Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents — particularly maltoses — of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.
{"title":"Iron and bones: Effects of iron overload, deficiency and anemia treatments on bone","authors":"Felix N von Brackel, Ralf Oheim","doi":"10.1093/jbmrpl/ziae064","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae064","url":null,"abstract":"\u0000 Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents — particularly maltoses — of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140980733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brandon R. Grossardt, Hilal Maradit Kremers, Adam R Miller, Bertram L. Kasiske, Arthur J Matas, Sundeep Khosla, Walter K. Kremers, Hatem Amer, Rajiv Kumar
In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared to matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products (AGEs) in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P < 0.001), increases in both parathyroid hormone (PTH when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P = 0.03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P < 0.001) and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency towards thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures.
{"title":"Persistent changes in calcium-regulating hormones and bone turnover markers in living kidney donors more than 20 years after donation","authors":"Brandon R. Grossardt, Hilal Maradit Kremers, Adam R Miller, Bertram L. Kasiske, Arthur J Matas, Sundeep Khosla, Walter K. Kremers, Hatem Amer, Rajiv Kumar","doi":"10.1093/jbmrpl/ziae067","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae067","url":null,"abstract":"\u0000 In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared to matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products (AGEs) in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P < 0.001), increases in both parathyroid hormone (PTH when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P = 0.03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P < 0.001) and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency towards thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140982050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Dahir, Steven W Ing, Chad Deal, Andrew Messali, Toby Bates, E. Rush
Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. This study assessed the impact of treatment with asfotase alfa on patient-reported outcomes (PROs) in adults with pediatric-onset HPP. A longitudinal telephone-based survey was administered to eligible individuals enrolled in a patient support program. Interviews were conducted at study entry (prior to asfotase alfa initiation) and after 3, 6, and 12 months. PROs—Patient Health Questionnaire-9 [PHQ-9], Work Productivity and Activity Impairment–Specific Health Problem [WPAI:SHP], Patient-Reported Outcomes Measurement Information System 29 [PROMIS-29], and Routine Assessment of Patient Index Data 3 [RAPID3]—were assessed at each time point. Appropriate statistical tests were performed to assess score changes. Among 50 enrolled patients (mean age: 46 years [SD: 15.4]; 80% female; 94% white), 49 were evaluable at 3 months, 44 at 6 months, and 29 at 12 months. By Month 3, statistically significant improvements from baseline were detected in PHQ-9 scores (10.6 vs. 5.8 [p < 0.0001]), PROMIS-29 domain scores (overall physical function: 38.0 vs. 43.0 [p = 0.001]; anxiety: 57.5 vs. 51.5 [p = 0.0011]; fatigue: 63.3 vs. 55.3 [p < 0.0001]; sleep disturbances: 58.8 vs. 54.3 [p = 0.0099]; ability to participate in social roles and activities: 42.6 vs. 47.7 [p = 0.0012]; and pain interference: 63.8 vs. 58.4 [p = 0.001]) and RAPID3 domain scores (functional status: 2.7 vs. 1.1 [p < 0.0001]; pain tolerance: 6.0 vs. 3.2 [p < 0.0001]; and global health estimate: 5.1 vs. 2.7 [p < 0.0001]). Improvements persisted at Month 12. Patients also showed improvements in WPAI:SHP domain scores at Month 6 (presenteeism: 39.6% vs. 14.1% [p < 0.0001] and work productivity loss: 41.9% vs. 14.1% [p < 0.0001]). Treatment with asfotase alfa was associated with improved quality of life across several domains.
低磷酸盐血症（HPP）是一种罕见的遗传性代谢性疾病，由组织非特异性碱性磷酸酶活性不足引起。本研究评估了使用阿斯福通α治疗对儿童型HPP成人患者报告结果（PROs）的影响。研究人员通过电话对参加患者支持计划的合格患者进行了纵向调查。访谈在研究开始时（开始使用阿斯福太酶α之前）以及 3、6 和 12 个月后进行。在每个时间点都对PROs--患者健康问卷-9 [PHQ-9]、工作效率和活动障碍--特定健康问题[WPAI:SHP]、患者报告结果测量信息系统29 [PROMIS-29]和患者指数数据常规评估3 [RAPID3]进行了评估。对评分变化进行了适当的统计检验。在 50 名入组患者中（平均年龄：46 岁 [标码：15.4]；80% 为女性；94% 为白人），49 人在 3 个月时接受了评估，44 人在 6 个月时接受了评估，29 人在 12 个月时接受了评估。到第 3 个月时，PHQ-9 评分（10.6 vs. 5.8 [p < 0.0001]）、PROMIS-29 领域评分（总体身体功能：38.0 vs. 43.0 [p<0.0001]）与基线相比均有统计学意义上的显著改善：63.3 vs. 55.3 [p < 0.0001]；睡眠障碍：58.8 vs. 54.3 [p = 0.0099]；参与社会角色和活动的能力：42.6 vs. 47.7 [p = 0.0012]；疼痛干扰：63.8 vs. 58.4 [p = 0.001]）和 RAPID3 领域得分（功能状态：2.7 vs. 1.1 [p < 0.0001]；疼痛耐受性：6.0 vs. 3.2 [p < 0.0001]；总体健康估计：5.1 vs. 2.7 [p < 0.0001]）。这些改善在第 12 个月仍在持续。第 6 个月时，患者的 WPAI:SHP 领域得分也有所改善（缺勤率：39.6% vs. 14.0% [p < 0.0001]）：39.6% vs. 14.1% [p < 0.0001]）和工作效率损失（41.9% vs. 14.1% [p < 0.0001]）：41.9% vs. 14.1% [p < 0.0001]）。阿斯福通α治疗与多个领域的生活质量改善相关。
{"title":"Improvement in quality of life after Asfotase Alfa treatment in adults with Pediatric-onset Hypophosphatasia: data from 5 patient-reported outcome measures","authors":"K. Dahir, Steven W Ing, Chad Deal, Andrew Messali, Toby Bates, E. Rush","doi":"10.1093/jbmrpl/ziae062","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae062","url":null,"abstract":"\u0000 Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. This study assessed the impact of treatment with asfotase alfa on patient-reported outcomes (PROs) in adults with pediatric-onset HPP. A longitudinal telephone-based survey was administered to eligible individuals enrolled in a patient support program. Interviews were conducted at study entry (prior to asfotase alfa initiation) and after 3, 6, and 12 months. PROs—Patient Health Questionnaire-9 [PHQ-9], Work Productivity and Activity Impairment–Specific Health Problem [WPAI:SHP], Patient-Reported Outcomes Measurement Information System 29 [PROMIS-29], and Routine Assessment of Patient Index Data 3 [RAPID3]—were assessed at each time point. Appropriate statistical tests were performed to assess score changes. Among 50 enrolled patients (mean age: 46 years [SD: 15.4]; 80% female; 94% white), 49 were evaluable at 3 months, 44 at 6 months, and 29 at 12 months. By Month 3, statistically significant improvements from baseline were detected in PHQ-9 scores (10.6 vs. 5.8 [p < 0.0001]), PROMIS-29 domain scores (overall physical function: 38.0 vs. 43.0 [p = 0.001]; anxiety: 57.5 vs. 51.5 [p = 0.0011]; fatigue: 63.3 vs. 55.3 [p < 0.0001]; sleep disturbances: 58.8 vs. 54.3 [p = 0.0099]; ability to participate in social roles and activities: 42.6 vs. 47.7 [p = 0.0012]; and pain interference: 63.8 vs. 58.4 [p = 0.001]) and RAPID3 domain scores (functional status: 2.7 vs. 1.1 [p < 0.0001]; pain tolerance: 6.0 vs. 3.2 [p < 0.0001]; and global health estimate: 5.1 vs. 2.7 [p < 0.0001]). Improvements persisted at Month 12. Patients also showed improvements in WPAI:SHP domain scores at Month 6 (presenteeism: 39.6% vs. 14.1% [p < 0.0001] and work productivity loss: 41.9% vs. 14.1% [p < 0.0001]). Treatment with asfotase alfa was associated with improved quality of life across several domains.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141001986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saija Mikkilä, B. Handegård, Jonas Johansson, L. Hopstock, Roland van den Tillaar, N. Emaus, B. Morseth, Boye Welde
Positive associations between physical activity and bone health have been found in population-based studies, however, mostly based on self-reported physical activity. Therefore, we investigated the association between accelerometer-measured physical activity, measured in steps per day and minutes of moderate to vigorous physical activity (MVPA) per day, and total hip areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry in a general population, utilizing multiple regression models. The study participants, 1560 women and 1177 men aged 40–84 years, were part of the seventh survey of the Tromsø Study (2015–2016). In both genders, we found a positive association between the number of daily steps and aBMD adjusted for age, body mass index (BMI), and smoking status (p < .001). In women, an increase of 1000 steps per day was associated with 0.005 g/cm2 higher aBMD. For men, a polynomial curve indicated a positive association with aBMD up to 5000 steps per day, plateauing between 5000 and 14 000 steps, and then increasing again. Additionally, MVPA duration was positively associated with aBMD in both women (p < .001) and men (p = .004) when adjusted for age, BMI, and smoking status. Specifically, each 60-minute increase in daily MVPA was associated with 0.028 g/cm2 and 0.023 g/cm2 higher aBMD in women and men, respectively. Despite positive associations, the clinical impact of physical activity on aBMD in this general population of adults and older adults was relatively small, and a large increase in daily MVPA might not be achievable for most individuals. Therefore, further longitudinal population-based studies, incorporating device-based measures of physical activity could add more clarity to these relationships.
{"title":"Cross-sectional associations between accelerometer-measured physical activity and hip bone mineral density. The Tromsø study 2015–2016","authors":"Saija Mikkilä, B. Handegård, Jonas Johansson, L. Hopstock, Roland van den Tillaar, N. Emaus, B. Morseth, Boye Welde","doi":"10.1093/jbmrpl/ziae061","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae061","url":null,"abstract":"\u0000 Positive associations between physical activity and bone health have been found in population-based studies, however, mostly based on self-reported physical activity. Therefore, we investigated the association between accelerometer-measured physical activity, measured in steps per day and minutes of moderate to vigorous physical activity (MVPA) per day, and total hip areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry in a general population, utilizing multiple regression models. The study participants, 1560 women and 1177 men aged 40–84 years, were part of the seventh survey of the Tromsø Study (2015–2016).\u0000 In both genders, we found a positive association between the number of daily steps and aBMD adjusted for age, body mass index (BMI), and smoking status (p < .001). In women, an increase of 1000 steps per day was associated with 0.005 g/cm2 higher aBMD. For men, a polynomial curve indicated a positive association with aBMD up to 5000 steps per day, plateauing between 5000 and 14 000 steps, and then increasing again. Additionally, MVPA duration was positively associated with aBMD in both women (p < .001) and men (p = .004) when adjusted for age, BMI, and smoking status. Specifically, each 60-minute increase in daily MVPA was associated with 0.028 g/cm2 and 0.023 g/cm2 higher aBMD in women and men, respectively.\u0000 Despite positive associations, the clinical impact of physical activity on aBMD in this general population of adults and older adults was relatively small, and a large increase in daily MVPA might not be achievable for most individuals. Therefore, further longitudinal population-based studies, incorporating device-based measures of physical activity could add more clarity to these relationships.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dorina Condurache, Stefania D’angelo, Ahmed M. Salih, Liliana Szabo, C. Mccracken, Adil Mahmood, Elizabeth M Curtis, André Altmann, Steffen E Petersen, N. C. Harvey, Z. Raisi-Estabragh
This study examined the association of estimated heel bone mineral density (eBMD, derived from quantitative ultrasound) with: 1) prevalent and incident cardiovascular diseases (CVDs: ischaemic heart disease (IHD), myocardial infarction (MI), heart failure, non-ischaemic cardiomyopathy (NICM), arrhythmia), 2) mortality (all-cause, CVD, IHD), and 3) cardiovascular magnetic resonance (CMR) measures of left ventricular and atrial structure and function and aortic distensibility, in the UK Biobank. Clinical outcomes were ascertained using health record linkage over 12.3 years of prospective follow-up. Two-sample Mendelian randomization (MR) was conducted to assess causal associations between BMD and CMR metrics using genetic instrumental variables identified from published genome-wide association studies. The analysis included 485 257 participants (55% women, mean age 56.5 ± 8.1 years). Higher heel eBMD was associated with lower odds of all prevalent CVDs considered. The greatest magnitude of effect was seen in association with heart failure and NICM, where 1-SD increase in eBMD was associated with 15% lower odds of heart failure and 16% lower odds of NICM. Association between eBMD and incident IHD and MI were non-significant; the strongest relationship was with incident heart failure (SHR: 0.90 [95% CI: 0.89-0.92]). Higher eBMD was associated with a decreased risk in all-cause, CVD, and IHD mortality, in the fully adjusted model. Higher eBMD was associated with greater aortic distensibility; associations with other CMR metrics were null. Higher heel eBMD is linked to reduced risk of a range of prevalent and incident CVD and mortality outcomes. While observational analyses suggest associations between higher eBMD and greater aortic compliance, MR analysis did not support a causal relationship between genetically predicted BMD and CMR phenotypes. These findings support the notion that bone-cardiovascular associations reflect shared risk factors/mechanisms rather than direct causal pathways.
{"title":"Bone health, cardiovascular disease and imaging outcomes in UK biobank: a causal analysis","authors":"Dorina Condurache, Stefania D’angelo, Ahmed M. Salih, Liliana Szabo, C. Mccracken, Adil Mahmood, Elizabeth M Curtis, André Altmann, Steffen E Petersen, N. C. Harvey, Z. Raisi-Estabragh","doi":"10.1093/jbmrpl/ziae058","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae058","url":null,"abstract":"\u0000 This study examined the association of estimated heel bone mineral density (eBMD, derived from quantitative ultrasound) with: 1) prevalent and incident cardiovascular diseases (CVDs: ischaemic heart disease (IHD), myocardial infarction (MI), heart failure, non-ischaemic cardiomyopathy (NICM), arrhythmia), 2) mortality (all-cause, CVD, IHD), and 3) cardiovascular magnetic resonance (CMR) measures of left ventricular and atrial structure and function and aortic distensibility, in the UK Biobank.\u0000 Clinical outcomes were ascertained using health record linkage over 12.3 years of prospective follow-up. Two-sample Mendelian randomization (MR) was conducted to assess causal associations between BMD and CMR metrics using genetic instrumental variables identified from published genome-wide association studies.\u0000 The analysis included 485 257 participants (55% women, mean age 56.5 ± 8.1 years). Higher heel eBMD was associated with lower odds of all prevalent CVDs considered. The greatest magnitude of effect was seen in association with heart failure and NICM, where 1-SD increase in eBMD was associated with 15% lower odds of heart failure and 16% lower odds of NICM. Association between eBMD and incident IHD and MI were non-significant; the strongest relationship was with incident heart failure (SHR: 0.90 [95% CI: 0.89-0.92]). Higher eBMD was associated with a decreased risk in all-cause, CVD, and IHD mortality, in the fully adjusted model. Higher eBMD was associated with greater aortic distensibility; associations with other CMR metrics were null.\u0000 Higher heel eBMD is linked to reduced risk of a range of prevalent and incident CVD and mortality outcomes. While observational analyses suggest associations between higher eBMD and greater aortic compliance, MR analysis did not support a causal relationship between genetically predicted BMD and CMR phenotypes. These findings support the notion that bone-cardiovascular associations reflect shared risk factors/mechanisms rather than direct causal pathways.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Britt Opdebeeck, Astrid Van den Branden, Saar Adriaensen, I. Orriss, J. Patel, Hilde Geryl, Kathleen Zwijsen, P. D’Haese, A. Verhulst
Arterial media calcification or pathological deposition of calcium-phosphate crystals in the vessel wall contributes significantly to the high mortality rate observed in patients with chronic kidney disease (CKD). Extracellular nucleotides (i.e. ATP or UTP) regulate the arterial calcification process by interacting with (i) purinergic receptors and (ii) breakdown via ecto-nucleotidases such as NPP1 or NPP3 affecting the local levels of calcification inhibitor, pyrophosphate, and –stimulator inorganic phosphate (PPi/Pi ratio). Also, it has been shown that ATP analogs (i.e. β,γ-meATP) inhibit vascular smooth muscle cell calcification in vitro. In the first experiment, daily dosing of β,γ-meATP (2 mg/kg) was investigated in rats, receiving a warfarin diet to trigger the development of non-CKD related arterial medial calcifications. This study showed that β,γ-meATP significantly lowered the calcium scores in the aorta and peripheral vessels in warfarin-exposed rats. In a second experiment, daily dosing of 4 mg/kg β,γ-meATP, and its metabolite medronic acid (MDP) was analyzed in rats receiving an adenine diet to promote the development of CKD-related arterial medial calcification. β,γ-meATP, and MDP did not significantly decrease aortic calcification scores in this model. Moreover, both compounds induced deleterious effects on physiological bone mineralization causing an imminent risk for worsening the already compromised bone status in CKD. Due to this, it was not possible to raise the dosage of both compounds to tackle CKD-related arterial calcification. Again, this points out the difficult task; targeting solely ectopic calcifications without negatively affecting physiological bone mineralization. On the other hand, aortic mRNA expression of Enpp1 and Enpp3 was significantly and positively associated with aortic calcification scores, suggesting that normalizing the aortic NPP1/3 activity to control values might be a possible target to treat (CKD-induced) arterial media calcifications.
{"title":"β,γ-methylene-ATP and its metabolite medronic acid affect both arterial media calcification and bone mineralization in non-CKD and CKD ratso","authors":"Britt Opdebeeck, Astrid Van den Branden, Saar Adriaensen, I. Orriss, J. Patel, Hilde Geryl, Kathleen Zwijsen, P. D’Haese, A. Verhulst","doi":"10.1093/jbmrpl/ziae057","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae057","url":null,"abstract":"\u0000 Arterial media calcification or pathological deposition of calcium-phosphate crystals in the vessel wall contributes significantly to the high mortality rate observed in patients with chronic kidney disease (CKD). Extracellular nucleotides (i.e. ATP or UTP) regulate the arterial calcification process by interacting with (i) purinergic receptors and (ii) breakdown via ecto-nucleotidases such as NPP1 or NPP3 affecting the local levels of calcification inhibitor, pyrophosphate, and –stimulator inorganic phosphate (PPi/Pi ratio). Also, it has been shown that ATP analogs (i.e. β,γ-meATP) inhibit vascular smooth muscle cell calcification in vitro. In the first experiment, daily dosing of β,γ-meATP (2 mg/kg) was investigated in rats, receiving a warfarin diet to trigger the development of non-CKD related arterial medial calcifications. This study showed that β,γ-meATP significantly lowered the calcium scores in the aorta and peripheral vessels in warfarin-exposed rats. In a second experiment, daily dosing of 4 mg/kg β,γ-meATP, and its metabolite medronic acid (MDP) was analyzed in rats receiving an adenine diet to promote the development of CKD-related arterial medial calcification. β,γ-meATP, and MDP did not significantly decrease aortic calcification scores in this model. Moreover, both compounds induced deleterious effects on physiological bone mineralization causing an imminent risk for worsening the already compromised bone status in CKD. Due to this, it was not possible to raise the dosage of both compounds to tackle CKD-related arterial calcification. Again, this points out the difficult task; targeting solely ectopic calcifications without negatively affecting physiological bone mineralization. On the other hand, aortic mRNA expression of Enpp1 and Enpp3 was significantly and positively associated with aortic calcification scores, suggesting that normalizing the aortic NPP1/3 activity to control values might be a possible target to treat (CKD-induced) arterial media calcifications.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140677671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-20eCollection Date: 2024-05-01DOI: 10.1093/jbmrpl/ziae043
Alexandra Kachaner, Raphaèle Seror, Fleur Cohen Aubart, Julien Henry, Thierry Lazure, Jean François Emile, Xavier Mariette, Samuel Bitoun
Langerhans cell histiocytosis (LCH) is a rare disease with limited treatment options. We present a case involving a 57-year-old woman afflicted with an isolated LCH bone osteolytic lesion. A single bisphosphonate infusion significantly alleviated pain, and follow-up scans via CT, PET-CT, and MRI revealed a substantial recalcification of the lesion. Conducting an extensive literature review, we identified 46 cases documenting the efficacy of bisphosphonates in the context of LCH. These findings have raised interest in bisphosphonate infusion as a simple therapeutic alternative in similar situations, with benefits in terms of bone recalcification and pain control for individuals with LCH.
{"title":"Complete remission after a single bisphosphonate infusion in isolated bone Langerhans cell histiocytosis lesion: a case report and a narrative review of the literature.","authors":"Alexandra Kachaner, Raphaèle Seror, Fleur Cohen Aubart, Julien Henry, Thierry Lazure, Jean François Emile, Xavier Mariette, Samuel Bitoun","doi":"10.1093/jbmrpl/ziae043","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae043","url":null,"abstract":"<p><p>Langerhans cell histiocytosis (LCH) is a rare disease with limited treatment options. We present a case involving a 57-year-old woman afflicted with an isolated LCH bone osteolytic lesion. A single bisphosphonate infusion significantly alleviated pain, and follow-up scans via CT, PET-CT, and MRI revealed a substantial recalcification of the lesion. Conducting an extensive literature review, we identified 46 cases documenting the efficacy of bisphosphonates in the context of LCH. These findings have raised interest in bisphosphonate infusion as a simple therapeutic alternative in similar situations, with benefits in terms of bone recalcification and pain control for individuals with LCH.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11032215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Large-scale studies on the risk of fragility fractures in patients with primary biliary cholangitis (PBC) are limited due to low incidence. We aimed to investigate whether PBC is associated with fragility fractures using real-world nationwide data. The Korean National Health Insurance Service claims data from 2007 to 2020 were analyzed in this population-based cohort study. Patients with PBC (n = 4951) were matched with controls (n = 19 793) using a 1:4 ratio based on age, sex, and follow-up duration. The primary outcome was fragility fracture, which comprised fractures of the vertebra, hip, distal radius, and proximal humerus. The incidence rates (IRs) and hazard ratios (HRs) were determined to assess the impact of PBC on fragility fractures. During the median follow-up period of 5.37 years, 524 patients in the PBC group had fragility fractures (IR, 18.59/1000 person-years [PYs]). After adjusting for covariates, PBC increased the risk of fragility fractures by 1.63-fold (95% confidence interval, 1.20–2.22; P = 0.002). The vertebra and hip were particularly susceptible to fracture in patients with PBC, with adjusted HRs of 1.77 and 2.23, respectively. In the subgroup analysis, the risk of fragility fracture was 2.53-fold higher in men and 1.59-fold higher in women with PBC than that in the respective matched control groups. Considering the morbidity and mortality related to fragility fractures, increasing awareness of fragility fracture risk and implementing appropriate preventive measures in patients with PBC are imperative.
{"title":"Increased Risk of Fragility Fractures in Patients with Primary Biliary Cholangitis","authors":"Jihye Lim, Ye-Jee Kim, Sehee Kim, Jonggi Choi","doi":"10.1093/jbmrpl/ziae056","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae056","url":null,"abstract":"\u0000 Large-scale studies on the risk of fragility fractures in patients with primary biliary cholangitis (PBC) are limited due to low incidence. We aimed to investigate whether PBC is associated with fragility fractures using real-world nationwide data. The Korean National Health Insurance Service claims data from 2007 to 2020 were analyzed in this population-based cohort study. Patients with PBC (n = 4951) were matched with controls (n = 19 793) using a 1:4 ratio based on age, sex, and follow-up duration. The primary outcome was fragility fracture, which comprised fractures of the vertebra, hip, distal radius, and proximal humerus. The incidence rates (IRs) and hazard ratios (HRs) were determined to assess the impact of PBC on fragility fractures. During the median follow-up period of 5.37 years, 524 patients in the PBC group had fragility fractures (IR, 18.59/1000 person-years [PYs]). After adjusting for covariates, PBC increased the risk of fragility fractures by 1.63-fold (95% confidence interval, 1.20–2.22; P = 0.002). The vertebra and hip were particularly susceptible to fracture in patients with PBC, with adjusted HRs of 1.77 and 2.23, respectively. In the subgroup analysis, the risk of fragility fracture was 2.53-fold higher in men and 1.59-fold higher in women with PBC than that in the respective matched control groups. Considering the morbidity and mortality related to fragility fractures, increasing awareness of fragility fracture risk and implementing appropriate preventive measures in patients with PBC are imperative.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140683474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Low back pain derived from intervertebral disc (IVD) degeneration is a debilitating spinal condition that, despite its prevalence, does not have any intermediary guidelines for treatment between palliative care and invasive surgery. The development of treatments for the IVD is complicated by the variety of resident cell types needed to maintain the regionally distinct structural properties of the IVD that permit the safe, complex motions of the spine. Osteoporosis of the spine increases the risk of vertebral bone fracture and can increase the incidence of back pain. Fortunately, there are a variety of pharmacological treatments for osteoporosis that target osteoblasts, osteoclasts and/or osteocytes to build bone and prevent vertebral fracture. Of particular note, clinical and preclinical studies suggest that commonly prescribed osteoporosis drugs like bisphosphonates, intermittent parathyroid hormone, anti-sclerostin antibody, selective estrogen receptor modulators (SERM) and anti-RANKL inhibitor denosumab may also relieve back pain. Here, we cite clinical and preclinical studies and include unpublished data to support the argument that a subset of these therapeutics for osteoporosis may alleviate low back pain by also targeting the IVD.
{"title":"Osteoporosis treatments for intervertebral disc degeneration and back pain: a perspective","authors":"Neharika Bhadouria, N. Holguin","doi":"10.1093/jbmrpl/ziae048","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae048","url":null,"abstract":"\u0000 Low back pain derived from intervertebral disc (IVD) degeneration is a debilitating spinal condition that, despite its prevalence, does not have any intermediary guidelines for treatment between palliative care and invasive surgery. The development of treatments for the IVD is complicated by the variety of resident cell types needed to maintain the regionally distinct structural properties of the IVD that permit the safe, complex motions of the spine. Osteoporosis of the spine increases the risk of vertebral bone fracture and can increase the incidence of back pain. Fortunately, there are a variety of pharmacological treatments for osteoporosis that target osteoblasts, osteoclasts and/or osteocytes to build bone and prevent vertebral fracture. Of particular note, clinical and preclinical studies suggest that commonly prescribed osteoporosis drugs like bisphosphonates, intermittent parathyroid hormone, anti-sclerostin antibody, selective estrogen receptor modulators (SERM) and anti-RANKL inhibitor denosumab may also relieve back pain. Here, we cite clinical and preclinical studies and include unpublished data to support the argument that a subset of these therapeutics for osteoporosis may alleviate low back pain by also targeting the IVD.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140687098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gang Peng, Padmini J. Deosthale, Roquelina Pianeta, Hannah M Messermith, Lilian I Plotkin
Low levels of the microRNA (miR) 21 may explain the increase in osteocyte apoptosis with Cx43-deficient and aged female mice. However, miR21 exerts a sex-divergent role in osteocytes, regulating bone mass and architecture through non-cell autonomous effects on osteoblasts and osteoclasts, via sex-specific regulation of osteocyte cytokine production. miR21 deficiency improves bone strength in females, and, to a higher extent, in male miR21-deficient mice. To understand the molecular basis for the effects of miR21 deletion, mRNA was isolated from miR21fl/fl (controls) or miR21-deficient (by deletion in cells expressing Cre recombinase under the control of the 8 kb fragment of the DMP1 promoter (miR21ΔOt mice). miR21 was 50% lower in miR21ΔOt whole calvaria bone, compared to control mice of the corresponding sex. RNAseq was performed in 4 samples/sex and genotype. There were 152 genes with <0.05 p-value and > 1 absolute log2 fold change in the male data analysis, and expression of most genes was higher in the miR21fl/fl group. Two of the genes, Actn3 and Myh4, had a false discovery rate < 0.1. Gene enrichment analysis of significant genes on both KEGG pathways and GO gene sets shows the significant genes were enriched in muscle contraction. Some muscle related genes like Actn3 were included in multiple significant pathways. For females, only 65 genes had p-value <0.05 and > 1 absolute log2 fold change. Yet, no significant KEGG or GO pathways including ≥5 significant genes were seen, and no overlap of significant genes was found between male and female samples. Therefore, deletion of miR21 has a stronger effect on male transcriptome in calvaria, compared to females. Further, no enrichment of any pathway was detected in female samples. Thus, either there are no differences between two groups in female or the effect size is small, and a larger sample size is needed to uncover miR21-dependent differences.
{"title":"Sex dimorphic response to osteocyte miR21 deletion in murine calvaria bone as determined by RNAseq analysis","authors":"Gang Peng, Padmini J. Deosthale, Roquelina Pianeta, Hannah M Messermith, Lilian I Plotkin","doi":"10.1093/jbmrpl/ziae054","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae054","url":null,"abstract":"\u0000 Low levels of the microRNA (miR) 21 may explain the increase in osteocyte apoptosis with Cx43-deficient and aged female mice. However, miR21 exerts a sex-divergent role in osteocytes, regulating bone mass and architecture through non-cell autonomous effects on osteoblasts and osteoclasts, via sex-specific regulation of osteocyte cytokine production. miR21 deficiency improves bone strength in females, and, to a higher extent, in male miR21-deficient mice. To understand the molecular basis for the effects of miR21 deletion, mRNA was isolated from miR21fl/fl (controls) or miR21-deficient (by deletion in cells expressing Cre recombinase under the control of the 8 kb fragment of the DMP1 promoter (miR21ΔOt mice). miR21 was 50% lower in miR21ΔOt whole calvaria bone, compared to control mice of the corresponding sex. RNAseq was performed in 4 samples/sex and genotype. There were 152 genes with <0.05 p-value and > 1 absolute log2 fold change in the male data analysis, and expression of most genes was higher in the miR21fl/fl group. Two of the genes, Actn3 and Myh4, had a false discovery rate < 0.1. Gene enrichment analysis of significant genes on both KEGG pathways and GO gene sets shows the significant genes were enriched in muscle contraction. Some muscle related genes like Actn3 were included in multiple significant pathways. For females, only 65 genes had p-value <0.05 and > 1 absolute log2 fold change. Yet, no significant KEGG or GO pathways including ≥5 significant genes were seen, and no overlap of significant genes was found between male and female samples. Therefore, deletion of miR21 has a stronger effect on male transcriptome in calvaria, compared to females. Further, no enrichment of any pathway was detected in female samples. Thus, either there are no differences between two groups in female or the effect size is small, and a larger sample size is needed to uncover miR21-dependent differences.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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