bluuebunny/crossref_metadata_2025_split huggingface dataset:
PTH Protects Osteocytes From Oxidative Stress and Cellular Senescence
Authors: Uda Yuhei , Santos Roberto , Kochen Alejandro , Newell Carly , Huang Tim Y , Pajevic Paola Divieti 
Published: May 2021

Abstract
Age-induced osteoporosis is characterized by a progressive decline in bone formation and increase in bone resorption with uncoupled activities of osteoblasts and osteoclasts. Parathyroid hormone (PTH) is used in the clinic to treat osteoporosis due to its anabolic actions on bone via binding to the PTH receptor (PPR). The receptor is highly expressed in cells of the osteoblastic lineage, including osteocytes. Osteocytes are the most abundant cells in bone and serve as a key regulator of bone remodeling. Despite the significant role of PPR signaling in skeletal homeostasis, its function in osteocytes during aging remains unclear. We have gathered preliminary data demonstrating that mice lacking PPR predominantly in osteocytes (Dmp1-PPRKO) have marked age-induced bone loss due to increased bone resorption and suppressed bone formation. These mice, with aging, develop characteristics of skeletal senescence: a decrease in osteoprogenitors and an increase in bone marrow adiposity and p16Ink4a/Cdkn2a expression in bone. Since senescence of cells in the bone microenvironment has been reported as a cause of age-induced bone loss, we hypothesized that PPR signaling protects osteocytes from senescence. To test this hypothesis, we generated osteocytes (Ocy454-12H), in which the PPR expression was ablated using CRISPR/Cas9 technique. Ocy454-12H-PPRKO and Ocy454-12H-PPRCtrl cells were treated with PTH followed by an exposure to hydrogen peroxide (H2O2). High levels of intracellular reactive oxygen species (ROS), including H2O2, promote protein and DNA oxidation, resulting in cell death and senescence. PTH treatment significantly suppressed the increase in H2O2-induced cell death, measured by resazurin-based assays, in PPRCtrl but not in PPRKO cells. We analyzed intracellular ROS levels using a fluorescent probe and found that PTH treatment significantly suppressed the increase in ROS upon H2O2 exposure, suggesting an antioxidant function of PTH in osteocytes. To further investigate if PTH prevents osteocytes from oxidative stress-induced senescence, we examined senescence-associated β-galactosidase (SA β-gal) activity in cells that were treated with PTH followed by an exposure to low doses of H2O2. Compared to untreated and PPRKO groups, treatment with PTH significantly decreased the number of SA β-gal positive cells, demonstrating that PPR signaling protects osteocytes, and possibly other osteoblastic cells, from H2O2-induced cellular senescence. PTH treatment reduced mRNA expression of p21/Cdkn1a. Taken together these results demonstrate that PPR signaling is important to protect osteocytes from cellular senescence.
Sarcopenic Obesity Indices Are Major Determinants of Bone Strength in Older Adults With Obesity
Authors: Gregori Giulia , Paudyal Arjun , Barnouin Yann , Celli Alessandra , Villareal Reina Condevillamar , Qualls Clifford , Villareal Dennis Tan 
Published: May 2021

Abstract
Background: The increasing number of older adults with obesity is a growing public health problem because of increased risk of fractures especially at the ankle and upper leg despite normal or high bone mineral density. Among the contributory factors for fracture risk in this population may be aging- and obesity- associated physical frailty and impaired bone quality. However, how the adverse changes in physical function and body composition in this aging and obese population contribute to bone quality as assessed by finite element analyses (FEA) of bone strength has not been determined. Methods: One-hundred sixty-nine older (age ≥ 65 yrs.) adults with obesity (BMI ≥ 30 kg/m2) were recruited to participate in lifestyle intervention trials at our Medical Center. All underwent baseline measurements of bone strength (failure load [N] and stiffness [N.mm-1]) as estimated using FEA from high-resolution peripheral quantitative tomography (HR-pQCT) of the distal radius and tibia. In addition, body composition (appendicular lean mass/BMI [ALMBMI], fat mass/height2 [FMI]) was assessed by dual-energy x-ray absorptiometry (DXA) and physical function by the modified physical performance test (PPT), knee extension strength (isokinetic dynamometry), hand grip strength, and 4-meter gait speed. Results: Bivariate analyses showed that ALMBMI (r=.57 to .58), FMI (r=-.16 to -.17), gait speed (r=.20 to .21), grip strength (.56 to .57), and knee extension strength (r=.40 to .42) correlated with stiffness and failure load at the distal radius (all P&lt;0.05). In addition, ALMBMI (r=.65 to .67), FMI (r=-.22 to .23), gait speed (r+.18 to .19), grip strength (r=.58 to .59), and knee extension strength (r=.44 to .45) correlated with stiffness and failure load at the distal tibia (all P&lt;0.05). Controlling for age and sex, multiple regression analyses revealed that ALMBMI (β=.34 to .35) and grip strength (β=.28 to .29) were the independent predictors of stiffness and failure load at the distal radius, explaining 45% to 46% of the variance in stiffness and failure load (P&lt;0.001). On the other hand, multiple regression analyses revealed that ALMBMI (β=.45 to .52), grip strength (β=.27 to .28), and FMI (β=.17 to .18) were the independent predictors of stiffness and failure load at the distal tibia, explaining 74% to 75% of the variance in stiffness and failure load (P&lt;0.001). Conclusions: These findings suggest the importance of preserving muscle mass while reducing fat mass and improving physical function to maintain bone quality and decrease the risk of fractures when older adults with obesity undergo lifestyle intervention.
Aromatase Inhibitor Induced Bone Loss: Do International Guidelines Accurately Stratify Fracture Risk and Selection of Anti-Osteoporosis Treatment?
Authors: Gandhi Shriya , Bullock Cydney A , Ritz Ethan M , Beck Todd , Baim Sanford 
Published: May 2021

Abstract
Introduction: Aromatase inhibitors (AI) are used for adjunctive treatment of estrogen receptor-positive (ER+) breast cancer. Aromatase converts androgens to estrogens in the ovaries and peripheral tissues such as adipose, liver, muscle, and breast. In breast, estrogens increase cell proliferation in both normal and ER+ malignant tissue. AIs globally suppress estrogen production, and thereby can decrease tumor progression. However, in bone, estrogens suppress osteoclast activity and decrease bone resorption so AI use results in increased bone resorption and decreased bone mineral density (BMD). Several guidelines exist to direct management of AI-associated bone loss, but it is unclear whether adherence to these guidelines translates to decreased fracture risk. The International Osteoporosis Foundation (IOF) et al 2017 guidelines for the prevention of osteoporotic fractures in patients treated with AI recommended BMD measurement at the onset of AI use and use of anti-osteoporosis therapy (anti-OP) in those who met T-score and clinical risk factor (CRF) criteria. Hypothesis: We explored application of these guidelines and whether they were able to stratify patients according to risk, initiation of treatment, and fracture outcomes. Methods: 1517 charts were extracted from the electronic medical record (EMR) of a tertiary academic medical center based on history of breast cancer and use of AIs between 2008 and 2017. Charts were retrospectively analyzed to determine baseline BMD, osteoporosis risk factors, duration of AI use, duration of anti-OP therapy, and fractures. The IOF criteria were applied to each patient to determine applicability of anti-OP therapy. Fracture rates were compared using chi square test or Fisher’s exact test. Results: 1517 patients were included in the analysis. Regardless of whether criteria were met for treatment based on baseline BMD and CRF, the fracture rate was significantly higher in the treated versus the untreated group, 13.78% (CI: 9.56–18.99) versus 2.24% (p &lt; 0.0001, CI: 1.51–3.21). Similarly, among those that met criteria, the fracture rate was significantly higher in the treated versus the untreated group, 10.24% (CI: 5.56–16.87) versus 2.61% (p = 0.0005, CI: 1.20–4.89). There was no significant difference in fractures between those who did versus did not meet treatment criteria, 4.66% (CI: 2.94–6.97) versus 3.64% (p = 0.34, CI 2.59–4.96). Conclusions: This retrospective EMR analysis of 1517 breast cancer patients on AIs between 2008 and 2017 observed a higher fracture incidence in patients who received anti-OP treatment compared to those who did not, regardless of meeting criteria for treatment per the IOF guidelines. It is possible that patients who initiated anti-OP therapy had additional CRFs not captured in the EMR and not factored into our analyses.
Fall Patterns Are Independent Risk Factors for Mortality After Hip Fracture in Older Adults
Authors: Hong Namki , Burm Seungwon , Rhee Yumie 
Published: May 2021

Abstract
Hip fracture is becoming a major health problem with high mortality and morbidity in older adults. However, whether specific fall patterns could act as independent risk factors for predicting mortality after hip fracture remains unknown. We aimed to investigate whether fall patterns can serve as an independent risk factor for mortality after hip fracture. Electronic medical records (EMR) of individuals who visited emergency room or admitted to the Severance hospital, Seoul, Korea, between January 2005 to December 2019 were reviewed to categorize fall patterns. Fall patterns were categorized upon review of explanatory description in EMR, using modified classification based on motion analysis of video-captured falls in a prior study. Among 1,991 study subjects (mean age 77 years, 71% women), 211 patients died (10.6%; median survival 296 days). Fall location was divided into home (67.4%) and outdoor (32.6%) with mortality rate of 11.9% and 8.0% (p=0.009), respectively. Fall patterns were specified by “cause of fall” (6 categories; slip [29.6%], trip or stumble [17.5%], etc.) and by “activity at time of fall” (6 categories; walking [54.8%], getting up or rising [14.1%], etc). Among the combinations of both causes and activities, individuals who sustained hip fracture during “incorrect weight shift while sitting down or lowering”(hazard ratio [HR] 3.35, p=0.003), “collapsed during unclassified activity”(HR 2.37, p=0.006), “incorrect weight shift while getting up or rising”(HR 2.13, p=0.003), and “slipped while walking”(HR 1.83, p=0.004) had increased mortality after hip fracture compared to those with outdoor falls, after adjustment for age, sex, and Charlson comorbidity index. Specific fall patterns in individuals who sustained hip fracture predicted excess mortality in older adults, independent of age, sex, and comorbidities. Acknowledgement: We thank Doori Cho of the the SENTINEL (Severance ENdocrinology daTa scIeNcE pLatform) team (4-2018-1215) for the data acquisition process. Conflict of Interest: SB, NH, and YR have nothing to declare.
Targeting the Fragility Fracture Prevention Message
Authors: Blank Robert Daniel , Choi Yoonah , Song Hae-Jin , (Derrick) Chan Ding-Cheng , Lee Joon Kiong 
Published: May 2021

Abstract
Background: The impact of fragility fractures on human suffering is underappreciated. Fragility fractures increase mortality and the risk of recurrent fracture. Notwithstanding these facts, only a minority of patients suffering osteoporotic fractures receive fracture preventing therapy. Education about the burden of disease and the benefits of prompt treatment are important means to increase the treatment rate. We propose that the focus of the educational message should be varied for distinct audiences.
Method: We searched existing literature to determine perceptions about the importance of treating fractures and osteoporosis among the following groups: the general population, primary care physicians, specialist physicians, hospital administrators, and government health officials.
Result: Extensive data focusing on patients and primary care physicians exist about barriers to treatment initiation. In these groups, lack of perceived treatment benefit is a widespread, common finding. To address this gap, we have produced a primary care education toolkit, patient booklet and education directory as Asia Pacific Fragility Fracture Alliance (APFFA)-sponsored initiatives.
Data are more limited for specialist physicians, hospital administrators, and government officials. Health economic arguments have been found to be persuasive among policy makers.
Conclusion: Information about the importance of treating fragility fractures and osteoporosis is far more abundant with reference to patients and primary care providers than to specialty physicians, hospital administrators, and government officials. Understanding the state of knowledge and belief is an essential first step in developing educational materials that address the concerns and misperceptions of each key constituency. Existing data suggest that patients will be more receptive to materials emphasising independence and quality of life, while policy makers will be more receptive to materials highlighting the burden of disease.
Basal Ganglia Calcification in Hypoparathyroidism Is Associated With Low Serum Calcium/Phosphate Ratio
Authors: Zavatta Guido , Tebben Peter J , Clarke Bart Lyman 
Published: May 2021

Abstract
Background: Basal ganglia calcification (BGC) is a well-known complication of hypoparathyroidism. It is currently thought that increased serum phosphate or calcium x phosphate product may be major risk factors. However, the pathophysiology of BGC is still unclear, since the literature is largely based on limited case series or case reports. Methods: We identified a large cohort of patients with hypoparathyroidism diagnosed between 2000 and 2020 and evaluated those with head CT scans performed over this interval. Etiology and date of onset of hypoparathyroidism were determined by medical records review. All head CT scan images were reviewed to confirm radiology reports reporting BGC. We retrieved laboratory data within 10 years before the first head CT that showed incident BGC. Three age- and sex- matched controls with head CT scans were selected for each patient, and compared to the patients with hypoparathyroidism. Results: Of 1014 unique patients with a verified diagnosis of hypoparathyroidism, 142 had a head CT scan performed between 2000 and 2020. Head CT scans were performed for reasons unrelated to hypoparathyroidism in 96.5% of patients. In this cohort, 80.3% of patients (n=114) had post-surgical hypoparathyroidism. Age at which the first head CT in patients was done was 62±20.6 (range 11–97), and duration of hypoparathyroidism at the time of first head CT was 11.0±14.4 years (0–71). Prevalence of BGC in patients with hypoparathyroidism was 25.4% (n=36), as compared with 7.3% in the control group (31/426) (P&lt;0.001). Patients and controls were similar in terms of cardiovascular risk factors (diabetes, hypertension, dyslipidemia, alcohol consumption, smoking status and BMI). In patients with non-surgical hypoparathyroidism (n=28), prevalence of BGC was 71.4% vs. 14.0% in the postsurgical cohort (OR 15.4; 95% CI 5.8–40, P&lt;0.001). Compared to patients with hypoparathyroidism without BGC, those with BGC had lower time-weighted average serum calcium (8.4±0.8 vs. 8.8±0.8, P=0.002; normal range, 8.6–10.2 mg/dL), and lower time-weighted average calcium/phosphate ratio (Ca/P) (1.83±0.52 vs. 2.13±0.47, P=0.007). Conclusions: Basal ganglia calcification in hypoparathyroidism is associated with low serum calcium and low Ca/P ratio. This may allow increased bioavailability of phosphate in the extracellular space, leading to calcium phosphate crystal formation within the basal ganglia. Assessing Ca/P ratio may be useful to identify patients at risk for BGC. Prevalence of BGC is significantly higher in patients with non-surgical hypoparathyroidism.
Creation of an Evidence-Based Physical Therapy Program for Adults with XLH: Translational Application of an Interprofessional Clinical Study
Authors: Kanamalla Karthik , Fuchs Rebekah , Herzog Casey , Steigbigel Keith , Macica Carolyn Marie 
Published: May 2021

Abstract
X-linked hypophosphatemia (XLH) arises due to inactivating mutations of the PHEX gene resulting in elevated circulating levels of the hormone FGF23, producing phosphaturia and impaired intestinal phosphate absorption. XLH is a lifelong metabolic disease with musculoskeletal comorbidities that dominate the adult clinical picture, and are resistant to standard therapies. We have previously reported the physical and functional impact of the adult disorder (J Clin Endocrinol Metab. 2020 Apr 1;105(4)). Bilateral and diffuse enthesophytes, degenerative arthritis and osteophytes were reported at the spine and synovial joints across subjects. Passive range of motion (ROM) was decreased at the spine, hips, knees, and ankles compared to controls. Gait analysis, relative to controls, revealed increased step width, markedly increased lateral trunk sway, and physical restriction at the hip, knees and ankle joints that translated into limitations through the gait cycle. These studies have been translated into an evidence-based physical therapy (PT) intervention study to address these major physical and functional comorbidities. Participants were enrolled in a remote 12-week PT program consisting of balance exercises and basic stretches with/without resistance. Subjects were evaluated at baseline and at every 4-weeks to assess ROM, gait, and functional ability. Several validated tools were employed to assess overall function: Berg Balance Scale, the Timed Up and Go (TUG) Test, and the Five Times Sit to Stand Test (5XSST). Subjective questionnaires, including the Lower Extremity Functional Scale (LEFS) and Activities-Specific Balance Confidence (ABC) Scale, were administered along with a weekly survey. At the conclusion of the study, minimal to modest improvements were seen in active ROM for the upper and lower extremity which reflect the significant bony restriction caused by XLH. However, improvements were seen in functional measures including the Berg Balance Scale, TUG, 5XSST, LEFS, and ABC. Weekly surveys indicated that participants improved their ability to balance, perform activities of daily living (ADLs), walk, and bend down to reach the ground. Results from this study will be applied to the creation of an evidence-based PT program to maintain functional capacity and improved ability to perform ADLs across the lifespan.
Improving Knowledge of MRONJ Risk Among Singapore Dental Practitioners Using an Educational Lecture With an Incorporated Quiz
Authors: Gani Linsey , Chionh Siok Bee 
Published: May 2021

Abstract
Background: Fear of rare medication side effects, such as medication related osteonecrosis of the jaw (MRONJ) in patients and dentists remains a major reason for the low rate of antiresorptive initiation for osteoporosis, and for the poor adherence after starting treatment. In this study, we assessed the understanding of osteoporosis treatment and its risk in dental professionals pre and post an education lecture. Method: Dental professionals were invited to an educational lecture on osteoporosis treatment and benefits. 2 lectures were conducted over the course of a year, with the 2nd lecture conducted virtually due to physical meeting restrictions in place for the COVID 19 pandemic. Attendees were invited to submit responses to a pre- and post- lecture survey assessing their knowledge of the current osteoporosis treatments and MRONJ. Results: There were 126 responses to the survey conducted. Majority (87%) of responders were dentists in private, including group dental practices, with 74% having more than 11 years of working experience. Most (81 %) have not had any encounters with patients with MRONJ. The pre-lecture survey showed that 60% of responders expressed slight or no confidence at all in treating patients who are on osteoporosis treatment. Only 19% of all responders were able to correctly identify the risk of MRONJ in patients on osteoporosis treatment. Majority of responders tended to inflate MRONJ risk by as much as 100 times the quoted baseline risk in the literature. One third of dentists would not perform any invasive treatments on patients on osteoporosis treatment. Post-lecture, the percentage of responders with slight and no confidence at all in treating patients who are on osteoporosis treatment decreased to 18%. 65% of responders were able to correctly identify the risk of MRONJ in patients on osteoporosis treatment as quoted in the literature. Only 3% of dentists would not perform any invasive treatments on patients on osteoporosis treatment. 95% of responders correctly stated that maintenance of good oral hygiene is the most important measure to prevent MRONJ. Attendees suggested the creation of a joint guidance from local osteoporosis and dental societies may better improve knowledge and instill confidence in treating osteoporosis patients. Conclusion: There is a significant knowledge gap within the dental practitioners in Singapore on the risk of MRONJ associated with osteoporosis treatments. This may result in dentists discouraging patients from starting osteoporosis medications and dentists not performing necessary dental treatments on patients on osteoporosis treatment. Both physical and virtual dental education lectures are effective in increasing the level of confidence and in correcting misconceptions on MRONJ risk. Continued engagement of the dental community would be important in reducing fear of MRONJ and facilitate treatment of osteoporosis in the population.