Bone Mineral Density of the 1/3 Radius Refines Osteoporosis Diagnosis,Correlates With Prevalent Fractures,and Enhances Fracture Risk Estimates

ObjectiveTo investigate the added value of 1/3 radius (1/3R) for the diagnosis of osteoporosis by spine and hip sites and its correlation with prevalent fractures and predicted fracture risk.MethodsFracture Risk Assessment Tool (FRAX) scores for hip and major osteoporotic fractures (MOF) with/without trabecular bone score were considered proxy for fracture risk. The contribution of 1/3R to risk prediction was depicted via linear regression models with FRAX score as the dependent variable—first only with central and then with radius T-score as an additional covariate. Significance of change in the explained variance was compared by F-test.ResultsThe study included 1453 patients, 86% women, aged 66 ± 10 years. A total of 32% (n = 471) were osteoporotic by spine/hip and 8% (n = 115) by radius only, constituting a 24.4% increase in the number of subjects defined as osteoporotic (n = 586, 40%). Prior fracture prevalence was similar among patients with osteoporosis by spine/hip (17.4%) and radius only (19.1%) (P = .77).FRAX prediction by a regression model using spine/hip T-score yielded explained variance of 51.8% and 49.9% for MOF and 39.8% and 36.4% for hip (with/without trabecular bone score adjustment, respectively). The contribution of 1/3R was statistically significant (P < .001) and slightly increased the explained variance to 52.3% and 50.4% for MOF and 40.9% and 37.4% for hip, respectively.ConclusionReclassification of BMD results according to radius measurements results in higher diagnostic output. Prior fractures were equally prevalent among patients with radius-only and classic-site osteoporosis. FRAX tool performance slightly improved by incorporating radius BMD. Whether this approach may lead to a better fracture prediction warrants further prospective evaluation.     

Parathyroid hormone (1-34) regulates integrin expression in vivo in rat osteoblasts.

Intermittent administration of parathyroid hormone (PTH) activates new sites of bone formation by stimulating osteoblast differentiation and function resulting in an increase in bone mass. Because integrins have been shown to play a crucial role in osteoblast differentiation and bone formation, in the present study, we evaluated whether human PTH (1-34) upon administration to rats, influenced integrin expression in osteoblastic cells isolated from the metaphysis and the diaphysis of rat long bones. Initial immunohistochemical evaluation of bone sections demonstrated that the osteoblasts expressed at least alphav, alpha2, alpha3, and alpha5beta1 integrins. Immunocolocalization studies for integrins and vinculin established that alphav, alpha2, and alpha5beta1, but not alpha3 integrins were present in the focal adhesion sites of osteoblasts attached to FN coated surfaces. Osteoprogenitor cells isolated from metaphyseal (but not diaphyseal) marrow of rats injected with intermittent PTH (1-34) exhibited greater alphav and reduced alpha2 levels, with no apparent changes in alpha3, and alpha5beta1 integrin levels, as assessed by immunohistochemistry, Northern, and Western blot analyses. However, these changes were not observed on the same cells treated with PTH in vitro. These observations suggest that integrin modulation by PTH is likely to be indirect and that selective phenotypic expression of integrin subtypes is part of the cascade of events that lead to PTH (1-34) mediated osteoblast differentiation.     

Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression

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Discovery of potential sclerostin inhibitors from plants with loop2 region of sclerostin inhibition by interacting with residues outside Pro-Asn-Ala-Ile-Gly motif

Abstract

Sclerostin, an antagonist of the Wnt/β-catenin signaling pathway, was discovered as a potential therapeutic target for stimulating bone formation in osteoporosis. In this study, molecular docking was employed to predict the binding of 29 herbal compounds, which were reported as bone formation stimulators, to the loop2 region of sclerostin. Then, the 50 ns molecular dynamics (MD) simulation of the complexes between sclerostin and the top 10 hits obtained from molecular docking were carried out. Root mean square deviations (RMSDs) analysis of MD trajectories pointed out that all ligands-complexes remain stable throughout the duration of MD simulations. In addition, the molecular mechanics/generalized born surface area (MM/GBSA) binding free energy and energy decomposition analyses were determined. The results here suggested that baicalin is the most promising inhibitor of sclerostin. Interestingly, baicalin binds to sclerostin via the hydrophobic interaction with the amino acid residues on loop2 region but outside the Pro-Asn-Ala-Ile-Gly (PNAIG) motif, particularly the Arg-Gly-Lys-Trp-Trp-Arg (RGKWWR) motif. This finding could be a novel strategy for developing new sclerostin inhibitors in the future.

Communicated by Ramaswamy H. Sarma     

Sodium fluoride induces changes on proteoglycans synthesized by avian osteoblasts in culture.

The results reported here show that sodium fluoride (NaF) at low concentration (up to 10 microM) increased four times the proliferation rate of avian osteoblasts in culture. Also NaF increases, in a concentration dependent manner, 10 times the alkaline phosphatase activity. However, NaF decreased the incorporation of 35S-sulfate into proteoglycans (PGs) synthesized by osteoblasts (60-65%). Also, we observed that PGs synthesized in the presence of NaF (50 microM) exhibited a higher sensitivity to chondroitinase ABC than PGs synthesized by osteoblasts in the absence of NaF, suggesting an increase in the chondroitin sulfate moieties associated with the core protein of PGs. The modification of glycosaminoglycan (GAG) chains composition was evidenced also by change in the mean charge density of the PGs observed by ion exchange chromatography. Since the ratio of 35SO4/3H-glucosamine incorporated into PGs was similar in the presence and in the absence of NaF (8.2 and 7, respectively), it is not possible to explain differences in mean charge density by changes in the sulfation extent of PGs. No differences were observed in the hydrodynamic size of PG synthesized in the presence of NaF, nor in the hydrodynamic size of the GAG chains. According to these results, we speculate that the stimulatory effect of fluoride on bone mineralization may be mediated, in part, by the changes in the rate of synthesis or in the structural characteristics of bone PGs. The changes produced by fluoride in PGs suggest that these molecules play an inhibitory role in the bone mineralization process.     

Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow

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Modified Tetrachrome Method for Osteoid and Defectively Mineralized Bone in Paraffin Sections

A new modification of the tetrachrome method for bone osteoid in paraffin sections has been designed. The modified tetrachrome method suitable for routine use in any histology laboratory retains the simplicity of the original method and gives good results on the freshly fixed, decalcified, paraffin embedded material. Osteoid tissue is stained deep blue and normally mineralized bone is stained red. Defectively mineralized bone stains pale blue or pink and the cellular population is clearly identifiable. The ability to distinguish the osteoid tissue from mineralized bone and connective tissue and cartilage makes diagnosis of osteomalacia or osteoid producing tumors or assessment of ossification process straightforward, without the need for un-decalcified sections. By displaying simultaneously irregularities in the mineralized matrix and morphology of bone cells, the method also permits the diagnosis of conditions recently described in patients with osteoporotic fractures, such as osteocytic degeneration and bone tissue defects.     

Radiogrammetry of the humerus: an examination of indices

Humeral cortical thickness is a simple and convenient method of assessing the bone mineralisation status of anthropological remains. The present study was devised to assess the comparative values of indices originally devised for other bones. The smoothest curve in response to increasing age was seen with the CCT, and this value also showed a relatively narrow range in young subjects. As none of the indices were found to have an advantage over the CCT in assessing age changes, we recommend measurement of the humeral CCT for assessment of bone mineralization status of anthropological remains.     

Patterns of Osteoporosis Medications Selection After Drug Holiday or Continued Therapy: A Real-World Experience

ObjectivePublished literature on physicians’ preferences and sequential treatment patterns of osteoporosis therapy is scarce.MethodsA retrospective cohort study of patients who received bisphosphonates, denosumab, and/or raloxifene for at least 3 consecutive years or teriparatide for at least 18 months for osteoporosis. Data collection spanned 10 years, from October 2007 to September 2016, at a tertiary care center in the United States.ResultsIn total, 12 885 patients were identified on the basis of receiving at least 1 treatment at any point in time; 1814 patients were randomly reviewed, and 274 patients met the inclusion criteria. The mean age was 68.8 ± 10.7 years, and women represented 90.9% of all the cases. Primary care physicians and rheumatologists constituted 65.7% and 22.6% of the prescribers, respectively. Before instituting a drug holiday, alendronate was the most common initial treatment (percentage, mean duration ± standard deviation in years: 69%, 5.4 ± 2.4 years) followed by ibandronate (9.5%, 4.9 ± 2.1 years) and raloxifene (9.1%, 5.2 ± 1.6 years). Denosumab was the most common second course of treatment, accounting for 29.3% of 82 patients who were subsequently prescribed another therapy, followed by alendronate (24.4%) and zoledronate (20.7%). Among patients who were placed on a drug holiday and eventually restarted on osteoporosis therapy, denosumab was the most common treatment instituted (n = 21), accounting for 40% of the total patients, followed by alendronate (32%) and zoledronate (16%). There was a progressive decline in osteoporosis therapy over the duration of the study.ConclusionAlendronate was the most common initial therapy. Denosumab was the most common second course of treatment prescribed.     

Bone Fragility in Hereditary Connective Tissue Disorders: A Systematic Review and Meta-Analysis

ObjectiveTo investigate bone fragility in patients with hereditary connective tissue disorders (HCTD), including Ehlers-Danlos syndrome (EDS), Marfan’s syndrome (MFS) and Loeys-Dietz syndrome (LDS).MethodsFrom inception to June 2022, potentially eligible studies were identified in the Medline and EMBASE databases using search strategy that included terms for “HCTD”, “Fracture” and “Osteoporosis”. Eligible studies must consist of a group of patients with HCTD and report prevalence/incidence of fracture/osteoporosis in their participants, with or without comparison with healthy individuals. Point estimates with standard errors were obtained from each study and combined using the generic inverse variance method.ResultsAmong the 4206 articles identified, 19 studies were included. The pooled prevalence of fracture in EDS, MFS, and LDS were 44% (95% confidence interval [CI], 25% to 65%, I² 88%), 17% (95% CI, 11% to 26%, I² 68%), 69% (95% CI, 47% to 85%, I² 83%), respectively. The pooled prevalence of osteoporosis in EDS was 17% (95% CI, 8% to 34%, I² 96%). EDS was associated with fracture [pooled odds ratio {OR} 4.90 (95% CI, 1.49 – 16.08, I² 86%)], but not osteoporosis [pooled OR 1.34 (95% CI, 0.28 – 6.36, I² 87%). One study reported a 5% (95% CI, 3% to 8%) prevalence of osteoporosis in MFS, which was associated with fracture [incidence rate ratio 1.35 (95% CI, 1.18 – 1.55)] and osteoporosis [subhazard ratio 3.97 (95% CI, 2.53 – 6.25)].ConclusionEDS was associated with fracture, which could be independent of osteoporosis status. MFS had a milder degree of increased risk of fracture and osteoporosis. Despite no data from cohort studies, there was a significantly higher rate of fracture in LDS.