Endocrinology and Metabolism

Original Articles

Calcium & Bone Metabolism
Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis: Sung Hye Kong, Han Na Jang, Jung Hee Kim, Sang Wan Kim, Chan Soo Shin; Endocrinol Metab. 2022;37(2):344-358. Published online April 25, 2022; DOI: https://doi.org/10.3803/EnM.2021.1374

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Background
Although recent studies comparing various dosages and intervals of vitamin D supplementation have been published, it is yet to be elucidated whether there is an appropriate dose or interval to provide benefit regarding fracture risk. We aimed to assess the published evidence available to date regarding the putative beneficial effects of vitamin D supplements on fractures and falls according to various dosages and intervals.
Methods
We performed a meta-analysis of randomized controlled studies reporting associations between vitamin D supplementation and the risks of fractures and falls in PubMed, EMBASE, and Cochrane library. Studies with supplements of ergocalciferol or calcitriol, those with a number of event ≤10, or those with a follow-up duration of less than 6 months were also excluded.
Results
Thirty-two studies were included in the final analysis. Vitamin D supplementation with daily dose of 800 to 1,000 mg was associated with lower risks of osteoporotic fracture and fall (pooled relative risk [RR], 0.87; 95% confidence interval [CI], 0.78 to 0.97 and RR, 0.91; 95% CI, 0.85 to 0.98), while studies with <800 or >1,000 mg/day did not. Also, among intervals, daily administration of vitamin D was associated with the reduced risk of falls, while intermittent dose was not. Also, patients with vitamin D deficiency showed a significant risk reduction of falls after vitamin D supplementation.
Conclusion
Daily vitamin D dose of 800 to 1,000 IU was the most probable way to reduce the fracture and fall risk. Further studies designed with various regimens and targeted vitamin D levels are required to elucidate the benefits of vitamin D supplements.

Citations

Citations to this article as recorded by

Ukrainian Consensus on Diagnosis and Management of Vitamin D Deficiency in Adults
Nataliia Grygorieva, Mykola Tronko, Volodymir Kovalenko, Serhiy Komisarenko, Tetiana Tatarchuk, Ninel Dedukh, Mykola Veliky, Serhiy Strafun, Yulia Komisarenko, Andrii Kalashnikov, Valeria Orlenko, Volodymyr Pankiv, Oleg Shvets, Inna Gogunska, Svitlana Reg
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Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population
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Clinical Characteristics and Outcomes of Limb Fractures in Saudi Children
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Clinical Rheumatology.2024; 43(5): 1421. CrossRef
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Bone Reports.2024; 20: 101750. CrossRef
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The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review
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Nutrients.2024; 16(15): 2420. CrossRef
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Gianpaolo Voltan, Nicola Veronese
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Frontiers in Nutrition.2023;[Epub] CrossRef
Vitamin D and Calcium in Osteoporosis, and the Role of Bone Turnover Markers: A Narrative Review of Recent Data from RCTs
Gavriela Voulgaridou, Sousana K. Papadopoulou, Paraskevi Detopoulou, Despoina Tsoumana, Constantinos Giaginis, Foivi S. Kondyli, Evgenia Lymperaki, Agathi Pritsa
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Yaohui Yu, Yudan Wang, Xiaoli Hou, Faming Tian
Frontiers in Public Health.2023;[Epub] CrossRef
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Safety Profile of Vitamin D in Italy: An Analysis of Spontaneous Reports of Adverse Reactions Related to Drugs and Food Supplements
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Cholecalciferol Use Is Associated With a Decreased Risk of Incident Morphometric Vertebral Fractures in Acromegaly
Sabrina Chiloiro, Stefano Frara, Irene Gagliardi, Antonio Bianchi, Antonella Giampietro, Margherita Medici, Agnese Allora, Luigi di Filippo, Maria Rosaria Ambrosio, Alfredo Pontecorvi, Maria Chiara Zatelli, Laura De Marinis, Andrea Giustina
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Diagnosis, prevention and treatment of vitamin D deficiency in adults: Ukrainian experts consensus statement
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Serum 25-Hydroxyvitamin D Level Is Negatively Associated with Fatigue in Elderly Maintenance Hemodialysis Patients
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Dario Calafiore, Leonzio Fortunato, Mario Migliario
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Malnutrition in Older Adults—Effect on Falls and Fractures: A Narrative Review
Malgorzata Kupisz-Urbanska, Ewa Marcinowska-Suchowierska
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Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group
Thierry Chevalley, Maria Luisa Brandi, Kevin D. Cashman, Etienne Cavalier, Nicholas C. Harvey, Stefania Maggi, Cyrus Cooper, Nasser Al-Daghri, Oliver Bock, Olivier Bruyère, Mario Miguel Rosa, Bernard Cortet, Alfonso J. Cruz-Jentoft, Antonio Cherubini, Bes
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The Relationship of Osteoporosis with Menopause: Review of Article
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Calcium & Bone Metabolism
Development of a Spine X-Ray-Based Fracture Prediction Model Using a Deep Learning Algorithm: Sung Hye Kong, Jae-Won Lee, Byeong Uk Bae, Jin Kyeong Sung, Kyu Hwan Jung, Jung Hee Kim, Chan Soo Shin; Endocrinol Metab. 2022;37(4):674-683. Published online August 5, 2022; DOI: https://doi.org/10.3803/EnM.2022.1461

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Background
Since image-based fracture prediction models using deep learning are lacking, we aimed to develop an X-ray-based fracture prediction model using deep learning with longitudinal data.
Methods
This study included 1,595 participants aged 50 to 75 years with at least two lumbosacral radiographs without baseline fractures from 2010 to 2015 at Seoul National University Hospital. Positive and negative cases were defined according to whether vertebral fractures developed during follow-up. The cases were divided into training (n=1,416) and test (n=179) sets. A convolutional neural network (CNN)-based prediction algorithm, DeepSurv, was trained with images and baseline clinical information (age, sex, body mass index, glucocorticoid use, and secondary osteoporosis). The concordance index (C-index) was used to compare performance between DeepSurv and the Fracture Risk Assessment Tool (FRAX) and Cox proportional hazard (CoxPH) models.
Results
Of the total participants, 1,188 (74.4%) were women, and the mean age was 60.5 years. During a mean follow-up period of 40.7 months, vertebral fractures occurred in 7.5% (120/1,595) of participants. In the test set, when DeepSurv learned with images and clinical features, it showed higher performance than FRAX and CoxPH in terms of C-index values (DeepSurv, 0.612; 95% confidence interval [CI], 0.571 to 0.653; FRAX, 0.547; CoxPH, 0.594; 95% CI, 0.552 to 0.555). Notably, the DeepSurv method without clinical features had a higher C-index (0.614; 95% CI, 0.572 to 0.656) than that of FRAX in women.
Conclusion
DeepSurv, a CNN-based prediction algorithm using baseline image and clinical information, outperformed the FRAX and CoxPH models in predicting osteoporotic fracture from spine radiographs in a longitudinal cohort.

Citations

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Review Articles

Calcium & bone metabolism
Acromegaly and Bone: An Update: Andrea Giustina; Endocrinol Metab. 2023;38(6):655-666. Published online December 22, 2023; DOI: https://doi.org/10.3803/EnM.2023.601

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Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment.

Citations

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New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases
Luigi di Filippo, John P. Bilezikian, Ernesto Canalis, Umberto Terenzi, Andrea Giustina
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Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience
Sabrina Chiloiro, Antonella Giampietro, Amato Infante, Pier Paolo Mattogno, Liverana Lauretti, Alessandro Olivi, Laura De Marinis, Alfredo Pontecorvi, Francesco Doglietto, Antonio Bianchi
Pituitary.2024; 27(3): 303. CrossRef
Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE)
Andrea Giustina, M. M. Uygur, S. Frara, A. Barkan, N. R. Biermasz, P. Chanson, P. Freda, M. Gadelha, L. Haberbosch, U. B. Kaiser, S. Lamberts, E. Laws, L. B. Nachtigall, V. Popovic, M. Reincke, A. J. van der Lely, J. A. H. Wass, S. Melmed, F. F. Casanueva
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Nicholas A. Tritos
Pituitary.2024; 27(4): 311. CrossRef
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Tongxin Xiao, Xinxin Mao, Ou Wang, Yong Yao, Kan Deng, Huijuan Zhu, Lian Duan
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Skeletal fragility in pituitary disease: how can we predict fracture risk?
Fabio Bioletto, Alessandro Maria Berton, Marco Barale, Luigi Simone Aversa, Lorenzo Sauro, Michela Presti, Francesca Mocellini, Noemi Sagone, Ezio Ghigo, Massimo Procopio, Silvia Grottoli
Pituitary.2024; 27(6): 789. CrossRef
Vitamin D in pituitary driven osteopathies
Sabrina Chiloiro, Flavia Costanza, Elena Riccardi, Antonella Giampietro, Laura De Marinis, Antonio Bianchi, Alfredo Pontecorvi, Andrea Giustina
Pituitary.2024; 27(6): 847. CrossRef
GH receptor polymorphisms guide second-line therapies to prevent acromegaly skeletal fragility: preliminary results of a pilot study
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Simona Bolamperti, Isabella Villa, Luigi di Filippo
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Calcium & Bone Metabolism
Update on Preoperative Parathyroid Localization in Primary Hyperparathyroidism: Hye-Sun Park, Namki Hong, Jong Ju Jeong, Mijin Yun, Yumie Rhee; Endocrinol Metab. 2022;37(5):744-755. Published online October 25, 2022; DOI: https://doi.org/10.3803/EnM.2022.1589

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Parathyroidectomy is the treatment of choice for primary hyperparathyroidism when the clinical criteria are met. Although bilateral neck exploration is traditionally the standard method for surgery, minimally invasive parathyroidectomy (MIP), or focused parathyroidectomy, has been widely accepted with comparable curative outcomes. For successful MIP, accurate preoperative localization of parathyroid lesions is essential. However, no consensus exists on the optimal approach for localization. Currently, ultrasonography and technetium-99m-sestamibi–single photon emission computed tomography/computed tomography are widely accepted in most cases. However, exact localization cannot always be achieved, especially in cases with multiglandular disease, ectopic glands, recurrent disease, and normocalcemic primary hyperparathyroidism. Therefore, new modalities for preoperative localization have been developed and evaluated. Positron emission tomography/computed tomography and parathyroid venous sampling have demonstrated improvements in sensitivity and accuracy. Both anatomical and functional information can be obtained by combining these methods. As each approach has its advantages and disadvantages, the localization study should be deliberately chosen based on each patient’s clinical profile, costs, radiation exposure, and the availability of experienced experts. In this review, we summarize various methods for the localization of hyperfunctioning parathyroid tissues in primary hyperparathyroidism.

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Calcium & bone metabolism
Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis: Brendan F. Boyce, Jinbo Li, Zhenqiang Yao, Lianping Xing; Endocrinol Metab. 2023;38(5):504-521. Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.501

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Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

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Original Article

Calcium & Bone Metabolism
Decreased Serum Level of Sclerostin in Older Adults with Sarcopenia: Seong Hee Ahn, Hee-Won Jung, Eunju Lee, Ji Yeon Baek, Il-Young Jang, So Jeong Park, Jin Young Lee, Eunah Choi, Yun Sun Lee, Seongbin Hong, Beom-Jun Kim; Endocrinol Metab. 2022;37(3):487-496. Published online May 27, 2022; DOI: https://doi.org/10.3803/EnM.2022.1428

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Background
Although muscles and bones interact with each other through various secretory factors, the role of sclerostin, an osteocyte-secreted factor, on muscle metabolism has not been well studied. We investigated the levels of serum sclerostin in Korean older adults with sarcopenia.
Methods
Blood samples were collected from 129 participants who underwent evaluation of muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related parameters were determined using cutoff values for the Asian population. Serum sclerostin levels were measured using an enzyme-linked immunosorbent assay.
Results
The mean age of the participants was 69.6 years, and 20 participants (15.5%) were classified as having sarcopenia. After adjusting for age, sex, and body mass index, serum sclerostin levels were significantly lower in participants with sarcopenia, low muscle mass, or weak muscle strength (P=0.003 to 0.045). Serum sclerostin levels were positively associated with skeletal muscle index and grip strength after adjusting for confounders (P=0.001 and P=0.003), whereas sarcopenic phenotype score showed a negative association (P=0.006). These increases in muscle mass and strength were also dose dependent as serum sclerostin levels increased (P for trends=0.003 and P for trends=0.015). Higher serum sclerostin levels were associated with lower odds ratio (ORs) for sarcopenia, low muscle mass, and weak muscle strength after adjusting for confounders (OR, 0.27 to 0.50; P<0.001 to 0.025).
Conclusion
Higher serum sclerostin levels were associated with a lower risk of sarcopenia, low muscle mass, and weak muscle strength in Korean older adults.

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Zhonghan Zhao, Kai Yan, Qiao Guan, Qiang Guo, Can Zhao
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Viktoria N. Karetnikova, Anastasiya G. Neeshpapa, Evgenia I. Carpova, Olga L. Barbarash
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Anika Shimonty, Lynda F. Bonewald, Fabrizio Pin
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Liu Guo, Menchus Quan, Weijun Pang, Yulong Yin, Fengna Li
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Antimo Moretti, Giovanni Iolascon
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Review Article

Calcium & Bone Metabolism
Discontinuing Denosumab: Can It Be Done Safely? A Review of the Literature: Wei Lin Tay, Donovan Tay; Endocrinol Metab. 2022;37(2):183-194. Published online April 14, 2022; DOI: https://doi.org/10.3803/EnM.2021.1369

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Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.

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Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity
Christine H. Andreassen, Rune Holt, Li Juel Mortensen, Nadia Krarup Knudsen, John E. Nielsen, Nadia Nicholine Poulsen, Sam K. Yahyavi, Ida M. Boisen, Zhihui Cui, Luisina Ongaro, Jasmin P. Hjerresen, Birgitte G. Toft, Thomas Hasselager, Niklas R. Jørgensen
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Original Articles

Calcium & Bone Metabolism
Association between Elevated Plasma Homocysteine and Low Skeletal Muscle Mass in Asymptomatic Adults: Jae-Hyeong Choi, Jin-Woo Seo, Mi-Yeon Lee, Yong-Taek Lee, Kyung Jae Yoon, Chul-Hyun Park; Endocrinol Metab. 2022;37(2):333-343. Published online February 8, 2022; DOI: https://doi.org/10.3803/EnM.2021.1202

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Background
Homocysteine has been drawing attention with a closed linkage with skeletal muscle. However, the association of hyperhomocysteinemia with decreased skeletal muscle mass remains unclear. We aimed to investigate the association of hyperhomocysteinemia with low skeletal muscle mass (LMM) in asymptomatic adults.
Methods
This was a cross-sectional study of 114,583 community-dwelling adults without cancer, stroke, or cardiovascular diseases who underwent measurements of plasma homocysteine and body composition analysis from 2012 to 2018. Hyperhomocysteinemia was defined as >15 μmol/L. Skeletal muscle mass index (SMI) was calculated based on appendicular muscle mass (kg)/height (m)². Participants were classified into three groups based on SMI: “normal,” “mildly low,” and “severely low.”
Results
The prevalence of hyperhomocysteinemia was the highest in subjects with severely LMM (12.9%), followed by those with mildly LMM (9.8%), and those with normal muscle mass (8.5%) (P for trend <0.001). In a multivariable logistic regression model, hyperhomocysteinemia was significantly associated with having a mildly LMM (odds ratio [OR], 1.305; 95% confidence interval [CI], 1.224 to 1.392) and severely LMM (OR, 1.958; 95% CI, 1.667 to 2.286), respectively. One unit increment of log-transformed homocysteine was associated with 1.360 and 2.169 times higher risk of having mildly LMM and severely LMM, respectively.
Conclusion
We demonstrated that elevated homocysteine has an independent association with LMM in asymptomatic adults, supporting that hyperhomocysteinemia itself can be a risk for decline in skeletal musculature.

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Tae Kyung Yoo, Hye Chang Rhim, Yong-Taek Lee, Kyung Jae Yoon, Chul-Hyun Park
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Hongwei Yu, Gan Luo, Tianwei Sun, Qiong Tang
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Calcium & Bone Metabolism
Real-World Safety and Effectiveness of Denosumab in Patients with Osteoporosis: A Prospective, Observational Study in South Korea: Yumie Rhee, Dong-Gune Chang, Jeonghoon Ha, Sooa Kim, Yusun Lee, Euna Jo, Jung-Min Koh; Endocrinol Metab. 2022;37(3):497-505. Published online June 3, 2022; DOI: https://doi.org/10.3803/EnM.2022.1427

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Background
The efficacy and safety of denosumab have been established in a phase 3, randomized, placebo-controlled trial in Korean postmenopausal women with osteoporosis. This postmarketing surveillance study was aimed to investigate the safety and effectiveness of denosumab in Korean real-world clinical practice.
Methods
Patients with osteoporosis who had received denosumab per the Korean approved indications in the postmarketing setting between September 2014 and September 2019 were enrolled. The primary endpoint was the incidence of adverse events (AEs) and adverse drug reactions (ADRs). The secondary endpoint was the percent change from baseline in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck.
Results
Of the 3,221 patients enrolled, 3,185 were included in the safety analysis set; 2,973 (93.3%) were female, and the mean± standard deviation (SD) age was 68.9±9.9 years. The mean±SD study period was 350.0±71.4 days. AEs, fatal AEs, and ADRs occurred in 19.3%, 0.8%, and 1.6%, respectively. The most frequent AEs, occurring in >0.5% of patients, were dizziness (0.7%), arthralgia (0.7%), back pain (0.6%), and myalgia (0.6%). Hypocalcemia occurred in 0.3% of patients. There were no cases of osteonecrosis of the jaw and atypical femoral fracture. Mean±SD percent change from baseline in BMD of the lumbar spine, total hip, and femoral neck was 7.3%±23.6%, 3.6%±31.4%, and 3.2%±10.7%, respectively.
Conclusion
The safety and effectiveness of denosumab in Korean patients with osteoporosis in this study were comparable with those in the Korean randomized controlled trial, with no new safety findings.

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Endocrinology and Metabolism.2023; 38(2): 260. CrossRef
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Denosumab

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Sung Hye Kong
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Review Articles

Calcium & Bone Metabolism
Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer: Siva Swapna Kasarla, Vannuruswamy Garikapati, Yashwant Kumar, Sujatha Dodoala; Endocrinol Metab. 2022;37(3):392-407. Published online June 3, 2022; DOI: https://doi.org/10.3803/EnM.2021.1349

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Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.

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Calcium & bone metabolism
New Insights into Calorie Restriction Induced Bone Loss: Linyi Liu, Clifford J. Rosen; Endocrinol Metab. 2023;38(2):203-213. Published online April 27, 2023; DOI: https://doi.org/10.3803/EnM.2023.1673

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Caloric restriction (CR) is now a popular lifestyle choice due to its ability in experimental animals to improve lifespan, reduce body weight, and lessen oxidative stress. However, more and more emerging evidence suggests this treatment requires careful consideration because of its detrimental effects on the skeletal system. Experimental and clinical studies show that CR can suppress bone growth and raise the risk of fracture, but the specific mechanisms are poorly understood. Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in peripheral depots with calorie restriction, bone marrow adipose tissue (BMAT) increases, and this may play a significant role in this pathological process. Here, we update recent advances in our understanding of the effects of CR on the skeleton, the possible pathogenic role of BMAT in CR-induced bone loss, and some strategies to mitigate any potential side effects on the skeletal system.

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Original Article

Calcium & Bone Metabolism Big Data Articles (National Health Insurance Service Database)
Hip Fracture Risk According to Diabetic Kidney Disease Phenotype in a Korean Population: Seung Eun Lee, Juhwan Yoo, Kyoung-Ah Kim, Kyungdo Han, Han Seok Choi; Endocrinol Metab. 2022;37(1):148-158. Published online February 28, 2022; DOI: https://doi.org/10.3803/EnM.2021.1315

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Background
Diabetic kidney disease (DKD) is associated with an elevated risk of fractures. However, little is known about the association between proteinuric or non-proteinuric DKD and the risk of hip fracture. Thus, we investigated the incidence of hip fractures among Korean adults with type 2 diabetes mellitus (T2DM) stratified by DKD phenotype.
Methods
In this retrospective cohort study using the Korean National Health Insurance Service database, patients with T2DM who received at least one general health checkup between 2009 and 2012 were followed until the date of hip fracture, death, or December 31, 2018. We classified the DKD phenotype by proteinuria and estimated glomerular filtration rate (eGFR), as follows: no DKD (PU⁻GFR⁻), proteinuric DKD with normal eGFR (PU⁺GFR⁻), non-proteinuric DKD with reduced eGFR (PU⁻GFR⁺), and proteinuric DKD with reduced eGFR (PU⁺GFR⁺)
Results
The cumulative incidence of hip fractures was highest in the PU⁺GFR⁺ group, followed by the PU⁻GFR⁺ group and the PU⁺GFR⁻ group. After adjustment for confounding factors, the hazard ratio (HR) for hip fracture was still highest in the PU⁺GFR⁺ group. However, the PU⁺GFR⁻ group had a higher HR for hip fracture than the PU⁻GFR⁺ group (PU⁺GFR⁺ : HR, 1.69; 95% confidence interval [CI], 1.57 to 1.81; PU⁺GFR⁻ : HR, 1.37; 95% CI, 1.30 to 1.46; PU⁻GFR⁺ : HR, 1.20; 95% CI, 1.16 to 1.24 using the PU⁻GFR⁻ group as the reference category).
Conclusion
The present study demonstrated that DKD was significantly associated with a higher risk of hip fracture, with proteinuria as a major determinant.

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Clinical Kidney Journal.2024;[Epub] CrossRef
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Diabetes Research and Clinical Practice.2023; 197: 110576. CrossRef
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Review Articles

Calcium & bone metabolism
Skeletal Senescence with Aging and Type 2 Diabetes: Joshua Nicholas Farr; Endocrinol Metab. 2023;38(3):295-301. Published online June 14, 2023; DOI: https://doi.org/10.3803/EnM.2023.1727

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Osteoporosis and type 2 diabetes (T2D) are common diseases that often coexist. While both of these diseases are associated with poor bone quality and increased fracture risk, their pathogenesis of increased fracture risk differs and is multifactorial. Mounting evidence now indicates that key fundamental mechanisms that are central to both aging and energy metabolism exist. Importantly, these mechanisms represent potentially modifiable therapeutic targets for interventions that could prevent or alleviate multiple complications of osteoporosis and T2D, including poor bone quality. One such mechanism that has gained increasing momentum is senescence, which is a cell fate that contributes to multiple chronic diseases. Accumulating evidence has established that numerous boneresident cell types become susceptible to cellular senescence with old age. Recent work also demonstrates that T2D causes the premature accumulation of senescent osteocytes during young adulthood, at least in mice, although it remains to be seen which other bone-resident cell types become senescent with T2D. Given that therapeutically removing senescent cells can alleviate age-related bone loss and T2D-induced metabolic dysfunction, it will be important in future studies to rigorously test whether interventions that eliminate senescent cells can also alleviate skeletal dysfunction in context of T2D, as it does with aging.

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Calcium & Bone Metabolism
A Key Metabolic Regulator of Bone and Cartilage Health: Elizabeth Pérez-Hernández, Jesús Javier Pastrana-Carballo, Fernando Gómez-Chávez, Ramesh C. Gupta, Nury Pérez-Hernández; Endocrinol Metab. 2022;37(4):559-574. Published online August 8, 2022; DOI: https://doi.org/10.3803/EnM.2022.1443; Correction in: https://doi.org/

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Taurine, a cysteine-derived zwitterionic sulfonic acid, is a common ingredient in energy drinks and is naturally found in fish and other seafood. In humans, taurine is produced mainly in the liver, and it can also be obtained from food. In target tissues, such as the retina, heart, and skeletal muscle, it functions as an essential antioxidant, osmolyte, and antiapoptotic agent. Taurine is also involved in energy metabolism and calcium homeostasis. Taurine plays a considerable role in bone growth and development, and high-profile reports have demonstrated the importance of its metabolism for bone health. However, these reports have not been collated for more than 10 years. Therefore, this review focuses on taurine–bone interactions and covers recently discovered aspects of taurine’s effects on osteoblastogenesis, osteoclastogenesis, bone structure, and bone pathologies (e.g., osteoporosis and fracture healing), with due attention to the taurine–cartilage relationship.

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Calcium & bone metabolism
Cardiovascular Impact of Calcium and Vitamin D Supplements: A Narrative Review: Fatima Zarzour, Ahmad Didi, Mohammed Almohaya, David Kendler; Endocrinol Metab. 2023;38(1):56-68. Published online February 16, 2023; DOI: https://doi.org/10.3803/EnM.2022.1644

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Calcium and vitamin D play an important role in mineral homeostasis and the maintenance of skeletal health. Calcium and vitamin D supplements have been widely used for fracture prevention in elderly populations. Many trials have studied the effectiveness and cardiovascular safety of calcium and vitamin D supplementation, with disparate results. In this review, we summarize the most important trials and systematic reviews. There is significant heterogeneity in clinical trial design, differences in the nature of trial outcomes (self-reported vs. verified), prior calcium intake, and trial size. Inconsistent results have been reported concerning the effects of calcium and vitamin D supplementation on cardiovascular outcomes. Most current guidelines recommend calcium intake of up to 1,200 mg daily, preferably from the diet, without concern for cardiovascular risk. Recommendations regarding vitamin D supplementation vary widely. There is compelling evidence from well-conducted randomized trials that modest vitamin D supplementation is safe but does not confer cardiovascular benefit or cardiovascular harm.

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