Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial.

BACKGROUND: Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline-recommended mineralocorticoid receptor antagonist (MRA) treatment. OBJECTIVES: To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well-being. METHODS: A total of 41 patients with PA on a stable antihypertensive regimen-including MRA-followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well-being by validated questionnaires. RESULTS: Dietary salt intake significantly decreased from 9.1 to 5.2 g/d at the end of the study. In parallel, systolic (130 vs. 121 mm Hg) and diastolic blood pressure (BP) (84 vs. 81 mm Hg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4 g/d). Salt restriction entailed a significant weight loss of 1.4 kg, improvement in pulse pressure (46 vs. 40 mm Hg) and normalization of depressive symptoms (PHQD scale, p < 0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin-angiotensin-aldosterone-system (RAAS) blockers were independently associated with BP reduction. CONCLUSION: A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk.

Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added. Titration with excess equivalents of donor is used to determine the binding coefficient, ln(Keq ). Over 100 titrations were performed for a variety of biologically relevant compounds. This data enabled development a multiple linear regression model that is capable of predicting 95 % of ln(Keq ) values within 1 unit, allowing for the estimation of hydrogen bonding affinity from a single measurement. To show the effectiveness of the single point measurements, hydrogen bond strengths were obtained for a set of carboxylic acid bioisosteres. The values from the single point measurements were validated with full titrations.

Relationship between Atomic Force Microscopy and Centrifugation Measurements for Dust Fractions Implicated in Solar Panel Soiling.

This work tests the reliability of a simple, rapid centrifugal technique to estimate the removal force necessary to detach common airborne particles from the surface of a photovoltaic panel. Previously, we have used atomic force microscopy (AFM) to obtain the surface-particle adhesion force for different pollutant types that generally contribute to panel soiling. To overcome the limitations of AFM, the same particles were studied as a population using an ultracentrifuge. Detachment was quantified at speeds between 1000 and 10,000 rpm, both as individual particle counts and as projected surface area coverage. The force of centrifugal detachment for each particle type followed a similar trend as the adhesion force given by AFM. Organic and carbon-based materials needed higher centrifugal speeds to be removed, suggesting a stronger attachment to the surface. However, the technique also highlighted the importance of particle diameter, aggregates, and individual particle characteristics, which should be considered when predicting the probability of detachment. We have identified the relationship between AFM-derived adhesion and centrifugal detachment forces using model particle fractions of materials commonly found to soil solar panels, demonstrating the utility in using the more easily applied to centrifugal method to obtain information that can be calibrated to direct measurements of the force of particle attachment. This technique could be applied effectively in further studies on the influence of dust composition on long-term soiling and its reversibility.

Effect of Dust Composition on the Reversibility of Photovoltaic Panel Soiling.

Eight types of common airborne particles were used to investigate whether the composition of dust influences its soiling potential on photovoltaic panels. Chosen model particles were roughly spherical, 10-30 µm in diameter to minimize the differences in size and shape. While the predicted van der Waals forces were lower than the adhesion forces measured with an atomic force microscope (AFM), the adhesion potential as a function of surface energy did follow the theoretical pattern. The organic and carbon-based materials, namely the pollen grains and spherical graphite, exhibited a significantly larger adhesion force to the glass surface, indicating high attachment efficiency. The developed generalized linear model confirmed that the type of material should be included in soiling models as a variable, as it provides information on the likelihood of particles sticking to and remaining on the surface. The adhesion force between soiled particles and the surface can be estimated based on the local ambient dust composition to predict the short-term fate of the depositing particles and develop cleaning schedules and techniques accordingly. The results also highlight the need to study dust composition to understand long-term soiling, where chemical characteristics and changing environmental conditions may lead to cementation.

Design and Synthesis of 56 Shape-Diverse 3D Fragments.

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol-1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.

Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate.

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.

Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries.

Fragment-based drug discovery (FBDD) has grown into a well-established approach in the pursuit of new therapeutics. Key to the success of FBDD is the low molecular complexity of the initial hits and this has resulted in fragment libraries that mainly contain compounds with a two-dimensional (2D) shape. In an effort to increase the chemical diversity and explore the impact of increased molecular complexity on the hit rate of fragment library screening, several academic and industrial groups have designed and synthesised novel fragments with a three-dimensional (3D) shape. This review provides an overview of 25 synthetic 3D fragment libraries from the recent literature. We calculate and compare physicochemical properties and descriptors that are typically used to measure molecular three-dimensionality such as fraction sp3 (Fsp3), plane of best fit (PBF) scores and principal moment of inertia (PMI) plots. Although the libraries vary widely in structure and properties, some key common features can be identified which may have utility in designing the next generation of 3D fragment libraries.

Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates.

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed excellent biological activity and specificity.

Study Protocol: A randomized controlled trial evaluating the effect of family-based behavioral treatment of childhood and adolescent obesity-The FABO-study.

BACKGROUND: The purpose of the FABO-study is to evaluate the effect of family-based behavioral social facilitation treatment (FBSFT), designed to target children's family and social support networks to enhance weight loss outcomes, compared to the standard treatment (treatment as usual, TAU) given to children and adolescents with obesity in a routine clinical practice. METHODS: Randomized controlled trial (RCT), in which families (n = 120) are recruited from the children and adolescents (ages 6-18 years) referred to the Obesity Outpatient Clinic (OOC), Haukeland University Hospital, Norway. Criteria for admission to the OOC are BMI above the International Obesity Task Force (IOTF) cut-off ≥ 35, or IOTF ≥ 30 with obesity related co-morbidity. Families are randomized to receive FBSFT immediately or following one year of TAU. All participants receive a multidisciplinary assessment. For TAU this assessment results in a plan and a contract for chancing specific lifestyle behaviors. Thereafter each family participates in monthly counselling sessions with their primary health care nurse to work on implementing these goals, including measuring their weight change, and also meet every third month for sessions at the OOC. In FBSFT, following assessment, families participate in 17 weekly sessions at the OOC, in which each family works on changing lifestyle behaviors using a structured cognitive-behavioral, socio-ecological approach targeting both parents and children with strategies for behavioral maintenance and sustainable weight change. Outcome variables include body mass index (BMI; kg/m2), BMI standard deviation score (SDS) and percentage above the IOTF definition of overweight, waist-circumference, body composition (bioelectric impedance (BIA) and dual-X-ray-absorptiometry (DXA)), blood tests, blood pressure, activity/inactivity and sleep pattern (measured by accelerometer), as well as questionnaires measuring depression, general psychological symptomatology, self-esteem, disturbed eating and eating disorder symptoms. Finally, barriers to treatment and parenting styles are measured via questionnaires. DISCUSSION: This is the first systematic application of FBSFT in the treatment of obesity among youth in Norway. The study gives an opportunity to evaluate the effect of FBSFT implemented in routine clinical practice across a range of youth with severe obesity. TRIAL REGISTRATION: ClinicalTrails.gov NCT02687516 . Registered 16th of February, 2016.

Mental health and psychosocial support in humanitarian emergencies.

Armed conflicts and natural disasters impact negatively on the mental health and well-being of affected populations in the short- and long-term and affect the care of people with pre-existing mental health conditions. This paper outlines specific actions for mental health and psychosocial support by the health sector in the preparedness, response and recovery phases of emergencies. Broad recommendations for ministries of health are to: (1) embed mental health and psychosocial support in national health and emergency preparedness plans; (2) put in place national guidelines, standards and supporting tools for the provision of mental health and psychosocial support during emergencies; (3) strengthen the capacity of health professionals to identify and manage priority mental disorders during emergencies; and (4) utilize opportunities generated by the emergency response to contribute to development of sustainable mental health-care services.

Association between urinary C-telopeptide fragments of type II collagen and knee structure in middle-aged women without clinical knee disease.

OBJECTIVE: There is evidence for an association between levels of urinary C-telopeptide fragments of type II collagen (uCTX-II) and risk of knee osteoarthritis (OA). The aim of this cohort study was to examine the association between uCTX-II levels and knee cartilage and bone changes in middle-aged women without clinical knee disease. DESIGN: 140 women, aged 40-67 years, with no significant knee pain, knee injury or any forms of arthritis, underwent knee magnetic resonance imaging (MRI) at baseline and 2 years later. Cartilage volume, cartilage defects, tibial plateau bone area and bone marrow lesions (BMLs) were measured using validated methods. Baseline uCTX-II was measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: For every one unit (natural logarithm transformed) increase in baseline uCTX-II level, there was an increase in the prevalence of medial tibiofemoral cartilage defects (Odds ratio (OR) 4.36, 95% confidence interval (CI) 1.58-12.04), medial (80.2 mm(2), 95% CI 9.3-151.1) and lateral (86.0 mm(2), 95% CI 33.3-138.7) tibial plateau bone area, and the prevalence of lateral tibiofemoral BMLs (OR 10.62, 95% CI 1.82-61.85). Baseline uCTX-II levels were not significantly associated with baseline tibial cartilage volume or changes in knee cartilage volume or defects or bone area over 2 years, although there was a trend for the deterioration of medial tibiofemoral BMLs (P = 0.06). CONCLUSION: In middle-aged women without clinical knee disease, higher uCTX-II levels were associated with early detrimental structural changes at the knee (cartilage defects, tibial bone expansion and BMLs) at baseline but not over 2 years. Further work will be needed to determine its sensitivity to change and whether it predicts disease progression over longer time periods.

Multifaceted metabolic role of infections in the tumor microenvironment.

The impact of bacteria and viruses on tumor growth has long been recognized. In recent decades, interest in the role of microorganisms in the tumor microenvironment (TME) has expanded. Infections induce metabolic reprogramming and influence immune responses within the TME that may either support proliferation and metastasis or limit tumor growth. The natural ability to infect cells and alter the TME is also utilized for cancer detection and treatment. In this review, we discuss recent discoveries about the mechanisms of bacteria and viruses affecting TME, as well as strategies in cancer therapy focusing on metabolic alterations. Infections with engineered bacteria and viruses represent promising therapeutic approaches to develop novel and more effective therapies to constrain tumor growth.

The Landscape of Androgens in Cushing's Syndrome.

Hyperandrogenemia in patients with Cushing's syndrome (CS) presents a diagnostic pitfall due to its rare occurrence and overlapping symptoms with more common conditions like polycystic ovary syndrome (PCOS). This review explores the significance of androgen dysregulation in CS, focusing on both classical and 11-oxygenated androgens. While classical androgens contribute to hyperandrogenism in CS, their levels alone do not fully account for clinical symptoms. Recent research highlights the overlooked role of 11oxC19 androgens, particularly 11OHA4 and 11KT, in driving hyperandrogenic manifestations across all CS subtypes. These adrenal-specific and highly potent androgens offer stable expression throughout the lifespan of a woman, serving as valuable diagnostic biomarkers. Understanding their prominence not only aids in subtype differentiation but also provides insights into the complex nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches and improve clinical management strategies for patients with CS.

Total Syntheses of Clausenawallines A and E.

The first total syntheses of glycoborinine, clausenawalline A, and clausenawalline E were achieved. The key step employed a vanadium-catalyzed oxidative coupling of two hydroxycarbazole monomers. High-throughput experimentation was used to identify conditions favoring selective heterocoupling of these monomers that possess similar redox potentials. A combination of a vanadium catalyst and 4-acetamido-TEMPO gives rise to greatly enhanced cross selectivity relative to the vanadium catalyst alone. Conditions to selectively form homodimer clausenawalline A or heterodimer clausenawalline E as the major product were found.

Moderate salt restriction in primary aldosteronism improves bone metabolism through attenuation of urinary calcium and phosphate losses.

Accumulating evidence links osteoporosis and dietary salt consumption. Primary aldosteronism (PA) is a model disease with increased dietary salt intake and constitutes an independent risk factor for osteoporosis. We, thus, assessed whether a short-term moderate reduction in salt intake in PA results in detectable osteoanabolic effects. Forty-one patients with PA on stable mineralocorticoid receptor antagonist therapy were subjected to a 12-week salt restriction. Serum and urinary electrolytes, markers of bone turnover, and a 15 steroids plasma profile were registered. After 12 weeks, urinary calcium and phosphate decreased, while plasma testosterone, serum phosphate, and bone alkaline phosphatase (BAP) all increased significantly. Longitudinal changes in BAP were independently correlated with changes in serum phosphate, parathyroid hormone, and urinary calcium in multivariate analysis. Salt restriction in PA limits urinary calcium and phosphate losses and may confer favorable osteoanabolic effects. Our findings suggest that salt restriction should be considered in patients with PA to improve bone health.

The RNA helicase HrpA rescues collided ribosomes in E. coli.

Although many antibiotics inhibit bacterial ribosomes, loss of known factors that rescue stalled ribosomes does not lead to robust antibiotic sensitivity in E. coli, suggesting the existence of additional mechanisms. Here, we show that the RNA helicase HrpA rescues stalled ribosomes in E. coli. Acting selectively on ribosomes that have collided, HrpA uses ATP hydrolysis to split stalled ribosomes into subunits. Cryo-EM structures reveal how HrpA simultaneously binds to two collided ribosomes, explaining its selectivity, and how its helicase module engages downstream mRNA, such that by exerting a pulling force on the mRNA, it would destabilize the stalled ribosome. These studies show that ribosome splitting is a conserved mechanism that allows proteobacteria to tolerate ribosome-targeting antibiotics.

Frequency of stress dosing and adrenal crisis in paediatric and adult patients with congenital adrenal hyperplasia: a prospective study.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents. DESIGN: Prospective, observational study. METHODS: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed. RESULTS: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026). CONCLUSION: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.

Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors.

Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery.  However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B  (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau  (tau K18M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads.

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping.

BACKGROUND: Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS: We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS: Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11ß-OH-An + 11ß-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION: GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING: The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Aromatase inhibitors associated with knee subchondral bone expansion without cartilage loss.

BACKGROUND: The profound estrogen depletion caused by aromatase inhibitors (AIs) is associated with musculoskeletal symptoms, but the underlying pathophysiology remains unclear. OBJECTIVE: To assess the effects of AI therapy on structural changes in knee cartilage and subchondral bone over 2 years in postmenopausal women. Setting and participants Thirty women with breast cancer, mean age 58.5 (standard deviation ± 5.6) years and 62 healthy controls, mean age 56.5 (standard deviation ± 4.6) years. MAIN OUTCOME MEASURES: Annualized changes in tibial cartilage volume and subchondral bone area, and worsening of tibiofemoral cartilage defects from paired knee magnetic resonance imaging 2 years apart were compared between the two groups. RESULTS: The AI-treated women had significantly greater expansion of the tibial plateau than the control group. The mean annualized differences, after adjusting for age, body mass index and baseline bone area, were 22.1 mm(2) (95% confidence interval (CI) 7.6-36.6, p = 0.003) for the medial tibial plateau and 19.1 mm(2) (95% CI 9.6-28.5, p < 0.001) for the lateral tibial plateau. The annual change in tibial cartilage volume and the worsening of cartilage defects did not differ between women taking AI therapy and controls. CONCLUSIONS: AI therapy is associated with knee subchondral bone expansion knee with no effect on knee cartilage in postmenopausal women without pre-existing joint symptoms. This suggests the effect of severe estrogen depletion on knee is on bone, with the tibial bone expansion most likely a response to mechanical load in the setting of bone loss. Whether this then results in an increased risk of knee osteoarthritis will need to be determined.