Showing papers in "Journal of Bone and Mineral Research in 2023"
TL;DR: In this article , the authors investigated the efficacy of a three-day course of dexamethasone 4'mg daily in reducing incidence of acute phase response (APR), an inflammatory reaction characterized by fever, musculoskeletal pain, headache, and nausea.
Abstract: Zoledronate is a potent intravenous bisphosphonate effective in the management of osteoporosis, Paget's disease and skeletal‐related events in malignancy. Its most frequent adverse effect is the acute phase response (APR), an inflammatory reaction characterized by fever, musculoskeletal pain, headache, and nausea. This randomized, placebo‐controlled, double‐blind study investigated the efficacy of a three‐day course of dexamethasone 4 mg daily in reducing incidence of APR. Participants (n = 60) were randomized to receive either 4 mg of oral dexamethasone 1.5 hours before zoledronate and once a day for the following 2 days, or placebo. Oral temperature was measured at baseline and three times a day for the following 3 days, and questionnaires assessing symptoms of the APR were completed at baseline and for 3 days following zoledronate. Use of anti‐inflammatory medication in the 3 days following zoledronate was recorded. The primary outcome was the temperature change from baseline. There was a significant difference in the primary outcome between the dexamethasone and placebo groups (p < 0.0001), with a mean decrease in temperature of 0.10°C (95% confidence interval [CI], −0.34 to 0.14) in the dexamethasone group compared with a mean increase in temperature of 0.84°C (95% CI, 0.53–1.16) in the placebo group on the evening following zoledronate. There was also a difference in APR‐related symptom score over time between the two groups (p = 0.0005), with a median change in symptom score in the dexamethasone group 1 day after zoledronate of 0 (95% CI, 0–1) compared with 3 (95% CI, 0–5) in the placebo group. An increase in temperature of ≥1°C to a temperature of >37.5°C occurred in two of 30 (6.7%) participants in the dexamethasone group compared with 14 of 30 participants (46.7%) in the placebo group (p = 0.0005). This study demonstrates that a 3‐day course of dexamethasone substantially reduces the APR following zoledronate infusion. © 2023 American Society for Bone and Mineral Research (ASBMR).
3 citations
TL;DR: In this paper , an anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody was used to prevent the development of myeloma-induced bone loss through preventing bone resorption.
Abstract: An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt‐targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf‐1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti–low‐density lipoprotein receptor‐related protein 6 (LRP6) antibody, which potentiates Wnt1‐class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma‐induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti‐LRP6 treatment alone. Micro–computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti‐LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti‐LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1‐bearing mice by 111%, which was also superior to anti‐LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1‐bearing mice compared to their controls, providing greater protection against fracture compared to anti‐LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1‐bearing mice treated with the anti‐LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt‐targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane‐bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
3 citations
TL;DR: Recently, increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells as mentioned in this paper .
Abstract: Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
3 citations
TL;DR: In this article , the authors evaluated whether abaloparatide improves trabecular bone score (TBS) and whether TBS trends were associated with vertebral fracture risk reduction.
Abstract: Although bone mineral density (BMD) is a predictor of fracture, many fractures occur in women with T‐scores > −2.5. Bone microarchitecture, assessed by trabecular bone score (TBS), predicts fracture risk independent of BMD. We evaluated whether abaloparatide improves TBS and whether TBS trends were associated with vertebral fracture risk reduction. Women with osteoporosis randomized to abaloparatide or placebo for 18 months (ACTIVE), followed by alendronate for 24 months (ACTIVExtend), with evaluable TBS, were included in this post hoc analysis (N = 911). TBS was calculated from spine BMD scans using an algorithm adjusted for tissue thickness (TBSth) at baseline, 6, 18, and 43 months. Mean increments in TBSth from baseline within and between treatment groups, proportion of women with TBSth increments above least significant change (LSC) and proportion with degraded TBSth (<1.027) were calculated. Risk estimates for vertebral fracture were compared using binary logistic regressions adjusted for baseline age and spine BMD. At baseline, 42% had degraded TBSth. Mean TBSth increased 4% after 18 months abaloparatide (p < 0.001) and was unchanged with placebo. After 2 subsequent years of alendronate, the total cumulative TBSth increase was 4.4% with abaloparatide/alendronate and 1.7% with placebo/alendronate (group difference, p < 0.001). At 43 months, the proportion of women with degraded TBSth had declined to 21% with abaloparatide/alendronate and 37% with placebo/alendronate (p < 0.05). An increase in TBSth ≥ LSC was observed in 50% of abaloparatide‐treated women at 18 months and was associated with decreased odds (odds ratio [OR]; 95% confidence interval [CI]) of vertebral fracture (0.19; 95% CI, 0.04–0.80, 6 months; 0.30; 95% CI, 0.11–0.79, 43 months). In conclusion, abaloparatide increased TBSth rapidly and progressively over 18 months and increments were maintained over 2 years with alendronate. TBSth increase was associated with vertebral fracture risk reduction. Microarchitectural improvement may be one mechanism by which abaloparatide strengthens vertebral bone. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
2 citations
TL;DR: In this paper , the authors tracked annual daily doses of calcium and active vitamin D supplements, calciotropic biochemistries, estimated glomerular filtration rate (eGFR), and aBMD measurements in 27 HypoPT patients (16 postsurgical, 11 nonsurgical) who were treated with recombinant human parathyroid hormone (1−84) [rhPTH(1•84)] for at least 8 and up to 12 (n = 27) years.
Abstract: Hypoparathyroidism (HypoPT) is a disorder characterized by hypocalcemia, low or absent parathyroid hormone (PTH) levels, reduced bone remodeling, and high areal bone mineral density (aBMD). PTH is a therapeutic option, yet data on the prolonged clinical and skeletal effects of PTH treatment are limited. We tracked annual daily doses of calcium and active vitamin D supplements, calciotropic biochemistries, estimated glomerular filtration rate (eGFR), and aBMD measurements in 27 HypoPT patients (16 postsurgical, 11 nonsurgical) who were treated with recombinant human PTH(1‐84) [rhPTH(1‐84)] for at least 8 (n = 27) and up to 12 (n = 14) years. We also performed high‐resolution‐peripheral quantitative computed tomography (HRpQCT) imaging and report results at baseline, 5, 8, and 12 years of rhPTH(1‐84) treatment. With prolonged use of rhPTH, reductions in the need for supplemental calcium and active vitamin D were maintained. The eGFR did not decline. Serum calcium was maintained within the lower limit of the normal range. aBMD by dual‐energy X‐ray absorptiometry (DXA) showed an increase at the lumbar spine and a decrease at the distal 1/3 radius. By HRpQCT, cortical volumetric BMD (vBMD) at the tibia decreased at year 5: −20.0% ± 1.5%. The magnitude of this reduction was mitigated in year 8: −8.5% ± 1.6% and in year 12: −10.3% ± 2.2% but all were significantly below the mean baseline value (p < 0.001). A similar pattern of decline was observed at the radius. Cortical porosity progressively increased at the tibia in year 5: 17.4% ± 10% (p < 0.05), year 8: 55.2% ± 11% (p < 0.001), and year 12: 83.5% ± 14% (p < 0.001). A similar pattern of increase was observed at the radius. Failure load, which was higher than normal at baseline, decreased but remained above normal at year 12. This is the longest experience, to date, with PTH therapy in HypoPT. These results demonstrate sustained biochemical stability but overall decreases in bone mass. © 2023 American Society for Bone and Mineral Research (ASBMR).
2 citations
TL;DR: In this article , a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected, including moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly.
Abstract: Lethal short‐limb skeletal dysplasia Al‐Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al‐Gazali type, is an ultra‐rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al‐Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short‐limb skeletal dysplasia Al‐Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease‐causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al‐Gazali skeletal dysplasia and identifies it as a semi‐lethal part of the spectrum of ADAMTSL2‐related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease‐causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
2 citations
TL;DR: In this article , the role of USP53 in bone has been investigated and it has been shown that Usp53 null mice exhibit a low bone mass phenotype in vivo, and they also exhibit a pronounced decrease in trabecular bone indices.
Abstract: In the skeleton, osteoblasts and osteoclasts synchronize their activities to maintain bone homeostasis and integrity. Investigating the molecular mechanisms governing bone remodeling is critical and helps understand the underlying biology of bone disorders. Initially, we have identified the ubiquitin‐specific peptidase gene (Usp53) as a target of the parathyroid hormone in osteoblasts and a regulator of mesenchymal stem cell differentiation. Mutations in USP53 have been linked to a constellation of developmental pathologies. However, the role of Usp53 in bone has never been visited. Here we show that Usp53 null mice have a low bone mass phenotype in vivo. Usp53 null mice exhibit a pronounced decrease in trabecular bone indices including trabecular bone volume (36%) and trabecular number (26%) along with an increase in trabecular separation (13%). Cortical bone parameters are also impacted, showing a reduction in cortical bone volume (12%) and cortical bone thickness (15%). As a result, the strength and mechanical bone properties of Usp53 null mice have been compromised. At the cellular level, the ablation of Usp53 perturbs bone remodeling, augments osteoblast‐dependent osteoclastogenesis, and increases osteoclast numbers. Bone marrow adipose tissue volume increased significantly with age in Usp53‐deficient mice. Usp53 null mice displayed increased serum receptor activator of NF‐κB ligand (RANKL) levels, and Usp53‐deficient osteoblasts and bone marrow adipocytes have increased expression of Rankl. Mechanistically, USP53 regulates Rankl expression by enhancing the interaction between VDR and SMAD3. This is the first report describing the function of Usp53 during skeletal development. Our results put Usp53 in display as a novel regulator of osteoblast–osteoclast coupling and open the door for investigating the involvement of USP53 in pathologies. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
2 citations
TL;DR: In this paper , a review endorsed by the European Calcified Tissue Society (ECTS), a working group of investigators from Europe and the US provides an overview of the strengths and limitations of experimental animal models, including rodents, fish, and large animals, as well the potential and short comings of in vitro and in silico technologies in skeletal research.
Abstract: Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques. 3D culture, organ-on-a-chip, and computer models have improved enormously over the last years. Nevertheless, the overall complexity of bone tissue-cross talk and the systemic and local regulation of bone physiology can often only be addressed in entire vertebrates. Powerful genetic methods such as conditional mutagenesis, lineage tracing, and modeling of the diseases enhanced the understanding of the entire skeletal system. In this review endorsed by the European Calcified Tissue Society (ECTS), a working group of investigators from Europe and the US provides an overview of the strengths and limitations of experimental animal models, including rodents, fish, and large animals, as well the potential and short comings of in vitro and in silico technologies in skeletal research. We propose that the proper combination of the right animal model for a specific hypothesis and state-of-the-art in vitro and/or in silico technology is essential to solving remaining important questions in bone research. This is crucial for executing most efficiently the 3R principles to reduce, refine and replace animal experimentation, for enhancing our knowledge of skeletal biology, and for the treatment of bone diseases that affect a large part of society. This article is protected by copyright. All rights reserved.
1 citations
TL;DR: In this article , in vitro functional experiments demonstrated an inhibitory effect of miR-196b-5p on osteoblast differentiation and showed significant reduction of bone mass, whereas osteoclasts, marrow adipocytes and serum levels of bone resorption markers were increased.
Abstract: miR-196b-5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how miR-196b-5p affects bone cells and bone homeostasis. In this study, in vitro functional experiments demonstrated an inhibitory effect of miR-196b-5p on osteoblast differentiation. Mechanistic explorations revealed that miR-196b-5p directly targeted semaphorin 3a (Sema3a) and inhibited Wnt/β-catenin signaling. SEMA3A attenuated the impaired osteogenesis induced by miR-196b-5p. Osteoblast-specific miR-196b transgenic mice showed significant reduction of bone mass. Trabecular osteoblasts were reduced and bone formation was suppressed, whereas osteoclasts, marrow adipocytes and serum levels of bone resorption markers were increased in the transgenic mice. The osteoblastic progenitor cells from the transgenic mice had decreased SEMA3A level and exhibited retarded osteogenic differentiation, while those marrow osteoclastic progenitors exhibited enhanced osteoclastogenic differentiation. miR-196b-5p and SEMA3A oppositely regulated the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin. The calvarial osteoblastic cells expressing the transgene promoted, while the osteoblasts overexpressing Sema3a inhibited osteoclastogenesis. Finally, in vivo transfection of miR-196b-5p inhibitor to the marrow reduced ovariectomy-induced bone loss in mice. Our study has identified that miR-196b-5p plays a key role in osteoblast and osteoclast differentiation and regulates bone homeostasis. Inhibition of miR-196b-5p may be beneficial for amelioration of osteoporosis.
1 citations
TL;DR: In this article , a binarization approach based on a Laplace-Hamming (LH) segmentation was proposed to optimize fine structure segmentation in both trabecular and cortical compartments.
Abstract: Although second‐generation high‐resolution peripheral quantitative computed tomography (XCTII) provides the highest‐resolution in vivo bone microstructure assessment, the manufacturer's standard image processing protocol omits fine features in both trabecular and cortical compartments. To optimize fine structure segmentation, we implemented a binarization approach based on a Laplace–Hamming (LH) segmentation and documented the reproducibility and accuracy of XCTII structure segmentation using both the standard Gaussian‐based binarization and the proposed LH segmentation approach. To evaluate reproducibility, 20 volunteers (9 women, 11 men; aged 23–75 years) were recruited, and three repeat scans of the radii and tibias were acquired using the manufacturer's standard in vivo protocol. To evaluate accuracy, cadaveric structure phantoms (14 radii, 6 tibias) were scanned on XCTII using the same standard in vivo protocol and on μCT at 24.5 μm resolution. XCTII images were analyzed twice—first, with the manufacturer's standard patient evaluation protocol and, second, with the proposed LH segmentation approach. The LH approach rescued fine features evident in the grayscale images but omitted or overrepresented (thickened) by the standard approach. The LH approach significantly reduced error in trabecular volume fraction (BV/TV) and thickness (Tb.Th) compared with the standard approach; however, higher error was introduced for trabecular separation (Tb.Sp). The LH approach improved the correlation between XCTII and μCT for cortical porosity (Ct.Po) and significantly reduced error in cortical pore diameter (Ct.Po.Dm) compared with the standard approach. The LH approach resulted in improved precision compared with the standard approach for BV/TV, Tb.Th, Ct.Po, and Ct.Po.Dm at the radius and for Ct.Po at the tibia. Our results suggest that the proposed LH approach produces substantially improved binary masks, reduces proportional bias, and provides greater accuracy and reproducibility in important outcome metrics, all due to more accurate segmentation of the fine features in both trabecular and cortical compartments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
1 citations
TL;DR: In this paper , the functional role of Igf1 in fibrocartilage stem cells (FCSCs) for TMJ cartilage growth and homeostasis was investigated by lineage tracing.
Abstract: Temporomandibular joint (TMJ) growth requires orchestrated interactions between various cell types. Recent studies revealed that fibrocartilage stem cells (FCSCs) in the TMJ cartilage play critical roles as cell resources for joint development and repair. However, the detailed molecular network that influences FCSC fate during TMJ cartilage development remains to be elucidated. Here, we investigate the functional role of Igf1 in FCSCs for TMJ cartilage growth and homeostasis by lineage tracing using Gli1‐CreER+; Tmflfl mice and conditional Igf1 deletion using Gli1‐/Col2‐CreER+; Igf1fl/fl mice. In Gli1‐CreER+; Tmflfl mice, red fluorescence+ (RFP+) FCSCs show a favorable proliferative capacity. Igf1 deletion in Gli1+/Col2+ cell lineages leads to distinct pathological changes in TMJ cartilage. More serious cartilage thickness and cell density reductions are found in the superficial layers in Gli1‐CreER+; Igf1fl/fl mice. After long‐term Igf1 deletion, a severe disordered cell arrangement is found in both groups. When Igf1 is conditionally deleted in vivo, the red fluorescent protein‐labeled Gli1+ FCSC shows a significant disruption of chondrogenic differentiation, cell proliferation, and apoptosis leading to TMJ cartilage disarrangement and subchondral bone loss. Immunostaining shows that pAkt signaling is blocked in all cartilage layers after the Gli1+‐specific deletion of Igf1. In vitro, Igf1 deletion disrupts FCSC capacities, including proliferation and chondrogenesis. Moreover, the deletion of Igf1 in FCSCs significantly aggravates the joint osteoarthritis phenotype in the unilateral anterior crossbite mouse model, characterized by decreased cartilage thickness and cell numbers as well as a loss of extracellular matrix secretions. These findings uncover Igf1 as a regulator of TMJ cartilage growth and repair. The deletion of Igf1 disrupts the progenitor capacity of FCSCs, leading to a disordered cell distribution and exaggerating TMJ cartilage dysfunction. © 2023 American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this article , the authors measured changes in bone mineral density (BMD) during the menopausal transition in urban-dwelling South African women with and without HIV and determine whether HIV infection modified the effect of menopause on BMD changes.
Abstract: An estimated 25% of South African women live with human immunodeficiency virus (HIV). Antiretroviral therapy roll‐out has improved life expectancy, so many more women now reach menopause. We aimed to quantify changes in bone mineral density (BMD) during the menopausal transition in urban‐dwelling South African women with and without HIV and determine whether HIV infection modified the effect of menopause on BMD changes. A 5‐year population‐based longitudinal study recruited women aged 40–60 years residing in Soweto and collected demographic and clinical data, including HIV status, anthropometry, and BMD, at baseline and at 5‐year follow‐up. All women were staged as pre‐, peri‐, or postmenopausal at both time points. Multivariable linear regression assessed relationships and interactions between HIV infection, menopause, and change in BMD. At baseline, 450 women had mean age 49.5 (SD 5.7) years, 65 (14.4%) had HIV, and 140 (31.1%), 119 (26.4%), and 191 (42.4%) were pre‐, peri‐, and postmenopausal, respectively; 34/205 (13.6%) women ≥50 years had a total hip (TH) or lumbar spine (LS) T‐score ≤ −2.5. At follow‐up 38 (8.4%), 84 (18.7%), and 328 (72.9%) were pre‐, peri‐, and postmenopausal. Those with HIV at baseline lost more total body (TB) BMD (mean difference −0.013 [95% confidence interval −0.026, −0.001] g/cm2, p = 0.040) and gained more weight 1.96 [0.32, 3.60] kg; p = 0.019 than HIV‐uninfected women. After adjusting for age, baseline weight, weight change, and follow‐up time, the transition from pre‐ to postmenopause was associated with greater TB BMD losses in women with HIV (−0.092 [−0.042, −0.142] g/cm2; p = 0.001) than without HIV (−0.038 [−0.016, −0.060] g/cm2, p = 0.001; interaction p = 0.034). Similarly, in women who were postmenopausal at both time points, those with HIV lost more TB BMD (−0.070 [−0.031, −0.108], p = 0.001) than women without HIV (−0.036 [−0.015, −0.057], p = 0.001, interaction p = 0.049). Findings were consistent but weaker at the LS and TH. Menopause‐related bone loss is greater in women with HIV, suggesting women with HIV may be at greater risk of osteoporotic fractures. HIV services should consider routine bone health assessment in midlife women as part of long‐term HIV care delivery. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , the authors examined factors that were associated with a change in lumbar spine trabecular bone score (TBS) from dual-energy X-ray absorptiometry (DXA) images.
Abstract: Lumbar spine trabecular bone score (TBS), a gray‐level texture measure derived from spine dual‐energy X‐ray absorptiometry (DXA) images, is a bone mineral density (BMD)‐independent risk factor for fracture. An unresolved question is whether TBS is sufficiently responsive to change over time or in response to widely used osteoporosis therapy at the individual level to serve as a useful biomarker. Using the Manitoba DXA Registry, we identified 11,643 individuals age 40 years and older with two fan‐beam DXA scans performed on the same instrument within 5 years (mean interval 3.2 years), of whom 6985 (60.0%) received antiresorptive osteoporosis medication (majority oral bisphosphonate) between the scans. We examined factors that were associated with a change in lumbar spine TBS, lumbar spine BMD, and total hip BMD exceeding the 95% least significant change (LSC). Change exceeding the LSC was identified in 23.0% (9.3% increase, 13.8% decrease) of lumbar spine TBS, 38.2% (22.1% increase, 16.1% decrease) lumbar spine BMD, and 42.5% (17.6% increase, 24.9% decrease) total hip BMD measurement pairs. From regression models, the variables most strongly associated with significant change in TBS (decreasing order) were tissue thickness change, acquisition mode change, weight change, and spine percent fat change. Consistent with the insensitivity of TBS to oral antiresorptive therapies, use of these agents showed very little effect on TBS change. In contrast, for both spine BMD change and total hip BMD change, osteoporosis medication use was the most significant variable, whereas tissue thickness change, acquisition mode change, and weight change had relatively weak effects. In summary, change in spine TBS using the present algorithm appears to be strongly affected by technical factors. This suggests a limited role, if any, for using TBS change in untreated individuals or for monitoring response to antiresorptive treatment in routine clinical practice with the current version of the TBS algorithm. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , the authors explored magnesium ascorbyl phosphate (MAP), a hydrophilic and stable ascorbic acid derivative, as a potential treatment option for bone loss disorder by boosting osteoblastogenesis and bone formation, and found that MAP could promote the proliferation and osteoblastic differentiation of human skeletal stem and progenitor cells (SSPCs) in vitro.
Abstract: Dysregulation of bone homeostasis is closely related to the pathogenesis of osteoporosis. Suppressing bone resorption by osteoclasts to attenuate bone loss has been widely investigated, but far less effort has been poured toward promoting bone formation by osteoblasts. Here, we aimed to explore magnesium ascorbyl phosphate (MAP), a hydrophilic and stable ascorbic acid derivative, as a potential treatment option for bone loss disorder by boosting osteoblastogenesis and bone formation. We found that MAP could promote the proliferation and osteoblastic differentiation of human skeletal stem and progenitor cells (SSPCs) in vitro. Moreover, MAP supplementation by gavage could alleviate bone loss and accelerate bone defect healing through promoting bone formation. Mechanistically, we identified calcium/calmodulin‐dependent serine/threonine kinase IIα (CaMKIIα) as the target of MAP, which was found to be directly bound and activated by MAP, then with a concomitant activation in the phosphorylation of ERK1/2 (extracellular regulated kinase 1/2) and CREB (cAMP‐response element binding protein) as well as an elevation of C‐FOS expression. Further, blocking CaMKII signaling notably abolished these effects of MAP on SSPCs and bone remodeling. Taken together, our data indicated that MAP played an important role in enhancing bone formation through the activation of CaMKII/ERK1/2/CREB/C‐FOS signaling pathway and may be used as a novel therapeutic option for bone loss disorders such as osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).
TL;DR: Inorganic pyrophosphate (PPi) has long been recognized as the most potent endogenous inhibitor of biomineralization and has been intensively studied as both a marker and a potential therapeutic for ectopic calcification as discussed by the authors .
Abstract: Ectopic calcification is characterized by inappropriate deposition of calcium mineral in nonskeletal connective tissues and can cause significant morbidity and mortality, particularly when it affects the cardiovascular system. Identification of the metabolic and genetic determinants of ectopic calcification could help distinguish individuals at the greatest risk of developing these pathological calcifications and could guide development of medical interventions. Inorganic pyrophosphate (PPi) has long been recognized as the most potent endogenous inhibitor of biomineralization. It has been intensively studied as both a marker and a potential therapeutic for ectopic calcification. Decreased extracellular concentrations of PPi have been proposed to be a unifying pathophysiological mechanism for disorders of ectopic calcification, both genetic and acquired. However, are reduced plasma concentrations of PPi a reliable predictor of ectopic calcification? This perspective article evaluates the literature in favor and against a pathophysiological role of plasma versus tissue PPi dysregulation as a determinant of, and as a biomarker for, ectopic calcification. © 2023 American Society for Bone and Mineral Research (ASBMR).
TL;DR: The Fracture Risk Assessment Tool (FRAX®) was created to predict major osteoporotic fractures (MOF) and hip fractures in the general population as mentioned in this paper , but whether FRAX accurately predicts fractures in men with prostate cancer is unknown.
Abstract: The Fracture Risk Assessment Tool (FRAX®) was created to predict major osteoporotic fractures (MOF) and hip fractures in the general population. Whether FRAX accurately predicts fractures in men with prostate cancer is unknown. Our objective was to assess the performance of FRAX for predicting incident fractures in men with prostate cancer. Men from the Manitoba Bone Mineral Density (BMD) Registry (1996–2018) with prostate cancer diagnoses in the 3 years prior to dual‐energy X‐ray absorptiometry (DXA) were identified. FRAX scores with and without BMD were calculated. From population‐based healthcare data we identified incident MOF, hip fracture, any osteoporotic fracture and death from the date of BMD testing to March 31, 2018. Cox regression was performed to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) per standard deviation increase in FRAX score. Observed 10‐year probability (estimated with competing risk of mortality) was compared with 10‐year FRAX‐predicted fracture probability to assess calibration. The study population included 684 men with prostate cancer (mean age 74.6 years) and 8608 men without prostate cancer (mean age 65.5 years). FRAX stratified risk for MOF (HR 1.91, 95% CI 1.48–2.45 with BMD; HR 1.96, 95% CI 1.43–2.69 without BMD) and hip fracture (HR 3.37, 95% CI 1.90–6.01 with BMD; HR 4.58, 95% CI 2.17–9.67 without BMD) in men with prostate cancer. There was no effect modification observed with prostate cancer status or current androgen deprivation therapy. Observed 10‐year fracture probability in men with prostate cancer showed good agreement with FRAX with and without BMD included in the calculation (observed/predicted calibration ratios MOF 0.97, hip 1.00 with BMD; MOF 0.92, hip 0.93 with BMD). In conclusion, FRAX reliably predicts incident fractures in men with prostate cancer. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , the effect of sigmoid gastrectomy on the lumbar spine by biomechanical CT analysis in adolescents/young adults with obesity was investigated. And the results showed significant reductions in abdominal adipose tissue and thigh muscle area in the SG group compared with controls.
Abstract: Sleeve gastrectomy (SG) is effective in treating cardiometabolic complications of obesity but is associated with bone loss. Our aim was to determine the effect of SG on the lumbar spine by biomechanical CT analysis in adolescents/young adults with obesity. We hypothesized that SG would lead to a decrease in strength and bone mineral density (BMD) compared with nonsurgical controls. In a 12‐month prospective nonrandomized study, adolescents/young adults with obesity underwent SG (n = 29, 18.0 ± 2.1 years, 23 female) or were followed without surgery (controls, n = 30, 17.95 ± 3.0 years, 22 female). At baseline and 12 months, participants underwent quantitative computed tomography (QCT) of L1 and L2 for biomechanical assessment and MRI of the abdomen and mid‐thigh for body composition assessment. Twelve‐month changes between groups and within groups were assessed. Analyses were controlled for baseline and 12‐month changes in body mass index (BMI) by multivariable analyses. Regression analysis was performed to evaluate the effect of body composition on bone parameters. Our institutional review board (IRB) approved the study, and informed consent/assent was obtained. Participants in the SG group had a higher baseline BMI than controls (p = 0.01) and lost an average of 34.3 ± 13.6 kg 12 months after surgery, whereas weight was unchanged in controls (p < 0.001). There were significant reductions in abdominal adipose tissue and thigh muscle area in the SG group compared with controls (p < 0.001). Bone strength, bending stiffness, and average and trabecular volumetric BMD decreased in the SG group compared with controls (p < 0.001). After controlling for change in BMI, a 12‐month reduction in cortical BMD was significant in the SG group compared with controls (p = 0.02). Reductions in strength and trabecular BMD were associated with reductions in BMI, visceral adipose tissue, and muscle (p ≤ 0.03). In conclusion, SG in adolescents decreased strength and volumetric BMD of the lumbar spine compared with nonsurgical controls. These changes were associated with decreases in visceral fat and muscle mass. © 2023 American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , a systematic review and meta-analysis aimed to investigate the effect of nonalcoholic fatty liver disease (NAFLD) on bone mineral density (BMD) and the risk of osteoporosis and osteoporrotic fracture in adults.
Abstract: This systematic review and meta-analysis aimed to investigate the effect of nonalcoholic fatty liver disease (NAFLD) on bone mineral density (BMD), and the risk of osteoporosis and osteoporotic fracture in adults. We searched PubMed, MEDLINE, Embase, CINAHL, Web of Science, Cochrane Library, and Scopus for observational studies published from inception to January 2023 that reported adjusted effect sizes of NAFLD on BMD, osteopenia/osteoporosis, and osteoporotic fracture. The data were synthesized using multilevel and random-effects models. A total of 19 studies were included; of these, nine (21,294 participants) evaluated the effect of NAFLD on BMD, six (133,319 participants) investigated the risk of osteoporosis, and five (227,901 participants) assessed the risk of osteoporotic fracture. This meta-analysis showed that NAFLD was associated with decreased BMD (mean difference: -0.019 g/cm2 , 95% confidence interval [CI]: -0.036 to -0.002, I2 : 93%) and increased risks of osteoporosis (adjusted risk ratio [RR]: 1.28, 95% CI: 1.08 to 1.52, I2 : 84%) and osteoporotic fractures (adjusted RR: 1.17, 95% CI: 1.00 to 1.37, I2 : 67%). Subgroup analyses revealed that NAFLD had a significantly detrimental effect on BMD in men and on the BMD of the femoral neck and total hip. Stratified analyses by ethnicity demonstrated that NAFLD was not associated with BMD, osteoporosis, or osteoporotic fracture in non-Asian populations. The publication bias of all included studies was low; however, there was considerable heterogeneity among the studies, warranting a careful interpretation of the findings. Overall, our results suggest that NAFLD is associated with decreased BMD and an increased risk of osteoporosis or osteoporotic fractures. Male sex and the BMD of the femoral neck and total hip may be potential risk factors for decreased BMD in adults with NAFLD. Additionally, ethnic disparities were observed between Asian and non-Asian populations regarding BMD and osteoporotic fractures. This article is protected by copyright. All rights reserved.
TL;DR: Faes et al. as discussed by the authors performed a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 mg (0.625 mg) in postmenopausal women with vitamin D deficiency.
Abstract: Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short‐term clinical trials, its effects after long‐term monthly administration have been studied less extensively. This report describes the results of a 1‐year, phase III‐IV, double‐blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention‐to‐treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment‐related safety issues were reported in any of the groups. The results confirm that long‐term treatment with monthly calcifediol in vitamin D‐deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long‐term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , the authors developed an economic model to estimate the benefits and budget impact of fracture liaison services (FLSs) and support their wider international implementation, which was run for an exemplar country the size of the United Kingdom.
Abstract: Osteoporotic‐related fractures cause significant patient disability, leading to a growing burden on health care systems. Effective secondary fracture prevention can be delivered by fracture liaison services (FLSs), but these are not available in most countries. A major barrier is insufficient policy prioritization, helped by the lack of economic assessments using national data and providing estimates of patient outcomes alongside health care resource use and cost impacts. The aim of this study was to develop an economic model to estimate the benefits and budget impact of FLSs and support their wider international implementation. Five interconnected stages were undertaken: establishment of a generic patient pathway; model design; identification of model inputs; internal validation and output generation; and scenario analyses. A generic patient pathway including FLS activities was built to underpin the economic model. A state‐based microsimulation model was developed to estimate the impact of FLSs compared with current practice for men and women aged 50 years or older with a fragility fracture. The model provides estimates for health outcomes (subsequent fractures avoided and quality‐adjusted life years [QALYs]), resource use, and health and social care costs, including those necessary for FLSs to operate, over 5 years. The model was run for an exemplar country the size of the United Kingdom. FLSs were estimated to lead to a reduction of 13,149 subsequent fractures and a gain of 11,709 QALYs. Hospital‐bed days would be reduced by 120,989 and surgeries by 6455, while 3556 person‐years of institutional social care would be avoided. Expected costs per QALY gained placed FLSs as highly cost‐effective at £8258 per QALY gained over the first 5 years. Ten different scenarios were modeled using different configurations of FLSs. Further work to develop country‐specific models is underway to delivery crucial national level data to inform the prioritization of FLSs by policy makers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this article, the effects of PHOSPHO1 ablation on the growth plate lipidome were investigated in healthy mouse knee using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS).
Abstract: Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix‐assisted laser desorption ionization imaging mass spectrometry (MALDI‐IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially‐resolved profiling of PHOSPHO1‐knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild‐type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1‐KO versus WT. Our imaging pipeline has established a spatially‐resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1‐mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , Sostdc1 (Wise) was co-inhibited along with sclerostin to enhance the effects of Wnt modulation on bone homeostasis.
Abstract: The development of Wnt‐based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co‐inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild‐type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , Bmi-1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4-dependent SASP activation led to sarcopenia.
Abstract: Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH)2D3 deficiency could cause cellular senescence and a senescence‐associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH)2D3 deficiency to promote SASP, and whether Bmi‐1 reduces the expression of GATA4 and GATA4‐dependent SASP induced by 1,25(OH)2D3 deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2‐month‐old young and 2‐year‐old physiologically aged wild‐type (WT) mice and 8‐week‐old WT, Bmi‐1 mesenchymal transgene (Bmi‐1Tg), Cyp27b1 homozygous (Cyp27b1−/−), and Bmi‐1TgCyp27b1−/− mice were observed for grip strength, cell senescence, DNA damage, and NF‐κB‐mediated SASP signaling of skeletal muscle. We found that muscle‐derived Bmi‐1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4‐dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH)2D3 deficiency promoted DNA damage‐induced GATA4 accumulation in muscles. GATA4 upregulated Rela at the region from −1448 to −1412 bp at the transcriptional level to cause NF‐κB‐dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. Bmi‐1 overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH)2D3 deficiency. Thus, Bmi‐1 overexpression improves sarcopenia induced by 1,25(OH)2D3 deficiency, downregulates GATA4‐dependent Rela transcription, and sequentially inhibits GATA4‐dependent SASP in muscle cells. Therefore, Bmi‐1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. © 2023 American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this article , a cis-double-variant c.187T>A was identified from a 5-year-old OI patient by whole-exome sequencing (WES) and three peptide nucleic acids (PNAs) were designed and then transfected into patient-derived fibroblasts.
Abstract: Osteogenesis imperfecta (OI) is a hereditary skeletal disorder that is mainly caused by variants in COL1A1/2. So far, no specific treatment has been developed to correct its underlying etiology. We aimed to gain a better understanding of the pathological mechanisms of OI and develop gene therapies to correct OI‐causing variants. A de novel cis‐double‐variant c.[175C>T; 187T>A] in COL1A1 was identified from a 5‐year‐old OI patient by whole‐exome sequencing (WES). Three peptide nucleic acids (PNAs) were designed and then transfected patient‐derived fibroblasts. PNA2 affected the translational strand and induced an optimal interfering effect at 0.25μM concentration, proved by Sanger sequencing, qPCR, Western blot, and immunostaining. Additionally, induced pluripotent stem cells (iPSCs) were cultured from patient‐derived fibroblasts. Clones of iPSCs with c.187T>A variant and those with both variants largely restored their osteogenic capacities after CRISPR/Cas9 gene editing, which corrected the variants. Importantly, correcting c.187T>A variant alone in CRISPR‐edited iPSCs was sufficient to alleviate OI phenotypes, as indicated by increased levels of COL1A1, COL1A2, ALP mRNAs, and COL1A1 protein. Our findings suggest that c.187T>A is the dominant variant of cis‐double‐variant in COL1A1 that led to OI, and PNA interference and CRISPR/Cas9 gene editing may be new therapeutic tools for OI treatment. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this paper , the effect of high dose vitamin D3 on radial and tibial total bone mineral density (TtBMD) measured by high resolution peripheral quantitative tomography (HR-pQCT) was examined.
Abstract: In a 36 month RCT examining the effect of high dose vitamin D3 on radial and tibial total bone mineral density (TtBMD), measured by high resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with DXA T-scores > -2.5, without vitamin D deficiency) were randomized to receive 400 IU (N = 109); 4,000 IU (N = 100); 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24 and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D3 ; 24,25-(OH)2 D3 ; 1,25-(OH)2 D3 ; and 1,24,25-(OH)3 D3 ]. Relationship between peak values in vitamin D metabolites and change in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D3 , 24,25-(OH)2 D3 and 1,24,25-(OH)3 D3 , but no dose-related change in plasma 1,25-(OH)2 D3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH)3 D3 (-0.05, 95%CI -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D3 (female: -0.01, 95%CI -0.12,-0.07; male: -0.04, 95%CI -0.06,-0.01, p = 0.001) and 24,25-(OH)2 D3 (female: -0.75, 95%CI -0.98, -0.52; male: -0.35, 95%CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D3 (-0.03, 95%CI -0.05, -0.01, p < 0.001), and 24,25-(OH)2 D3 (-0.30, 95%CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH)3 D3 (-0.03, 95%CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH)2 D3 may be responsible for the bone loss seen in the Calgary vitamin D Study. Although plasma 1,25-(OH)2 D3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH)3 D3 prevented detection of a dose-related rise in plasma 1,25-(OH)2 D3 . This article is protected by copyright. All rights reserved.
TL;DR: In this paper , the authors present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS.
Abstract: Mild or asymptomatic disease is now the dominating presentation of primary hyperparathyroidism (PHPT). However, bone involvement with decreased bone mineral density (BMD) and an increased risk of fractures has been demonstrated. Indications for parathyroidectomy (PTX) in mild PHPT have been debated for years. There is a need of long‐term randomized studies comparing PTX with observation without intervention (OBS). Here, we present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS. This study included 191 patients (96 OBS/95 PTX), and 129 patients (64 OBS/65 PTX) were followed for 10 years to the end of study (EOS). BMD was measured with dual‐energy X‐ray absorptiometry (DXA), peripheral fractures were noted, and spine radiographs were obtained for vertebral fracture assessment. There was a significant treatment effect of PTX on BMD compared with OBS for all analyzed compartments, most explicit for the lumbar spine (LS) and femoral neck (FN) (p < 0.001). The mean changes in T‐score from baseline to 10 years were from 0.41 for radius 33% (Rad33) to 0.58 for LS greater in the PTX group than in the OBS group. There was a significant decrease in BMD for all compartments in the OBS group, most pronounced for FN, Rad33, and ultradistal radius (UDR) (p < 0.001). Even though there was a significant treatment effect of PTX compared with OBS, there was only a significant increase in BMD over time for LS (p < 0.001). We found no difference between groups in fracture frequency in the 10‐year cohort, neither with modified intention‐to‐treat (mITT) analysis nor per protocol analysis. Because BMD is only a surrogate endpoint of bone health and PTX did not reduce fracture risk, observation could be considered a safe option for many patients with mild PHPT regarding bone health in a 10‐year perspective. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this article , the authors conducted a nationwide register-based cohort study in Finland from 1998 to 2017 and utilized the Medical Birth Register and Care Register for Healthcare to analyze bone fractures during childhood in preterm, and low-birthweight newborns compared to full term and normal birthweight infants.
Abstract: Preterm birth and low birthweight have been associated with increased fracture risk in children. Our aim was to analyze bone fractures during childhood in preterm, and low-birthweight newborns compared to full term and normal birthweight newborns. We conducted a nationwide register-based cohort study in Finland from 1998 to 2017 and utilized the Medical Birth Register and Care Register for Healthcare. All newborns alive 28 days after birth were included and data on all fracture visits in specialized healthcare units were gathered. Incidences per 100,000 person-years with 95% confidence intervals (CI) were calculated, and comparisons were made by incidence rate ratios (IRR). Kaplan-Meier analysis was used to analyze the timing of fractures during childhood (0-20 years). We included a total of 997,468 newborns and 95,869 fractures, the mean follow-up was 10.0 years and the overall incidence of fractures 963 per 100,000 person-years. Very preterm (<32 gestational weeks) newborns had 23% lower fracture incidence than term newborns (IRR 0.77; CI 0.70-0.85). Preterm newborns (32 to 36 gestational weeks) had similar fracture rate (IRR 0.98; CI 0.95-1.01) to term newborns. Birthweight showed linear increase in the fracture rates as newborns with birthweight less than 1000 g had the lowest fracture incidence 773 per 100,000 person-years and the highest incidence (966 per 100,000 person-years) was among newborns with birthweight 2500 g or more. Children born very preterm or with extremely low birth weight have in general a lower fracture incidence during childhood compared to children born full term and with normal birthweight. These findings possibly reflect, in addition to improvements of neonatal intensive care and early nutrition, the fact that childhood fracture incidences are more dependent on other issues than early life events.
TL;DR: In this article , the authors investigated a pedigree with unexplained high bone mass within the UK HBM study, a national cohort of probands with HBM and their relatives, and found that rare heterozygous loss of function variants in GALNT3 may cause HBM without altering phosphate concentration.
Abstract: Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo‐Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt‐bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi‐allelic loss‐of‐function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome‐wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome‐wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss‐of‐function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
TL;DR: In this article , the authors reported that the tube current was set to 320 mA, when in fact the setting was 200 mA and captured 15 cm each of the distal femur and proximal tibia.
Abstract: We wish to correct a statement in our manuscript regarding the computed tomography acquisition settings. In the CT Imaging section, we originally reported that the tube current was set to 320 mA, when in fact the setting was 200 mA. The correct sentence should appear as: Regardless of machine, all CT scans were acquired with settings of 120 kVp and 200 mA, and captured 15 cm each of the distal femur and proximal tibia.