Trabecular Sites Research Articles

Osteoprogenitor recruitment and differentiation during intracortical bone remodeling of adolescent humans.

Recruitment and proliferation of osteoprogenitors during the reversal-resorption phase, and their differentiation into mature bone-forming osteoblasts is crucial for initiation of bone formation during bone remodeling. This study investigates the osteoprogenitors' gradual recruitment, proliferation, and differentiation into bone-forming osteoblasts within intracortical remodeling events of healthy adolescent humans. The study was conducted on cortical bone specimens from 11 adolescent human controls - patients undergoing surgery due to coxa valga. The osteoprogenitor recruitment route and differentiation into osteoblasts were backtracked using immunostainings and in situ hybridizations with osteoblastic markers (CD271/NGFR, osterix/SP7, COL3A1 and COL1A1). The osteoblastic cell populations were defined based on the pore surfaces, and their proliferation index (Ki67), density and number/circumference were estimated in multiplex-immunofluorescence (Ki67, TRAcP, CD34) stained sections. During the reversal-resorption phase, osteoclasts are intermixed with (COL3A1+NFGR+) osteoblastic reversal cells, which are considered to be osteoprogenitors of (COL1A1+SP7+) bone-forming osteoblasts. Initiation of bone formation requires a critical density of these osteoprogenitors (43±9 cells/mm), which is reached though proliferation (4.4±0.5% proliferative) and even more so through recruitment of osteoprogenitors, but challenged by the ongoing expansion of the canal circumference. These osteoprogenitors most likely originate from osteoblastic bone lining cells and mainly lumen osteoprogenitors, which expand their population though proliferation (4.6±0.3%) and vascular recruitment. These lumen osteoprogenitors resemble canopy cells above trabecular remodeling sites, and like canopy cells they extend above bone-forming osteoblasts where they may rejuvenate the osteoblast population during bone formation. Initiation of bone formation during intracortical remodeling requires a critical density of osteoprogenitors on eroded surfaces, which is reached though proliferation and recruitment of local osteoprogenitors: bone lining cells and lumen osteoprogenitors.

OR13-01 Type 1 Diabetes Is Associated With Differential Skeletal Effects At The Onset Of Peak Bone Accrual

Abstract Disclosure: A.V. Brossfield: None. K.M. Williams: None. A.B. Sopher: None. D.J. McMahon: None. J. Fernando: None. S. Agarwal: None. M.R. Rubin: None. Objective: Type 1 diabetes (T1D) often develops prior to attainment of peak bone mass, yet few data exist regarding bone accretion in the peri-pubertal period. We hypothesized that T1D have disrupted bone architecture at the onset of peak bone mass accrual in association with hyperglycemia and advanced glycation endproduct (AGE) accumulation. Methods: We enrolled T1D and controls at onset of peak bone accretion (Tanner: girls 2/3, boys 3/4) and assessed aBMD by DXA and volumetric BMD (vBMD), microarchitecture, and bone strength by high resolution peripheral quantitative computed tomography (HRpQCT) with finite element analysis (µFE) at the distal (4%) and proximal (30%) radius and tibia. We assessed time in hyperglycemia (>180 mg/dL) by continuous glucose monitoring and AGE accumulation by skin autofluorescence (SAF). Results: T1D (n=29, age 12.5 ± 0.3 [SE] yr, 79% male, 68% white) vs controls (n=31, 12.2 ± 0.3 yr, 55% male, 68% white) had higher BMI (21.3 ± 1 vs 18.4 ± 0.5 kg/m2; p=0.04), fasting glucose (168.5 ± 9 vs 88.4 ± 2 mg/dL; p<0.0001) and HbA1c (8.4 ± 0.8 vs 5.0 ± 0.2%; p=0.05) with a trend toward higher bone age (13.5 ± 0.3 vs 12.6 ± 0.3 yr, p=0.07) and lower 25OHD (24.0 ± 1 vs 34.8 ± 3 ng/mL, p=0.08). After multivariate adjustment (sex, bone age, height and weight), DXA showed decreased bone area in T1D at the total, sub-total, leg, rib and ultradistal radius, and decreased bone mineral content at the rib, leg and trochanter (ranging from -4.1% to -13.5%, all p <0.05). Multivariate adjusted HRpQCT data showed decreased trabecular area in T1D at the distal radius (169.9 ± 8 vs 201.2 ± 8 mm2; p=0.007) and tibia (578 ± 17 vs 631 ± 17 mm2; p=0.04) and decreased cortical perimeter at the distal radius (56.0 ± 1 vs 60.1 ± 1 mm2; p=0.009). However, T1D had increased cortical vBMD at the distal (698.2 ± 8 vs 663.5 ± 8 mg HA/cm3; p=0.004) and proximal radius (998 ± 6 vs 977 ± 6 mg HA/cm3; p=0.02) and tibia (998 ± 6 vs 977 ± 6 mg HA/cm3; p=0.02) and increased cortical thickness at the distal radius (0.74 ± 0.03 vs 0.64 ± 0.03 mm; p=0.03). There was no difference in bone strength by µFE. Within T1D, lower trabecular area at the distal radius was associated with higher SAF (β -69.26 ± 30 mm2; p=0.04) while higher cortical vBMD at the distal tibia was associated with higher time in hyperglycemia (β 0.633 ± 0.3 mg HA/cm3; p=0.03). Conclusion: T1D at the onset of peak bone accrual have decreased bone area and mineral content by DXA. They also have decreased trabecular area but increased cortical vBMD by HRpQCT, in association with AGE accumulation and hyperglycemia. We speculate that reduced bone turnover with hyperglycemia might lead to reduced area at more metabolically active trabecular sites but is compensated for by excess mineral accumulation at less active cortical sites, with overall maintenance of bone strength. Follow up will elucidate progression of these alterations during the growth spurt. Presentation: Friday, June 16, 2023

Site specific differences in vBMD and geometry in postmenopausal women with primary hyperparathyroidism.

Primary Hyperparathyroidism (PHPT) is associated with catabolic effects at both trabecular and cortical bone. Mechanical loading is one of the most important natural anabolic stimuli for bone at all ages. The present study was designed to assess the impact of PHPT on vBMD and bone geometry using peripheral quantitative computed tomography (pQCT) at the radius and tibia, sites with similar structural characteristics, but subject to different loading conditions. We evaluated the impact of PHPT on bone, by comparing the z-scores of volumetric Bone Mineral Density (vBMD) and indices of bone geometry simultaneously at the tibia and the radius by pQCT, skeletal sites with similar structure, but subject to different loading conditions. Forty-one postmenopausal women with PHPT and 79 controls, comprised the study group. At both trabecular and cortical sites, vBMD and bone geometry indices were significantly lower in patients compared with controls. In patients with PHPT, apart from a lower z-score for total vBMD (p = 0.01) at the radius, there was no other difference between the radius and the tibia at the trabecular sites. On the contrary, at cortical sites, the z-scores of cortical bone mineral content (p = 0.02), cortical vBMD (p = 0.01) and cortical cross-sectional area (p = 0.05) were significantly lower at the radius compared with the tibia, indicating that cortical bone at the weight bearing tibia might be less affected by the catabolic actions of continuous parathyroid hormone (PTH) exposure. PTH levels were positively associated with the difference in z-scores of cort BMD (r = 0.439, p < 0.01) indicating that in more severe cases, as expressed by higher PTH levels, the deleterious effects at the non-weight bearing radius might be accentuated. We found that in postmenopausal women with PHPT, both trabecular and cortical bone are adversely affected. However, at the weight bearing tibia as compared with the radius, the deleterious effects, especially on cortical bone, seem to be attenuated. NCT05426512, 21/06/2022, "retrospectively registered".

Bone health evaluation in primary hyperparathyroidism using dual-energy X-ray absorptiometry and trabecular bone score.

Bone involvement in primary hyperparathyroidism (PHPT) is characterized by reduced bone mineral density (BMD) using dual X-ray absorptiometry (DXA). A hallmark of PHPT is BMD loss at cortical sites while trabecular bone remains relatively preserved. PHPT is associated with increased fracture risk at both trabecular and cortical skeletal sites, which cannot be explained based on BMD values alone. The application of the trabecular bone score (TBS), an index of the lumbar spine DXA bone microarchitecture, showed lower TBS values and increased risk of fractures in PHPT patients, independent of BMD. Although further prospective studies are needed, promising data have been published with the use of TBS and some advanced DXA-based imaging modalities in patients with PHPT.

Prevalence of low bone mineral density (T-score ≤ - 2.5) in the whole spectrum of chronic kidney disease: a systematic review and meta-analysis.

The prevalence of low bone mineral density (LBMD) in people with chronic kidney disease (CKD) remains unknown. We identified a high prevalence of LBMD in CKD population. Thus, public health strategies should include efforts to prevent, early detect, and manage LBMD in CKD patients, especially in patients undergoing kidney replacement therapy. Mineral and bone disorders are common among patients with CKD, which affects bone mineral density. We conducted a systematic review and meta-analysis to estimate the prevalence of low bone mineral density (LBMD) in adults with CKD. We searched MEDLINE, EMBASE, Web of Science, CINAHL, and LILACS databases from inception to February 2021. Observational studies that reported the prevalence of LBMD in adults with CKD stages 3a-5D were included. The LBMD was defined according to the World Health Organization criterion (T-score ≤ - 2.5). Random-effect model meta-analyses were used to estimate the pooled prevalence of LBMD. Meta-regressions and subgroup analyses were conducted for stages of CKD, dialysis modality, gender, bone sites and morphology, and geographical region. This study was registered in PROSPERO, number CRD42020211077. One-hundred and fifty-three studies with 78,092 patients were included. The pooled global prevalence of LBMD in CKD was 24.5% (95% CI, 21.3 - 27.8%). Subgroup analyses indicated a higher prevalence of LBMD in dialysis patients (30%, 95% CI 25 - 35%) compared with non-dialysis CKD patients (12%, 95% CI 8 - 16%), cortical bone sites (28%, 95% CI 23 - 35%) relative to trabecular sites (19%, 95% CI 14 - 24%), while similar estimates in the European and the Asiatic continents (26%, 95% CI 21 - 30% vs 25%, 95% CI 21 - 29). The prevalence of LBMD in CKD patients is high, particularly in those undergoing dialysis and in cortical bone sites. Therefore, efforts to early diagnosis and management strategies should be implemented in clinical routine for an epidemiological control of LBMD in CKD patients.

GPR109A gene deletion ameliorates gonadectomy-induced bone loss in mice.

Sex steroid deficiency plays critical roles in the pathophysiology of bone as the result of uncertain bone remodeling, i.e., increased bone resorption with equivocal bone formation. We have previously shown that GPR109A, a G protein coupled receptor, controls osteoclastogenesis and bone resorption, where global GPR109A deletion decreased osteoclast bone resorption and increased bone mass. Here, we used global GPR109A gene deletion, ovariectomized (OVX) and orchidectomized (ORX) mouse models to probe the role of GPR109A in gonadectomy-induced bone loss in female and male mice. Six months old GPR109A-/- mice and their wild type littermates were allocated to Sham or gonadectomized groups for six weeks. Using densitometric micro-CT confirmed by peripheral quantitative CT (pQCT) scans on tibia and spine, and three-point bending test on femur ex vivo, we found the bone volume, trabecular number, as well as bone mineral density and content in both trabecular and cortical sites were significantly decreased in wild type OVX and ORX compared with respective Sham groups. While bone mass in both male and female GPR109A-/- Sham groups were significantly higher compared with their respective wild type Sham groups, global GPR109A gene deletion ameliorated gonadectomy-induced bone loss. In GPR109A-/- females, most of bone mass and strength parameters measured by micro-CT, pQCT and three-point bending test were not different between Sham and OVX groups. In wild type but not in GPR109-/- mice, bone remodeling marker measurements indicated that both bone resorption (Cathepsin K) and bone formation (osteocalcin) markers were increased in gonadectomized mice compared to sham, with the exception of bone specific ALP, which was decreased in gonadectomized mice. Expression of bone resorption markers (Cathepsin K) were significantly lower, but β-catenin expression was higher in GPR109A-/- mice compared with their wild type littermates. Collectively, these data indicate that global GPR109A deletion ameliorates gonadectomy-induced bone loss through suppression of bone resorption.

Commentaries on Viewpoint: Fragile bones of elite cyclists: to treat or not to treat?

Commentaries on Viewpoint: Fragile bones of elite cyclists: to treat or not to treat?

Peak vertical jump power predicts radial bone strength better than hand grip strength in healthy individuals.

Osteoporosis is considered a pediatric disease with geriatric consequences. However, measuring bone strength in children is complex and creates a practical problem for health professionals, teachers and parents. A non-invasive measure of muscle fitness that correlates to bone strength may provide a means to monitor bone strength throughout the lifespan. Therefore, the purpose of this study was to investigate the relationship between common muscle function tests (relative grip strength (RGS), peak vertical jump power (PP)) and bone strength in the radial diaphysis and epiphysis of a healthy population. Healthy participants (n=147 (81 female)) performed a bilateral grip strength test using a hand dynamometer, and a maximal vertical jump test. Peak vertical jump power was calculated from maximal jump height using the Sayer’s equation. Moment of inertia (MoI), cortical area (CoA), cortical bone mineral density (cBMD), and polar strength-strain index (SSIp) were measured using peripheral Quantitative Computed Tomography (pQCT) to determine bone strength parameters at the 66% radial site (predominantly cortical bone). At the 4% site (trabecular bone site), bone mineral content (vBMC.tb), bone mineral density (vBMD.tb), total area (ToA.tb) and bone strength index (BSIc) were measured. Hierarchical multiple regression analyses determined the relationship of each muscle function test for each bone envelope (cortical and trabecular). For the cortical bone measurements: RGS, and PP were both significantly correlated with CoA, MoI, and SSIp. Peak vertical jump power predicted bone strength parameters to a greater extent compared to RGS. For the trabecular bone envelope, RGS was not a predictor of bone strength however peak power was a significant predictor of bone strength parameters. Peak vertical jump power was a significant predictor of bone strength at both trabecular and cortical radial sites. Interestingly PP, a lower limb measurement explained the most variance in the bone strength of the upper limb.

P196 Predictors of fracture in patients with primary hyperparathyroidism

Abstract Background Primary hyperparathyroidism (PHPT) is a recognised risk factor for fractures as the persistently elevated parathyroid hormone levels are associated with lower bone mineral density (BMD). In early osteoporosis (&amp;lt;65 years), there is mainly trabecular bone loss while with increasing age, the largest loss of absolute bone mass occurs in cortical sites. Our aim was to compare cortical versus trabecular bone sites to determine which sites better predict fracture in PHPT patients referred for dual-energy X-ray absorptiometry (DEXA) scan in an observational cohort. Methods 508 patients with PHPT referred for DEXA scan at Royal Lancaster Infirmary (UK) between 2006-2016 were included in a retrospective data analysis. Data collected included femoral and lumbar BMD, age, gender, height, weight, BMI, rheumatoid arthritis, smoking, alcohol, family history of fractures, secondary osteoporosis and long-term steroid use and was used to look at predictors of fractures using BMD at different sites. Simple statistics using independent t-tests and chi-squared tests were initially used and subsequently, logistic models were fitted unadjusted and adjusted confounding variables. Results 97 males (19%) and 411 females (81%) were included, with 111 patients sustaining at least one fracture (21.9%). Mean age was 65 years (SD 0.55). Advanced age, female gender and a reduced BMD were all statistically significant factors associated with an increased risk of fractures. Smoking and long-term steroid use were also shown to increase risk of fracture however these were non-statistically significant. Adjusting for age and gender, a reduced L4 BMD was the strongest statistically significant predictor of fracture (OR 0.139, 95% CI: 0.112-0.782). Multivariate analysis revealed that a reduced L3 BMD was the strongest statistically significant predictor of fracture (OR 0.170, 95% CI: 0.071-0.72). Conclusion Overall, our study suggests that a reduced BMD at trabecular sites is a stronger predictor of fracture compared to cortical sites [Table 1]. Older age and female gender significantly increased the risk of fracture in PHPT patients. To the best of our knowledge, this is the first study looking at specific bone sites as independent predictors of fracture in PHPT patients. This analysis should be repeated using a larger cohort to validate our results. Disclosures D. Mariannis None. M. Bukhari None.

The effect of selective serotonin reuptake inhibitors on the human mandible.

Selective serotonin reuptake inhibitors (SSRI) are a group of drugs that selectively and strongly block the serotonin transporter. Aim of this study was to evaluate the mandibular bone structure of patients who are using SSRIs with fractal analysis and panoramic morphometric indices [mandibular cortical width (MCW), panoramic mandibular index (PMI) and Klemetti index (KI)] and to compare with control group. Patients who declared using SSRIs for more than six months had been included in the study group. In total, 212 dental panoramic radiographs (DPR) were assessed. For fractal analysis; three regions of interest (ROIs) were determined: ROI1 and ROI2 were chosen within trabecular bone, ROI3 was selected from cortical bone. MCW, PMI, and KI were obtained from DPRs. The study group was categorized into five subgroups of various SSRIs. The fractal dimension (FD) values and panoramic morphometric indices of these subgroups were also compared. There was no significant difference between the groups for age and gender (p = 0.57, p = 0.5). There were significant differences in the mean FD values between the study and control groups both for the ROI1 and ROI2 (p < 0.01, p < 0.01). There was no significant difference between the groups for the mean FD value of ROI3, MCW, PMI and KI (p = 0.93, p = 0.98, p = 0.74, p = 0.06). There were no significant differences for all the values between the SSRI subgroups (p = 0.52, p = 0.7, p = 0.76, p = 0.24, p = 0.31, p = 0.08) CONCLUSIONS: Trabecular rich sites of the mandible were found to be affected by SSRI usage.

The evaluation of the mandibular bone structure changes related to lactation with fractal analysis.

Lactation-induced bone loss of lumbar spine, hip, femur and distal radius are well documented in the literature. The aim of this article is to investigate whether lactation affects the trabecular and cortical bone structure of human mandible. 120 dental panoramic radiographs (DPR) of the lactating women who were breastfeeding for 3-6months (study group) and 120 DPRs of the nulliparous women (control group) were evaluated. Regions of interest (ROI) were chosen from the geometric center of ramus, the geometric center of angulus and the cortical bone. ROIs were examined with fractal analysis method. Fractal dimension (FD) values of each ROI were compared with each other. In addition, the study group was divided into four subgroups according to age, and FD values were compared within the subgroups. The control and study groups were age-matched. FD values of mandibular ramus and angulus were significantly lower in the study group (p < 0.001, p < 0.001). There was no significant difference for FD values of cortical bone between the groups.(p = 1.49). There was no significant difference for FD values of ROIs between the age subgroups (p = 0.05, p = 0.94, p = 0.91). This is the first study to investigate the possible effect of lactation in human jaws. Trabecular rich sites of the mandible were found affected by lactation. Dentists who encounter with lactating patients must be careful during the dental processes such as tooth extraction, implant surgery, and orthodontic treatment.

Bone mineral density, structure, distribution and strength in men with prostate cancer treated with androgen deprivation therapy.

Androgen deprivation therapy (ADT) improves survival in men with advanced prostate cancer (PCa), but has been associated with compromised skeletal health and increased fracture risk. However, limited previous research has investigated determinants of bone strength beyond DXA-derived areal bone mineral density (aBMD) in this population group. The aim of this cross-sectional study was to investigate the effects of ADT in men with PCa on BMD, bone structure, estimates of whole bone strength and cortical bone distribution. A total of 70 ADT-treated men, 52 PCa controls and 70 healthy controls had DXA lumbar spine and proximal femur aBMD and pQCT distal (4%) and proximal (66%) tibia and radius cortical and trabecular volumetric BMD (vBMD), bone structure, strength and cortical bone distribution assessed. Analyses included BMI and/or tibia/radius length as covariates. On average, ADT-treated men had a higher BMI than PCa (P < 0.05) but not healthy controls. ADT-treated men had 7.2-7.8% lower lumbar spine aBMD than PCa (P = 0.037) and healthy controls (P = 0.010), with a trend for a lower total hip aBMD in the ADT-treated men (P = 0.07). At the distal tibia, total bone area was 6.2-7.3% greater in ADT-treated men than both controls (P < 0.01), but total vBMD was 8.4-8.7% lower in ADT-treated men than both controls (P < 0.01). Moreover, bone strength index (BSI) was 10.8% lower relative to healthy controls only (P < 0.05). At the distal radius, ADT-treated men had lower total and trabecular vBMD (10.7-14.8%, P < 0.05) and BSI (23.6-27.5%, P < 0.001) compared to both controls. There were no other differences in bone outcomes at the proximal tibia or radius. In conclusion, ADT treatment for PCa was associated with lower BMD and estimated compressive bone strength, particularly at trabecular skeletal sites (lumbar spine, and distal tibia and radius), compared to controls, but there were no consistent differences in cortical bone structure, distribution or bending strength.

1202-P: Glucose Lowering with an SGLT2I Improves Trabecular Bone but Does Not Correct Bone Brittleness in TallyHo Model of T2D

Higher fracture risk in T2D is attributed to disease specific deficits in micro-structural and material properties of bone. The TallyHO (TH) mouse is a polygenic model of early-onset T2D/obesity analogous to adolescent-onset T2D in humans. Male TH mice commence rapid weight gain at 4 weeks of age and by ∼10-14 weeks insulin resistance progressing to frank hyperglycemia is apparent in ∼75% of mice. Compared to SWR/J control strain, TH mice exhibit lower: 1) bone formation markers; 2) trabecular bone volume; and 3) fracture resistance. Utilizing this model, we examined the impact of glucose-lowering therapy by SGLT2I on diabetic bone. TH male mice (8-10 weeks) with confirmed hyperglycemia and age-matched, nondiabetic, male SWR/J mice were monitored ± canagliflozin (CANA: 125 ppm in chow) for 10 weeks of treatment. At study end, measurements of body weight, BG, HbA1c, serum insulin, and urine calcium/CR were obtained; femurs were harvested for analysis by µCT and three-point bending. At 20 weeks, these severely hyperglycemic TH mice (BG: 687±106 vs. 151±26 mg/dL; p&amp;lt;0.0001) were obese and had longer femurs with increased cortical bone (↑Ct.Ar, Ct.Th; p&amp;lt;0.001 for all) compared to SWR/J. However, trabecular bone was reduced (↓Tb.BV/TV, Conn.D, Tb.N, Tb.TMD; p&amp;lt;0.001 for all) and TH bones were more brittle (↓toughness; p&amp;lt;0.0001). CANA treatment of TH mice significantly lowered BG and HbA1c while increasing weight gain and insulin secretion (p&amp;lt;0.0001 for all). With glycemic improvement, trabecular bone improved (↑Tb.BV/TV, p=0.0002; Tb.Th, p&amp;lt;0.0001; Tb.TMD; p=0.002) compared to untreated TH mice, but toughness was not altered. Unexpectedly, CANA treatment of SWR/J mice lowered toughness of the femur diaphysis. Hypercalciuria was a consistent feature of both groups of TH mice; CANA also increased Ca excretion in SWR/J mice. CANA therapy may protect against elevated fracture risk in T2D with respect to trabecular rich sites but may not be beneficial if bone becomes brittle with duration. Disclosure K.M. Thrailkill: None. R. Bunn: None. S. Uppuganti: None. P.D. Ray: None. I. Popescu: None. E. Kalaitzoglou: None. J. Fowlkes: None. J.S. Nyman: Advisory Panel; Self; ActiveLife Scientific, Inc. Consultant; Self; Sanofi Genzyme. Research Support; Self; ActiveLife Scientific, Inc., Sanofi Genzyme. Funding National Institutes of Health (R21AR070620, R01DK084045); U.S. Department of Veterans Affairs (1l01BX001018)

Paget\u2019s Disease of Long Bones: Microstructural Analyses of Historical Bone Samples

Although Paget’s disease of bone (PDB) is the second most common metabolic bone disease, there is only limited information about the microarchitecture of affected bones. Therefore, the aim of this study was to determine cortical and trabecular bone properties in clinically relevant locations by microcomputed tomography (µCT). Ten femora and ten tibiae affected by Paget’s disease taken from the Natural History Museum Vienna were compared to 13 femora and 10 tibiae of non-affected body donors. Digitization of the cortical and trabecular bone microarchitecture was performed with an X-ray-based µCT scanner. Additionally, semi-quantitative gradings of trabecular and cortical architectural parameters of the femora and the tibiae were generated. Microcomputed tomography images showed changes in the thickness of cortices, cortical porosity, and trabecularization of cortical structures. Moreover, severe disorganization of trabecular structures, trabecular defects, and thickening of (remaining) trabeculae were detected. Numerical cortical analyses showed lower total bone volume (BV) and lower BV in the outer region (66–100%) (− 36%, p = 0.004, and − 50%, p < 0.001, respectively), lower total volume (TV) in the outer region (66–100%) (− 42%, p < 0.001), lower total bone volume fraction (BV/TV) and BV/TV in the outer region (66–100%) (− 23%, and − 12%, p < 0.001, respectively), higher BV and TV in the middle region (33–66%) and higher BV/TV in the inner region (0–33%) (123%, p = 0.011, 147%, p = 0.010, and 33%, p = 0.025, respectively) in Pagetic compared to non-affected bones. Trabecular analyses showed higher BV/TV (96%, p = 0.008) and Tb.Th (43%, p = 0.004) in Pagetic compared to non-affected bones. There is a major and consistent structural alteration of PDB at cortical and trabecular sites in weight-bearing long bones. Our findings are relevant for the differential diagnosis of PDB and for the pathogenesis of associated complications, since the disorder produces abnormalities in the structure that might lead to bone fragility.

Bone accrual in oligo-amenorrheic athletes, eumenorrheic athletes and non-athletes.

Mechanical loading improves bone mineral density (BMD) and strength while decreasing fracture risk. Cross-sectional studies show that exercise advantage is lost in oligo-amenorrheic athletes (OA). Longitudinal studies examining the opposing effects of exercise and hypogonadism on bone are lacking in adolescents/young adults. Evaluate differences in bone accrual over 12 months in OA, eumenorrheic athletes (EA) and non-athletes (NA). We hypothesized that bone accrual would be lower in OA than EA and NA, with differences most pronounced at non-weight bearing trabecular sites. 27 OA, 29 EA, and 22 NA, 14-25 years old, completed 12-months of the prospective study. Athletes were weight-bearing endurance athletes. Subjects were assessed for areal BMD and bone mineral content (BMC) using DXA at the femoral neck, total hip, lumbar spine and whole body (WB). Failure load (a strength estimate) at the distal radius and tibia was assessed using microfinite element analysis of data obtained via high resolution peripheral quantitative computed tomography (HRpQCT). The primary analysis was a comparison of changes in areal BMD, BMC, and failure load across groups over 12-months at the respective sites. Groups did not differ for baseline age, height or BMI. Percent body fat was lower in both OA and EA compared to NA. OA attained menarche later than EA and NA. Over the follow-up period, OA gained 1.9 ± 2.7 kg of weight compared to 0.5 ± 2.4 kg and 0.8 ± 2.3 kg in EA and NA respectively (p = 0.09); 39% of OA resumed menses. Changes in BMD, BMD Z-scores, and tibial failure load over 12-months did not differ among groups. At follow up, EA had higher femoral neck, hip and WB BMD Z-scores than NA, and higher hip BMD Z-scores than OA (p < 0.05) after adjusting for covariates. At follow-up, radial failure load was lower in OA vs. NA, and tibial failure load lower in OA and NA vs. EA (p ≤ 0.04 for all). Change in weight and fat mass were associated with changes in BMD measures at multiple sites. Despite weight gain and menses recovery in many OA during follow-up, residual deficits persist without catch-up raising concerns for suboptimal peak bone mass acquisition.

A multi-method assessment of bone maintenance and loss in an Imperial Roman population: Implications for future studies of age-related bone loss in the past.

One of the hallmarks of contemporary osteoporosis and bone loss is dramatically higher prevalence of loss and fragility in females post-menopause. In contrast, bioarchaeological studies of bone loss have found a greater diversity of age- and sex-related patterns of bone loss in past populations. We argue that the differing findings may relate to the fact that most studies use only a single methodology to quantify bone loss and do not account for the heterogeneity and complexity of bone maintenance across the skeleton and over the life course. We test the hypothesis that bone mass and maintenance in trabecular bone sites versus cortical bone sites will show differing patterns of age-related bone loss, with cortical bone sites showing sex difference in bone loss that are similar to contemporary Western populations, and trabecular bone loss at earlier ages. We investigated this hypothesis in the Imperial Roman population of Velia using three methods: radiogrammetry of the second metacarpal (N = 71), bone histology of ribs (N = 70), and computerized tomography of trabecular bone architecture (N = 47). All three methods were used to explore sex and age differences in patterns of bone loss. The suite of methods utilized reveal differences in the timing of bone loss with age, but all methods found no statistically significant differences in age-related bone loss. We argue that a multi-method approach reduces the influence of confounding factors by building a reconstruction of bone turnover over the life cycle that a limited single-method project cannot provide. The implications of using multiple methods beyond studies of bone loss are also discussed.

Bone Density in Patients With Berardinelli-Seip Congenital Lipodystrophy Is Higher in Trabecular Sites and in Type 2 Patients

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty storing lipid in adipocytes, low body fat, hypoleptinemia, and hyperinsulinemia. We report here laboratory, bone mineral density (BMD), and bone mineral content findings of 21 patients (24.1 ± 8.4 yr old, 14 females, 18 diabetics, 5.3% total body fat) with BSCL. The mean leptin was very low (0.91 ± 0.42 ng/mL), and the mean values of the Z-scores for all studied sites were positive, except for the 33% radius (Z-score −0.5 standard deviation [SD]). Twelve patients (57.1%) had a BMD Z-score higher than +2.5 SD in at least 1 site. There was no significant difference in the Z-scores between males and females. None of type 1 (AGPAT2) patients had Z-scores higher than +2.5 SD, and these patients had a smaller Z-score of BMD total body (0.26 SD vs 1.90 SD, p = 0.022) and of bone mineral content (1.59 SD vs 3.3 SD, p = 0.032) than type 2 (seipin) patients. Insulin, as well as HOMAIR (homeostasis model assessment), correlated positively with the BMD of all sites, except for the 33% radius. Z-Scores on this site (33% radius) were the smallest of all. More than half of our patients with BSCL have BMD Z-scores higher than +2.5 SD on at least 1 site, and this increase is more pronounced in the trabecular sites and in type 2 patients.

Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model

Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation.

Guidelines for Dual Energy X-Ray Absorptiometry Analysis of Trabecular Bone-Rich Regions in Mice: Improved Precision, Accuracy, and Sensitivity for Assessing Longitudinal Bone Changes.

Trabecular bone is frequently studied in osteoporosis research because changes in trabecular bone are the most common cause of osteoporotic fractures. Dual energy X-ray absorptiometry (DXA) analysis specific to trabecular bone-rich regions is crucial to longitudinal osteoporosis research. The purpose of this study is to define a novel method for accurately analyzing trabecular bone-rich regions in mice via DXA. This method will be utilized to analyze scans obtained from the International Space Station in an upcoming study of microgravity-induced bone loss. Thirty 12-week-old BALB/c mice were studied. The novel method was developed by preanalyzing trabecular bone-rich sites in the distal femur, proximal tibia, and lumbar vertebrae via high-resolution X-ray imaging followed by DXA and micro-computed tomography (micro-CT) analyses. The key DXA steps described by the novel method were (1) proper mouse positioning, (2) region of interest (ROI) sizing, and (3) ROI positioning. The precision of the new method was assessed by reliability tests and a 14-week longitudinal study. The bone mineral content (BMC) data from DXA was then compared to the BMC data from micro-CT to assess accuracy. Bone mineral density (BMD) intra-class correlation coefficients of the new method ranging from 0.743 to 0.945 and Levene's test showing that there was significantly lower variances of data generated by new method both verified its consistency. By new method, a Bland-Altman plot displayed good agreement between DXA BMC and micro-CT BMC for all sites and they were strongly correlated at the distal femur and proximal tibia (r=0.846, p<0.01; r=0.879, p<0.01, respectively). The results suggest that the novel method for site-specific analysis of trabecular bone-rich regions in mice via DXA yields more precise, accurate, and repeatable BMD measurements than the conventional method.

Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status.

Sclerostin and parathyroid hormones are strong negative and positive regulators of bone formation, respectively. The anabolic response induced by intermittent (iPTH) treatment is sclerostin status-dependent. However, the interaction between sclerostin and iPTH at the matrix level is unknown. The goal of the current study was to determine if iPTH treatment affects matrix composition and, if so, whether these effects are dependent on sclerostin status. Humeral trabecular and cortical bone sites from 16 week old male wild-type (WT) and sclerostin knockout (KO) mice, which had been treated with vehicle or iPTH from age 10-16 weeks, were examined by micro-computed tomography (µCT) to measure bone volume, backscatter scanning electron microscopy (bSEM) to assess global mineralization, and Fourier transform infrared microspectroscopy (FTIRM) to examine matrix composition (mineral-to-matrix ratio, crystallinity, collagen cross-link ratio, and carbonate substitution). The FTIRM measurements were restricted to the tissue formed during the 6-week treatment period. iPTH treatment led to increased trabecular bone volume (p < 0.001) and this effect was much greater in KO mice than WT mice (interaction effect, p < 0.001). iPTH treatment led to reduced trabecular crystallinity (p = 0.047), increased cortical bone area (p < 0.001), decreased cortical bone crystallinity (p = 0.002) and increased cortical bone collagen cross-linking (p = 0.028) to similar degrees in both WT and KO mice. Compared to WT mice, sclerostin KO mice had higher trabecular and cortical bone mass (p < 0.001) and lower mineral-to-matrix ratio in the trabecular (p = 0.010) and cortical (p = 0.016) compartments. Thus, iPTH-induced changes in bone mass are dependent upon sclerostin status in the trabecular compartment, but not in the cortical compartment. In contrast, iPTH-induced changes in matrix composition are sclerostin-independent in both trabecular and cortical compartments.