Bone Mineral Density Deficits Research Articles

Long-term Pegvisomant Therapy of Acromegaly: Effects on Bone Density, Turnover and Microstructure Using HRpQCT.

Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Diabetes Risk Factors and Bone Microarchitecture as Assessed by High-Resolution Peripheral Quantitative Computed Tomography in Adults With Long-Standing Type 1 Diabetes.

To determine whether type 1 diabetes and its complications are associated with bone geometry and microarchitecture. This cross-sectional study was embedded in a long-term observational study. High-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal and diaphyseal tibia were performed in a subset of 183 participants with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and 94 control participants without diabetes. HbA1c, skin advanced glycation end products (AGEs), and diabetes-related complications were assessed in EDIC participants with >30 years of follow-up. Compared with control participants (aged 60 ± 8 years, 65% female), EDIC participants (aged 60 ± 7 years, diabetes duration 38 ± 5 years, 51% female) had lower total bone mineral density (BMD) at the distal radius (-7.9% [95% CI -15.2%, -0.6%]; P = 0.030) and distal tibia (-11.3% [95% CI -18.5%, -4.2%]; P = 0.001); larger total area at all sites (distal radius 4.7% [95% CI 0.5%, 8.8%; P = 0.030]; distal tibia 5.9% [95% CI 2.1%, 9.8%; P = 0.003]; diaphyseal tibia 3.4% [95% CI 0.8%, 6.1%; P = 0.011]); and poorer radius trabecular and cortical microarchitecture. Estimated failure load was similar between the two groups. Among EDIC participants, higher HbA1c, AGE levels, and macroalbuminuria were associated with lower total BMD. Macroalbuminuria was associated with larger total area and lower cortical thickness at the distal radius. Higher HbA1c and AGE levels and lower glomerular filtration rate, peripheral neuropathy, and retinopathy were associated with deficits in trabecular microarchitecture. Type 1 diabetes is associated with lower BMD, larger bone area, and poorer trabecular microarchitecture. Among participants with type 1 diabetes, suboptimal glycemic control, AGE accumulation, and microvascular complications are associated with deficits in bone microarchitecture and lower BMD.

Identification of Bone Mineral Density Deficit Using L1 Trabecular Attenuation by Opportunistic Multidetector CT Scan in Adult Patients

Multidetector computer tomography (CT) has been used to diagnose pathologies such as osteoporosis via opportunistic screening, where the assessment of the bone structure and the measurement of bone mineral density (BMD) are of great relevance. To construct reference BMD values based on the measurement of the attenuation of the L1 vertebral body by multidetector CT scan (in the soft tissue and bone windows) in adult patients and to establish normative ranges by sex and age of BMD values. A retrospective cross-sectional study of 5080 patients who underwent multidetector CT scan between January and December 2021. Adult patients (≥18 years) with non-contrast multidetector CT scan of the abdomen or thorax-abdomen at a voltage 120 kV. The attenuation of the L1 vertebral body in Hounsfield units (HU) in both windows were compared using the Mann-Whitney U-test with α = 0.05. Additionally, the quartiles of the BMD were constructed (in both windows) grouped by sex and age. Only 454 (51.30 ± 15.89 years, 243 women) patients met the inclusion criteria. There is no difference in BMD values between windows (soft tissue: 163.90 ± 57.13, bone: 161.86 ± 55.80, p = 0.625), mean L1 attenuation decreased linearly with age at a rate of 2 HU per year, and the presence of BMD deficit among patients was high; 152 of 454 (33.48%) patients presented BMD values suggestive of osteoporosis, and of these, approximately half 70 of 454 (15.42%) corresponded to patients with BMD values suggestive of a high risk of osteoporotic fracture. From clinical practice, the bone mineral density (BMD) of a patient in either window below the first quartile for age- and sex-matched peers suggests a deficit in BMD that cannot be ignored and requires clinical management that enables identification of the etiology, its evolution, and the consequences of this alteration.

Bone mineral density (BMD) deficits in adult survivors of childhood cancer: Attributable risks and long-term consequences.

e22021 Background: Survivors of childhood cancer are at risk for BMD deficits. Contributions of treatment, physical and lifestyle factors to overall risk are unknown as are long-term consequences of moderate and severe deficits. Methods: BMD deficits were evaluated in 3919 five-year childhood cancer survivors in the St. Jude Lifetime Cohort (median age 31.7 [range 18.0-69.9] years, 52.6% male, 80.4% non-Hispanic White) using lumbar quantitative computed tomography and classified by age- and sex-specific Z-scores as moderate (<-1SD) or severe deficit (<-2SD). Multivariable logistic regression estimated odds ratios (OR), risk factor attributable fractions (AF), and associations between BMD deficits and long-term outcomes (social/functional outcomes, fracture, mortality). Results: BMD deficits were moderate in 21.7% (95% CI 20.4%-23.0%) and severe in 6.9% (95% CI 6.1%-7.7%) of survivors. Risk factors for moderate deficit included age 5-9 years at diagnosis (OR 1.63, 95% CI 1.31-2.03), >20Gy cranial radiotherapy (OR 1.75, 95% CI 1.41-2.18), >3240 mg/m2 glucocorticoids (OR 1.34, 95% CI 1.09-1.66), and smoking (OR 1.55, 95% CI 1.27-1.90). AF were 7.2%, 0.7%, 5.9%, and 6.1% respectively; 80.1% of risk was unexplained. Risk factors for severe deficits included age 5-9 years at diagnosis (OR 1.95, 95% CI 1.36-2.80), BMI<18.5 kg/m2 (OR 3.95, 95% CI 2.28-6.85), >20Gy cranial radiotherapy (OR 5.22, 95% CI 3.74-7.30), testicular/pelvic radiation (OR 1.70, 95% CI 1.19-2.44), smoking (OR 1.71, 95% CI 1.21-2.43), and physical inactivity (OR 1.91, 95% CI 1.10-3.33). AFs were 10.9%, 7.0%, 2.9%, 11.5%, 6.7%, and 3.2% respectively; 57.8% of risk was unexplained. Those with deficits were less likely to live independently, to be employed, and more likely to require assistance with personal care needs (Table). Fracture risk was greatest among those with any BMD deficit, and mortality risk was greatest among those with severe deficits. Conclusions: Deficits in BMD among childhood cancer survivors are related not only to treatment, but also to modifiable health behaviors. In this population, children exposed to radiation or glucocorticoids are at greatest risk for poor bone quality and should be counselled to optimize health behaviors.[Table: see text]

Changes in Bone Mineral Density of the Femur and Tibia Before Injury to 2 Years After Anterior Cruciate Ligament Reconstruction in Division I Collegiate Athletes

Background: Osteoarthritis (OA) is a significant long term concern after anterior cruciate ligament (ACL) reconstruction (ACLR). A low bone mineral density (BMD), particularly in the subchondral region, has been associated with the development of OA and is evident at the knee in patients long after ACLR. It is unknown if persistent BMD deficits are present in high level collegiate athletes. Purpose/Hypothesis: The purpose of this study was to evaluate bilateral changes in the BMD of the femur and tibia from before the injury to 24 months after ACLR in collegiate athletes. We hypothesized that the BMD of both the distal femur and the proximal tibia would be significantly reduced within the surgical limb initially postoperatively but return to preinjury levels by 24 months after ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 33 Division I collegiate athletes were identified between 2010 and 2021 (13 female) who underwent total body dual-energy X-ray absorptiometry (DXA) before sustaining an ACL injury. DXA was repeated at 6, 12, and 24 months after ACLR. Linear mixed effects models assessed differences in the BMD at 5%, 15%, and 50% of the femur's length (F5, F15, F50) and at 5%, 15%, and 50% of the tibia's length (T5, T15, T50) within each limb from before the injury to 24 months after ACLR, reported as Tukey-adjusted P values. Results: Compared with before the injury, the BMD at F5 of the surgical limb was reduced by 0.15 g/cm2 (SE, 0.02 g/cm2) at 6 months (P < .001). The BMD at F15 of the surgical limb was reduced by 0.06 g/cm2 (SE, 0.01 g/cm2), 0.09 g/cm2 (SE, 0.01 g/cm2), and 0.09 g/cm2 (SE, 0.01 g/cm2) at 6, 12, and 24 months, respectively (all P < .001). The BMD at T5 of the nonsurgical limb was reduced by 0.07 g/cm2 (SE, 0.02 g/cm2) at 12 months (P = .02) and 0.10 g/cm2 (SE, 0.02 g/cm2) at 24 months (P = .001). The BMD at T15 of the surgical limb was reduced by 0.07 g/cm2 (SE, 0.01 g/cm2) at 6 months and 0.08 g/cm2 (SE, 0.02 g/cm2) at 12 months (P < .001). Conclusion: BMD deficits at F15 of the surgical limb persisted out to 24 months (–7.1%) after ACLR compared with before the injury in collegiate athletes. The BMD at F5 and T15 of the surgical limb was reduced at 6 and 12 months but not at 24 months compared with preinjury levels. For the nonsurgical limb, no significant differences were detected, except for the T5 region at 12 months (–5.1%) and 24 months (–7.2%). The BMD at F50 and T50 of both limbs was not significantly different than preinjury levels at any time after ACLR.

Molecular characterization and frequency of transforming growth factor beta 1 gene polymorphism and its relation to bone complications in Egyptian patients with β-thalassemia

Objective The objective of this study was to determine the frequency of transforming growth factor beta 1 (TGFβ1) C-509T gene polymorphism and its relation to bone complications in patients with β-thalassemia major in Egypt. Background Osteoporosis is the most prevalent bone complication in patients with β-thalassemia major despite regular blood transfusions and iron chelation therapy. It is characterized by low bone mineral density (BMD) resulting in reduced bone strength and increased risk of fractures. Genetic factors play an important role in the determination of BMD. The TGFβ1 gene, which encodes TGFβ1, is a strong candidate for susceptibility to osteoporosis, and several studies have reported associations between BMD and different polymorphisms of TGFβ1, although these studies have yielded conflicting results. Study design and methods Single nucleotide polymorphism in the TGFβ1 gene promoter (C-509T) was investigated in 100 regularly treated Egyptian children with β-thalassemia major by PCR/RFLP genotyping. BMD was measured by dual-energy radiograph absorptiometry and expressed as Z score. Results The frequency of TGFβ1 gene polymorphism C-509T genotypes in all studied patients was 6% for homozygous CC, 85% for heterozygous CT, and 9% for homozygous TT. C allele frequency was 48.5%, whereas T allele frequency was 51.5%. BMD Z score was significantly higher in TT genotype compared with CC genotype, with P value less than 0.05. Patients were grouped on the basis of BMD Z score: 51 (51%) patients with BMD deficit (Z score <−1) and 49 (49%) with normal BMD (Z score ≥−1). TGFβ1 gene polymorphism C-509T genotypes were distributed differently between the two groups; the TT genotype frequency was lower in patients with BMD deficit (P<0.05). Conclusion TGFB1 gene polymorphism C-509T is associated with BMD and genetic susceptibility to osteoporosis and may play a role in the pathogenesis and modification of bone complication in β-thalassemia major. BMD deficit is common in Egyptian children with β-thalassemia major. Analysis of this polymorphism at an early age could help in identification of thalassemic children at risk of osteoporosis and early management. However, large-scale studies are required to confirm these findings.

Bone microarchitecture and estimated failure load are deteriorated whether patients with chronic kidney disease have normal bone mineral density, osteopenia or osteoporosis.

Measurement of bone mineral density (BMD) is recommended in patients with chronic kidney disease (CKD). However, most persons in the community and most patients with CKD have osteopenia, suggesting fracture risk is low. Bone loss compromises bone microarchitecture which increases fragility disproportionate to modest deficits in BMD. We therefore hypothesized that patients with CKD have reduced estimated failure load due to deterioration in microarchitecture irrespective of whether they have normal femoral neck (FN) BMD, osteopenia or osteoporosis. We measured distal tibial and distal radial microarchitecture in 128 patients with CKD and 275 age- and sex-matched controls using high resolution peripheral quantitative computed tomography, FN-BMD using bone densitometry and estimated failure load at the distal appendicular sites using finite element analysis. Patients versus controls respectively had: lower tibial cortical area 219 (40.7) vs. 237 (35.3) mm2, p=0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm3 due to higher porosity 69.6 (6.19) vs. 61.9 (6.48)% and lower matrix mineral density 64.2 (0.62) vs. 65.1 (1.28)%, lower trabecular vBMD 92.2 (41.1) vs. 149 (43.0) mgHA/cm3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm2 and reduced estimated failure load 3825 (1152) vs. 5778 (1467) N, all p<0.001. Deterioration in microarchitecture and estimated failure load was most severe in patients and controls with osteoporosis. Patients with CKD with osteopenia and normal FN-BMD had more deteriorated tibial microarchitecture and estimated failure load than controls with BMD in the same category. In univariate analyses, microarchitecture and FN-BMD were both associated with estimated failure load. In multivariable analyses, only microarchitecture was independently associated with estimated failure load and accounted for 87% of the variance. Bone fragility is likely to be present in patients with CKD despite them having osteopenia or normal BMD. Measuring microarchitecture may assist in targeting therapy to those at risk of fracture.

Evaluation of nutritional status and related factors in children with cystic fibrosis.

This study aimed to evaluate the nutritional status and body composition in children with cystic fibrosis (CF), in accordance with the new nutritional targets defined by European Society for Clinical Nutrition and Metabolism (ESPEN), the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Cystic Fibrosis Society (ECFS) 2016. In this cross-sectional study, data were collected prospectively in a single centre. A record was made for a total of 95 patients with CF of clinical data. Anthropometric data were evaluated using the World Health Organization growth standards. The bone mineral density (BMD) z-score was adjusted for height by measuring dual-energy X-ray absorptiometry (DXA). The speed of sound z-score values were measured with quantitative ultrasound (QUS). The nutritional status was normal in 37.9% of patients aged < 2 years and 33.3% of patients aged 2-18 years. When the DXA BMD z-score values were corrected for height, it was determined that the BMD deficit was less. The calcaneus QUS SOS z-score mean value was lower than the mean height for age z-score adjusted BMD (BMDHAZ). The malnutrition rates of CF patients were higher than the rates previously reported in literature. As there are insufficient nutritional data in Turkey, there is a need for multi-centre studies to determine the frequency of malnutrition according to the new classifications. It is clear that QUS measurements cannot replace DXA in the diagnosis of osteopenic bone disease. However, when low values are determined with QUS as the first recommended measurement in the screening of bone status, it can be considered appropriate to confirm the status with DXA.

Effect of gender, diabetes duration, inflammatory cytokines, and vitamin D level on bone mineral density among Thai children and adolescents with type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is considered a risk factor for osteoporosis in adults; however, studies in bone mineral density (BMD) in children with T1DM reported conflicting results. The aim of this study was to compare BMD between T1DM youth and healthy controls, and to identify factors that affect BMD in T1DM youth. One hundred T1DM youths and 100 healthy controls (both groups aged 5-20 years) were recruited. BMD of total body, lumbar (L2-4), femoral neck, and total hip were assessed using dual energy X-ray absorptiometry. Blood investigations, including hemoglobin A1c (HbA1c), 25-hydroxyvitamin D, and inflammatory cytokines, were performed. Forty-four boys and 56 girls with T1DM were enrolled [mean age 14.5 ± 2.7 years, median (IQR) duration of T1DM 5.80 (2.97-9.07) years, and mean HbA1c entire duration 9.2 ± 1.4%]. T1DM girls had a lower height Z-score than control girls (p < 0.05), and 25-hydroxyvitamin D level was higher in T1DM youth than in controls (p < 0.001). After adjusting for pubertal status, height Z-score, and 25-hydroxyvitamin D, T1DM youth had a significantly lower lumbar BMD Z-score and femoral neck BMD than controls (p = 0.027 and p = 0.025, respectively). We also found that T1DM boys had a significantly lower lumbar BMD Z-score (p = 0.028), femoral neck BMD (p = 0.004), and total hip BMD (p = 0.016) than control boys. In contrast, these significant differences were not found in T1DM girls. Factors affecting BMD were different between T1DM boys and girls, and among different BMD sites. IL-13 was positively correlated with BMD in the total cohort and among girls. In boys - IL-2 and 25-hydroxyvitamin D were positively associated with BMD, and duration of diabetes was found to negatively affect BMD. Deleterious effect of T1DM on BMD is gender specific. The longer the duration of T1DM, the greater the deficit in BMD found among boys with T1DM.

Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth.

Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1-/- mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH (1-34) enhanced and PTH (7-34) attenuated cell proliferation, cAMP signaling, cAMP response element-binding protein (CREB) phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1-/- mice were injected with Pth1r ligand PTH (7-34) daily for the first 4 weeks of life. PTH (7-34) reversed the abnormal growth plate and long-bone growth phenotypes of Phlpp1-/- mice but did not rescue deficits in bone mineral density or trabecular number. These results show that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1-/- chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth. © 2021 American Society for Bone and Mineral Research (ASBMR).

Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome.

All individuals with Down syndrome (DS), which results from trisomy of human chromosome 21 (Ts21), present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits.

Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes.

Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). Retrospective with cross-sectional health outcomes analysis. Established cohort; tertiary care center. Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

Abaloparatide increases bone mineral density and bone strength in ovariectomized rabbits with glucocorticoid-induced osteopenia

SummaryGlucorticoid (GC) therapy is the commonest cause of secondary osteoporosis. Ovariectomized rabbits receiving the GC methylprednisolone for 6 weeks exhibited relatively lower vertebral and femoral bone mass. Treatment with the PTH receptor agonist abaloparatide for 12 weeks during ongoing methylprednisolone administration increased cortical and trabecular bone mass and femur bending strength.IntroductionAbaloparatide, an osteoanabolic PTHrP analog, increases bone mineral density (BMD) and reduces fracture risk in women with postmenopausal osteoporosis. This study assessed abaloparatide effects on BMD and bone strength in ovariectomized (OVX) rabbits with glucocorticoid (GC)-induced osteopenia.MethodsThirty-two rabbits underwent OVX and 8 underwent sham surgery. One day later, 24 OVX rabbits began daily s.c. GC injections (methylprednisolone, 1 mg/kg/day) for 6 weeks, while 8 OVX and 8 sham controls received no GC. GC-challenged rabbits (8/group) then received GC (0.5 mg/kg/day) along with daily s.c. vehicle (GC-OVX), abaloparatide 5 μg/kg/day (ABL5), or 25 μg/kg/day (ABL25) for 12 weeks, and the no-GC OVX and sham controls received daily vehicle.ResultsGC-OVX rabbits showed significant deficits in vertebral and proximal femur areal BMD, lower cortical area, thickness and volumetric BMD of the femur diaphysis, and reduced trabecular bone volume and volumetric BMD in the vertebra and distal femur versus sham controls. These deficits were significantly reversed in the ABL25 group, which also showed enhanced trabecular micro-architecture versus GC-OVX controls. Destructive bending tests showed significantly lower femur diaphysis ultimate load and bending rigidity of the femoral diaphysis in the GC-OVX group versus sham controls, whereas these parameters were similar in the ABL25 group vs sham controls.ConclusionsAbaloparatide 25 μg/kg/day mitigated the adverse effects of GC administration on cortical and trabecular bone and improved femoral strength in OVX rabbits. These results suggest potential promise for abaloparatide as an investigational therapy for glucocorticoid-induced osteoporosis.

Bone Densitometry in Children with Idiopathic Nephrotic Syndrome

Childhood nephrotic syndrome (NS) is defined by nephrotic-range proteinuria, generalized edema, hypoalbuminemia, and hyperlipidemia with normal renal function. Dual-energy X-ray absorptiometry (DXA) is a two-dimensional imaging technology developed to assess bone mineral density (BMD) of the entire human skeleton.The aim of our study to assess bone mineral density among pediatrics with idiopathic nephrotic syndrome undergoing corticosteroids treatment.This study was a cross sectional study, which was done on 30 cases with idiopathic nephrotic syndrome undergoing corticosteroids treatment (at Nephrology clinic pediatric department Benha University Hospital) in the period from January 2019 till June 2019, the other group formed of 25 children with age and sex matched to the first group and apparently healthy, considered as a control group. The following investigations were done (serum creatinine, blood urea nitrogen (BUN), phosphorous (P),calcium (total and ionized; Ca),alkaline phosphatase (ALP), parathyroid hormone (PTH).BMD was measured. There was highly statistically significant increase in PTH, Ph, and ALP among Cases than Controls. There was statistically significant decrease in Ca among Cases than Controls. There was highly statistically significant decrease in z score, BMD and BMC among Cases than Controls. Patients with INS would have BMD deficits when compared to their peers. Osteopenia and osteoporosis assessed by DXA was frequent in children with INS.Bone mineralization was negatively affected by steroid treatment in children with INS.

Surveillance results and bone effects in the Gulf War depleted uranium-exposed cohort

ABSTRACTA small group of Gulf War I veterans wounded in depleted uranium (DU) friendly-fire incidents have been monitored in a clinical surveillance program since 1993. During the spring of 2017, 42 members of the cohort were evaluated with a protocol which includes exposure monitoring for total and isotopic uranium concentrations in urine and a comprehensive assessment of health outcomes including measures of bone metabolism, and for participants >50 years, bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained DU shrapnel fragments. Only the mean serum estradiol concentration, a marker of bone metabolism, was found to be significantly different for lower-vs- higher urine U (uU) cohort sub-groups. For the first time, a significant deficit in BMD was observed in the over age 50, high uU sub-group. After more than 25 years since first exposure to DU, an aging cohort of military veterans continues to exhibit few U-related adverse health effects in known target organs of U toxicity. The new finding of reduced BMD in older cohort members, while biologically plausible, was not suggested by other measures of bone metabolism in the full (all ages) cohort, as these were predominantly within normal limits over time. Only estradiol was recently found to display a difference as a function of uU grouping. As BMD is further impacted by aging and the U-burden from fragment absorption accrues in this cohort, a U effect may be clarified in future surveillance visits.

RISK FACTORS OF BONE MINERAL DENSITY DEFICIT AND LOW-ENERGY FRACTURES IN PRIMARY OSTEOPOROSIS IN MEN

Purpose:to evaluate the role of well-known factors on the formation of bone mineral density (BMD) and risk of fractures in primary osteoporosis in men.Patients and methods.The influence of well-known osteoporosis risk factors such as age, smoking, alcohol consumption, obesity, genetic disorders in genes encoding COL1A1, COL1A2 and VDR-receptor products, history of low-energy fractures in first-line relatives upon the BMD value and risk of fractures was evaluated in 231 patients with primary osteoporosis. All patients were divided into three age groups according to the following forms of osteoporosis: 17-20 years (n=26) – juvenile form, 21-50 (n=103) – idiopathic form, patients over 51 years (n=102). To assess the influence of study factors on the risk of fractures the patients were subdivided into 5 groups according to fracture localization.Results.The relationship between BMD deficit and mutations in homozygous form of gene rs2412298 (encodes collagen), and the tendency to a reliable increase of BMD deficit in L1 – L4 vertebrae under polymorphism in homozygous form of 1800012 gene was noted that might be evidence of their contribution to the development of primary osteoporosis in men. At the same time, smoking, alcohol consumption, age, mutations in homozygous form of gene rs2412298 and a history of low-energy fractures in first-line relatives increased the risk of low-energy fractures of the vertebral bodies and proximal femur.

25-Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density: Secondary Analysis of a Randomized Controlled Trial.

Most trials of vitamin D supplementation have shown no benefits on bone mineral density (BMD), although severe vitamin D deficiency causes osteomalacia, which is associated with profound BMD deficits. Recently, the ViDA-BMD study from New Zealand demonstrated a threshold of baseline 25-hydroxyvitamin D (25OHD; 30 nmol/L) below which vitamin D supplementation did benefit BMD. We have now reexamined data from a similar trial in Aberdeen to determine whether a baseline 25OHD threshold of 30 nmol/L is also observed in that database. The Aberdeen study recruited 305 postmenopausal women in late winter and randomized them to receive placebo, vitamin D 400 IU/d, or vitamin D 1000 IU/d over 1 year. As previously reported, BMD loss at the hip was reduced by vitamin D 1000 IU/d only, and there was no significant treatment effect of either dose at the lumbar spine. In the present analysis, when the trial participants were grouped according to whether their baseline 25OHD was ≤30 nmol/L or above this threshold, significant treatment effects were apparent at both the spine and hip in those with baseline 25OHD ≤30 nmol/L, but no significant effects were apparent in those with baseline 25OHD above this level. There was evidence of a similar threshold for effects on parathyroid hormone, but no groups showed changes in bone turnover markers during the study. It is concluded that vitamin D supplements only increase bone density in adults with nadir 25OHD ≤30 nmol/L. This moves us further toward a trial-based definition of vitamin D deficiency in adults with adequate calcium intakes and suggests that supplement use should be targeted accordingly. Future trials of vitamin D supplementation should focus on individuals with 25OHD concentrations in this range. © 2018 American Society for Bone and Mineral Research.

ENPP1 Enzyme Replacement Prevents the Osteomalacia and Paradoxical Mineralization in the Enpp1asj/asj mouse model of Autosomal Recessive Hypophosphatemic Rickets Type‐2.

A paradoxical feature of several disorders of the skeleton involves deficits in bone mineral density yet progressive increases in vascular and/or soft tissue calcifications. ENPP1 loss of function (LOF) mutations represent this combination of defects, in that both life threatening vascular calcifications in Generalized Arterial Calcification of Infancy (GACI) and a severe rickets in Autosomal Recessive Hypophosphatemic Rickets Type-2 (ARHR2) are observed with this mutation. Disease in ARHR2 is severe and symptomatic, leading to repeated fractures of the long bones, rachitic deformities, and impaired growth and development. ENPP1 LOF mutations in mice induces paradoxical mineralization characterized by increased cardiovascular and periarticular calcifications and an osteopenic bone phenotype, reflecting important aspects of both GACI and ARHR2. Here, we report that the osteopenic phenotype in Enpp1asj/asj mice results from an osteomalacia, the histologic hallmark of rickets. The osteomalacia present in Enpp1asj/asj mice occurs in the presence of normal plasma [Pi] in mice fed a high phosphate diet. Treatment of Enpp1asj/asj mice with ENPP1 enzyme replacement therapy (ERT) eliminates the osteomalacia, increases bone mineral density, and markedly improves bone strength and ductility. Our work demonstrates that ENPP1 ERT addresses the pathologic etiology of ARHR2, but phosphate supplementation does not. Combined with our previous studies demonstrating the efficacy of ENPP1-Fc suppressing lethal vascular and connective tissue calcifications, this study establishes a role for ENPP1 in paradoxical mineralization disorders and suggests a therapeutic strategy for treating these diseases. Support or Funding Information The studies were financially supported by research grants from Inozyme Pharmaceuticals Inc., and The Connecticut Bioscience Innovation Fund (to DTB). Funding to the George M O'Brien Kidney Center at Yale, NIH grant P30DK079310, supported the evaluation of plasma analytes. Histology of the proximal tibias of 5-week old mice on the high phosphate diet are displayed from each experimental cohort to compare histologic changes. Deficiency in ENPP1 resulted in morphologically apparent reductions in trabecular bone and markedly thinner growth plates in the Enpp1asj/asj mice. Treating Enpp1asj/asj mice with mENPP1-Fc markedly increased trabecular bone volume and growth plate thickness. WT and Enpp1asj/asj mice treated with vehicle or ENPP1-Fc were loaded to failure in three-point bending. a. Stiffness – slope of the load vs. displacement curve; Max Load – highest load reached during the test.; Total Work – The energy needed to fracture the bone. b. Post-yield deflection of experimental cohorts – defined as the amount of deformation after the yield point. *p < 0.05, **p< 0.01, ***p<0.001, ANOVA. Histomorphometry, 5 week females, High Phosphate Diet, osteoid. Genotypes/Treatment WT/PBS N=6 asj-asj/PBS n=7 asj-asj/mENPP1 n=6 BV/TV 19.23 ± 3.42 24.61 ± 6.45 20.63 ± 4.58 OV/TV 1.38 ± 0.31 2.35 ± 0.57** 1.78 ± 0.50 OV/BV 6.99 ± 1.76 9.72 ± 1.57* 8.60 ± 1.45 OS/BS 27.89 ± 4.66 42.83 ± 4.52*** 33.68 ± 6.41 OTh 3.01 ± 0.29 3.53 ± 0.29** 3.30 ± 0.12 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Risk factors of bone mineral density deficit and low-energy fractures in primary osteoporosis in men

Purpose: to evaluate the role of well-known factors on the formation of bone mineral density (BMD) and risk of fractures in primary osteoporosis in men. Patients and methods. The influence of well-known osteoporosis risk factors such as age, smoking, alcohol consumption, obesity, genetic disorders in genes encoding COL1A1, COL1A2 and VDR-receptor products, history of low-energy fractures in first-line relatives upon the BMD value and risk of fractures was evaluated in 231 patients with primary osteoporosis. All patients were divided into three age groups according to the following forms of osteoporosis: 17-20 years (n=26) - juvenile form, 21-50 (n=103) - idiopathic form, patients over 51 years (n=102). To assess the influence of study factors on the risk of fractures the patients were subdivided into 5 groups according to fracture localization. Results. The relationship between BMD deficit and mutations in homozygous form of gene rs2412298 (encodes collagen), and the tendency to a reliable increase of BMD deficit in L1 - L4 vertebrae under polymorphism in homozygous form of 1800012 gene was noted that might be evidence of their contribution to the development of primary osteoporosis in men. At the same time, smoking, alcohol consumption, age, mutations in homozygous form of gene rs2412298 and a history of low-energy fractures in first-line relatives increased the risk of low-energy fractures of the vertebral bodies and proximal femur.

Sclerostin Antibody Reverses Bone Loss by Increasing Bone Formation and Decreasing Bone Resorption in a Rat Model of Male Osteoporosis.

Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased bone mineral density (BMD) and decreased skeletal fragility fracture risk have been reported in postmenopausal osteoporotic women receiving Scl-Ab. In males, loss of androgen leads to rapid decreases in BMD and an increased risk of fragility fractures. We hypothesized that Scl-Ab could reverse the loss of bone mass and strength caused by androgen ablation in the orchiectomized (ORX) rat model of male osteoporosis. We treated 9-month-old ORX Sprague Dawley rats (3 months after ORX) subcutaneously twice weekly with vehicle or Scl-Ab (5 or 25 mg/kg) for 6 weeks (n = 10 per group). Both doses of Scl-Ab fully reversed the BMD deficit in the lumbar spine and femur and tibia in ORX rats. Microcomputed tomography showed that the bone mass in the fifth lumbar vertebral body, femur diaphysis, and femoral neck were dose-dependently restored by Scl-Ab. The bone strength at these sites increased significantly with Scl-Ab to levels matching those of sham-operated controls and correlated positively with improvements in bone mineral content, demonstrating bone quality maintenance. Dynamic histomorphometry of the tibial diaphysis and second lumbar vertebral body demonstrated that Scl-Ab significantly increased bone formation on periosteal, endocortical, and trabecular surfaces and significantly decreased bone resorption on endocortical and trabecular surfaces. The effects of Scl-Ab on increasing bone formation and decreasing bone resorption led to restoration of bone mass and strength in androgen-deficient rats. These findings support the ongoing evaluation of Scl-Ab as a potential therapeutic agent for osteoporosis in men.