Deterioration Of Cortical Bone Research Articles

PASSIVE BICYCLE TRAINING STIMULATES EPIPHYSEAL BONE FORMATION AND RESTORES BONE INTEGRITY INDEPENDENT OF LOCOMOTOR RECOVERY IN A RAT SPINAL CORD INJURY MODEL.

It is unknown whether activity-based physical therapy (ABPT) modalities that mobilize the paralyzed limbs improve bone integrity at the highly fracture-prone epiphyseal regions of the distal femur and proximal tibia following severe spinal cord injury (SCI). In this study, four-months-old skeletally-mature littermate-matched male Sprague-Dawley rats received SHAM surgery or severe contusion SCI. At 1-week post-surgery, SCI rats were stratified to undergo no-ABPT or two 20-minute bouts/day of quadrupedal bodyweight-supported treadmill training (qBWSTT) or hindlimb passive-isokinetic bicycle (Cycle) training, 5-days/week for another 3-weeks. We assessed locomotor recovery and plantar flexor muscle mass, tracked cancellous and cortical bone microstructure at the distal femoral and proximal tibial epiphyses using in vivo microCT, and evaluated bone turnover at the tibial epiphysis with histomorphometry. All SCI animals displayed persistent hindlimb paralysis and pervasive muscle atrophy. Over the initial 2-weeks, which included 1-week of no exercise and 1-week of ABPT acclimation, a similar magnitude of bone loss developed in all SCI groups. Thereafter, cancellous bone loss and cortical bone decrements increased in the SCI no-ABPT group. qBWSTT attenuated this trabecular bone loss but did not prevent the ongoing cortical bone deficits. In comparison, twice-daily Cycle training increased the number and activity of osteoblasts vs other SCI groups and restored all bone microstructural parameters to SHAM levels at both epiphyseal sites. These data indicate that a novel passive-isokinetic Cycle training regimen reversed cancellous and cortical bone deterioration at key epiphyseal sites after experimental SCI, via osteoblast-mediated bone anabolic mechanisms, independent of locomotor recovery or increased muscle mass.

Inhibition of RANKL improves the skeletal phenotype of adenine-induced chronic kidney disease in mice.

Skeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2). In study 1, we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10wk of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high PTH. Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In study 2, male mice with established AD CKD were either given a single injection of an anti-RANKL antibody (5mg/kg) 8wk post-induction of CKD or subjected to 3×/wk dosing with risedronate (1.2μg/kg) for 4wk. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical pore surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.

Upacicalcet, a positive allosteric modulator of the calcium-sensing receptor, prevents vascular calcification and bone disorder in a rat adenine-induced secondary hyperparathyroidism model.

Secondary hyperparathyroidism (SHPT) is a major comorbidity of chronic kidney disease (CKD). Chronic elevation of PTH levels is associated with cortical bone deterioration and increase in the risk of fractures in CKD patients. Here, we evaluated the effect of repeated administration of upacicalcet, a novel positive allosteric modulator of the calcium-sensing receptor, in a rat model of adenine-induced renal failure, by determining serum levels of intact PTH (iPTH), calcium, phosphorus, creatinine, and urea nitrogen. Furthermore, parathyroid hyperplasia (parathyroid gland weight and Ki-67-positive cell density), ectopic calcification (calcium content in the thoracic aorta, kidney and heart and positive von Kossa staining in the thoracic aorta), and bone morphometry parameters (cortical porosity and fibrosis volume) were evaluated. Rats treated with either 0.2mg/kg or 1mg/kg upacicalcet exhibited significantly lower serum iPTH levels than CKD-control rats, as early as 7days after the first dose. Repeated administration of upacicalcet reduced serum iPTH levels and inhibited parathyroid hyperplasia in rats with adenine-induced severe renal failure. Moreover, it suppressed ectopic calcification and cortical pore formation. In contrast, serum calcium and phosphorus levels were not significantly affected, suggesting a low risk of hypocalcemia, which often occurs with SHPT treatment. In conclusion, repeated administration of upacicalcet decreased serum iPTH levels and suppressed parathyroid hyperplasia in the adenine-induced CKD rat model of SHPT. Furthermore, ectopic calcification and cortical pore formation were suppressed without significant changes in blood mineral parameters. Upacicalcet safely inhibited the progression of SHPT in an adenine-induced CKD rat model.

SIRT1 haplo-insufficiency results in reduced cortical bone thickness, increased porosity and decreased estrogen receptor alpha in bone in adult 129/Sv female mice.

Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ ) and their wild type (WT) counterparts. In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.

Cortical thickness mapping at segmented regions in the distal radius using HR-pQCT.

An advanced method of analyzing the cortical bone microarchitecture of the distal radius using high-resolution peripheral quantitative computed tomography (HR-pQCT) was developed. The subjects were 60 women (20: aged 30-49, 20: aged 50-69, and 20: aged 70-89years). The distal radius was scanned by HR-pQCT, and its cortical volumetric bone mineral density (Ct.vBMD), cortical porosity (Ct.Po), and cortical thickness (Ct.Th) were measured. The cortical bone was also divided into three areas according to whether its thickness was < 0.5mm, 0.5-1.0mm, or > 1.0mm, and the percentage of each surface area in the total surface area of cortical bone was calculated(Ct.Th(<0.5), Ct.Th(0.5-1.0), Ct.Th (>1.0), respectively). The cortical bone at the distal radius was further segmented into dorsal, palmar, radial, and ulnar sides, and the above-described parameters were measured in these regions. Integral analysis showed that Ct.vBMD and Ct.Th decreased and Ct.Po increased with age (R = -0.62, -0.55, and 0.54). Ct.Th (< 0.5) expanded with age (R = 0.49), with the rate of change between those aged 30-49years and those aged 50-69years being 106.7%. On regional analysis, the expansion of Ct.Th (< 0.5) with age was particularly marked on the dorsal and palmar side (R = 0.51 and 0.49), where the rate of change between those aged 30-49years and those aged 50-69years was the highest, at 196.1 and 149.6%. The method to identify areas of cortical bone thinning in the segmented regions of the dorsal, palmar, radial, and ulnar sides of the distal radius using HR-pQCT may offer a sensitive assessment of age-related deterioration of cortical bone.

Cortical porosity is elevated after a single dose of zoledronate in two rodent models of chronic kidney disease

PurposePatients with chronic kidney disease (CKD) have high risk of fracture in part due to cortical bone deterioration. The goal of this study was to assess the impact of two different bisphosphonates and dosing regimens on cortical microstructure (porosity, thickness, area) and bone mechanical properties in animal models of CKD. MethodsIn experiment 1, Male Cy/+ (CKD) rats were treated with either a single dose or ten fractionated doses of zoledronate at 18 weeks of age. Fractionated animals received 1/10th of single dose given weekly for 10 weeks, with study endpoint at 28 weeks of age. In experiment 2, male C57Bl/6 J mice were given dietary adenine (0.2%) to induce CKD. Bisphosphonate treated groups were given either a single dose of zoledronate or weekly risedronate injections for 4 weeks. Cortical microstructure was assessed via μCT and mechanical parameters evaluated by monotonic bending tests. ResultsExp 1: CKD rats had higher blood urea nitrogen (BUN) and parathyroid hormone (PTH) compared to NL littermate controls. Single dose zoledronate had significantly higher cortical porosity in CKD S.Zol (2.29%) compared to NL control (0.04%) and untreated CKD (0.14%) (p = 0.004). Exp 2: All adenine groups had significantly higher BUN and PTH compared to control mice. Mice treated with single dose zoledronate (Ad + Zol) had the highest porosity (~6%), which was significantly higher compared to either Ad or Ad + Ris (~3%; p < 0.0001) and control mice had the lowest cortical porosity (0.35%). In both experiments, mechanics were minimally affected by any bisphosphonate dosing regimen. ConclusionA single dose of zoledronate leads to higher cortical porosity compared to more frequent dosing of bisphosphonates (fractionated zoledronate or risedronate). Bisphosphonate treatment demonstrated limited effectiveness in preventing cortical bone microstructure deterioration with mechanical parameters remaining compromised due to CKD and/or secondary hyperparathyroidism irrespective of bisphosphonate treatment.

CKD Stages, Bone Metabolism Markers, and Cortical Porosity Index: Associations and Mediation Effects Analysis

Chronic kidney disease (CKD) has a significant negative impact on bone health. However, the mechanisms of cortical bone deterioration and cortical porosity enlargement caused by CKD have not been fully described. We therefore examined the association of CKD stages with cortical porosity index (PI), and explored potential mediators of this association. Double-echo ultrashort echo-time magnetic resonance imaging (UTE MRI) provides the possibility of quantifying cortical porosity in vivo. A total of 95 patients with CKD stages 2-5 underwent 3D double-echo UTE-Cones MRI (3.0T) of the midshaft tibia to obtain the PI. PI was defined as the ratio of the image signal intensity of a sufficiently long echo time (TE) to the shortest achievable TE. Parathyroid hormone (PTH), β-CrossLaps (β-CTX), total procollagen type I amino-terminal propeptide (T-P1NP), osteocalcin (OC), 25-hydroxyvitamin D (25OHD), and lumbar bone mineral density (BMD) were measured within one week of the MRI. Partial correlation analysis was performed to address associations between PI, eGFR and potential mediators (PTH, β-CTX, T-P1NP, OC, 25OHD, BMD, and T-score). Multiple linear regression models were used to assess the association between CKD stages and PI value. Then, a separate exploratory mediation analysis was carried out to explore the impact of CKD stages and mediators on the PI value. The increasing CKD stages were associated with a higher PI value (Ptrend < 0.001). The association of CKD stages and PI mediated 34.4% and 30.8% of the total effect by increased PTH and β-CTX, respectively. Our study provides a new idea to monitor bone health in patients with CKD, and reveals the internal mechanism of bone deterioration caused by CKD to some extent.

Adjuvant endocrine therapy effects on bone mineral density and microstructure in women with breast cancer

Although aromatase inhibitors (AIs) are typical drugs for cancer treatment-induced bone loss, their effects on the bone microstructure remain unclear. In this study, we evaluated changes in the bone mineral density (BMD) and bone microstructure associated with AI treatment using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with early breast cancer. This prospective, single-arm, observational study included non-osteoporotic, postmenopausal women with hormone receptor-positive breast cancer. Patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide measurements at baseline and 6 and 12months after AI therapy. The primary endpoint was changes in the total volumetric BMD (Tt.vBMD), trabecular vBMD (Tb.vBMD), and cortical vBMD (Ct.vBMD) longitudinally at the distal radius and tibia. Twenty women were included (median age 57.5years; range 55-72years). At 12months, HR-pQCT indicated a significant decrease in the Tt.vBMD (median distal radius -5.3%, p < 0.01; distal tibia -3.2%, p < 0.01), Tb.vBMD (-3.2%, p < 0.01; -1.0%, p < 0.05, respectively), and Ct.vBMD (-3.2%, p < 0.01; -2.7%, p < 0.01, respectively). Estimated bone strength was also significantly decreased. The DXA BMD value in the total hip (p < 0.01) and femoral neck (p = 0.03), but not in the lumbar spine, was significantly decreased. The TRACP-5b levels was significantly negatively associated with changes in the Tt.vBMD in both the distal radius and tibia (r = -0.53, r = -0.47, respectively) CONCLUSION: Postmenopausal women who received AIs for early breast cancer experienced significant trabecular and cortical bone deterioration and a decrease in estimated bone strength within only 1year.

English

BACKGROUND The peculiar waddling gait of a female attracts most of the anatomists to measure and compare the neck-shaft angle (NSA) of the femora. The femoral neck shaft angle is greater in women due to greater pelvic breadth and shorter femur. Neck-shaft angle was measured by the angle that the neck makes with the shaft of the femur and it is measured on the ventral surface of femur taking the long axis of femoral neck with the long axis of the proximal end of the femur. It gives information about the race it belongs to and normally measures 120° to 140°. The intention of this study was to establish the femoral neck shaft angle variations in adult male and female for medico-legal and anthropometric studies. METHODS This cross-sectional study was conducted on 84 adult human femora of unknown sex in the anatomy department, Sriram Chandra Bhanja (SCB) Medical College, Cuttack, Odisha, from May 2018 to April 2019. We included all the femora which were free of damage or deformity and fully ossified indicating adult bone. Femora with any pathological changes i.e., cortical bone deterioration, extreme osteophyte activity, osteoarthritis and fracture etc. were excluded from the study. The NSA was measured by protractor and goniometer. RESULTS In the present study the NSA range for the right femur of male was 108° - 135° and for the right femur of females 117° - 135°. The left male femur was 118° - 135° and the left female femur was 120° - 135°. The mean neck shaft angle of male femora was 125.9° and the female femora was 125.7°. These measurements show that the values were more in males than the females. The value of the present study was statistically significant between male and female i.e., P &lt; 0.0001. CONCLUSIONS These measurements are important in the medico-legal cases, reconstructive orthopaedic surgeries, hip replacement surgeries and also while constructing suitable prosthesis. This will also be helpful in the detection of sex by anatomists and forensic experts. KEY WORDS Neck Shaft Angle, Medico-Legal, Anthropometry and Goniometer

Abstract PS9-23: Second-generation HR-pQCT analysis of bone mineral density and microstructure in women with breast cancer who underwent adjuvant endocrine therapy

Abstract Background: Adjuvant endocrine therapy for 5-10 years reduces breast cancer (BC) mortality in women with hormone receptor-positive BC. However, aromatase inhibitors (AIs) decrease bone mineral density (BMD), and increase fractures, joint stiffness, and joint pain. Although dual energy X-ray absorptiometry (DXA) is widely used to assess BMD, it is a two-dimensional method and thus cannot analyze trabecular and cortical bone microstructure. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows in vivo analysis of peripheral bone microarchitecture with high spatial resolution and low radiation exposure. We used HR-pQCT to evaluate changes in volumetric bone density and microstructure consisting of trabecular and cortical bone associated with AI treatment in patients with early BC. Methods: This was a prospective single-center observational study of nonosteoporotic, postmenopausal women with hormone receptor-positive BC, whose baseline DXA lumber spine and femoral neck T-scores were &amp;gt; −2.5. All patients were scheduled to receive DXA and HR-pQCT at baseline and at 6 and 12 months after starting AI therapy. The primary endpoint was to examine changes in total volumetric BMD (Tt. vBMD), trabecular volumetric BMD (Tb. vBMD), cortical volumetric BMD (Ct. vBMD) change at the distal radius and the distal radius between baseline and 6 and 12 months after starting endocrine therapy. Results: Of the 20 women in the study (median age: 57.5 years; range: 55-72 years), 8 had undergone chemotherapy before registration. Their mean change in Tt. vBMD between baseline and 1 year were distal radius: −5.7% (SD: 2.5%, P&amp;lt;0.01); distal tibia: −3.8% (SD: 1.8%, P&amp;lt;0.01), Tb. vBMD distal radius: −4.0% (SD: 3.9%, P&amp;lt;0.01); distal tibia: −0.9% (SD: 2.4%, P&amp;lt;0.05), Ct. vBMD distal radius: −3.1% (SD: 1.6%, P&amp;lt;0.01); distal tibia: −2.9% (SD: 1.7%, P&amp;lt;0.01). Furthermore, at 1 year in trabecular bone, mean trabecular bone volume fraction (p&amp;lt;0.01), trabecular thickness (p&amp;lt;0.05), and trabecular number (p&amp;lt;0.01) were significantly decreased, and trabecular separation (p&amp;lt;0.01) increased, in both the distal radius and tibia. At 1 year in cortical bone, mean changes in cortical thickness (p&amp;lt;0.01) and cortical bone area (p&amp;lt;0.01) were significantly decreased in both the distal radius and tibia; however, the endocortical perimeter of cortical bone did not significantly change and cortical porosity (p&amp;lt;0.05) was significantly greater than that at baseline. At 1 year, DXA decreased at the total hip (−4.4%, P&amp;lt;0.01) and femoral neck (−0.6%, P=0.03) compared with baseline. However, no significant difference was seen in median values for lumbar spine BMD at 1 year, or for tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide (PINP). Conclusion: Postmenopausal women who took AIs for early BC experience volumetric bone density decline and both trabecular and cortical bone deterioration. A decade of AI treatment is a standard treatment for early BC; however, healthcare professionals should monitor bone health during and after these treatments. Citation Format: Sayaka Kuba, Konosuke Watanabe, Megumi Matsumoto, Ko Chiba, Kosho Yamanouchi, Ayako Fukushima, Michi Morita, Ryota Otsubo, Hiroshi Yano, Kengo Kanetaka, Makoto Osaki, Takeshi Nagayasu, Susumu Eguchi. Second-generation HR-pQCT analysis of bone mineral density and microstructure in women with breast cancer who underwent adjuvant endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-23.

Effect of Calcium Supplementation in Glucocorticoid-Induced Osteoporosis

The commonest secondary cause of osteoporosis is Glucocorticoid-induced osteoporosis (GIO) which is also the commonest cause of iatrogenic osteoporosis. Chronic glucocorticoids (GCs) treatment may cause fractures in 30-50% of patients. Fracture risk is increased among those using oral glucocorticoids. On long-term glucocorticoids therapy, deterioration of cortical bone progressively detected and long bones became increasingly fragile. Any patient with chronic glucocorticoids therapy should be expected as suffering from GIO. Patients on glucocorticoids should receive supplementation with calcium. These deleterious influences are the result of suppression of bone formation that occurs with an early but temporal rise in the process of bone resorption. Numbers of osteoclast also rapidly rise, and accompanied by inactivation of osteoblast and decline of bone formation, these changes cause the fastest bone loss during the initial phase disease. Glucocorticoids cause inhibition of osteoblasts replication and function and accelerate their apoptosis. Calcium is fundamental for bone, and assuring sufficient calcium intake is important. It is said that when children and adolescents ingest large amount of calcium could result in a decrease in the danger of developing osteoporosis when they got old, however, some researches propose that solitary use of calcium supplementation might not be enough for lowering the danger for fracture. Conflicting results were reported about the effects of the use of supplemental calcium on the bone mineral content in those taking glucocorticoids therapy. Whereas, calcium supplementations were used in most bone protective treatment trials and therefore should be used as an adjunct to GIO therapy.

Development of a QUS Device to Evaluate Deterioration of Cortical Bone: Verification by HR-pQCT and Measurements in Healthy Individuals and Dialysis Patients

Introduction: The objectives of this study were to identify what is reflected in cortical speed of sound (cSOS) measured by a cortical quantitative ultrasound (cortical QUS) device we have developed, and to investigate cSOS measurements in healthy individuals and dialysis patients. Methods: The cSOS and the SOS were measured by cortical QUS and conventional QUS in 20 volunteers, and the correlations between these measurements and areal bone mineral density measured by dual-energy X-ray absorptiometry and bone microstructural parameters on high-resolution peripheral quantitative computed tomography were analyzed. The cSOS and the SOS were measured in 91 young adults (47 men, 44 women), 64 elderly people (30 men, 33 women), and 64 dialysis patients (33 men, 31 women). The period of hemodialysis and intact parathyroid hormoneevels were also investigated in the dialysis patients. Results: cSOS was correlated with cortical tissue mineral density (tibia: r = 0.74, radius: r = 0.72) on high-resolution peripheral quantitative computed tomography, reflecting the degree of minaralization and microporosity of cortical bone. There was no correlation with the thickness of cortical bone, suggesting that it measured the bone quality rather than bone mass. Elderly women had lower cSOS than young adults (3865 ± 74 vs 3971 ± 63 m/s, p < 0.01). Many of dialysis patients showed very low cSOS and it was related to higher intact parathyroid hormone levels (male: ß = −0.67, female: ß = −0.60). Conclusions: Our cortical QUS device is capable of evaluating the qualitative degradation of cortical bone, which cannot be assessed by conventional QUS, and its use in combination with conventional QUS may provide a better understanding of fracture risk.

Collagen XIII-derived ectodomain regulates bone angiogenesis and intracortical remodeling

Osteoporosis is the most common degenerative bone disease that occurs when the balance of bone production and resorption is perturbed. Loss of bone mass or alteration in its quality leads to significant weakening of the bones and subsequently to higher fracture risk. Collagen XIII (ColXIII) is a conserved transmembrane protein expressed in many mesenchymal tissues. Here we show that ColXIII is a regulator of bone remodeling niche. In this study, we found that ColXIII expression is significantly upregulated in osteoporotic patients. In view of that, we studied bone homeostasis in ColXIII-overexpressing mice (Col13a1oe) up to 72 weeks of age and observed a cortical bone overgrowth followed by a drastic bone loss, together with increased bone vascularization. Moreover, our results demonstrate that the ColXIII-derived ectodomain enhances angiogenesis through β1-integrins and the JNK pathway. Consequently, these data suggest that ColXIII has a role in age-dependent cortical bone deterioration with possible implications for osteoporosis and fracture risk.

Relationship Between Sex Steroids and Deterioration of Bone Microarchitecture in Older Men: The Prospective STRAMBO Study.

In older men, low estrogen levels are associated with poor bone microarchitecture. Data on androgens are discordant. We studied the link between baseline sex steroid levels (total 17β -estradiol [17βE2], total testosterone [tT], calculated bioavailable 17βE2 [bio-17βE2], and apparent free testosterone concentration [AFTC]) and bone microarchitecture deterioration assessed prospectively in a 820 older men followed for 8 years. Bone microarchitecture was assessed by HR-pQCT at baseline, then after 4 and 8 years. At both the skeletal sites, the bone microarchitecture deterioration rate did not correlate with serum levels of tT and 17βE2. At the distal radius, cortical area (Ct.Ar) decreased more rapidly in the lowest versus the highest AFTC quartile. At the distal tibia, cortical thickness (Ct.Th) decreased and trabecular area (Tb.Ar) increased more rapidly in the highest versus the lowest AFTC quartile. At the tibia, bone mineral content (BMC), total volumetric bone mineral density (Tt.vBMD), Ct.Th, and Ct.Ar decreased, whereas Tb.Ar increased faster in the lowest versus the highest bio-17βE2 quartile. In men who had both AFTC and bio-17βE2 in the lowest quartile (high-risk group), distal radius cortical vBMD (Ct.vBMD) decreased more rapidly compared with men who had both hormones in the three upper quartiles (reference group). At the distal tibia, Tt.vBMD, Ct.Th, Ct.Ar, and Ct.vBMD decreased, whereas Tb.Ar increased more rapidly in the high-risk group versus the reference group. In men receiving androgen deprivation therapy (ADT) for prostate cancer, BMC, Tt.vBMD, Ct.Th, Ct.Ar, and Ct.vBMD decreased, whereas Tb.Ar increased more rapidly than in men not receiving ADT at both the skeletal sites. Thus, in older men followed up prospectively, low levels of bio-17βE2, and to a smaller extent AFTC, are associated with accelerated cortical bone deterioration. Cortical bone deterioration was strongly accelerated in men receiving ADT who had very low levels of all sex steroids. © 2019 American Society for Bone and Mineral Research.

Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis

BackgroundIn the present study, we investigated bone geometry, microstructure, and volumetric bone mineral density (vBMD) in a cohort of patients with nonradiographic axial spondyloarthritis (nr-axSpA) in order to define the early bone changes occurring in axial spondyloarthritis (axSpA) and to define potential factors for deterioration of bone microstructure.MethodsPatients with axSpA (n = 107) and healthy control subjects (n = 50) of similar age and sex were assessed for geometric, volumetric, and microstructural parameters of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius. Additionally, demographic and disease-specific characteristics of patients with axSpA were recorded.ResultsPatients with nr-axSpA and control subjects were comparable in age, sex, and body mass index. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p = 0.022) and cortical thickness (p = 0.006) in patients with nr-axSpA compared with control subjects. Total and cortical vBMD were significantly reduced in patients with nr-axSpA (p = 0.042 and p = 0.007, respectively), whereas there was no difference in trabecular vBMD. Patients with a short disease duration (< 2 years; n = 46) also showed significant reduction of cortical thickness and cortical area compared with control subjects. Patients with disease duration > 2 years (n = 55) additionally developed a decrease of cortical and total vBMD. Multiple regression models identified male sex to be associated with lower cortical vBMD and female sex to be associated with lower trabecular vBMD.ConclusionsBone microstructure in patients with nr-axSpA is characterized primarily by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of the disease.

Thoracic SBRT Induces Early Deterioration of Cortical Bone in Ribs

Thoracic SBRT Induces Early Deterioration of Cortical Bone in Ribs

Role of cortical bone in bone fragility.

Trabecular bone loss and vertebral fractures are historical hallmarks of osteoporosis. During the past 70 years, this view has dominated research aiming to understand the structural basis of bone fragility. We suggest this notion needs to be revised to recognize and include the role of cortical bone deterioration as an important determinant of bone strength throughout life. About 80% of the fragility fractures involve the appendicular skeleton, at regions comprising large amounts of cortical bone. Up to 70% of the age-related bone loss at these locations is the result of intracortical remodeling that cavitates cortical bone producing porosity. It is now possible to accurately quantify cortical porosity in vivo and use this information to understand the pathogenesis of bone fragility throughout life, assist in identifying patients at risk for fracture, and use this as a potential marker to monitor the effects of treatment on bone structure and strength. Cortical bone has an important role in determining bone strength. The loss of strength is the result of intracortical and endocortical remodeling imbalance that produces cortical porosity and thinning. Studies are needed to determine whether porosity is an independent predictor of fracture risk and whether a reduction in porosity serves as a surrogate of antifracture efficacy.

Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells

In diabetes mellitus (DM), high glucose (HG) and advanced glycation end products (AGEs) are involved in bone quality deterioration. Osteocytes produce sclerostin and receptor activator of nuclear factor-кB ligand (RANKL) and regulate osteoblast and osteoclast function. However, whether HG or AGEs directly affect osteocytes and regulate sclerostin and RANKL production is unknown. Here, we examined the effects of HG, AGE2, and AGE3 on the expression of sclerostin and RANKL and on apoptosis in osteocyte-like MLO-Y4-A2 cells. Treatment of the cells with 22 mM glucose, 100 μg/mL either AGE2 or AGE3 significantly increased the expression of sclerostin protein and mRNA; however, both AGEs, but not glucose, significantly decreased the expression of RANKL protein and mRNA. Moreover, treatment of the cells with HG, AGE2, or AGE3 for 72 h induced significant apoptosis. These detrimental effects of HG, AGE2, and AGE3 on sclerostin and RANKL expressions and on apoptosis were antagonized by pretreatment of the cells with 10−8 M human parathyroid hormone (PTH)-(1–34). Thus, HG and AGEs likely suppress bone formation by increasing sclerostin expression in osteocytes, whereas AGEs suppress bone resorption by decreasing RANKL expression. Together, these processes may cause low bone turnover in DM. In addition, HG and AGEs may cause cortical bone deterioration by inducing osteocyte apoptosis. PTH may effectively treat these pathological processes and improve osteocyte function.

Longitudinal in vivo micro-CT assessment in osteopenic women demonstrated that risedronate reduced the deterioration of cortical bone

Longitudinal in vivo micro-CT assessment in osteopenic women demonstrated that risedronate reduced the deterioration of cortical bone

Functional mechanism of glucocorticoid in bone turnover and bone structure

The functional mechanism of glucocorticoid (GC)-induced osteoporosis is not fully understood. We examined to the effects of GC on bone turnover, minerals, structure, and bone strength in growing minipigs. GC administration caused prolongation of the period of bone tissue turnover in both trabecular and cortical bone and imbalance in bone formation and resorption, consequently leading to osteoporosis in growing minipigs. Bone structure were deteriorated both trabeculare and cortex. Deterioration of cortical bone rather than trabecular bone could play a role as main factor of bone fragilities in GC-induced osteoporosis.