Biomarkers Of Bone Resorption Research Articles

Systematic review and meta-analyses on the effects of whole-body vibration on bone health

ObjectiveTo determine whole body vibration influence on human bone density and bone biomarkers. MethodsWe identified studies in Medline, Web of Science, Cumulative Index of Nursing and Allied Health, SPORTDiscus, Embase and Cochrane from inception to November 2021. Human randomized controlled trials involving commercially available whole body vibration platforms were included. Outcomes included bone density mean difference and serum concentrations of biomarkers (Procollagen type 1 N-terminal Propeptides, Osteocalcin, Bone specific alkaline phosphatase, and C-terminal Telopeptide of type 1 collagen). Random effects model (Hedges’ g effect-size metric and 95% confidence-intervals) compared whole body vibration effect on bone density and bone biomarkers. Moderator analyses assessed health status, age, menopausal status, vibration type, vibration frequency, and study duration influence. ResultsMeta-analysis of 30 studies revealed bone density improvement after whole body vibration (Hedges’ g = 0.11; p = 0.05; 95% CI = 0.00, 0.22). Whole body vibration improved bone density in healthy (Hedges’ g = 0.10; p = 0.01; 95% CI = 0.02, 0.17) and postmenopausal women (Hedges’ g = 0.09; p = 0.02; 95% CI = 0.01, 0.18). Bone density also increased following side-alternating whole body vibration intervention (Hedges’ g = 0.21; p = 0.02; 95% CI = 0.04, 0.37). Whole body vibration had no significant effect on either bone formation biomarkers (Hedges’ g = 0.22; p = 0.01; 95% CI = 0.05, 0.40) or bone resorption biomarkers (Hedges’ g = 0.03; p = 0.74; 95% CI = −0.17, 0.23). ConclusionWhole body vibration may be clinically useful as non-pharmacological/adjunct therapy to mitigate osteoporosis risk in healthy postmenopausal females. Additional studies are needed to determine the underlying mechanisms.

Protective effect of aqueous extracts from Taxillus chinensis (DC.) Danser on ovariectomy-induced osteoporosis in rats

As one of classic Chinese kidney-tonifying herbal medicines, Taxillus chinensis (DC.) Danser is widely applied in Chinese folk medicine as herbal tea for nutraceutical purposes including nourishing kidney, strengthening muscle and bone to against weakness, etc. In the present study, we investigated the protective effect of aqueous extracts from Taxillus chinensis (AETCs) on the ovariectomy (OVX)-induced osteoporosis in rats. Results showed that AETC treatment at the dose of 12.0 g raw materials/kg for 12 weeks significantly enhanced the bone mineral densities of femur and tibia, improved the trabecular microarchitecture compared with OVX controls. The serum levels of osteogenic markers alkaline phosphatase and osteocalcin were increased, and the levels of bone resorption biomarkers tartrate-resistant acid phosphatase 5b and telopeptides of collagen type I were suppressed by AETCs. Moreover, 12.0 g raw materials/kg AETC treatment significantly reduced the OVX-induced up-regulation of cyclooxygenase (COX)-2 mRNA and protein expression in bone tissues. Data suggested that AETCs showed anti-osteoporotic effect in OVX rats, possibly via promoting bone formation and inhibiting bone absorption. The down-regulation of inflammatory COX-2 might be involved in the protection of AETCs against OVX –induced osteoporosis.

Rhizoma drynariae total flavonoids combined with calcium carbonate ameliorates bone loss in experimentally induced Osteoporosis in rats via the regulation of Wnt3a/\u03b2-catenin pathway

BackgroundRhizoma drynariae, a traditional Chinese herb, is commonly used in treatment of bone healing in osteoporotic fractures. However, whether the Rhizoma drynariae total flavonoids (RDTF) can promote the absorption of calcium and enhance the bone formation is unclear. The aim of the present study was to investigate the preventive effects of RDTF combined with calcium carbonate (CaCO3) on estrogen deficiency-induced bone loss.MethodsThree-month-old Sprague–Dawley rats were ovariectomized (OVX) and then treated with CaCO3, RDTF, and their admixtures for ten weeks, respectively. The bone trabecular microstructure, bone histopathological examination, and serum biomarkers of bone formation and resorption were determined in the rat femur tissue. The contents of osteoprotegerin (OPG), receptor activator of the NF-κB (RANK), and its ligand (RANKL) in marrow were analyzed by ELISA, and the protein expressions of Wnt3a, β-catenin, and phosphorylated β-catenin (p-β-catenin) were analyzed by Western blot. Statistical analysis was conducted by using one-way analysis of variance (ANOVA) followed by LSD post hoc analysis or independent samples t test using the scientific statistic software SPSS version 20.0ResultsRDTF combined with CaCO3 could promote osteosis and ameliorate bone loss to improve the repair of cracked bone trabeculae of OVX rats. Furthermore, RDTF combined with CaCO3 also could prevent OVX-induced decrease in collagen fibers in the femoral tissue of ovariectomized rats and promote the regeneration of new bone or cartilage tissue, while CaCO3 supplementation promoted the increase in bone mineral content. Nevertheless, there was no difference in the expression of Wnt3a, β-catenin and p-β-catenin between osteopenic rats and RDTF treated rats, but RDTF combined with CaCO3 could activate the Wnt3a/β-catenin pathway.ConclusionsRDTF combined with CaCO3 could ameliorate estrogen deficiency-induced bone loss via the regulation of Wnt3a/β-catenin pathway.

Effect of n-3 polyunsaturated fatty acid on bone health: A systematic review and meta-analysis of randomized controlled trials.

Bone metabolism is a complicated process, which involves bone modeling and remodeling. If this process is unbalanced, bone loss and resultant osteoporosis might occur. Recently, nutrition supplementations such as n‐3 polyunsaturated fatty acids (PUFAs) are considered to be used on improving the bone metabolism and reducing the risk of osteoporosis. To more precisely assess the effects of n‐3 PUFA supplementation on bone mass and clarify its potential mechanism, we have conducted a systematic review and meta‐analysis. Based on the strict inclusion and exclusion criteria, 12 articles were included in this meta‐analysis. The results in articles show that n‐3 PUFAs could slightly enhance the level of bone mineral density (BMD) (0.005 g/cm2; 95% CI, 0.000–0.010) (n = 7), which was the primary outcome for the research in comparison with the control group. In addition, the results also illustrate that the increasing effect on BMD (0.024 g/cm2; 95% CI, 0.020–0.028) became more significant for postmenopausal women. N‐3 PUFAs had no significance on the level of bone‐specific alkaline phosphatase (BALP) (−0.24 µg/L; 95% CI, −0.86 to 0.39) and osteocalcin (−0.63 μg/L; 95% CI, −1.84 to 0.57) (n = 5), which are the specific markers of bone formation. When compared with the eicosapentaenoic acid + docosahexaenoic acid supplementation, the supplementation form of α‐linolenic acid significantly increased the content of BALP (0.396 µg/L; 95% CI, 0.069–0.724). The effects of n‐3 PUFAs on bone resorption biomarkers containing type I collagen cross‐linked C‐terminal peptide (CTX) and type I collagen cross‐linked N‐terminal peptide (NTX) are considered and used in our study. Results indicated that participants who received n‐3 PUFAs significantly decreased the level of CTX in the human body (−0.367 μg/L; 95% CI, −0.726 to −0.007) (n = 4). However, there was no significant difference in NTX levels in humans after supplementation with n‐3 PUFA (−1.744 µg/L; 95% CI, −3.970–0.481) (n = 3). For postmenopausal women, it presented a significant decreasing level of CTX (−0.393 µg/L; 95% CI, −0.651 to −0.135) and NTX (−2.082 µg/L; 95% CI, −2.970 to −1.195) within their bodies. In conclusion, these findings suggested that n‐3 PUFAs might have a beneficial effect on bone health, especially for α‐linolenic acid supplementation form or for postmenopausal women.

Impact of Daratumumab Monotherapy on Bone Metabolism Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor: Outcomes of the Phase 2 Rebuild Study

Impact of Daratumumab Monotherapy on Bone Metabolism Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor: Outcomes of the Phase 2 Rebuild Study

MicroRNAs in Peri-implant Crevicular Fluid Can Predict Peri-implant Bone Resorption: Clinical Trial with a 5-Year Follow-up

To evaluate the predictive value of microRNAs (miRNAs) found in peri-implant crevicular fluid (PICF) in the prognosis of peri-implant bone resorption. Seven patients were rehabilitated with fixed partial dentures each supported by two dental implants (total of 14 implants). At 3 months post-implant insertion, a sample of peri-implant mucosa and a sample of PICF were taken at each implant site. MiRNAs were extracted from the samples and analyzed through microarray technology. MiRNAs extracted from PICF were compared with miRNAs extracted from soft peri-implant tissue and related with peri-implant bone resorption measured at the 5-year follow-up. During the 5-year follow-up, no dropouts and no implant failures were recorded. The mean bone resorption was 1.98 mm (median: 2 mm). Extracellular miRNAs were recovered in well-detectable amounts in all PICF samples. Specific miRNA expression profiles were predictive of bone resorption. Fourteen miRNAs that were altered in PICF in case of bone resorption were also altered in the soft peri-implant tissue of the same implant sites. MiRNAs may be used as biomarkers of peri-implant bone resorption, and their presence in PICF lays the foundations for the development of a noninvasive and site-specific liquid biopsy.

The Efficacy and Safety of Multiple Dose Regimens of Kudzu (Pueraria lobata) Root Extract on Bone and Cartilage Turnover and Menopausal Symptoms.

Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata, Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear. Purpose: This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms. Materials and Methods: Fifty postmenopausal women were randomized equally into five different dose regimen groups of Kudzu root extract in a four-week, parallel group, open-label, single-center, exploratory study design. Biomarkers CTX-I and CTX-II reflecting bone and cartilage degradation, respectively, were assessed in blood samples and 24-h urine samples. Change from baseline in the Menopause Rating Scale (MRS) and subscales was evaluated. Safety endpoints were frequency of adverse events, changes in hematology and safety chemistry data, vital signs and electrocardiogram. Results: Fifty women (Age 54.2 years, SD: 2.9) were randomized. After 4 weeks of treatment, biomarkers of bone resorption and cartilage degradation were statistically significantly reduced from baseline levels in the group receiving two capsules three times a day, serum/urine CTX-I (−18.4%, 95% CI: −8.1 to −27.5, p = 0.001/−34.2%, 95% CI: −21.6 to −44.7, p < 0.0001), urine CTX-II (−17.4% 95% CI: −2.5 to −30.0, p = 0.02). The observed effects were consistent across study groups but appeared to favour three times daily dosing. Four weeks of treatment led to statistically significant reductions in the MRS Total Score (p < 0.0001–0.03) in four out of five treatment groups. Kudzu root extract was well tolerated in all dose regimens, and no serious adverse events were reported. Conclusion: The results indicate that Kudzu extract may possess beneficial effects on bone and cartilage health and may be a promising natural alternative to existing treatments for menopausal symptoms. Kudzu root extract was well tolerated for short-term treatment of mild to severe menopausal symptoms in women in all tested doses and dose frequencies.

Effect of 6-month high-impact step aerobics and resistance training on BMD and tibial bending strength in sedentary premenopausal women.

To determine the effectiveness of 6months of high-impact step aerobics (SA) or moderate-intensity resistance training (RT) on areal bone mineral density (aBMD) and tibial bending strength in sedentary premenopausal women. Sixty-nine women (20-35years old) who were randomly assigned to RT (n = 22), SA (n = 26), or non-treatment control (CON, n = 21) groups completed the study. SA had a minimum of 50 high-impact landings each training session. RT had a periodized lower body resistance training program incorporating eight exercises (65-85% of 1 repetition maximum: 1-RM). Both RT and SA met 3 times weekly. aBMD was assessed using dual X-ray absorptiometry (DXA). Tibial bending strength was assessed using mechanical response tissue analysis (MRTA). Measurements at 6months were compared to baseline using ANCOVA, adjusted for baseline measures and covariates with α = 0.05. Calcaneus aBMD (0.0176 vs -0.0019 or -0.0009g/cm2 relative to RT, p < 0.004, and CON, p < 0.006, respectively), lower leg aBMD (0.0105 vs -0.0036g/cm2, relative to RT, p = 0.02), and lumbar spine 2 (L2) aBMD (0.0082 vs -0.0157g/cm2 relative to CON, p < 0.02) were significantly greater in the SA group after 6months. Tibial bending strength and bone resorption biomarkers were unchanged in all three groups after 6months. Sedentary premenopausal women engaging in 6months of high-impact aerobic exercise improved aBMD in the calcaneus, lower leg, and L2.

A Comprehensive Review on the Biomarkers of Bone Remodeling in Vitamin D Deficiency

Vitamin D (Vit.D) has been well regarded as one of the essential micronutrients for several biological functions in humans, including bone structure and function. The deficiency of Vit.D due to various environmental, lifestyle, and genetic factors affect bone remodeling, including bone mineralization and resorption. Consequently, several changes occur in the level of biochemicals which are implied in bone remodeling, either directly or via secondary pathways. Intriguingly, the levels of these biomolecules are hypothesized to have a strong association with the prognosis of Vit. D deficiency (VDD) related health complications. However, the precise association of various bone turnover-derived biomolecules with VDD-related effects are largely elusive. Thus, the in-depth understanding of specific associations of VDD and bone mineralization, would establish novel bioanalytical approaches for early detection and devise alternative strategies to provide symptomatic clinical support to VDD patients. Hence this review collates the available literature to elucidate the association of various bone resorption biomarkers and their relevance to VDD.

Effect of Vitamin D-Enriched Gouda-Type Cheese Consumption on Biochemical Markers of Bone Metabolism in Postmenopausal Women in Greece.

Considering the role of bone metabolism in understanding the pathogenesis of osteoporosis, the aim of the present study was to examine the effects of vitamin D-enriched cheese on the serum concentrations of the parathyroid hormone (PTH) and certain bone remodeling biomarkers in postmenopausal women in Greece. In a randomised, controlled dietary intervention, 79 postmenopausal women (55–75 years old) were randomly allocated either to a control (CG: n = 39) or an intervention group (IG: n = 40), consuming 60 g of either non-enriched or vitamin D3-enriched Gouda-type cheese (5.7 μg of vitamin D3), respectively, daily and for eight weeks during the winter. The serum concentrations of 25-hydroxy vitamin D (25(OH)D), PTH, bone formation (i.e., osteocalcin, P1NP) and bone resorption (i.e., TRAP-5b) biomarkers were measured. Consumption of the vitamin D-enriched cheese led to higher serum 25(OH)D concentrations of 23.4 ± 6.39 (p = 0.022) and 13.4 ± 1.35 (p < 0.001) nmol/L in vitamin D-insufficient women being at menopause for less and more than 5 years, respectively. In vitamin D-insufficient women that were less than 5 years at menopause, consumption of vitamin D-enriched cheese was also associated with lower serum PTH (Beta −0.63 ± 1.11; p < 0.001) and TRAP-5b (Beta −0.65 ± 0.23; p = 0.004) levels at follow-up, compared with the CG. The present study showed that daily intake of 5.7 μg of vitamin D through enriched cheese increased serum 25(OH)D concentrations, prevented PTH increase and reduced bone resorption in vitamin D-insufficient early postmenopausal women, thus reflecting a potential food-based solution for reducing the risk of bone loss occurring after menopause.

Calcitonin gene-related peptide and brain-derived serotonin are related to bone loss in ovariectomized rats

ObjectivesPostmenopausal osteoporosis (PMO) and osteoporotic fracture seriously impair human health in developed countries. The present study aims to explore whether sensory nerves, calcitonin gene-related peptide (CGRP), and brain-derived serotonin are related to bone loss in ovariectomized (OVX) rats. MethodsFemale rats were grouped into the ovariectomized (OVX) and sham surgery (SHAM) groups. Immunocytochemistry, western blotting, and qPCR were performed to detect CGRP expression in the femurs. The expression levels of serotonin and CGRP in the spinal cord and brainstem were estimated using western blotting, immunofluorescence, and qPCR. ELISA was used to evaluate the serum biomarkers of bone formation and resorption. Bone mineral density was measured using dual-energy X-ray (DXA) analysis. Femur microstructure was imaged by Micro CT. P values less than 0.05 were considered statistically significant. ResultsELISA showed that serum bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRAP), β-crosslaps, and β-ctx were increased in the OVX group. In the OVX group, in vivo bone mineral density, trabecular bone mineral density, bone volume fraction (BV/TV), and trabecular number (Tb. N) were significantly decreased, while trabecular spacing (Tb. Sp) and trabecular bone pattern factor (Tb. Pf) were markedly increased. In the OVX group, the expression levels of CGRP of the femur were significantly downregulated. In contrast, CGRP and serotonin expression was increased in the spinal cord of the OVX group. Serotonin expression was increased in the brainstem, brainstem nucleus raphe magnus (RMG), and nucleus raphe dorsalis (DRN). ConclusionOur results indicated that the activation of osteoclast triggered the release of CGRP from nociceptive sensory nerve fibers and transmitted this painful stimulus to the dorsal horn of the spinal cord to release increased CGRP. The descending serotonergic inhibitory system was activated by increased CGRP levels of the spinal cord and promoted serotonin release in the brainstem RMG, DRN, and the spinal cord, contributing to the decreased CGRP level in bone tissue, which revealed a novel mechanism of bone loss in PMO.

Effect of GreenshellTM mussel on osteoarthritis biomarkers and inflammation in healthy postmenopausal women: a study protocol for a\xa0randomized double-blind placebo-controlled trial

BackgroundNew Zealand Greenshell™ mussels (GSM; Perna canaliculus) have recently been shown to decrease cartilage degradation in a rat model of induced metabolic osteoarthritis (MetOA). However, this effect has not been investigated in human subjects. This study aims to determine the effect of GSM powder on biomarkers of cartilage metabolism, bone resorption, and inflammation in New Zealand healthy overweight/obese postmenopausal women who are at early stage or at high risk of OA.MethodFifty overweight or obese (BMI 25–35 kg/m2) postmenopausal women (aged 55–75 years) will be recruited by advertisement. Participants will be randomized based on a double-blind randomization schedule and stratified randomization based on BMI and age distribution. The participant will be assigned with a 1:1 allocation ratio to receive 3 g/d whole meat GSM powder or placebo (sunflower seed protein) for 12 weeks. Data on socio-demographics, physical activity, and dietary intake will be collected for each subject. Cartilage turnover biomarkers [(C-telopeptide of type II collagen (CTX-II), C-propeptide of type II procollagen (CPII), Cartilage oligomeric matrix protein (COMP)], and bone resorption marker (CTX-I) will be measured in blood and urine samples. Inflammatory status (hs-CRP and cytokine panel) will be assessed and iron status will be measured. Body composition including fat mass (FM), lean mass (LM), and fat percentage will be measured using dual-energy X-ray absorptiometry (DXA). Joint pain and knee function will be assessed using a 100-mm visual analog scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, respectively.DiscussionThis trial will be the first to explore the effects of whole meat GSM powder on cartilage turnover, bone resorption, and inflammation biomarkers in overweight/obese postmenopausal women. The results from this trial will provide evidence on the efficacy of GSM in the prevention of OA.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000413921p. Registration on 27 March 2020.

Hemodiafiltration Is Associated With Reduced Inflammation and Increased Bone Formation Compared With Conventional Hemodialysis in Children: The HDF, Hearts and Heights (3H) Study

BackgroundPatients on dialysis have a high burden of bone-related comorbidities, including fractures. We report a post hoc analysis of the prospective cohort study HDF, Hearts and Heights (3H) to determine the prevalence and risk factors for chronic kidney disease-related bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD).MethodsThe baseline cross-sectional analysis included 144 children, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Circulating biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23, and klotho were measured.ResultsInflammatory markers interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein were lower in HDF than in HD cohorts at baseline and at 12 months (P < .001). Concentrations of bone formation (bone-specific alkaline phosphatase) and resorption (tartrate-resistant acid phosphatase 5b) markers were comparable between cohorts at baseline, but after 12-months the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio increased in HDF (P = .004) and was unchanged in HD (P = .44). On adjusted analysis, the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio was 2.66-fold lower (95% confidence interval, −3.91 to −1.41; P < .0001) in HD compared with HDF. Fibroblast growth factor-23 was comparable between groups at baseline (P = .52) but increased in HD (P < .0001) and remained unchanged in HDF (P = .34) at 12 months. Klotho levels were similar between groups and unchanged during follow-up. The fibroblast growth factor-23/klotho ratio was 3.86-fold higher (95% confidence interval, 2.15–6.93; P < .0001) after 12 months of HD compared with HDF.ConclusionChildren on HDF have an attenuated inflammatory profile, increased bone formation, and lower fibroblast growth factor-23/klotho ratios compared with those on HD. Long-term studies are required to determine the effects of an improved bone biomarker profile on fracture risk and cardiovascular health.

Abstract 1392: Synergistic antitumor efficacy of radium-223 in combination with enzalutamide in the intratibial LNCaP prostate cancer xenograft model

Abstract Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide is a second-generation androgen receptor inhibitor also used for treating the same patient population, and the combination of Ra-223 and enzalutamide is currently being investigated in clinical trials. We evaluated the antitumor efficacy of Ra-223 and enzalutamide in the LNCaP intratibial model mimicking prostate cancer metastasized to bone. LNCaP prostate cancer cells were inoculated into the right tibia of male NOD.scid mice. The mice were randomized (n=9/group) based on serum PSA and treated with vehicle, Ra-223 (330 kBq/kg, i.v., Q4W x 2), enzalutamide (30 mg/kg, p.o., QD) or with a combination treatment of Ra-223 and enzalutamide, for 28 days. Serum PSA levels were analyzed at the end of the study and compared to the pre-treatment levels. Serum bone formation and resorption biomarkers, PINP and CTX, respectively, were measured during the study. Tumor-induced abnormal bone area, Ra-223 uptake and bone formation were determined by X-ray, gamma counter and histomorphometry, respectively. The healthy tibiae were evaluated by microCT. Combination treatment showed synergistic antitumor efficacy as observed by lower PSA levels when compared to the vehicle, Ra-223 or enzalutamide monotherapies (p=0.04, p=0.008 and p=0.002, respectively). A statistical interaction between Ra-223 and enzalutamide treatments was found (p=0.003), confirming the synergistic effect. In combination treatment, the serum PSA change relative to pre-treatment levels was 18% of the vehicle. Accordingly, a decreasing trend (p=0.08) in tumor-induced abnormal bone changes was associated with the combination treatment in the tumor-bearing tibiae (46% of the vehicle), whereas no changes in total bone structure were observed in the healthy tibiae. The serum levels of PINP and CTX were lowest in mice treated with the combination treatment. Compared to Ra-223 monotherapy, concurrent administration of enzalutamide with Ra-223 did not affect either Ra-223 uptake or bone formation rate in tumor-bearing or healthy tibiae, respectively. Compared to Ra-223 and enzalutamide monotherapies, the combination treatment demonstrated synergistic antitumor efficacy by decreasing PSA levels in the LNCaP intratibial model. Despite of prominent effects on tumor growth, the combination treatment was not observed to compromise bone health in the healthy tibiae. In conclusion, these preclinical results support the ongoing phase 3 trials PEACE III (NCT02194842) &amp; ESCALATE (NCT04237584) of this combination. Citation Format: Mari I. Suominen, Matias Knuuttila, Jukka Vääräniemi, Birgitta Sjöholm, Esa Alhoniemi, Dominik Mumberg, Sanna-Maria Käkönen, Arne Scholz. Synergistic antitumor efficacy of radium-223 in combination with enzalutamide in the intratibial LNCaP prostate cancer xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1392.

Impact of Nutrition-Based Interventions on Athletic Performance during Menstrual Cycle Phases: A Review.

Despite the steady increase in female participation in sport over the last two decades, comprehensive research on interventions attenuating the influence of female menstrual physiology on performance remains scarce. Studies involving eumenorrheic women often only test in one menstrual phase to limit sex hormone variance, which may restrict the application of these findings to the rest of the menstrual cycle. The impacts of nutrition-based interventions on athletic performance throughout the menstrual cycle have not been fully elucidated. We addressed this gap by conducting a focused critical review of clinical studies that reported athletic outcomes as well as menstrual status for healthy eumenorrheic female participants. In total, 1443 articles were identified, and 23 articles were included. These articles were published between 2011 and 2021, and were retrieved from Google Scholar, Medline, and PubMed. Our literature search revealed that hydration-, micronutrient-, and phytochemical-based interventions can improve athletic performance (measured by aerobic capacity, anaerobic power, and strength performance) or attenuate exercise-induced damage (measured by dehydration biomarkers, muscle soreness, and bone resorption biomarkers). Most performance trials, however, only assessed these interventions in one menstrual phase, limiting the application throughout the entire menstrual cycle. Improvements in athletic performance through nutrition-based interventions may be contingent upon female sex hormone variation in eumenorrheic women.

Body Mass Index Predicts Cardiovascular Risk Factors and Inflammatory Status in Postmenopausal Women

ObjectivesSome studies have shown that hormonal changes during menopause transition may lead to weight gain. Higher body mass index (BMI) may be beneficial for bone health but not for heart health. However, these phenomena are still unclear. The present study aimed to determine whether BMI is associated with cardiovascular risk factors, and bone and inflammatory biomarkers in osteopenic postmenopausal women. MethodsIn a cross-sectional study, 132 healthy osteopenic postmenopausal women (1 to 10 years) not on hormone therapy (HT) and other pharmacological agents known to affect bone were recruited. Overnight fasting blood and urine samples were collected. Multiple linear regression analyses were conducted to examine the associations between BMI and changes in CVD risk factors and inflammatory and bone biomarkers. ResultsHigher BMI was significantly associated with elevated serum fasting glucose, C-reactive protein (CRP), apolipoprotein B (ApoB), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) levels after controlling for age, years of menopause, physical activity level, and total energy intake. Based on the regression model, every one unit increase in BMI was predicted to increase fasting glucose, CRP, ApoB, TC, LDL, TG by 1.0 mg/dL, 0.1 mg/L, 1.6 mg/dL, 2.8 mg/dL, 3.2 mg/dL, and 3.3 mg/dL, respectively. BMI was not associated with bone formation and resorption biomarkers. ConclusionsBMI is a good predictor of inflammatory marker and CVD risk factors but not bone biomarkers in postmenopausal women. Future studies are needed to examine the associations of body composition (lean mass and fat mass) on CVD risk factors and bone biomarkers. Funding SourcesN/A.

FC 133HEMODIAFILTRATION IS ASSOCIATED WITH REDUCED INFLAMMATION AND INCREASED BONE TURNOVER COMPARED TO CONVENTIONAL HEMODIALYSIS IN CHILDREN - THE HDF, HEART AND HEIGHT (3H) STUDY

Abstract Background and Aims Children on dialysis have a high burden of bone related comorbidities and fractures. We report a post-hoc analysis of the HDF-Hearts-Height study to determine the prevalence and risk factors for mineral bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD). Method 144 children were included in baseline cross-sectional analysis, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23 (FGF23) and klotho were measured. Results Inflammatory markers interleukin-6 [IL-6], tumor necrosis factor-alfa [TNF-α], and high-sensitivity CRP [hsCRP] were lower in the HDF compared to HD cohorts at baseline and 12 months (p&amp;lt;0.001). Concentrations of bone formation (bone-specific alkaline phosphatase, BAP) and resorption (tartrate-resistant acid phosphatase 5b [TRAP5b]) markers were comparable between cohorts at baseline, but after 12-months the BAP/TRAP5b ratio increased in HDF (p=0.004) and was unchanged in HD (p=0.44). On adjusted analysis the BAP/TRAP5b ratio was 2.66-fold lower (95%CI -3.91, -1.41; p&amp;lt;0.0001) in HD compared to HDF. FGF23 was comparable between groups at baseline (p=0.52) but increased in HD (p&amp;lt;0.0001) and remained static in HDF (p=0.34) at 12-months. Klotho levels were similar between groups and unchanged during follow-up. The FGF23/klotho ratio was 3.86-fold higher (95% CI 2.15, 6.93; p&amp;lt;0.0001) in HD compared to HDF. Conclusion We conclude that children on HDF have increased bone turnover, an attenuated inflammatory profile and lower FGF23/klotho ratios compared to those on HD. Long-term studies are required to determine the effect, if any, of an improved bone biomarker profile on fracture risk and growth.

Efficacy and safety of JMT103 in patients with giant cell tumor of bone: A multicenter, single-arm, open-label, phase Ib/II study.

11526 Background: JMT103 is a novel, fully humanized IgG4 monoclonal antibody targeting RANKL, inhibiting osteoclastogenesis and osteoclast-mediated bone resorption. A multicenter, single-arm, open-label, phase Ib/II study was conducted to evaluate the efficacy and safety of JMT103 in patients (pts) with Giant cell tumor of bone (GCTB). Methods: Eligible pts (ECOG: 0-2) were adults with pathologically confirmed unresectable GCTB or their planned surgery is associated with severe morbidity. Pts with active dental or jaw condition requiring oral surgery, other anti-tumor therapies, anti-RANKL antibody or concurrent use of bisphosphonates were excluded. 2 mg/kg JMT103 was administrated subcutaneously every 4 weeks with a loading dose on days 8 and day 15 of the first 4 week of therapy. The primary endpoint was tumor response, defined as elimination of at least 90% giant cells or objective response of the target lesion assessed by radiologic imaging as per Modified Inverse Choi density/size (ICDS) or the Modified European Organization for Research and Treatment of Cancer (EORTC) criteria within 12 weeks. Secondary endpoints included safety profile, change of pain score using Brief Pain Inventory-Short Form, and suppression of bone-resorption biomarkers. Results: 38 pts (14 males) were enrolled between June 3 and December 24, 2020. The median age was 31 years (range 18-57). Lesions sites included lower extremities (39.5%), upper extremities (31.6%), spine (21.1%) and pelvis (13.2%). Among 32 pts with at least 1 efficacy evaluation within 12 weeks, 26 (81.3%, 95% CI: 63.6-92.8) had a tumor response by at least one response criteria. All 7 pts who underwent histological assessments had a tumor response. 25 of 32 pts assessed by radiology had a tumor response. As per ICDS criteria, 23 of 32 (71.9%) had a response; as per EORTC criteria, 15 of 17 (88.2%) had a response. 21 of 26 (80.8%) pts who complained of pain at baseline experienced reduced pain during the treatment. The median reductions in bone-resorption biomarkers were 71.8% (IQR 67.7-82.4) for uNTx/Cr (p &lt; 0.001) and 81.4% (IQR 68.3-84.7) for sCTx (p &lt; 0.001) at day 8. Of all 38 pts who were included in safety analyses, treatment-related adverse events (TRAEs) occurred in 14 pts. The most common TRAEs were hypophosphatemia (18.4%), hypocalcemia (7.9%) and blood bilirubin increased (7.9%). 1 patient (2.6%) was reported a grade 3 AE but it was not related to the treatment; other AEs were grade 1–2. Conclusions: JMT103 demonstrated encouraging anti-tumor efficacy and manageable safety profile in pts with unresectable GCTB or at high risk of severe morbidity after surgery. Clinical trial information: NCT04255576.

Disturbance of osteonal bone remodeling and high tensile stresses on the lateral cortex in atypical femoral fracture after long-term treatment with Risedronate and Alfacalcidol for osteoporosis

An 83 year-old Japanese woman complained of left lateral thigh pain following a low-energy fall 4 months prior to admission. She had been treated for osteoporosis with Risedronate and Alfacalcidol for the previous five years. She was diagnosed with an atypical femoral fracture (AFF) according to the American Society for Bone and Mineral Research (ASBMR) Task Force revised criteria. Radiographs revealed cortical thickening and a transverse radiolucent fracture line in the lateral cortex of the shaft. MRI showed a high intensity signal on the T2WI image 1 cm long in the lateral cortex. The patient had normal levels of bone resorption and formation biomarkers except for low 25(OH) Vitamin D. Double fluorescent labeling was done preoperatively.Due to significant bowing, a corrective osteotomy and intramedullary nailing were performed, and the resected bone wedge was analyzed by bone histomorphometry. Three ground sections of the lateral cortex at the fracture site showed many and large pores, with or without tetracycline labeling. Histomorphometric assessment was done on intracortical pores, classified by a novel criteria, only to assess size of the pores to know prolonged osteoclastic activity and its characteristics of inner surfaces to assess whether bone formation has been occurring or not in labeling period in remodeling cycle, and coalition of multi-pores. Increased size with widespread variation of pores suggested prolonged osteoclastic activity in the reversal/resorptive phase. Bone labeling showed lamellar bone on the endocortical surface.We hypothesize that the case had developed from a regional disturbance of osteonal remodeling in the lateral cortex, in which accumulated microcracks might have initiated a resorption process resulting in resorption cavities, i.e., pores, which became larger due to prolonged activity of secondary osteoclasts. Various sized pores could form lamellar bone, still forming at the time of biopsy, some had formed lamellar bone, but stopped to form before labeling and not to start to form at all, probably due to incomplete coupling. Endocortical lamellar bone might had started to resorbed to smooth off endocortical surface, followed by formation of lamellar bone. The endocortical bone formation was assessed and its formation period is about 2.7 years.A finite element analysis using preoperative CT data revealed high tensile stresses on the lateral aspect of the femur. Histomorphometric results suggest that there might be more pores in the tensile area than the compressive area. These findings may subsequently connect accumulation of microcracks, an increase of size and number of pores and coalition and subsequent fracture in the lateral cortex.

Antioxidant Supplementation Does Not Affect Bone Turnover Markers During 60 Days of 6° Head-Down Tilt Bed Rest: Results from an Exploratory Randomized Controlled Trial.

Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34± 8 years; weight, 74± 6kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741mg/d polyphenols, 2.1g/d omega-3 fatty acids, 168mg/d vitamin E, and 80μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β-C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest-related changes were observed. Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.