obtained from different devices, can bridge this gap and enable the utilization and comparison of legacy data. The goal of this study was to establish cross-calibration equations to estimate XCTII measurements from XCTI data, using both the standard and Laplace-Hamming (LH) binarization approaches. Thirty-six volunteers (26-85 yr) were recruited and their radii and tibiae were scanned on both XCTI and XCTII scanners. XCTI images were analyzed using the manufacturer's standard protocol. XCTII images were analyzed twice: using the manufacturer's standard protocol and the LH segmentation approach previously developed and validated by our team. Linear regression analysis was used to establish cross-calibration equations. Results demonstrated strong correlations between XCTI and XCTII density and geometry outcomes. For most microstructural outcomes, although there were considerable differences in absolute values, correlations between measurements obtained from different scanners were strong, allowing for accurate cross-calibration estimations. For some microstructural outcomes with a higher sensitivity to spatial resolution (eg, trabecular thickness, cortical pore diameter), XCTII standard protocol resulted in poor correlations between the scanners, while our LH approach improved these correlations and decreased the difference in absolute values and the proportional bias for other measurements. For these reasons and due to the improved accuracy of our LH approach compared with the standard approach, as established in our previous study, we propose that investigators should use the LH approach for analyzing XCTII scans, particularly when comparing to XCTI data.

Chronic nonbacterial osteitis (CNO) is a rare auto-inflammatory bone disease affecting children and adults. Adult CNO is characterized by painful bone lesions, primarily of the anterior chest wall. There is no approved therapy for adult CNO. Current off-label treatments include intravenous bisphosphonates, which have been shown to alleviate pain through decreasing bone turnover. However, no adequately powered randomized controlled trials (RCTs) have been conducted. This double-blind, placebo-controlled RCT investigates the efficacy of intravenous pamidronate to decrease bone pain in adult CNO patients. Recruiting at the Dutch national referral center for CNO, adult patients with persistent bone pain despite non-steroidal anti-inflammatory drugs, or optionally other standard-of-care treatments are randomized to receive two courses of intravenous pamidronate (at 0 and 3 mo, 30 mg daily, on 3 consecutive d) or placebo. From 6 mo onwards, all patients receive open-label pamidronate for another two courses. The primary outcome is change in score for maximum pain from 0 to 6 mo. Secondary outcomes include change in quantitative intralesional bone turnover as measured on sodium-fluoride positron emission computed tomography ([¹⁸F]NaF-PET/CT), inflammation markers, shoulder function, general health, quality of life, fatigue, physical, and work activity. The pamidronate for pain in adult chronic nonbacterial osteitis trial addresses the need for evidence-based treatments in adult CNO. Results will directly impact daily clinical practice, either validating the use of intravenous pamidronate in CNO at the dose used in this trial or prompting the search for alternative regimens or agents. This trial was registered in EudraCT (reference 2020-001068-27) and the Dutch Trial Register (reference NL68020.058.20).

Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANK_F377del mutation (Ank^KI/KI ) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in Ank^KI/KI mice. PPi is a potent inhibitor of mineralization. To examine the extent to which restoration of circulating PPi levels may prevent the development of a CMD-like phenotype, we treated Ank^KI/KI mice with the recombinant human ENPP1-Fc protein IMA2a. ENPP1 hydrolyzes ATP into AMP and PPi. Male and female Ank^+/+ and Ank^KI/KI mice (n ≥ 6/group) were subcutaneously injected with IMA2a or vehicle weekly for 12 wk, starting at the age of 1 wk. Plasma ENPP1 activity significantly increased in Ank^KI/KI mice injected with IMA2a (Vehicle/IMA2a: 28.15 ± 1.65/482.7 ± 331.2 mOD/min; p <.01), which resulted in the successful restoration of plasma PPi levels (Ank^+/+ /Ank^KI/KI vehicle treatment/Ank^KI/KI IMA2a: 0.94 ± 0.5/0.43 ± 0.2/1.29 ± 0.8 μM; p <.01). We examined the skeletal phenotype by X-Ray imaging and μCT. IMA2a treatment of Ank^KI/KI mice did not significantly correct CMD features such as the abnormal shape of femurs, increased bone mass of mandibles, hyperostotic craniofacial bones, or the narrowed foramen magnum. However, μCT imaging showed ectopic calcification near basioccipital bones at the level of the foramen magnum and on joints of Ank^KI/KI mice. Interestingly, IMA2a treatment significantly reduced the volume of calcified nodules at both sites. Our data demonstrate that IMA2a is sufficient to restore plasma PPi levels and reduce ectopic calcification but fails to rescue skeletal abnormalities in Ank^KI/KI mice under our treatment conditions.

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction (n = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80⁺M1, CD206⁺M2 (anti-inflammatory macrophages), PDGFRα⁺MSC, and TNF-α⁺ cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm³ vs 0.02 mm³, p<.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p<.0001). Clodronate group showed significant reduction in mean number of CD80⁺, TNF-α⁺, PDGFRα⁺, and CD80⁺TNF-α⁺ cells on day 5 (306.5 vs 558.8, p<.0001; 280.5 vs 543.8, p<.0001; 365.0 vs 633.0, p<.0001, 29.0 vs 42.5, p<.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p=.0004; 479.3 vs 384.5, p=.0008; 593.0 vs 473.0, p=.0010, 41.0 vs 32.5, p=.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e, Gbp6, and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity.

In a recent study examining the effects of manipulating the gut microbiome on bone, a control group of mice in which the microbiome was altered using a non-caloric, aspartame-based sweetener resulted in whole bone strength being 40% greater than expected from geometry alone, implicating enhanced bone tissue strength. However, the study was not designed to detect changes in bone in this control group and was limited to young male mice. Here we report a replication study examining how changes in the gut microbiome caused by aspartame-based sweetener influence bone. Male and female C57Bl/6 J mice were untreated or treated with a high dose of sweetener (10 g/L) in their drinking water from either 1 to 4 mo of age (young cohort; n = 80) or 1 to 22 mo of age (aged cohort; n = 52). Sweetener did not replicate the modifications to the gut microbiome observed in the initial study and did not result in an increase in bone tissue strength in either sex at either age. Aged male mice dosed with sweetener had larger bones (+17% femur section modulus, p<.001) and greater whole bone strength (+22%, p=.006) but the increased whole bone strength was explained by the associated increase in body mass (+9%, p<.001). No differences in body mass, whole bone strength, or femoral geometry were associated with sweetener dosing in males from the young cohort or females at either age. As we were unable to replicate the gut microbiota observed in the initial experiment, it remains unclear if changes in the gut microbiome can enhance bone tissue strength. Although prior work studying gut microbiome-induced changes in bone with oral antibiotics has been highly repeatable, the current study highlights the variability of nutritional manipulations of the gut microbiota in mice.

Previous studies have demonstrated that the administration of zoledronic acid (ZOL) once yearly for 3 years or once over 3 years, yields similar antifracture efficacy. Bone turnover markers can predict the antifracture efficacy of antiresorptive agents, with procollagen type 1 N-terminal propeptide (P1NP) being the most useful marker. In this retrospective cohort study, we explored the effects of intravenous dosing of ZOL guided by serum (S)-P1NP assessment on bone mineral density (BMD) and fractures. Consenting patients (N = 202, mean age 68.2 years) with osteoporosis were treated with ZOL for an average of 4.4 (range 2-8) years. S-P1NP and BMD were measured at baseline and every 1-2 years. We assessed the number of subsequent vertebral and nonvertebral fractures in the 2-year time periods. The number of patients assessed was 202, 147, 69, and 29 at years 1-2, 3-4, 5-6, and 7-8, respectively. A new ZOL infusion was given if S-P1NP exhibited values above 35 μg/L. BMD increased by 6.2% (SD 4.0) over the first 2 years and stabilized in years 2-8 (P <.05). Median S-P1NP exhibited an initial reduction from 58.0 to 31.3 μg/L at year 2 and then increased to 39.0 μg/L at years 7-8. Compared with fractures observed in the last 2 years before baseline, fracture rates exhibited consistent reductions, for vertebral fractures odds ratio (OR) [95% confidence interval] = 0.61 [0.47, 0.80], P <.001 and for nonvertebral fractures OR = 0.23 [0.18, 0.31], P <.001. In conclusion, intermittent dosing of intravenous ZOL based on the assessment of S-P1NP with cut-off at 35 μg/L resulted in an initial increase followed by a stable BMD, suppression of S-P1NP, and stable reduction of fractures for 8 years. Only 39% of patients needed more than one infusion. This approach reduces healthcare costs and might also reduce the risk of rare side effects such as osteonecrosis of the jaw and atypical femoral fracture.