Journal of Bone and Mineral Research最新文献

Patients who have suffered an atypical femoral fracture while on bisphosphonates or denosumab may continue to be at risk for typical osteoporotic fractures. There are no studies to provide guidance on safe treatment for such patients. Instead, using an illustrative case, 5 principles of management are provided that may lead to decreased osteoporotic fracture risk. The first principle is to discontinue the anti-resorptive medications, which may be challenging for the patient on denosumab because of rebound vertebral fractures reported in patients stopping denosumab. The second principle is to maximize non-pharmacologic management to reduce falls and fractures. Home safety, other methods of fall risk reduction, adequate nutrition, and an exercise prescription should help reduce fracture risk. Investigating potential secondary causes of osteoporosis, particularly if the original workup was not comprehensive, is the third principle because treatment of some specific causes may lower fracture risk. Reviewing the medication list is the fourth principle, with the goal of eliminating drugs that may increase fracture risk, and considering thiazides for some patients, which may lower fracture risk. Finally, some patients may benefit from anabolic therapy. One potential (but not FDA-approved) method is to use long-term cyclic teriparatide or abaloparatide on a 3-mo on, 3-mo off schedule. Tailoring the approach to each patient is important, based on the 5 clinical principles, in the absence of evidence-based management recommendations.

Osteoclast (OC) formation and bone resorption are regulated by several factors, including V-ATPase, Wnt/β-catenin, and RANKL/RANK signaling. ATP6AP2, also known as the prorenin receptor (PRR), is an accessory subunit of V-ATPase and a regulator of Wnt/β-catenin signaling. While the V-ATPase subunit ATP6AP1 is essential for OC formation and function, the role of ATP6AP2 in OC-lineage cells is less clear. Here, we provide evidence that ATP6AP2 plays a negative role in osteoclastogenesis and function, contrasting with the positive role of ATP6AP1. Mice with conditional KO (cKO) of ATP6AP2 in OCs (Atp6ap2LysM) exhibit trabecular bone loss, likely due to the increased osteoclastogenesis and activity, since bone formation rates (BFRs) are comparable to control mice. In vitro assays using bone marrow macrophages (BMMs) show that Atp6ap2LysM cultures have more RANKL-induced TRAP+ OC-like cells and increased bone resorptive activity. Further studies reveal that while RANKL signaling and V-ATPase activity are normal, ATP6AP2 KO OCs, but not BMMs, have reduced basal levels of Wnt/β-catenin pathway proteins, such as LRP5/6 and β-catenin, compared to controls. Wnt3A treatment induces β-catenin and suppresses OC formation in both control and ATP6AP2 KO OC-lineage cells, indicating that Wnt/β-catenin signaling negatively regulates OC-formation and operates independently of ATP6AP2. Overall, these results suggest that ATP6AP2 is critical for maintaining basal levels of LRP5/6 receptors and β-catenin in OCs, thus acting as a negative regulator of osteoclastogenesis and activation.

Understanding bone accrual in adolescents may inform approaches to improve skeletal health and reduce adult fracture risk. We investigated the effect of HIV on bone mineral accrual assessed by peripheral quantitative computed tomography (pQCT). Children with HIV (CWH) on ART for ≥2 years, and children without HIV (CWOH), aged 8-16 years (n = 609), had tibial pQCT scans at 0 and 12 months. Linear regression estimated sex-stratified differences in change (∆) and mean pQCT bone density (trabecular and cortical), size (total cross-sectional area [CSA]), and strength (SSI) between CWH and CWOH, adjusting for socio-economic status (SES) and orphanhood and incorporating an interaction term for baseline pubertal status (Tanner 1-2[pre/early] vs 3-5[mid/late]). Structural equation modeling tested whether baseline height-for-age-Z-scores (HAZ) mediate the effect of HIV on ∆bone outcomes. CWH were more likely than CWOH to be orphans (44% vs 7%), of lower SES (43% vs 27%), and be stunted (30% vs 8%); but similar in age. At baseline and follow-up, CWH had lower trabecular density, CSA, and SSI than CWOH. After adjustment, bone density and strength increased similarly in CWH and CWOH. CWH in mid/late puberty at baseline had greater 12 months increases in CSA than CWOH, particularly males (mean difference [31.3(95%CI:-3.1, 65.6) mm2 in mid/late puberty vs -2.04(-23.8, 19.7) mm2 in pre/early puberty; interaction p-value = 0.013]). HAZ mediated the effect of HIV on ∆bone outcomes only in females. as follows: indirect pathways from HIV to ∆trabecular density [-2.47 (-4.4, -0.5) mg/cm3], ∆cortical density [-3.26 (-5.5, -0.9) mg/cm3], and ∆SSI [-15.76 (-27.3, -4.2) mm3]. In conclusion, CWH show bone deficits at follow-up. Investigations of bone mineral accrual earlier in life and post-puberty to peak bone mass are needed.

Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at 2 years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3 months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared with late postnatal treatment (from day 4, equivalent to ~5 months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared with late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50. Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described. We aimed to systematically identify atypical fracture cases excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than 3 yr. A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane, and Web of Sciences, and hand-searching of conference abstracts were undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 yr) and receiving anti-resorptive medication for >3 yr were included, with data extracted and analyzed by two independent reviewers. Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), and non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following an atypical fracture in the majority (89%). Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.

HR-pQCT has become standard practice when quantifying volumetric BMD (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of photon counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxyapatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan, the carpals were delineated. At bone level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodeling. For clinical usage, the least detectable remodeling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and a standard error of 96.23 mgHA/cm3. Least detectable remodeling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data, we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and young people. It can cause significant pain, reduced function, bone swelling, and even (vertebral body) fractures. Because of a limited understanding of its pathophysiology, the treatment of CNO remains empiric and is based on relatively small case series, expert opinion, and personal experience. Several studies have linked pathological NOD-kike receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation and the resulting imbalance between pro- and anti-inflammatory cytokine expression with CNO. This agrees with elevated pro-inflammatory (mostly) monocyte-derived protein signatures in the blood of CNO patients that may be used as future diagnostic and/or prognostic biomarkers. Recently, rare variants in the P2RX7 gene, encoding for an ATP-dependent transmembrane channel, were linked with increased NLRP3 inflammasome assembly and prolonged monocyte/macrophage survival in CNO. Although the exact molecular mechanisms remain unclear, this will inform future target-directed and individualized treatment. This manuscript reviews most recent developments and their impact on diagnostic and therapeutic strategies in CNO.

Extracellular vesicles (EVs) are key mediators of cell-cell communication and are involved in transferring specific biomolecular cargo to recipient cells to regulate their physiological functions. A major challenge in the understanding of EV function in vivo is the difficulty ascertaining the origin of the EV particles. The recent development of the "Snorkel-tag," which includes EV-membrane-targeted CD81 fused to a series of extra-vesicular protein tags, can be used to mark EVs originating from a specific source for subsequent isolation and characterization. We developed an in vivo mouse model, termed "CAGS-Snorkel," which expresses the Snorkel-tag under the control of the Cre-lox system, and crossed this mouse with either Prx1-Cre (mesenchymal progenitors) or Ocn-Cre (osteoblasts/osteocytes) and isolated Snorkel-tagged EVs from the mouse bone marrow plasma using a magnetic bead affinity column. miRNA-sequencing was performed on the isolated EVs, and although similar profiles were observed, a few key miRNAs involved in bone metabolism (miR-106b-5p, miRs-19b-3p, and miRs-219a-5p) were enriched in the Ocn-derived relative to the Prx1-derived EV subpopulations. To characterize the effects of these small EVs on a bone cell target, cultured mouse bone marrow stromal cells were treated with Prx1 or Ocn EVs, and mRNA-sequencing was performed. Pathways involved in ossification, bone development, and extracellular matrix interactions were regulated by both EV subpopulations, whereas a few pathways including advanced glycation end-products signaling were uniquely regulated in the Ocn EV subpopulation, underlying important biological effects of specific EV subpopulations within the bone marrow microenvironment. These data demonstrate that EV isolation in vivo using the CAGS-Snorkel mouse model is a useful tool in characterizing the cargo and understanding the biology of tissue-specific EVs. Moreover, while bone mesenchymal cell populations share a common EV secretory profile, we uncover key differences based on the stage of osteoblastic differentiation that may have important biological consequences.

The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of parathyroid hormone-related protein (PTHrP) but increased Indian Hedgehog (IHH) signaling throughout the growth plate. Attenuation of smoothened-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.