Accelerated Bone Loss Research Articles

A phase II RCT of high-dose vitamin D supplementation for androgen deprivation therapy (ADT)-induced bone loss among older prostate cancer (PCa) patients.

10113 Background: ADT is the most commonly used systemic therapy for treating locally advanced and metastatic PCa. ADT use causes hypogonadism, which can result in accelerated bone loss and fragility fractures. Vitamin D (VITD) may protect against bone loss; however it remains unclear if the recommended daily allowance (RDA) of VITD is sufficient to reduce bone loss or whether higher doses are needed. The aim of this phase II RCT was to collect preliminary data on the effect of high-dose VITD on bone mineral density (BMD) in ADT-treated PCa patients compared to the RDA of VITD. Methods: Older PCa patients (≥60 years old) with VITD insufficiency ( < 32 ng/ml), within 6 months of starting ADT and with 6 more planned months of ADT were randomized 1:1 to high-dose VITD (hVITD; 600 IU/daily plus 50,000 IU/weekly) or RDA of VITD (rVITD; 600 IU/daily plus placebo weekly) for 24 weeks. All subjects received 100% of the RDA for calcium (1,000 mg/day). BMD was assessed at the total hip (TH) and lumbar spine (LS) via DXA at pre- and post-intervention. ANCOVA was used to test the change in BMD between groups. Results: 59 PCa patients were accrued (85% white; mean age = 67.6). Serum analyses confirmed high compliance in both groups (25-OH VITD change: hVITD = +32.0 ng/ml vs rVITD = +4.3 ng/ml; p < 0.01). The safety of hVITD was similar to rVITD (Grade I hypercalcemia: hVITD: n = 1 vs rVITD: n = 0). Bone loss was significantly reduced for the hVITD group compared to rVITD group for total hip (TH BMD% change: hVITD = −1.5% vs rVITD = −4.1%; p = 0.02), with a trend for the femoral neck (BMD% change: hVITD = −1.7% vs rVITD = −4.3%; p = 0.06) and trochanter (BMD% change: hVITD = −1.0% vs rVITD = −2.8%; p = 0.10). There was no difference between groups for LS bone loss (LS BMD% change: hVITD = −0.8% vs rVITD = −0.6%; p = 0.75). Conclusions: High-dose VITD supplementation produced significantly greater reductions in hip BMD loss among older PCa patients receiving ADT compared to rVITD. Clinically, higher doses of VITD may be necessary to effectively prevent ADT-induced bone loss. A definitive phase III RCT is needed to confirm these findings. Funding: NCI R21CA175793, K07CA168911 & UG1CA189961. Bio-Tech Pharmacal Inc. supplied all agents. Clinical trial information: NCT02064946.

Bone-Protective Effects of Dried Plum in Postmenopausal Women: Efficacy and Possible Mechanisms.

Osteoporosis is an age-related chronic disease characterized by a loss of bone mass and quality, and is associated with an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to the cessation in ovarian hormone production, which causes accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. Certain lifestyle factors, including nutrition and exercise, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, accumulating evidence suggests that dried plum (Prunus domestica L.) is potentially an efficacious intervention for preventing and reversing bone mass and structural loss in an ovariectomized rat model of osteoporosis, as well as in osteopenic postmenopausal women. Here, we provide evidence supporting the efficacy of dried plum in preventing and reversing bone loss associated with ovarian hormone deficiency in rodent models and in humans. We end with the results of a recent follow-up study demonstrating that postmenopausal women who previously consumed 100 g dried plum per day during our one-year clinical trial conducted five years earlier retained bone mineral density to a greater extent than those receiving a comparative control. Additionally, we highlight the possible mechanisms of action by which bioactive compounds in dried plum exert bone-protective effects. Overall, the findings of our studies and others strongly suggest that dried plum in its whole form is a promising and efficacious functional food therapy for preventing bone loss in postmenopausal women, with the potential for long-lasting bone-protective effects.

Association of vertebral compression fractures with physical performance measures among community-dwelling Japanese women aged 40\xa0years and older

BackgroundNumerous reported studies have shown that vertebral compression fractures are associated with impaired function or disability; however, few examined their association with objective measures of physical performance or functioning.MethodsWe examined the association of vertebral compression fractures with physical performance measures in 556 Japanese women aged 40–89 years. Lateral spine radiographs were obtained and radiographic vertebral compression fractures were assessed by quantitative morphometry, defined as vertebral heights more than 3 SD below the normal mean. Measures of physical performance included walking speed, chair stand time and functional reach. Adjusted means of performance-based measures according to the number and severity of vertebral compression fractures were calculated using general linear modeling methods.ResultsAfter adjusting for age, body mass index, back pain, number of painful joints, number of comorbidities and regular physical activities, the walking speed of women with two or more compression fractures (1.17 m/s) was significantly slower than that of women without compression fracture (1.24 m/s) (p = 0.03). Compared with women without compression fracture, chair stand time was longer in women with two or more compression fractures (p = 0.01), and functional reach was shorter (p = 0.01). No significant differences were observed in walking speed, chair stand time, or functional reach between women with one compression fracture and those without compression fracture.ConclusionsHaving multiple vertebral compression fractures affects physical performance in community-dwelling Japanese women. Poor physical functioning may lead to functional dependence, accelerated bone loss, and increased risk for falls, injuries, and fractures. Preventing vertebral compression fracture is considered important for preserving the independence of older adults.

Changes in RANKL during the first two years after cART initiation in HIV-infected cART na\xefve adults

BackgroundBy assessing the changes in concentration of soluble receptor activator of nuclear factor κ B ligand (RANKL) and osteoprotegrin (OPG) after initiation of combination antiretroviral therapy (cART) in treatment-naïve HIV-infected patients we aimed to evaluate whether the initial accelerated bone loss could be mediated by increased soluble RANKL (sRANKL) levels associated with CD4+ T cell recovery.MethodsWe used multiplex immunoassays to determine sRANKL and OPG concentrations in plasma from 48 HIV patients at baseline and 12, 24, 48 and 96 weeks after cART initiation.ResultsSoluble RANKL changed significantly over time (overall p = 0.02) with 25% decrease (95% CI: -42 to −5) at week 24 compared to baseline and stabilized at a lower level thereafter. We found no correlation between CD4+ T cell count increment and changes in sRANKL or between percentage change in BMD and changes in sRANKL.ConclusionIn this study there was no indication that the accelerated bone loss after cART initiation was mediated by early changes in sRANKL due to CD4+ T cell recovery. Future studies should focus on the initial weeks after initiation of cART.Trial registrationClinical-Trial.gov. id NCT00135460, August 25, 2005. The study was approved by the Danish Data Protection Agency, Danish Medicines Agency and Regional Ethics Committee.

Dried Plum's Unique Ability to Prevent and Reverse Bone Loss in Ovarian Hormone Deficiency: Efficacy and Possible Mechanisms

Osteoporosis is a chronic disorder associated with aging that is characterized by a loss of bone mass and quality leading to an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to a cessation in ovarian hormone production, thus leading to accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. A search for promising non‐pharmacological alternative therapies for osteoporosis is of prime importance as medications used for the prevention and treatment of osteoporosis can be associated with side effects and low compliance. Certain lifestyle factors, including nutrition, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, dried plum (prune) has been shown to be one of the most efficacious interventions for preventing and reversing bone loss in an ovariectomized rat model of osteoporosis as well as in postmenopausal women. The purpose of this presentation is to provide an overview of the efficacy of dried plum for preventing and reversing bone loss associated with ovarian hormone deficiency and to highlight possible mechanisms of action. We end with the results of a follow‐up study demonstrating that postmenopausal women taking dried plums during our one year clinical trial conducted five years earlier retained bone mineral density compared to the control. Overall, these findings suggest that dried plum is a promising functional food therapy for postmenopausal bone loss with the potential for a long‐lasting bone‐protective effect.Support or Funding InformationUSDA, California Dried Plum, Abbott Laboratories

Reduced bone formation markers, and altered trabecular and cortical bone mineral densities of non-paretic femurs observed in rats with ischemic stroke: A randomized controlled pilot study.

BackgroundImmobility and neural damage likely contribute to accelerated bone loss after stroke, and subsequent heightened fracture risk in humans.ObjectiveTo investigate the skeletal effect of middle cerebral artery occlusion (MCAo) stroke in rats and examine its utility as a model of human post-stroke bone loss.MethodsTwenty 15-week old spontaneously hypertensive male rats were randomized to MCAo or sham surgery controls. Primary outcome: group differences in trabecular bone volume fraction (BV/TV) measured by Micro-CT (10.5 micron istropic voxel size) at the ultra-distal femur of stroke affected left legs at day 28. Neurological impairments (stroke behavior and foot-faults) and physical activity (cage monitoring) were assessed at baseline, and days 1 and 27. Serum bone turnover markers (formation: N-terminal propeptide of type 1 procollagen, PINP; resorption: C-terminal telopeptide of type 1 collagen, CTX) were assessed at baseline, and days 7 and 27.ResultsNo effect of stroke was observed on BV/TV or physical activity, but PINP decreased by -24.5% (IQR -34.1, -10.5, p = 0.046) at day 27. In controls, cortical bone volume (5.2%, IQR 3.2, 6.9) and total volume (6.4%, IQR 1.2, 7.6) were higher in right legs compared to left legs, but these side-to-side differences were not evident in stroke animals.ConclusionMCAo may negatively affect bone formation. Further investigation of limb use and physical activity patterns after MCAo is required to determine the utility of this current model as a representation of human post-stroke bone loss.

Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss

The components of renin-angiotensin system (RAS) are expressed in the kidney and bone. Kidney disease and bone injury are common complications associated with diabetes. This study aimed to investigate the effects of an angiotensin-converting enzyme inhibitor, captopril, on the kidney and bone of db/db mice. The db/db mice were orally administered by gavage with captopril for 8weeks with db/+ mice as the non-diabetic control. Serum and urine biochemistries were determined by standard colorimetric methods or ELISA. Histological measurements were performed on the kidney by periodic acid-schiff staining and on the tibial proximal metaphysis by safranin O and masson-trichrome staining. Trabecular bone mass and bone quality were analyzed by microcomputed tomography. Quantitative polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. Captopril significantly improved albuminuria and glomerulosclerosis in db/db mice, and these effects might be attributed to the down-regulation of angiotensin II expression and the expression of its down-stream profibrotic factors in the kidney, like connective tissue growth factor and vascular endothelial growth factor. Urinary excretion of calcium and phosphorus markedly increased in db/db mice in response to captopril. Treatment with captopril induced a decrease in bone mineral density and deterioration of trabecular bone at proximal metaphysis of tibia in db/db mice, as shown in the histological and reconstructed 3-dimensional images. Even though captopril effectively reversed the diabetes-induced changes in calcium-binding protein 28-k and vitamin D receptor expression in the kidney as well as the expression of RAS components and bradykinin receptor-2 in bone tissue, treatment with captopril increased the osteoclast-covered bone surface, reduced the osteoblast-covered bone surface, down-regulated the expression of type 1 collagen and transcription factor runt-related transcription factor 2 (markers for osteoblastic functions), and up-regulated the expression of carbonic anhydrase II (marker for bone resorption). Captopril exerted therapeutic effects on renal injuries associated with type 2 diabetes but worsened the deteriorations of trabecular bone in db/db mice; the latter of which was at least in part due to the stimulation of osteoclastogenesis and the suppression of osteogenesis by captopril.

Efficacy and Safety of Denosumab for the Treatment of Osteoporosis in Patients with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and may lead to metabolic abnormalities that accelerate bone loss. Bisphosphonates, the most widely used treatment for osteoporosis, are contraindicated in patients with severe renal impairment. In the present study, we assessed whether denosumab is a safe and effective treatment for osteoporosis in patients with CKD. Methods and Findings: A total of 143 patients with osteoporosis who were treated with denosumab were analyzed retrospectively. Of these patients, 40 had been previously treated with bisphosphonates. All patients received supplemental vitamin D. Effectiveness was assessed by analyzing changes in bone mineral density (BMD) and serum tartrate-resistant acid phosphatase (TRACP)-5b as a marker for serum bone resorption. More than fifty percent of the patients treated with bisphosphonates showed low BMD at the time their therapy was changed to denosumab. Denosumab was associated with a larger increase in both lumbar and femur neck BMD than were bisphosphonates (+4.8% and +5.5%, respectively). Denosumab decreased serum TRACP-5b while increasing BMD (P<0.001), and was well tolerated. Serum calcium levels decreased shortly after the injection of denosumab, but recovered within 14 days. Supplemental vitamin D (0.5 to 1.0 μg/day) appeared to prevent hypocalcemia and to support efficacy of denosumab. Conclusions: Denosumab increases BMD in the lumbar vertebra and femur neck in patients with CKD. The effect of denosumab on BMD is greater than that of bisphosphonates in these patients.

Effects of Lobeglitazone, a New Thiazolidinedione, on Osteoblastogenesis and Bone Mineral Density in Mice.

BackgroundBone strength is impaired in patients with type 2 diabetes mellitus despite an increase in bone mineral density (BMD). Thiazolidinedione (TZD), a peroxisome proliferator activated receptor γ agonist, promotes adipogenesis, and suppresses osteoblastogenesis. Therefore, its use is associated with an increased risk of fracture. The aim of this study was to examine the in vitro and in vivo effects of lobeglitazone, a new TZD, on bone.MethodsMC3T3E1 and C3H10T1/2 cells were cultured in osteogenic medium and exposed to lobeglitazone (0.1 or 1 µM), rosiglitazone (0.4 µM), or pioglitazone (1 µM) for 10 to 14 days. Alkaline phosphatase (ALP) activity, Alizarin red staining, and osteoblast marker gene expression were analyzed. For in vivo experiments, 6-month-old C57BL/6 mice were treated with vehicle, one of two doses of lobeglitazone, rosiglitazone, or pioglitazone. BMD was assessed using a PIXImus2 instrument at the baseline and after 12 weeks of treatment.ResultsAs expected, in vitro experiments showed that ALP activity was suppressed and the mRNA expression of osteoblast marker genes RUNX2 (runt-related transcription factor 2) and osteocalcin was significantly attenuated after rosiglitazone treatment. By contrast, lobeglitazone at either dose did not inhibit these variables. Rosiglitazone-treated mice showed significantly accelerated bone loss for the whole bone and femur, but BMD did not differ significantly between the lobeglitazone-treated and vehicle-treated mice.ConclusionThese findings suggest that lobeglitazone has no detrimental effects on osteoblast biology and might not induce side effects in the skeletal system.

Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton.

Bone marrow stromal cells maintain the adult skeleton by forming osteoblasts throughout life that regenerate bone and repair fractures. We discovered that subsets of these stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes secrete a C-type lectin domain protein, Clec11a, which promotes osteogenesis. Clec11a-deficient mice appeared developmentally normal and had normal hematopoiesis but reduced limb and vertebral bone. Clec11a-deficient mice exhibited accelerated bone loss during aging, reduced bone strength, and delayed fracture healing. Bone marrow stromal cells from Clec11a-deficient mice showed impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Clec11a promoted osteogenesis by stromal cells in culture and increased bone mass in osteoporotic mice in vivo. Recombinant human Clec11a promoted osteogenesis by human bone marrow stromal cells in culture and in vivo. Clec11a thus maintains the adult skeleton by promoting the differentiation of mesenchymal progenitors into mature osteoblasts. In light of this, we propose to call this factor Osteolectin.

BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.

Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and Eμ-BMI-1 transgenic mice with BMI-1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and RANKL production in T cells, thus enhancing osteoclastogenesis and accelerating bone loss. This study clarifies a novel mechanism regulating estrogen deficiency-induced bone loss. © 2016 American Society for Bone and Mineral Research.

Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

Loss of Rictor with aging in osteoblasts promotes age-related bone loss.

Osteoblast dysfunction is a major cause of age-related bone loss, but the mechanisms underlying changes in osteoblast function with aging are poorly understood. This study demonstrates that osteoblasts in aged mice exhibit markedly impaired adhesion to the bone formation surface and reduced mineralization in vivo and in vitro. Rictor, a specific component of the mechanistic target of rapamycin complex 2 (mTORC2) that controls cytoskeletal organization and cell survival, is downregulated with aging in osteoblasts. Mechanistically, we found that an increased level of reactive oxygen species with aging stimulates the expression of miR-218, which directly targets Rictor and reduces osteoblast bone surface adhesion and survival, resulting in a decreased number of functional osteoblasts and accelerated bone loss in aged mice. Our findings reveal a novel functional pathway important for age-related bone loss and support for miR-218 and Rictor as potential targets for therapeutic intervention for age-related osteoporosis treatment.

Short-Term Hypoxia Accelerates Bone Loss in Ovariectomized Rats by Suppressing Osteoblastogenesis but Enhancing Osteoclastogenesis.

BackgroundAlthough it has been reported that hypoxic exposure can attenuate hypertension, heart disease, diabetes, and some other diseases, effects of hypoxia on osteoporosis are still unknown.Material/MethodsThe current study investigated whether short-term hypoxic exposure (in comparison with normoxic conditions) affects bone metabolism in normal or ovariectomized (OVX) adult female rats in an vivo study. Micro-computed tomography bone volume/structural analyses, histological examination, and serum bone turnover biochemical assays were used. In addition, the expressions of some associated major regulatory molecules were measured in osteoblastic cultures.ResultsWhile the 14-day hypoxic exposure did not change the bone-remodeling process in normal adult female rats, it decreased bone volume, osteoclast density, and serum bone formation marker (alkaline phosphatase) level, but increased osteoclast density and serum bone resorption marker (C-telopeptide of collagen) level in OVX rats. The bone marrow adipocyte number and serum fatty acid binding protein-4 level were increased in OVX-hypoxic rats compared with OVX-normoxic rats. Consistently, in human MG-63 osteoblastic cultures, the hypoxic condition suppressed protein expression of osteogenic transcriptional factors Runx2 and osterix, elevated protein expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand, but reduced that of osteoclastogenic inhibitor osteoprotegerin.ConclusionsOur results suggest that, although no change occurred in the bone-remodeling process in normal adult female rats after hypoxic exposure, under the estrogen-deficient osteoporotic condition, the hypoxic condition can alter the bone microenvironment so that it may further impair osteoblastic differentiation and enhance osteoclastic formation, and thus reduce bone formation, enhance bone resorption, and accelerate bone loss.

The impact of depot medroxyprogesterone acetate on fracture risk: a case-control study from the UK.

DMPA has been associated with impaired bone mineral acquisition during adolescence and accelerated bone loss in later life. We performed this large population-based study to assess the association between use of DMPA or combined oral contraceptives and the incident risk of fracture. We identified 4189 women between 20 and 44years of age with a first-time fracture diagnosis, matched them with 4189 random controls using the Disease Analyzer database and investigated the relation with DMPA exposure. Overall, 11% of the fracture cases and 7.7% of the controls had DMPA use recorded. The adjusted OR for developing a fracture in patients with current use of DMPA compared to non-users was 0.97 (95% CI 0.51-1.86), 2.41 (95% CI 1.42-4.08), and 1.46 (95% CI 0.96-2.23) for 1-2, 3-9, and ≥10 prescriptions, respectively. The adjusted OR for developing a fracture in patients with past use of DMPA compared to non-users was 0.96 (95% CI 0.73-1.26), 1.14 (95% CI 0.86-1.51), and 1.55 (95% CI 1.07-2.27) for 1-2, 3-9, and ≥10 prescriptions, respectively. The highest fracture risk was identified in young patients less than 30years with longer DMPA exposure (≥10 prescriptions; OR 3.04, 95% CI 1.36-6.81), as well as in patients in the late reproductive years with past use of DMPA (OR 1.72, 95% CI 1.13-2.63). Our results indicate that DMPA exposure is associated with increased fracture risk and may have negative effects on bone metabolism, resulting in impaired bone mineral acquisition during adolescence and accelerated bone loss in adult life.

Network Analysis Implicates Alpha-Synuclein (Snca) in the Regulation of Ovariectomy-Induced Bone Loss.

The postmenopausal period in women is associated with decreased circulating estrogen levels, which accelerate bone loss and increase the risk of fracture. Here, we gained novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause, using co-expression network analysis. Specifically, we generated a co-expression network consisting of 53 gene modules using expression profiles from intact and OVX mice from a panel of inbred strains. The expression of four modules was altered by OVX, including module 23 whose expression was decreased by OVX across all strains. Module 23 was enriched for genes involved in the response to oxidative stress, a process known to be involved in OVX-induced bone loss. Additionally, module 23 homologs were co-expressed in human bone marrow. Alpha synuclein (Snca) was one of the most highly connected “hub” genes in module 23. We characterized mice deficient in Snca and observed a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the altered expression of specific network modules, including module 23. In summary, the results of this study suggest that Snca regulates bone network homeostasis and ovariectomy-induced bone loss.

Bone Disease in Thalassemia: A Molecular and Clinical Overview.

Thalassemia bone disease is a common and severe complication of thalassemia-an inherited blood disorder due to mutations in the α or β hemoglobin gene. In its more severe form, severe anemia is present, and treatment with frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incomplete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant complication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thalassemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and the clinical implications for monitoring and treating this disorder.

Assessment of bone health in breast cancer patients starting adjuvant aromatase inhibitors: A quality improvement clinical audit

IntroductionAdjuvant Aromatase Inhibitors (AIs) predispose breast cancer patients to accelerated bone loss. Guidelines recommend initial screening and follow up of bone mineral density with dual energy X-ray absorptiometry (DEXA) scan. In this audit we assessed the rate of adherence to these guidelines and introduced awareness measures to improve it. MethodsAll post-menopausal women who started upfront adjuvant AIs (letrozole in all patients) between January 2007 and December 2013 were retrospectively identified. The standard to be audited was “These patients should have a baseline DEXA scan requested within the first 3 months of starting adjuvant AIs therapy”. A 90% or more compliance was accepted as satisfactory. Corrective measures in the form of educational and awareness sessions followed by re-auditing of the practice over the subsequent 12 months were planned in case of lower compliance rate. ResultsThree hundred and sixty seven eligible patients were identified. Baseline DEXA scan was performed in 188 (51.2%) patients. As planned, this result triggered the conduction of 4 consecutive educational sessions over a period of 2 weeks. Re-auditing the practice in the pre-defined subsequent subjects showed compliance in 47/52 (90.4%) patients. ConclusionThis study of a sizable cohort confirms previous observations that adherence to skeletal health guidelines in this patient population is less than adequate. Adherence is improved dramatically by raising the awareness of relevant physicians.

BONADIUV trial: A single blind, randomized placebo controlled phase II study using oral ibandronate for osteopenic women receiving adjuvant aromatase inhibitors: Final safety analysis.

e12043Background: Aromatase inhibitors (AI) are a highly effective treatment for postmenopausal hormonal positive status breast cancer (BC). However its use is associated with accelerated bone loss and potential increase in treatment related adverse events. We present the final analysis concerning trial safety results. Methods: We enrolled between 2011 and 2014 osteopenic early BC patients candidate to 3-5 years of adjuvant AI. All patients were treated with vitamin D supplementation, for an overall treatment of 24 months. Patients were also stratified by menopausal age, body mass index and age. Adverse events monitoring was a secondary endpoint of trial. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 were utilized to record toxicity events. We performed different stratified analysis for bisphosphonate-related, AI-related, and overall symptoms incidence rates. The primary endpoint of the trial was the change in BMD at lumbar spine or hip after 12 and 24 months of follow up. Recruiting ...

Improving bone health in men with prostate cancer on ADT: Results of a randomized phase II trial.

10099Background: Androgen deprivation therapy (ADT) is widely used to treat men with PC but is associated with accelerated bone loss and fragility fractures. Although guidelines have recommended se...