Journal of Bone and Mineral Research最新文献

Clinical use of areal bone mineral density (aBMD) to identify fracture risk assumes that aBMD reflects bone mineral content (BMC). Yet, aBMD is calculated using a ratio of BMC and bone area, thus declines in aBMD may reflect a decline in BMC, an increase in bone area, or both. This study identifies groups of individuals defined based upon patterns of change in BMC and bone area across the menopausal transition (MT). The Michigan Bone Health and Metabolism Study is a longitudinal study of women; participants aged 24-50 were recruited in 1992 and followed near annually through 2010. At each visit, a DXA of the femoral neck was assessed. This analysis is based upon data from 97 women with an observed non-surgical final menstrual period (FMP); a dual-energy X-ray absorptiometry (DXA) scan 10 yr before FMP; and at least one post-FMP DXA. Group-based trajectory modeling identified distinct patterns of bone change across the MT. Three trajectory groups were identified for both bone area and BMC. For bone area, 27.8% of women showed initial steep increases in bone area followed by a continued increase around the FMP ("Highest Bone Area" group). For BMC, 26% of women experienced a substantial BMC decline after the FMP ("Fastest BMC Decline" group). Women in the both the "Highest Bone Area" and "Fastest BMC Decline" groups experienced the greatest aBMD decline (mean 12.8% decrease, SD 8.1%) despite higher baseline aBMD. Consideration of BMC and bone area changes across the lifecourse represents a novel approach to understanding overall bone health, and may elucidate an at-risk group not identified on aBMD alone. This information may be highly informative in identifying women at greatest risk for low aBMD and future risk for fracture.

High gastrin levels may help explain the association between several conditions and osteoporosis, such as pernicious anaemia, the use of proton pump inhibitors, and atrophic gastritis. This study aimed to determine whether administering a gastrin receptor antagonist (GRA) to older women would lower their bone turnover markers and, therefore, be a suitable preventive measure for osteoporosis. We conducted a randomised, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of an oral GRA (netazepide) 100 mg administered daily for 90 days in postmenopausal women. Our primary endpoint was the change in the bone turnover marker (BTM) plasma CTX (automated immunoassay analyser) at days 0, 7, 28, 56, and 90. We also measured other BTMs, and gastrin and group I pepsinogens (ELISA assays). We studied the effect of the drug on the log-transformed baseline scaled ratio for bone turnover marker and gastric markers using mixed-model ANOVA for the fixed effects of treatment, time, and the treatment-by-time interaction, with the baseline value included as a covariate. We studied 99 women, with a mean age of 60 years and BMD T- scores for the spine and total hip of -0.96 and -0.09, respectively. We found that gastrin increased by 90% in response to GRA as early as 7 days (p-value for treatment 0.0008), and group I pepsinogens decreased by 15% as early as 7 days (p-value 0.0002). There was no significant change in plasma CTX. A high percentage of women (81/99) completed the study, and the GRA was well tolerated. GRA had the expected effects on the gastric markers with an increase in gastrin and a decrease in group I pepsinogens. However, the absence of any change in the bone resorption marker plasma CTX was a bit surprising. Based on this study it appears that short term gastrin receptor antagonism is unlikely to be a successful strategy in the prevention of osteoporosis. However, this a preliminary exploration of a novel hypothesis and larger studies might be needed.

Treatment decisions are being made for a 74 year-old woman with multiple and recent vertebral fractures. Romosozumab therapy is considered because of superior efficacy compared to other osteoporosis therapies. However, because of her age, well controlled hypertension and mild hyperlipidemia, she is, according to a risk calculator, at high risk for cardiovascular (CV) disease. Romosozumab is contraindicated for patients at very high risk of CV disease, and clinicians are advised to consider the skeletal benefits vs potential CV risks in patients with CV risk factors. The background information leading to that contraindication and recent real-world evidence about the relationship between romosozumab and CV risk is reviewed to aid in the discussion with the patient and her primary care provider.

Current fracture risk assessment does not directly include fall probability, despite most hip fractures resulting from falls. Additionally, the role of trochanteric soft tissue thickness (TST) in hip fracture risk remains unclear. This study aimed to develop a subject-specific fall risk tool and test whether incorporating fall probability and TST improves hip fracture prediction beyond FRAX alone in older adults from the AGES-Reykjavik study. Baseline data from 3242 individuals (58% women) were used to predict repeated falls (≥2 in 12 months) at follow-up (~5 years later) via multivariate logistic regression, considering age, sex, fall history, neuromuscular function, dynamic balance, and medication use. In a case-cohort study (698 hip fractures, 1348 controls; median follow-up 10 years), Cox proportional hazards models assessed hip fracture risk. We compared the predictive value of fall probability and TST combined with FRAX against FRAX alone using time-dependent AUC at 5-, 10-, and 16-year follow-up. At follow-up, 295 individuals had ≥2 falls in the past year. The best model for future falls included a timed up-and-go test, fall history, and grip strength. The probability of falling predicted incident hip fracture and improved hip fracture prediction beyond FRAX, in both men and women. The improved predictive value of fall risk was greater among men than women (e.g. AUC for predicting 10 yrs hip fracture risk, 0.83 (95%CI 0.79-0.87) in men vs 0.75 (95%CI 0.72-0.78) in women). Lower TST was linked to higher hip fracture risk in women but not men. However, adding TST to a model with fall probability and FRAX among women did not enhance time-dependent AUC (p>0.10). In conclusion, fall probability significantly improves hip fracture prediction beyond FRAX, particularly in men. Thus, subject-specific fall risk assessment may enhance clinical evaluation of hip fracture risk in older adults.

Background: Early-onset osteoporosis (EOOP) is a rare form of primary osteoporosis defined by major skeletal fractures or low bone mineral density (BMD) that occurs in early age. However, the characteristics of the extracellular matrix that may contribute to bone fragility are unknown.

Purpose: We explored the microarchitecture and bone matrix composition in transiliac bone biopsies (BBs) obtained from adults with EOOP.

Methods: We compared EOOP BBs to historical control BBs. Microarchitecture was measured by μ-CT and bone matrix composition by Raman microspectroscopy and FTIR spectroscopy. Mechanical response of the bone matrix was investigated by nanoindentation. The contribution of each parameter was assessed by principal component analysis (PCA).

Results: We compared 18 BBs for EOOP patients (mean [SD] age 34 [8] years, lumbar-spine BMD Z-score -2.05 [1.04]) to 19 BBs for age-matched healthy individuals. Patients had vertebral fractures only (n=7), peripheral fracture only (n=6) and both vertebral and peripheral fractures (n=3). EOOP and controls had similar bone volume (bone volume/total volume, p=0.741). As compared with controls, EOOP BBs showed lower trabecular separation (p=0.026) and higher trabecular connectivity density (p<0.001); cortical thickness was lower in EOOP BBs (p<0.01). Also, GAG/Amide III and hydroxyproline/proline ratios as well as accumulation of AGEs were greater in EOOP than controls (all p<0.0001). Moreover, tissue mineralization was lower in EOOP than controls, as shown by v1PO4/CH2 ratio, mineral maturity crystallinity and crystal size index (all p<0.005). Hardness, indentation modulus and maximum load were all altered in EOOP. PCA revealed greater contribution of both the organic and mineral matrix phase at the trabecular and cortical EOOP bone rather than bone microarchitecture.

Conclusion: The matrix composition of bone showed greater damage of the organic matrix phase and reduced mineralization in EOOP patients than controls, which may explain the high risk of fracture in EOOP patients and may differentiate EOOP from other bone diseases.

The Fracture Risk Assessment Tool (FRAX) is widely used in osteoporosis management, yet its performance across diverse racial, ethnic, and genetic populations remains uncertain. We evaluated the accuracy of FRAX in predicting fracture risk, with and without bone mineral density (BMD) measurements, among 27,512 postmenopausal women aged 50 to 79 years participating in the Women's Health Initiative (WHI) with 10 years of follow-up. FRAX-predicted fracture risks were compared to observed outcomes, stratified by race/ethnicity and genetic risk categories derived from a Genome-Wide Polygenic Score (GPS), calculated using 103,155 genetic variants via the LDpred algorithm and UK Biobank GWAS data. FRAX with BMD information substantially overestimated fracture risk for African American women by 82% (hazard ratio [HR], 0.18; 95% CI, 0.10-0.36) and Hispanic women by 48% (HR, 0.52; 95% CI, 0.31-0.87), compared with non-Hispanic White women (both P < .001). Conversely, FRAX with BMD information significantly underestimated fracture risk in women with the highest genetic risk (top 5%; HR, 2.15; 95% CI, 1.22-3.68; P < .001), compared with the low GPS reference group. Calibration analyses revealed systematic inaccuracies, highlighting racial disparities in overestimating fracture risk and genetic disparities in underestimating fracture risk predictions. Sensitivity analyses confirmed these findings persisted regardless of estrogen use. Our results underscore critical limitations of FRAX, suggesting that integrating genetic risk profiling and implementing race-specific recalibrations can substantially improve fracture risk prediction accuracy, promote equity in osteoporosis care, and support personalized clinical decision-making.

The gut microbiome is associated with bone mass acquisition, yet evidence in childhood remains limited. Given that lower peak bone mass predicts osteoporosis in later life, understanding early influences is important. This analysis explores the association between the early life gut microbiome and bone health in later childhood. Data were obtained from 700 children recruited in pregnancy and followed prospectively within the Copenhagen Prospective Studies on Asthma in Childhood2010 cohort, a population-based mother-child cohort. The infant gut microbiome was measured at 1 wk (n = 445), 1 mo (n = 492), 1 yr (n = 508), 4 yr (n = 350), and 6 yr (n = 327) of age by 16S ribosomal ribonucleic acid amplicon sequencing targeting the fourth variable region. Total body less head BMD and area-adjusted BMC were measured by DXA at 6 yr of age. Associations were investigated by multiple linear regression, permutational analysis of variance, differential abundance analysis, and Random Forest machine learning. There were few associations between the early-life gut microbiome and bone health outcomes at age 6. We found negative associations between alpha (within-sample) diversity and area-adjusted BMC at 4 yr. Beta (between-sample) diversity of the gut microbiome at 6 yr was associated with concurrent BMD. Escherichia-Shigella abundance at 1 mo of age was associated with lower BMD. Sutterella abundance at 1 yr was associated with lower BMD and area-adjusted BMC at 6 yr. There were no other associations between the gut microbiome and bone outcome measures at any time point. In a well-powered unselected cohort study with longitudinal sampling of the gut microbiome, there were some suggestive but no consistent associations between the early gut microbiome and bone health outcomes at 6 yr of age.

We aimed to investigate associations between diabetes mellitus and incident fracture, stratified by diabetes type (1 or 2), disease duration and microvascular complications of diabetes. This prospective cohort analysis used data from the UK Biobank, a large population-based cohort of participants recruited 2006-2010 at age 40-69 yr. The exposure was type 1 or type 2 diabetes at baseline, with the outcome of first incident osteoporotic fracture. Poisson regression was used to calculate incidence rate ratios (IRRs) for osteoporotic fracture to investigate prospective relationships between diabetes type 1 or 2 and fracture risk independent of traditional clinical risk factors, estimated BMD by heel ultrasound (eBMD), adiposity, and C-reactive protein (CRP). The role of diabetic microvascular complications and associations between diabetes duration and fracture risk were studied. There were 498 949 participants (271 882 women, mean age 56 yr; 227 067 men, 57 yr). In fully adjusted models, type 1 and 2 diabetes were associated with increased fracture risk [type 1; IRR: 2.93 (95% CI: 2.37, 3.62); type 2: 1.25 (1.14, 1.38)], similar by sex. The magnitude of risk associated with type 2 diabetes increased with the duration of disease. Increasing number of microvascular complications was associated with greater fracture risk [any vs no complications, IRR 2.03 (1.57, 2.62)]. Diabetes is associated with increased risk of fracture (magnitude of effect greater in type 1 than type 2 diabetes). Associations were partly independent of traditional risk factors, adiposity, eBMD, and CRP. Type 2 diabetes disease duration and the presence of microvascular complications in both types were dose-dependent risk factors for fracture.