Preservation Of Bone Mineral Density Research Articles

Bisphosphonates Preserve Bone Mineral Density and Suppress Bone Turnover Markers in Early Menopausal Women: A Systematic Review and Meta-Analysis of Randomized Trials.

Most women do not qualify for pharmacologic osteoporosis treatment until more than a decade after menopause, by which time they will have lost up to 30% of their bone mass and may have already sustained fractures. Short or intermittent courses of bisphosphonate therapy, initiated around the time of menopause, might prevent excessive bone loss and lower long-term fracture risk. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effects of nitrogen-containing bisphosphonates on fracture incidence, bone mineral density (BMD), and bone turnover markers in early menopausal women (ie, perimenopausal or <5 years postmenopausal) over ≥12 months. Medline, Embase, CENTRAL, and CINAHL were searched in July 2022. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Random effect meta-analysis was undertaken using RevMan v5.3. In total, 12 trials were included (n = 1722 women); five evaluated alendronate, three risedronate, three ibandronate, and one zoledronate. Four were at low risk of bias; eight raised some concerns. Fractures were infrequent in the three studies that reported them. Compared with placebo, bisphosphonates improved BMD over 12 months (mean percentage difference, 95% confidence interval [CI]) at the spine (4.32%, 95% CI, 3.10%-5.54%, p < 0.0001, n = 8 studies), the femoral neck (2.56%, 95% CI, 1.85%-3.27%, p = 0.001, n = 6 studies), and the total hip (1.22%, 95% CI 0.16%-2.28%, p = 0.002, n = 4 studies). Over treatment durations of 24 to 72 months, bisphosphonates improved BMD at the spine (5.81%, 95% CI 4.71%-6.91%, p < 0.0001, n = 8 studies), femoral neck (3.89%, 95% CI 2.73%-5.05%, p = 0.0001, n = 5 studies) and total hip (4.09%, 95% CI 2.81%-5.37%, p < 0.0001, n = 4 studies). Bisphosphonates reduced urinary N-telopeptide (-52.2%, 95% CI -60.3% to -44.2%, p < 0.00001, n = 3 studies) and bone-specific alkaline phosphatase (-34.2%, 95% CI -42.6% to -25.8%, p < 0.00001, n = 4 studies) more than placebo at 12 months. This systematic review and meta-analysis shows that bisphosphonates improve BMD and lower bone turnover markers in early menopause, warranting further investigation of these agents for osteoporosis prevention. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dried Fruits: Bioactives, Effects on Gut Microbiota, and Possible Health Benefits—An Update

Dried fruits contain many bioactive compounds broadly classified as phytochemicals including phenolics, flavonoids, carotenoids, proanthocyanidins, stilbenes, chalcones/dihydrochalcones, and phytoestrogens. These compounds have antioxidant effects that may benefit health. Dried fruits are also a diverse group of foods with varying fibre contents. The evaluation of the biological activity of these bioactive compounds, including their bioaccessibility and bioavailability, may contribute to the understanding of the health effects of dried fruits. Limited evidence suggests that dried fruits (raisins, cranberries, dates, and prunes) affect human gut microbiota composition in a potentially beneficial manner (in terms of effects on Bifidobacteria, Faecalibacterium prausnitzii, Lactobacillus, Ruminococcaceae, Klebsiella spp., and Prevotella spp.). There is little epidemiological evidence about the association of dried fruit consumption with cardiovascular disease incidence and mortality, as well as the risk of type 2 diabetes or obesity. Clinical trial evidence for the effects of dried fruit consumption on cardiovascular risk factors, including glycaemic control, is mixed. Clinical trial evidence suggests prunes might preserve bone mineral density in postmenopausal women. Consumption of dried fruits is associated with higher-quality diets. Studies are needed to increase our understanding of the health effects of dried fruits and the underlying biological mechanisms.

Leisure time physical activity and bone mineral density preservation during the menopause transition and postmenopause: a longitudinal cohort analysis from the Study of Women's Health Across the Nation (SWAN)

Whether greater leisure time physical activity (LTPA) is associated with less bone mineral density (BMD) loss during the menopause transition (MT) remains an open question. We hypothesized that: 1) larger increases in LTPA from pre-/early perimenopause (period 1) to late perimenopause/postmenopause (period 2) would be associated with a slower period 2 BMD loss rate; and 2) greater entire-study LTPA levels would be associated with better final absolute BMD (g/cm2). Data were from of the Study of Women's Health Across the Nation (1996-2017). Exclusions were: bone beneficial medications, inability to identify start of the MT, and extreme BMD change rates. LTPA measures were a validated ordinal scale and number of metabolic equivalents per hour per week (MET hr wk-1) from sport/exercise. Multiply adjusted, linear regression models estimated: 1) BMD decline rate (annualized %) as a function of LTPA change; and 2) final BMD as a function of entire-study LTPA. Median [p25, p75] MET hr wk-1 were 4.2 [0.9, 10.1] and 4.9 [1.4, 11.2] in periods 1 and 2, respectively; walking was the commonest activity. In adjusted models (N=875), greater increases in LTPA ordinal score and MET hr wk-1 were statistically significantly associated with a slower decline in femoral neck (FN) BMD. Larger entire-study averages of each LTPA measure were statistically significantly related to better final FN and lumbar spine BMD levels. Findings suggest that LTPA, at modest levels, mitigate MT-related BMD decline and even small increases in intensity, duration or frequency of common activities may lessen bone loss at the population level. US-NIH.

Use of oral GnRH antagonists combined therapy in the management of symptomatic uterine fibroids.

Uterine fibroids have an impact on women's lives due to their high prevalence, physical symptoms, their consequences on patients' emotional and psychological well-being and loss of work productivity. The choice of therapeutical approaches varies depending on several factors, and therefore should be applied individually. Currently, there is an unmet need for good, reliable, uterine-sparing options. The oral GnRH antagonists (Elagolix, Relugolix, Linzagolix) represent a new alternative for the medical management of hormone-dependent gynaecological diseases such as uterine fibroids or endometriosis. They rapidly bind to the GnRH receptor, block endogenous GnRH activity and directly suppress LH and FSH production, avoiding unwanted flare-up effects. Some GnRH antagonists are marketed in combination with hormone replacement therapy add-back to counteract hypo-oestrogenic side effects. According to the registration trials, once-daily GhRH antagonist combination therapy results in a significant reduction in menstrual bleeding, as compared with placebo, and preserves bone mineral density, for up to 104 weeks. Further studies in the long term are needed to evaluate the whole impact of medical treatment of uterine fibroids on the management of this common women's disease.

Disease-Modifying Adjunctive Therapy of Osteopenia and Osteoporosis with a Multimineral Marine Extract, LithoLexal® Bone

There is evidence to suggest that restoration of major/rare biominerals by supplementation can produce osteogenic and anti-resorptive effects in humans. LithoLexal® is a natural extract harvested from a marine alga, Lithothamnion sp., with a porous microstructure and multimolecular composition rich in calcium (32% w/w) and magnesium (2.2% w/w) together with ~72 trace bioelements. In vitro, LithoLexal® demonstrated cellular-level osteogenic efficacy through enhancing the maturation and activity of pre-osteoblasts. This extract also expressed the ability to suppress osteoclastogenesis by downregulating the pro-resorptive cytokines TNF-α and IL-1β and the master regulator of inflammation NF-κB. Parathyroid hormone inhibition of parathyroid hormone secretion is another bioactivity of LithoLexal® Bone reported with both short- and long-term administration at a longer duration and higher magnitude than what calcium carbonate could induce. Due to these bioactivities that affect pathogenetic factors of osteoporosis, LithoLexal® Bone is referred to as a disease-modifying adjunctive therapy (DMAT). In postmenopausal animal models, LithoLexal® monotherapy preserved bone mineral density, microarchitecture, and biomechanical properties, while calcium carbonate failed to produce significant outcomes. The pro-resorptive effect of a high-fat diet was also efficiently counteracted in vivo by supplementary LithoLexal®. A large clinical trial on postmenopausal women verified the mitigating effects of LithoLexal® Bone on bone resorption and turnover rate. The characteristic composition of LithoLexal® together with its lattice microstructure are suggested to underlie its in vivo bioactivities. In conclusion, adjunctive therapy with LithoLexal® Bone is an attractive option for clinical prevention and treatment of osteopenia/osteoporosis.

EVALUATION OF PROXIMAL FEMORAL BONE MINERAL DENSITY IN CEMENTLESS TOTAL HIP ARTHROPLASTY: A THREE-ARM PROSPECTIVE RANDOMIZED CONTROL TRIAL

Femoral stem design affects periprosthetic bone mineral density (BMD), which may impact long term survival of cementless implants in total hip arthroplasty (THA). The aim of this study was to examine proximal femoral BMD in three morphologically different uncemented femoral stems designs to investigate whether one particular design resulted in improved preservation of BMDMethods: 119 patients were randomised to receive either a proximally coated dual taper wedge stem, a proximally coated anatomic stem or a fully coated collarless triple tapered stem. All surgeries were performed via the posterior approach with mobilization on the day of surgery. Dual energy x-ray absorptiometry scans (Lunar iDXA, GE Healthcare, Madison, WI) assessed BMD across the seven Gruen zones pre-operatively, and post-operatively at 6-weeks, 1-year, and 2-years and compared to the unoperated contralateral femur as a control. Patient reported outcome measures of pain, function and health were also included at these corresponding follow-ups.BMD increased in zones one (2.5%), two (17.1%), three (13.0%), five (10%) and six (17.9%) for all stems. Greater preservation of BMD was measured on the lateral cortex (zone 2) for both the dual taper wedge and anatomic stems (p = 0.019). The dual taper wedge stem also demonstrated preservation of BMD in the medial calcar (zone 7) whilst the anatomic and triple taper stem declined in this region, however this was not statistically significant (p = 0.059). BMD decreased on average by 2.1% inthe mid-diaphysis region, distal to the stem tip (zone 4) for all implants. All stems performed equivalently at final follow-up in all patient reported outcome measures.This study demonstrated maintenance of femoral BMD in three different cementless femoral stem designs, with all achieving excellent improvements in patient reported outcomes. There was no significant stress shielding observed, however longer follow-up is required to elucidate the impact of this finding on implant survivorship.

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. Myovant Sciences GmbH.

Longitudinal associations of insulin resistance with change in bone mineral density in midlife women.

BACKGROUNDThe effects of insulin resistance on bone mineral density (BMD) are unclear.METHODSIn Study of Women's Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site.RESULTSThe relation between HOMA-IR and BMD decline was biphasic. When average log2HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm2 per year slower BMD loss. When greater than or equal to 1.5, average log2HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT.CONCLUSIONWhen it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.FUNDINGThe SWAN has grant support from the NIH of the Department of Health and Human Services (DHHS) through the NIH National Institute on Aging (NIA), National Institute of Nursing Research (NINR), and Office of Research on Women's Health (ORWH) (grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, and U19AG063720).

Shilajit extract reduces oxidative stress, inflammation, and bone loss to dose-dependently preserve bone mineral density in postmenopausal women with osteopenia: A randomized, double-blind, placebo-controlled trial

BackgroundAccelerated bone loss associated with aging and estrogen withdrawal is mediated in part by increased oxidative stress and inflammation. ObjectiveInvestigate dietary supplementation with a standardized aqueous extract of shilajit with clinically demonstrated antioxidant, anti-inflammatory, and collagen-promoting activity on attenuating bone loss in postmenopausal women with osteopenia. DesignSixty postmenopausal women aged 45 – 65 years with osteopenia were randomized to receive 1 of 3 treatments daily for 48 weeks: (1) placebo, (2) 250 mg shilajit extract, or (3) 500 mg shilajit extract. Bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) were measured at weeks 0, 24, and 48, and circulating markers of bone turnover (CTX-1, BALP, RANKL, OPG), oxidative stress (MDA, GSH), and inflammation (hsCRP) at weeks 0, 12, 24, and 48. ResultsBMD of both the LS and FN progressively decreased in women receiving placebo but was dose-dependently attenuated with shilajit extract supplementation, resulting in significantly increased percentage changes from baseline in BMD at 24- and 48-weeks in both supplemented groups compared to placebo (p < 0.001). CTX-1, BALP, and RANKL decreased, whereas OPG increased, in both groups supplemented with the shilajit extract, but not in the placebo group, resulting in significantly decreased or increased percentage changes from baseline, respectively. MDA was significantly decreased (p < 0.001) and GSH was significantly increased (p < 0.001) in both supplemented groups compared to placebo from week 12 for the duration of the study. Progressive reductions in hsCRP were observed in both supplemented groups, resulting in significantly decreased percentage changes from baseline in supplemented women compared to placebo (p < 0.001). ConclusionDaily supplementation with this shilajit extract supports BMD in postmenopausal women with osteopenia in part by attenuating the increased bone turnover, inflammation and oxidative stress that coincides with estrogen deficiency in this population at increased risk for osteoporosis and bone fractures.

Moderate-Intensity Exercise Preserves Bone Mineral Density and Improves Femoral Trabecular Bone Microarchitecture in Middle-Aged Mice.

BackgroundAging leads to significant bone loss and elevated osteoporosis risk. Exercise slows age-related bone loss; however, the effects of various moderate-intensity exercise training volumes on bone metabolism remain unclear. This study aimed to determine the degree to which different volumes of moderate-intensity aerobic exercise training influence bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone microarchitecture, and cortical bone in middle-aged mice.MethodsTwenty middle-aged male C57BL/6 mice were randomly assigned 8 weeks of either (1) non-exercise (CON); (2) moderate-intensity with high-volume exercise (EX_MHV); or (3) moderate-intensity with low-volume exercise (EX_MLV) (N=6–7, respectively). Femoral BMD and BMC were evaluated using dual energy X-ray absorptiometry, and trabecular and cortical bone were measured using micro-computed tomography.ResultsFemoral BMD in EX_MHV but not EX_MLV was significantly higher (P<0.05) than in CON. The distal femoral fractional trabecular bone volume/tissue volume (BV/TV, %) was significantly higher (P<0.05) in both EX_MHV and EX_MLV than in CON mice. Increased BV/TV was induced by significantly increased trabecular thickness (mm) and tended to be higher (P<0.10) in BV (mm3) and lower in trabecular separation (mm) in EX_MHV and EX_MLV than in CON. The femoral mid-diaphysis cortical bone was stronger in EX_MLV than EX_MHV.ConclusionsLong-term moderate-intensity aerobic exercise with low to high volumes can be thought to have a positive effect on hindlimb BMD and attenuate age-associated trabecular bone loss in the femur. Moderate-intensity aerobic exercise may be an effective and applicable exercise regimen to prevent age-related loss of BMD and BV.

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.

Ось микробиота–кость: современные представления о механизмах взаимодействия

The discovery of the gut-bone axis promoted the development of treatment strategies aimed to preserve bone mineral density. Probiotics and probiotic complexes in combination with bone mineral matrix are gradually becoming a new treatment method for osteoporosis. This literature review aims to explore the role of gut microbiota in osteoclastogenesis, bone healing, mechanisms of its effects, and possible ways to modify the microbiota in order to improve bone metabolism. Key words: gut microbiota-bone axis, osteogenesis, osteoporosis, microbiota, nutritional support, baby formula, inulin

LIBERTY RANDOMIZED WITHDRAWAL STUDY: 2-YEAR EFFICACY AND SAFETY OF RELUGOLIX COMBINATION THERAPY IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

In the pivotal LIBERTY 1 and 2 trials and Long-Term Extension (LTE) study, once-daily relugolix combination therapy (Rel-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) reduced menstrual blood loss (MBL) volume and pain in women with uterine fibroids (UF). Rel-CT was well tolerated, with preservation of bone mineral density (BMD) through 52 weeks. Here we report results of the Phase 3 LIBERTY randomized withdrawal study (RWS), designed to evaluate the efficacy and safety of Rel-CT for up to 2 years.

EFFECTS OF RELUGOLIX COMBINATION THERAPY ON BONE MINERAL DENSITY THROUGH 2 YEARS IN WOMEN WITH HEAVY MENSTRUAL BLEEDING ASSOCIATED WITH UTERINE FIBROIDS

Relugolix 40 mg is a non-peptide gonadotropin-releasing hormone receptor antagonist being developed for use in combination with estradiol 1 mg and norethindrone acetate 0.5 mg (relugolix combination therapy; Rel-CT) to treat heavy menstrual bleeding (HMB) associated with uterine fibroids (UF). The rationale for combination therapy is to mitigate anticipated hypoestrogenic effects with relugolix monotherapy, including bone loss. Rel-CT preserved bone mineral density (BMD) in the pivotal LIBERTY 1/2 trials and Long-Term Extension (LTE) study.

IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis

Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in rheumatoid arthritis (RA). There are, however, no data describing association of IgA RF and IgG RF with systemic bone loss. This study was aimed to investigate the association of RF isotypes with systemic bone loss among patients with RA. RF isotypes and ACPA were measured by enzyme-linked immunosorbent assay among 153 patients with RA. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry. Ninety-four (61.4%) patients had positive IgA RF, 89 (58.2%) had positive IgG RF, 109 (71.2%) had positive IgM RF, whereas 122 (80.3%) RA patients tested positive for ACPA. Compared to the IgA RF-negative patients, IgA RF-positive patients exhibited higher disease activity and had higher RF titers. Seven (4.6%) patients had low BMD at femoral neck, 12 (7.8%) at total femur, and 47 (30.7%) at lumbar spine. IgA RF was found to be associated with protection against low BMD at spine (OR = 0.47, 95% CI = 0.23-0.95, p = 0.034). This association was further confirmed in the multivariate regression analysis taking into account several potential confounding factors(OR = 0.21, 95% CI = 0.06-0.65, p = 0.039). No association between low BMD and the presence of IgG RF or IgM RF or ACPA was found. IgA RF for the first time ever was shown to be associated with BMD preservation at spine in RA. Key points • IgA RF was associated with protection against low spinal BMD. • No association between low BMD and the presence of IgG RF or IgM RF was found.

Life quality of men with ankylosing spondylitis: association with the disease course and the structural and functional state of bone tissue

Background. Multiple peculiarities of ankylosing spondylitis clinical course have a significant influence on the physical, mental and social status of patients. Systemic loss of bone tissue manifesting itself through the development of osteoporosis and its complications is not excluded either. However, currently there is no sufficiently clear information on the influence of osteoporosis or its metabolic components, as well as peculiarities of the disease clinical course on the physical and mental health components in the patients suffering from ankylosing spondylitis. Purpose: to study the quality of life indices using the SF-36 and HAQ questionnaires in men suffering from ankylosing spondylitis and to assess the associations of these indexes with the disease clinical course as well as structural and functional state of bone tissue. Materials and methods. 105 men suffering from ankylosing spondylitis and 25 practically healthy persons of the appropriate age and sex forming the control group were examined. In order to assess the quality of life indices, the SF-36 and HAQ questionnaires were used. Results. It was established that men suffering from ankylosing spondylitis showed reliably lower indices of physical (37.3±1.5 points) and mental (44.2 ± 1.7 points) health components if compared to the control group (99.1 ± 0.3; 97.4±0.7 points respectively). Under conditions of the low bone mineral density, quality of life indices (PCS; MCS) were only 12.2–7.1% lower than in the patients with a preserved bone mineral density. It was shown that under conditions of the Vitamin D deficiency, quality of life components were significantly worse, specifically on account of the mental health component (р &lt; 0.05). It was also established that the lower quality of life was closely associated with a high activity of the inflammatory process (ASDAS-СRP, BASDAI) and a high dose of glucocorticoids. Conclusions. Men suffering from ankylosing spondylitis show a significant reduction of life quality indices by the SF-36 (PCS; MCS) and HAQ questionnaires, which demonstrate no association with the age of the patients (except for MCS), disease form and duration, structural and functional state of bone tissue. However, they are significantly worse in subjects with the Vitamin D deficiency, a high dose of glucocorticoids and high disease activity.

Sarcopenia and preserved bone mineral density in paediatric survivors of high-risk neuroblastoma with growth failure.

BackgroundSurvival from paediatric high‐risk neuroblastoma (HR‐NBL) has increased, but cis‐retinoic acid (cis‐RA), the cornerstone of HR‐NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR‐NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR‐NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR‐NBL survivors compared with controls.MethodsThis prospective cross‐sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual‐energy X‐ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex‐specific standard deviation scores (Z‐scores) included aBMD (adjusted for height Z‐score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole‐body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength‐Z). Muscle‐specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR‐NBL survivors and controls using Student's t‐test or Mann–Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes.ResultsWe enrolled 20 survivors of HR‐NBL treated with cis‐RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3–9.1) years] and 20 age‐, sex‐ and race‐matched controls. Height‐Z was significantly lower in HR‐NBL survivors compared with controls (−1.73 ± 1.38 vs. 0.34 ± 1.12, P < 0.001). Areal BMD‐Z, BMAD‐Z, FMI‐Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR‐NBL survivors compared with controls. Compared with controls, HR‐NBL survivors had lower leg lean mass‐Z (−1.46 ± 1.35 vs. − 0.17 ± 0.84, P < 0.001) and strength‐Z (−1.13 ± 0.86 vs. − 0.15 ± 0.71, P < 0.001). Muscle‐specific force was lower in HR‐NBL survivors compared with controls (P < 0.05).ConclusionsBone mineral density and adiposity are not severely impacted in HR‐NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle‐specific interventions in this population of cancer survivors.

The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation.

Zoledronate is used to prevent bone loss following denosumab discontinuation but its efficacy differs among studies. To test if the duration of denosumab treatment affects the efficacy of subsequent zoledronate infusion. This multicenter, prospective cohort study, conducted at 2 Greek and 1 Dutch bone centers, included 47 postmenopausal women (n = 47) who received a single zoledronate infusion 6 months after the last denosumab injection and then were followed for 1 year. Twenty-seven women received ≤ 6 denosumab injections (≤ 6 Group) and 20 received > 6 denosumab injections (> 6 Group). The main outcome measure was changes in lumbar spine (LS) bone mineral density (BMD). At 12 months LS-BMD values were maintained in the ≤ 6 Group (0.98 ± 0.10 to 0.99 ± 0.9 g/cm2, P = 0.409) but decreased significantly in the > 6 Group (1.0 ± 0.11 to 0.93 ± 0.12 g/cm2, P < 0.001). The percent change of LS-BMD of the ≤ 6 Group (+1.0%) was significantly different (P < 0.001) from the change of the > 6 Group (-7.0%). In the whole cohort, the duration of denosumab treatment was negatively correlated with the percentage change of LS-BMD (rs = -0.669, P < 0.001) but not with the change of femoral neck (FN)-BMD. Bone turnover markers increased in all patients 6 months following zoledronate administration with no difference between the 2 groups. The duration of denosumab treatment significantly affects the efficacy of subsequent zoledronate infusion to maintain BMD gains. Frequent follow-up of patients treated with denosumab longer than 3 years is advisable as additional therapeutic interventions may be needed.

Impact of Thyroid Disease on Bone Mineral Density Preservation in Patients With Osteoporosis and Idiopathic Hypercalciuria

Background: Idiopathic hypercalciuria (IHC) is associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fractures. It is not known if thyroid disease impacts the degree of urine and bone mineral abnormalities in patients with IHC and osteoporosis (OPO). Methods: Retrospective chart review from a private endocrinology clinic identified 62 consecutive patients with OPO (fragility fracture and/or t-score ≤-2.5 on bone density scan) and concomitant diagnosis of IHC (urine calcium > 4.0 mg/kg weight/d when intaking low-moderate calcium amounts). Patients were classified into two groups: those with thyroid disease (Thy+, if presence of autoimmune thyroid disease [AITD] with high antibody titers and/or long-term thyroid medication use) and those without (Thy-). Comparisons were made between the two groups for severity of renal disease (urine calcium) and bone disease (number of fragility fractures, and BMD response to therapy). Results: Of 55 women and 7 men identified with both OPO and IHC, 30 were Thy+ (4 with Graves’, 11 with confirmed Hashimoto’s, 13 taking levothyroxine for presumed Hashimoto’s and 2 with thyroid cancer), and 32 were Thy- (including 2 with type 1 DM, 1 with vitiligo, and 6 with non-toxic nodular goiters requiring biopsies). Thy+ were compared to Thy- with respect to: mean age (70.7 ± 7.3 vs. 70.8 ± 9.3 y), sex (97% vs. 81% women), 24-hr urine calcium at diagnosis (317 ± 75 vs. 311 ± 68 mg), presence of fragility fracture (50% vs. 59%), use of thiazide (83% vs. 78%), and use of anti-fracture pharmacotherapy (73% vs. 84%).50 patients had adequate comparative longitudinal BMD data. A (+) BMD response was based on consistent increases in BMD and/or t-scores across all spine and hip sites, and a (-) BMD response was classified by decreased BMD and/or t-scores across all sites. For Thy+ vs. Thy- patients, there were 25% vs. 69% (+) BMD response, 38% vs. 12% (-) BMD response, 21% vs. 4% with no significant BMD response, and 17% vs. 15% with mixed BMD responses. Conclusions: In this group at high risk for future fragility fractures, much lower rates of BMD preservation was seen in the Thy+ as compared to the Thy- patients. Overall, AITD and medical thyroid disease was very common (48%) in this cohort of patients with IHC and OP. However, this high rate may be confounded by the selective nature of the specialty clinic population. Further research needs to delineate the impact of AITD and thyroid medication use on the progression and treatment of patients with IHC and OPO.

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy

BackgroundUterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects.MethodsWe conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed.ResultsA total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy.ConclusionsOnce-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.)