Maintenance Of Bone Mineral Density Research Articles

Calcium-based phosphate binders and bone mineral density in patients undergoing hemodialysis: a retrospective cohort study.

Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients. Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated. The femoral neck's BMD decreased from 0.836g/cm2 (0.702-0.952) to 0.764g/cm2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833g/cm2 (0.736-0.965) to 0.824g/cm2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [β-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [β-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]. CBPB administration may be associated with BMD maintenance.

Differences in dietary intake in early postmenopausal women with different levels of areal and volumetric bone mineral density: a cross-sectional analysis of baseline data from an intervention study

Osteoporosis is a degenerative disease of the bone. The rate of bone loss is accelerated during the first postmenopausal years in women which results in their disproportionate prevalence of osteoporosis(2). Some of the factors contributing to the development and maintenance of bone mineral density (BMD) relate to diet, particularly the intake of protein, calcium and other micronutrients that play a crucial role in bone composition(3). The most common method of measuring BMD is dual-energy X-ray absorptiometry (DXA) which generates a two-dimensional image of the scan site (typically spine, hip and/or forearm) to determine areal BMD (aBMD). However, new methods have recently emerged, including High Resolution peripheral Quantitative Computed Tomography (HRpQCT), that offer more accurate three-dimensional measurements of volumetric BMD (vBMD) and microstructure of distal tibia and radius(4). The aim of this study was to examine the differences in the dietary intake of nutrients that represent organic or inorganic components of the bone, in early postmenopausal women with different spine aBMD and tibia and radius vBMD levels. One hundred and fourteen healthy early postmenopausal women with a lumbar spine or total hip BMD T score &gt; −2.5 (measured by DXA) were recruited as part of a larger interventional study. Dietary intake was recorded using a 297-point self-reported validated food frequency questionnaire(5) for assessing the intake of energy, macro and micronutrients. Physical activity was self-reported using the validated Active Australia Questionnaire. Years since menopause were self-reported. DXA and HRpQCT scans measured L1-L4 spine, proximal femur aBMD, and distal tibia and radius vBMD respectively. Non-parametric statistical tests examined differences in dietary intake and physical activity levels between women at different levels of aBMD and vBMD. Data reported as median and interquartile ranges. There were no significant differences observed in the total sample between tertiles of aBMD and vBMD, regarding nutrient intake. However, for women with less than 3 years since menopause (i.e., the time-period of accelerated bone loss), lower dietary intakes of energy [8,658(3,324) vs 10,068(3,688) kJ/day; p = 0.047], protein [94(29) vs 103(32) g/day; (p = 0.044)], sodium [1,927(992) vs 2,625(2,185) mg/d; (p = 0.044)], potassium [4,064(1,373) vs 5,121(2,377) mg/d; (p = 0.041)], calcium [969(325) vs 1,214(652) mg/d; (p = 0.028)] and zinc [10(3) vs 12(4) mg/d; (p = 0.005)] were observed for women with osteopenia (−1&lt; L1-L4 aBMD T-score &lt;2.5) compared to those with normal L1-L4 aBMD (i.e., T-score &gt; −1). No significant differences were observed for women with more than 3 years since menopause, with the only exception of alcohol intake (p = 0.033), which was found to be lower in women with osteopenia compared to those with normal aBMD. These findings highlight the importance of targeting osteopenic women within the first 3 years following menopause as candidates for tailored dietary intervention programs for preventing osteoporosis.

Single-Cell Integration of BMD GWAS Results Prioritize Candidate Genes Influencing Age-Related Bone Loss.

The regulation of bone mineral density (BMD) is highly influenced by genetics and age. Although genome-wide association studies (GWAS) for BMD have uncovered many genes through their proximity to associated variants (variant nearest-neighbor [VNN] genes), the cell-specific mechanisms of each VNN gene remain unclear. This is primarily due to the inability to prioritize these genes by cell type and age-related expression. Using age-related transcriptomics, we found that the expression of many VNN genes was upregulated in the bone and marrow from aged mice. Candidate genes from GWAS were investigated using single-cell RNA-sequencing (scRNA-seq) datasets to enrich for cell-specific expression signatures. VNN candidate genes are highly enriched in osteo-lineage cells, osteocytes, hypertrophic chondrocytes, and Lepr+ mesenchymal stem cells. These data were used to generate a "blueprint" for Cre-loxp mouse line selection for functional validation of candidate genes and further investigation of their role in BMD maintenance throughout aging. In VNN-gene-enriched cells, Sparc, encoding the extracellular matrix (ECM) protein osteonectin, was robustly expressed. This, along with expression of numerous other ECM genes, indicates that many VNN genes likely have roles in ECM deposition by osteoblasts. Overall, we provide data supporting streamlined translation of GWAS candidate genes to potential novel therapeutic targets for the treatment of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Maintenance of bone resorption markers in the low premenopausal range during the year following denosumab discontinuation is associated to bone density preservation. The ReoLaus study.

Denosumab discontinuation (DD) is associated with serum C-terminal X-linked telopeptides (sCTX) increase, bone mineral density (BMD) loss and vertebral fractures (VFs) risk increase. We compared clinical characteristics of women losing or not lumbar spine (LS) BMD one-year after DD, and their sCTX values at different time-points. We included women from the ReoLaus cohort having received ≥2 denosumab 60mg injections, with three BMD measurements on the same device (before (DXA1), at the end of denosumab treatment (DXA2), and one-year after (DXA3)) and sCTX measured at different time-points. Losers (LS DXA3-DXA2>2.8%) and stable groups were compared. 63 postmenopausal women were included (mean age 64.2±9.1years, 7.9±2.7 denosumab injections). 19months after last denosumab injection, 65% had lost LS BMD. Losers were younger, had lower BMD and higher sCTX before denosumab, received more injections and gained more BMD under denosumab, and had higher sCTX after DD. Same proportion of patients received bisphosphonates in both groups, but 11 (all in losers group) received ≥1 zoledronate infusion. Three women developed VFs in the losers group (none in the stable). Mean sCTX at 10 and 19months were 590±372 versus 221±101, and 598±324 versus 293±157ng/l, respectively (premenopausal range<573ng/l, p<0.01 for both). LS BMD loss and sCTX levels measured at 10 and 19months were correlated (r2=0.29, p=0.01, and r2=0.16, p<0.005). Maintenance of BMD gained with denosumab is associated with sCTX in the low premenopausal range after DD. Whether this could be achieved by regular sCTX monitoring and adjustment of bisphosphonates doses or frequency administration needs to be confirmed by further studies.

Fibroblast Growth Factor 23 Bone Regulation and Downstream Hormonal Activity.

Mineral homeostasis of calcium and phosphate levels is one critical component to the maintenance of bone mineral density (BMD) and strength. Diseases that disrupt calcium and phosphate balanced have highlighted not only the role these minerals play in overall bone homeostasis, but also the factors, hormones and downstream transporters, responsible for mineral metabolism. The key phosphaturic hormone elucidated from studying rare heritable disorders of hypophosphatemia is Fibroblast Growth Factor 23 (FGF23). FGF23 is predominantly secreted from bone cells in an effort to maintain phosphate balance by directly controlling renal reabsorption and indirectly affecting intestinal uptake of this mineral. Multiple factors have been shown to enhance bone mRNA expression; however, FGF23 can also undergo proteolytic cleavage to control secretion of the biologically active form of the hormone. The review focuses specifically on the regulation of FGF23 and its secretion from bone as well as its hormonal actions under physiological and disease conditions.

Dual-Energy X-Ray Absorptiometry (DEXA) Evaluation of the Bone Remodeling Effects of a Low-Modulus Composite Hip Stem After 2 Decades of Follow-Up.

Background: The Epoch FullCoat Hip Stem (Zimmer) was an isoelastic composite femoral stem developed to address stem stiffness concerns. Purpose: We sought to evaluate the long-term bone mineral density (BMD) of a cohort of patients who underwent total hip arthroplasty (THA) using the Epoch isoelastic stem and having more than 2-decade follow-up. Methods: We conducted a retrospective chart review of all patients who were study subjects at our institution in a multicenter prospective trial for the Food and Drug Administration of the Epoch implant in the mid-1990s. Through this, we identified 16 patients who had dual-energy X-ray absorptiometry (DEXA) scans, with which we could determine BMD preoperatively and at 3 points postoperatively. Of these, 5 agreed to participate in the study (the others were deceased, unable or declined to participate, or were lost to follow-up) with mean follow-up of 22 years. These participants underwent clinical and radiographic evaluation consisting of a Harris hip score, anteroposterior (AP) pelvis and AP and lateral hip X-rays, and DEXA evaluation of both hips. BMD in the 7 Gruen zones at last follow-up was compared with immediate postoperative and 2-year follow-up. Results: At last follow-up, all stems were well-fixed with signs of extensive osteointegration. In proximal Gruen zones 1 and 7, patients underwent a decrease in BMD with more modest losses in Gruen zone 1. All patients demonstrated an increase in BMD in zones 2 through 6 at latest follow-up, except for 1 patient in Gruen zone 6. BMD changes were not limited to the first 2 years of follow-up. Conclusion: This small follow-up cohort study found excellent long-term clinical results, no plain radiographic signs of notable stress shielding, and general maintenance of BMD at a follow-up of over 20 years for this isoelastic stem. Long-term bone remodeling after implantation of the isoelastic stem resulted in increased BMD in Gruen zones 2 through 6, suggesting that composite implant designs may still have a role in THA.

Movement control during one-leg standing is important for the bone mineral density maintenance or improvement.

Both hip fracture and bone mineral density (BMD) decline on the non-fractured side are more likely to occur within 1year. However, there are no longitudinal study reports on the factors associated with BMD maintenance or improvement within the first year after hip fracture. This study aimed to investigate the factors influencing the neck BMD maintenance or improvement in patients with hip fractures from within 2weeks-6months after surgery. Patients were hip fracture after surgery and were divided into two groups: Among neck BMD changes (6months minus 2weeks after surgery) were calculated. Based on among neck BMD change, patients were classified into the BMD maintenance or improvement (change ≥ 0) and the BMD decrease groups (change < 0). Propensity score matching was performed to adjust for confounding factors. To predict the factors affecting neck BMD, hierarchical logistic regression analysis was performed. The dependent variable was the BMD maintenance or improvement group and the BMD decrease group. The independent variables were basic and medical information, and physical functions. The hierarchical logistic regression analysis results showed that movement control during one-leg standing affected femoral neck BMD independently from age, sex. The odds ratio for movement control during one-leg standing was 8.22. The discrimination rate of the model was 69.7%. This study suggested that adequate movement control during one-leg standing is important to maintain or improve neck BMD.

69. Relugolix combination therapy in European women with symptomatic uterine fibroids in the liberty long-term extension (lte) study

Introduction and aims: In LIBERTY 1&2, once-daily relugolix combination therapy (Relugolix-CT; 40mg relugolix, estradiol 1mg, norethindrone acetate 0.5mg) improved uterine fibroid (UF)-associated heavy menstrual bleeding (HMB) versus placebo, was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. In LIBERTY LTE, MBL reduction was sustained with no new safety signals and BMD maintenance through 52 weeks. A descriptive subgroup analysis of European vs overall population is reported.

Characterization, pharmacokinetics, and pharmacodynamics of anti-Siglec-15 antibody and its potency for treating osteoporosis and as follow-up treatment after parathyroid hormone use.

Recent studies have established the idea that Siglec-15 is involved in osteoclast differentiation and/or function, and it is anticipated that therapies suppressing Siglec-15 function can be used to treat bone diseases such as osteoporosis. We have produced rat monoclonal anti-Siglec-15 antibody (32A1) and successively generated humanized monoclonal anti-Siglec-15 antibody (DS-1501a) from 32A1. Studies on the biological properties of DS-1501a showed its specific binding affinity to Siglec-15 and strong activity to inhibit osteoclastogenesis. 32A1 inhibited multinucleation of osteoclasts and bone resorption (pit formation) in cultured mouse bone marrow cells. 32A1 also inhibited pit formation in cultured human osteoclast precursor cells. Maximum serum concentration and serum exposure of DS-1501a in rats were increased in a dose-dependent manner after single subcutaneous or intravenous administration. Furthermore, single administration of DS-1501a significantly suppressed bone resorption markers with minimal effects on bone formation markers and suppressed the decrease in bone mineral density (BMD) of the lumbar vertebrae in ovariectomized (OVX) rats. In histological analysis, the osteoclasts distant from the chondro-osseous junction of the tibia tended to be flattened, shrunken, and functionally impaired in 32A1-treated rats, while alkaline phosphatase-positive osteoblasts were observed throughout the metaphyseal trabeculae. In addition, we compared the efficacy of 32A1 with that of alendronate (ALN) as follow-up medicine after treatment with parathyroid hormone (PTH) using mature established osteoporosis rats. The beneficial effect of PTH on bone turnover disappeared 8weeks after discontinuing the treatment. The administration of 32A1 once every 4weeks for 8weeks suppressed bone resorption and bone formation when the treatment was switched from PTH to 32A1, leading to the maintenance of BMD and bone strength. Unlike with ALN, the onset of suppression of bone resorption with 32A1 was rapid, while the suppression of bone formation was mild. The improvement of bone mass, beneficial bone turnover balance, and suppression of osteoclast differentiation/multinucleation achieved by 32A1 were supported by histomorphometry. Notably, the effects of 32A1 on bone strength, not only structural (extrinsic) but also material (intrinsic) properties, were significantly greater than those of ALN. Since the effect of 32A1 on BMD was moderate, its effect on bone strength could not be fully explained by the increase in BMD. The beneficial balance of bone turnover caused by 32A1 might, at least in part, be responsible for the improvement in bone quality. This is the first report describing the effects of anti-Siglec-15 antibody in OVX rats; the findings suggest that this antibody could be an excellent candidate for treating osteoporosis, especially in continuation therapy after PTH treatment, due to its rapid action and unprecedented beneficial effects on bone quality.

Management of Osteoporosis in Men: A Narrative Review.

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Sustained Efficacy and Safety of Relugolix Combination Therapy in Women with Endometriosis-Associated Pain: Spirit 52-Week Data

<h3>Study Objective</h3> To evaluate long-term safety and efficacy of relugolix combination therapy (Relugolix-CT) to treat endometriosis-associated pain. <h3>Design</h3> SPIRIT Extension was a Phase 3, open-label, single-arm, 80-week study. <h3>Setting</h3> 170 clinical research centers globally. <h3>Patients or Participants</h3> Premenopausal women (age 18–50 years) with endometriosis, moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline who completed the 24-week pivotal studies (SPIRIT 1/2) and were eligible to participate were enrolled. <h3>Interventions</h3> Once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg). <h3>Measurements and Main Results</h3> Co-primary endpoints: proportion of dysmenorrhea/NMPP responders at Week 52, using Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). Dysmenorrhea/NMPP responder: women who achieved a clinically meaningful reduction from baseline in NRS score (2.8/2.1, respectively) without increased analgesic use. Secondary endpoints: change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, analgesic/opioid use. Safety endpoints: adverse events, bone mineral density (BMD) evaluation. Of 1,261 women randomized in SPIRIT 1/2, 802 enrolled in the extension; 681 completed 52 weeks of treatment. Data are reported for women who received Relugolix-CT through 52 weeks. The proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea, NMPP and dyspareunia decreased from 7.4 (severe), 6.0 (moderate) and 5.9 (moderate) at pivotal baseline to 1.3 (mild), 2.2 (mild) and 2.4 (mild) at Week 52, equating to 82.8%, 62.9% and 60.1% reductions. Daily functioning (EHP-30 pain domain score) improved (–38.1 point); most women (85.6%) were opioid-free at Week 52. No disproportionate increase in adverse event incidence and no new safety signals were identified. Lumbar spine BMD was preserved, with LS mean change from baseline to Week 52 of –0.81% (95% CI: –1.26, –0.36). <h3>Conclusion</h3> Relugolix-CT was well tolerated and demonstrated sustained improvement of endometriosis-associated pain and maintenance of BMD through 52 weeks.

O-132 Sustained efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT 52-week data

Abstract Study question To assess the long-term (52-week) efficacy and safety of relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain. Summary answer Relugolix-CT demonstrated a sustained improvement of endometriosis-associated pain and maintenance of bone mineral density (BMD) over the extension treatment period. It was well tolerated. What is known already Endometriosis is a chronic condition characterized by symptoms of menstrual and non-menstrual pain, and dyspareunia, which have a substantial impact on women’s lives. SPIRIT 1 and 2 were Phase 3, randomized, double-blind, placebo-controlled studies of once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline. These trials demonstrated a significant improvement of dysmenorrhea, NMPP and dyspareunia in women treated with Relugolix-CT, with a minimal decline in BMD vs placebo over 24 weeks. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials) were eligible to enroll in an open-label, single-arm, long-term safety and efficacy extension study for an additional 80 weeks. All women received once-daily oral Relugolix-CT. Analyses were done based on original randomization in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Here, 52-week efficacy and safety outcomes are presented. Participants/materials, setting, methods The primary endpoints were the proportion of dysmenorrhea and NMPP responders at Week 52, based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). A responder was a woman who achieved a predefined, clinically meaningful reduction from baseline in NRS score with no increase in analgesic use. Secondary efficacy endpoints included change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, and analgesic/opioid use. Safety endpoints included adverse events (AEs) and BMD evaluation. Main results and the role of chance Of 1261 randomized patients, 1044 completed the primary studies; 802 enrolled in the long-term extension and 681 completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the extension population were consistent with those of the original randomized population. Sustained improvement of endometriosis-associated pain was demonstrated with Relugolix-CT through 52 weeks, the proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea and NMPP decreased from 7.4 (severe) and 6.0 (moderate) at SPIRIT study baseline to 1.3 (mild) and 2.2 (mild) at Week 52, equating to 82.8% and 62.9% reduction in dysmenorrhea and NMPP, respectively. Mean NRS for dyspareunia decreased from 5.9 (moderate) to 2.4 (mild), demonstrating 60.1% reduction with Relugolix-CT. Daily functioning measured by the EHP-30 pain domain score was improved (–38.1 point) and the majority of women (85.6%) were opioid-free at Week 52. There was no disproportionate increase in the incidence of AEs in the Relugolix-CT group with no new safety signals identified through the 52 weeks. BMD was preserved over the extension period with overall LS mean change from baseline to Week 52 of –0.83% (95% CI: –1.34, –0.32) for lumbar spine in the Relugolix-CT group. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 28 weeks of the extension period. Wider implications of the findings Relugolix-CT demonstrated a sustained improvement of dysmenorrhea, NMPP, and dyspareunia, and reduced pain-related functional limitations and the need for opioids over 52 weeks in women with moderate-to-severe endometriosis-associated pain. Relugolix-CT was generally well tolerated and associated with minimal BMD loss after treatment initiation followed by BMD maintenance over 52 weeks. Trial registration number NCT03654274

O-136 Once-daily relugolix combination therapy results in sustained reduction in symptoms and improved quality of life in women with uterine fibroids treated over 52 weeks

Abstract Study question What is the effect of relugolix combination therapy (Relugolix-CT) on symptom burden and health-related quality-of-life (HR-QoL) in patients with uterine fibroids (UF) over 52 weeks? Summary answer Relugolix-CT demonstrated sustained, clinically meaningful improvement in patient-reported symptom severity and HR-QoL over 52 weeks in women with UF. What is known already In LIBERTY 1 and 2 randomized clinical trials, once-daily Relugolix-CT (40 mg relugolix, an oral gonadotropin-releasing hormone receptor antagonist, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly reduced menstrual blood loss (MBL) and UF-associated pain versus placebo in women with UF and heavy menstrual bleeding (HMB), and was well tolerated, with bone mineral density (BMD) preservation through 24 weeks. In the LIBERTY long-term extension study, a sustained reduction in MBL was observed along with no new safety signals and BMD maintenance through 52 weeks. Relugolix-CT was previously shown to significantly improve patient-reported symptom severity and HR-QoL through 24 weeks. Study design, size, duration In the LIBERTY 1 and 2 studies, 770 premenopausal women with ultrasound-documented clinically significant UF and alkaline-hematin documented HMB were randomized 1:1:1 to Relugolix-CT for 24 weeks, relugolix 40 mg for 12 weeks followed by Relugolix-CT for 12 weeks, or placebo for 24 weeks. Women who completed the pivotal studies were eligible to enroll in the 28-week extension study (N = 477 enrolled). Patients included in the extension study received open-label once-daily Relugolix-CT. Participants/materials, setting, methods Changes from baseline to Weeks 24 and 52 in the Uterine Fibroid Symptom (UFS)-QoL symptom severity scale, Bleeding and Pelvic Discomfort scale (BPD; assessing distress due to HMB, passing blood clots, pelvic pressure/tightness); and HR-QoL (sub)scales were assessed. Higher symptom severity and BPD scores reflect higher severity and distress, respectively; higher HR-QoL scores indicate better outcomes. Least-squares mean changes were provided for the original pivotal-study randomized treatment groups Relugolix-CT and placebo. Main results and the role of chance A sustained improvement in symptom severity was observed for the Relugolix-CT group from baseline to Weeks 24 and 52, with LS mean changes of –36.9 and –37.3 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–10.8 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–35.0 points) after transitioning to Relugolix-CT. Considering the BPD, measuring distress from key UF symptoms, LS mean changes of –50.9 and –51.3 points were observed in the Relugolix-CT group from baseline to Week 24 and 52, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–15.9 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–48.6 points) after transitioning to Relugolix-CT. Treatment with Relugolix-CT also resulted in a sustained improvement in different aspects of HR-QoL. LS mean total HR-QoL score increased from baseline to Weeks 24 and 52 by 40.8 and 40.4 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (11.4 points), whereas a greater increase from baseline was demonstrated at Week 52 (39.0 points) after transitioning to Relugolix-CT at Week 24. Limitations, reasons for caution The 28-week LIBERTY long-term extension study was non-comparative. Analyses were performed in a subset of patients who completed the LIBERTY pivotal studies and were eligible for the extension study. However, it is important to note that the demographic and baseline disease characteristics were similar between pivotal and long-term extension populations. Wider implications of the findings Relugolix-CT resulted in a sustained reduction in UF symptom burden, particularly in terms of distress from key UF symptoms, and a sustained improvement of HR-QoL over 52 weeks. Improvements observed after transitioning from placebo to Relugolix-CT at 24 weeks confirmed the positive effect of Relugolix-CT on UF-associated symptoms and HR-QoL. Trial registration number NCT03412890

Effectiveness of Pilates and Yoga to improve bone density in adult women: A systematic review and meta-analysis.

The ageing population brings about the appearance of age-related health disorders, such as osteoporosis or osteopenia. These disorders are associated with fragility fractures. The impact is greater among postmenopausal women due to an acceleration of bone mineral density (BMD) loss. To estimate the effectiveness of Pilates or Yoga on BMD in adult women. Five electronics databases were searched up to April 2021. Randomized controlled trials (RCTs), non-RCTs and pre-post studies were included. The main outcome was BMD. Risk of bias was evaluated using the Cochrane risk of bias tool. A random effects model was used to pool data from primary studies. Subgroup analyses based on the type of exercise were conducted. Eleven studies including 591 participants aged between 45 and 78 years were included. The mean length of the interventions ranged from 12 to 32 weeks, and two studies were performed for a period of at least one year. The pooled effect size for the effect of the intervention (Pilates/Yoga) vs the control group was 0.07 (95% Confidence interval [CI]: -0.05 to 0.19; I2 = 0.0%), and 0.10 (95% CI: 0.01 to 0.18; I2 = 18.4%) for the secondary analysis of the pre-post intervention. Despite of the non-significant results, the BMD maintenance in the postmenopausal population, when BMD detrimental is expected, could be understood as a positive result added to the beneficial impact of Pilates-Yoga in multiple fracture risk factors, including but not limited to, strength and balance.

Effects of Lemon Beverage Containing Citric Acid with Calcium Supplementation on Bone Metabolism and Mineral Density in Postmenopausal Women: Double-Blind 11-Month Intervention Study

A critical factor for preventing osteoporosis after menopause is attenuation of the accelerated turnover rate of bone metabolism. The present randomized controlled study was conducted to clarify the effects of a lemon beverage with calcium (Ca) supplementation that makes use of the chelating action of citric acid. Comprehensive evaluations of bone were performed by assessments of bone mineral density (BMD) and biomarkers related to bone turnover. Seventy-nine postmenopausal women were enrolled and asked to participate in an 11-month continuous intake of the test beverages. The subjects were divided into three groups: those who consumed a lemon beverage containing citric acid with Ca supplementation (LECA group), those who consumed a lemon beverage containing citric acid without Ca supplementation (LE group), and those who consumed no test beverage (control group). Using a double-blind protocol, subjects in the LECA and LE groups consumed one bottle containing 290 mL of the test beverage each day. The ratio of change in BMD after 11 months was significantly higher in the LECA group as compared to the control and LE groups. The LECA group also showed significant decreases in concentrations of tartrate-resistant acid phosphatase 5b (TRACP-5b), a bone resorption marker, and bone alkaline phosphatase (BAP) as compared to the other groups, as well as a significant decrease in concentration of osteocalcin (OC), a bone formation marker, as compared to the LE group. Based on our findings, we speculated that bone resorption and bone formation in postmenopausal women might be suppressed along with an increase in Ca resorption caused by chelation of citric acid in association with continuous ingestion of a Ca-supplemented lemon beverage containing citric acid, resulting in suppression of high bone metabolic turnover. In addition, the results provide information regarding BMD maintenance in the bones of the trunk, including the lumbar spine and proximal femur.

Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Higher-Impact Physical Activity Is Associated With Maintenance of Bone Mineral Density But Not Reduced Incident Falls or Fractures in Older Men: The Concord Health and Aging in Men Project.

High-impact physical activities with bone strains of high magnitude and frequency may benefit bone health. This study aimed to investigate the longitudinal associations between changes in loading intensities and application rates, estimated from self-reported physical activity, with bone mineral density (BMD) changes over 5 years and also with incident falls over 2 years and long-term incident fractures in community-dwelling older men. A total of 1599 men (mean age 76.8 ± 5.4 years) from the Concord Health and Aging in Men Project (CHAMP) were assessed at baseline (2005-2007) and at 2- and 5-year follow-up. At each time point, hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry, and physical activity energy expenditure over the past week was self-reported via the Physical Activity Scale for the Elderly (PASE) questionnaire. Sum effective load ratings (ELRs) and peak force were estimated from the PASE questionnaire, reflecting the total and highest loading intensity and application rate of physical activities, respectively. Participants were contacted every 4 months over 2 years to self-report falls and over 6.0 ± 2.2 years for fractures. Hip fractures were ascertained by data linkage for 8.9 ± 3.6 years. Compared with sum ELR and PASE scores, peak force demonstrated the greatest standardized effect size for BMD maintenance at the spine (β = 9.77 mg/cm2 ), total hip (β = 14.14 mg/cm2 ), and femoral neck (β = 13.72 mg/cm2 ) after adjustment for covariates, including PASE components (all p < .01). Only PASE scores were significantly associated with reduced falls risk (standardized incident rate ratio = 0.90, 95% confidence interval 0.81-1.00, p = .04). All physical activity measures were significantly associated with reduced incident fractures in univariate analyses, but none remained significant after multivariable adjustments. Older men who engaged in physical activity of high and rapid impact maintained higher BMD, while higher energy expenditure was associated with reduced falls risk. Coupling traditional physical activity data with bone loading estimates may improve understanding of the relationships between physical activity and bone health. © 2020 American Society for Bone and Mineral Research (ASBMR).

Are drug holidays a safe option in treatment of osteoporosis? — Insights from an in silico mechanistic PK–PD model of denosumab treatment of postmenopausal osteoporosis

Recent reviews by the clinical bone research community suggest caution with prescription of drug holidays for patients with postmenopausal osteoporosis (PMO) treated with denosumab for an extended period of time. Main reasons for this suggestion are based on the fact that discontinuation of denosumab treatment leads to a relapse of osteoclastic bone resorption and a loss of bone mineral density (BMD) to pre-treatment levels at only 12–28 months. The question remains what is the best treatment option for cases where it is required to discontinue and/or reduce the drug dose and what are the consequences on BMD and bone turnover markers (BTMs). The latter questions are difficult to be addressed using clinical trials alone given the large number of parameter combinations involved to answer this problem.In this paper, we apply a recently developed in silico mechanistic pharmacokinetic–pharmacodynamic (PK–PD) model of the effect of denosumab on bone remodelling in PMO. To address the above clinical relevant questions, we design a wide range of current and virtual treatment regimens to study the effect of drug holiday duration and therapy resumption on the evolution of BTMs, BMD and mineral content. Our numerical simulation results indicate the symptomatic effect of denosumab, which is lost once treatment is stopped. This effect is most clearly seen on rapid loss of BMD to pre-treatment levels 12 months after the last injection (8% and 3.6% per year in the lumbar spine and femoral neck, respectively). Also, we identify that independently of the duration of drug holiday (i.e. 12, 16 or 18 months) resuming treatment can restore BMD quite effectively. However, the latter result does not consider the possibility of potential fractures that can occur during the drug holiday. Finally, we identify a treatment case most promising for achieving maintenance of BMD and mineral content, while moderately increasing BTMs. The latter case uses no drug holiday, but reduces the most commonly prescribed denosumab dose (60 mg every 6 months) by half at same interval.

The Effect of Exercise on Body Composition and Physical Performance in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy (ADT): A Narrative Synthesis.

This review sought to synthesize evidence examining the effect of exercise on prostate cancer patients undergoing androgen deprivation therapy (ADT). A systematic literature search was conducted in electronic databases (CINAHL, MEDLINE, APA PsychINFO, Scopus, SPORTDiscus, and Cochrane Library) from their inception to March 31, 2020. Inclusion criteria were randomized controlled trials (RCTs) testing the effect of exercise on body composition, muscle strength and physical performance. Fourteen RCTs were included. Participant numbers within the individual RCTs ranged from 19 to 163 with heterogeneity in prostate cancer stage (localized and locally advanced diagnoses) with age of participants ranging from 43 to 90 years. The length of the interventions ranged from 12 weeks to 12 months, with the number of sessions per week ranging from 2 to 5. Resistance training intensity ranged from 60% to 90% 1RM and the aerobic training ranged from 60% to 90% HRmax. Resistance training and sport (football) in the form of small sided games (SSGs) played an important role in preserving bone mineral density and lean mass as well as improving muscle strength and physical performance outcomes in men affected by prostate cancer undergoing ADT. Multimodal exercise, including resistance exercise and activity that includes repeated sprints (SSGs), benefit the maintenance of bone mineral density and lean mass as well as increase strength and physical performance in men affected by prostate cancer undergoing ADT. Based on this evidence, nurses should coordinate timely referrals to qualified exercise physiologists or physiotherapist with expertise in cancer care.

P1399SPARING EFFECT OF PERITONEAL DIALYSIS VS HEMODIALYSIS ON CHANGE OF BONE MINERAL DENSITY EVALUATED BY WHOLE-BODY DXA AFTER INITIATION OF DIALYSIS THERAPY AND ITS IMPACT ON CLINICAL OUTCOME

Abstract Background and Aims Bone loss is associated with progression of cardiac calcification and increased mortality in end stage renal disease (ESRD) patients but the relations and underlying causes are unclear. We investigated factors associated with changes of bone mineral density (BMD) during the first year after initiation of dialysis and the association between BMD changes and subsequent mortality in ESRD patients. Method In a prospective study of 242 ESRD patients (median age 55 years, 61% men) starting dialysis, total BMD and BMD at specific bone sites (including seven subregions: head, arms, legs, trunk, hip, pelvis and spine) was assessed by whole body dual-energy X-ray absorptiometry (DXA) at baseline and one year after dialysis start. Framingham cardiovascular disease (CVD) risk score, body composition, nutritional status, handgrip strength, various biochemical biomarkers (white blood cell, hemoglobin, albumin, creatinine, calcium, phosphate, intact parathyroid hormone, triglyceride, cholesterol, HDL cholesterol and high-sensitivity C-reactive protein) were recorded. We used multivariate linear regression analysis for BMD change analysis. We followed patients from 12 months after initiating of dialysis until renal transplantation, death or end of 60 months follow-up. During follow-up, 59 patients (24%) died due to CVD (n=33) or other causes (n=26) and 95 patients (39%) underwent renal transplantation. Fine and Gray competing risk analysis was used to ascertain associations of BMD changes with all-cause and CVD-related mortality. Results From baseline to one year after initiation of dialysis, there was a significant decrease of BMDtotal and BMDleg, trunk, rib, pelvis and spine in hemodialysis (HD) patients, whereas no difference was seen in peritoneal dialysis (PD) patients. In multivariate linear regression analysis adjusting for several confounders, HD therapy - compared to PD therapy - was significantly associated with negative changes in BMDtotal (β=-0.15), BMDhead (β=-0.14), BMDleg (β=-0.18) and BMDtrunk (β=-0.16). The direction and extent of changes in BMD, i.e. increase of BMD, associated with statistically significant lower all-cause mortality risk for BMDtotal (sHR, 0.91), BMDhead (sHR 0.91) and BMDleg (sHR 0.92), while for CVD-mortality a significant association with BMD changes was found only for changes in BMDhead (sHR 0.92). Conclusion In patients starting on dialysis, PD therapy appeared to have a beneficial effect on BMD changes as compared to HD during the first year of dialysis therapy. This difference may have implications for clinical outcomes as the degree of bone loss was associated with subsequent mortality. Changes towards increased BMDtotal, BMDhead and BMDleg associated with lower all-cause mortality. For head region – which is known as a cortical bone rich site – positive BMD change associated also with lower CVD mortality suggesting that increase or maintenance of BMD of cortical bone rich sites may have stronger association with clinical outcome in ESRD than BMD of trabecular bone.