Bone quality and mesenchymal stromal cell capacity in total hip replacement: Significance for stem osseointegration measured by radiostereometric analysis

Immediate implant stability is a key factor for success in cementless total hip arthroplasty (THA). Cementless techniques were originally designed for middle-aged patients with normal bone structure and healing capacity, but indications have expanded to also include elderly patients. Poor local bone quality, as a result of osteoporosis (OP), and age-related geometric changes of the proximal femur, may jeopardize initial implant stability and lead to increased migration of the implant components thereby compromising biological fixation and osseointegration. Mesenchymal stromal cells (MSCs) are essential in the process of osseointegration. Age-related dysfunction of MSCs is suggested to be a main contributory factor in altered bone repair with aging and therefore may influence osseointegration. The hypothesis of this prospective clinical study was that preoperative bone quality and MSC capacity dictate stability and osseointegration of femoral stems in cementless THA, especially in women after menopause. A total of 61 consecutive women (age <80 yrs) scheduled for cementless THA for primary hip osteoarthritis (OA) were screened for undiagnosed primary or secondary OP, vitamin D insufficiency and other metabolic bone diseases. Prior to THA, patients underwent aspiration of iliac crest bone marrow for analysis of MSC capacity using optimized isolation and culturing protocols. All patients received a cementless total hip implant with an anatomically designed hydroxyapatite (HA) coated femoral stem and ceramic-ceramic bearings. Per-operative biopsy of the intertrochanteric bone was taken for ex vivo analysis of the local cancellous bone quality using micro-CT imaging and biomechanical testing. After surgery, stem migration and osseointegration was monitored for two years using radiostereometric analysis. The majority of women with hip OA was osteopenic or osteoporotic. These conditions were associated with increased periprosthetic bone loss in the proximal femur and impaired initial stability and delayed osseointegration of the femoral stem. Altered intraosseous dimensions of the proximal femur, as well as aging, also had adverse effects on initial stem stability and were associated with delayed osseointegration. Local bone mineral density of the operated hip and the quality of intertrochanteric cancellous bone had less influence than expected on implant migration. The THA females showed differences in the osteogenic properties of their MSCs. Patients with MSCs of low in vitro osteogenic capacity displayed increased stem subsidence after the initial 3 months settling period and thereby delayed osseointegration. The results suggest that decreased skeletal health, such as low systemic BMD and decreased osteogenic properties of bone marrow MSCs, has major influence on early stability and osseointegration of cementless hip prostheses in female patients.Luun laadun ja mesenkymaalisten kantasolujen toiminnan vaikutus lonkan tekonivelen paranemiseen Tekonivelleikkaus on erinomainen toimenpide lonkan nivelrikon hoidossa. Jos leikkausmenetelmäksi valitaan biologisesti kiinnittyvä tekonivel, olennaisinta on saavuttaa komponenttien välitön stabiliteetti. Se mahdollistaa uudisluun kasvun implantin karhennetulle pinnalle. Ikääntymiseen liittyvä luuston haurastuminen ja reisiluun yläosan ydinontelon laajentuminen voivat heikentää tekonivelen komponenttien tukevuutta ja näin hidastaa niiden kiinnittymistä luuhun. Tällainen on mahdollista erityisesti naisilla vaihdevuosien jälkeen. Näiden potilaiden yksilölliset erot luun parantavien solujen (mesenkymaalisten kantasolujen) määrässä ja toiminnassa voivat osaltaan vaikuttaa heidän tekoniveltensä kiinnittymisnopeuteen. Tähän prospektiiviseen kliiniseen tutkimukseen osallistui 61 naispotilasta, joille tehtiin sementöimätön lonkan tekonivelleikkaus nivelrikon takia. Ennen leikkausta potilaille tehtiin seulontatutkimukset osteoporoosin ja muiden luuston aineenvaihduntasairauksien tunnistamiseksi. Leikkauksen yhteydessä potilailta otettiin luuydinnäyte suoliluusta, josta analysoitiin mesenkymaalisten kantasolujen jakautumis- ja erilaistumiskyky luunsoluiksi. Leikkauksen aikana otettiin näyte reisiluun yläosan hohkaluun hienorakenteen ja mekaanisten ominaisuuksien arvioimiseksi. Leikkauksen jälkeen tekonivelen reisikomponentin kolmiulotteista migraatiota ja kiinnittymistä seurattiin radiostereometrisellä analyysillä (RSA) 2 vuoden ajan. Valtaosalla potilaista oli alentunut luuntiheys (osteopenia tai osteoporoosi). Osteopeenisillä ja osteoporoottisilla potilailla todettiin kiihtynyttä luukatoa tekonivelen reisikomponentin ympärillä sekä komponentin lisääntynyttä migraatiota ja hidastunutta kiinnittymistä. Reisiluun yläosan ydinontelon laajentuminen ja potilaan korkea ikä lisäsivät reisikomponentin migraatiota, mutta reisiluun hohkaluun laatu ei vaikuttanut migraation määrään. Potilailla, joilla todettiin mesenkymaalisten kantasolujen alentunut kyky erilaistua luusoluiksi in vitro, todettiin reisikomponentin lisääntynyttä migraatiota ja hidastunutta kiinnittymistä. Tulokset osoittavat, että ikääntymiseen liittyvät luustomuutokset ja yksilölliset erot mesenkymaalisten kantasolujen määrässä ja toiminnassa voivat osaltaan vaikuttaa lonkan tekonivelten paranemiseen naisilla vaihdevuosien jälkeen.Siirretty Doriast

Regulatory and monetary policies meet "too big to fail"

In 2010, the U.S. economy has been showing signs of pulling out of its tailspin. But questions remain about why it took so much monetary policy firepower to deal with the crisis.Global financial crisis ; Monetary policy ; Regulation ; Bank failures ; Financial institutions

Fed intervention: managing moral hazard in financial crises

At the end of September 2008, U.S. policymakers had been working for more than a year to contain the shock waves from plunging home prices and the subsequent financial market turmoil. For the Federal Reserve, the crisis has given new meaning to the adage that extraordinary times call for extraordinary measures. The central bank has dusted off Depression-era powers and rewritten old rules to address serious risks to the global financial system.Monetary policy - United States ; Financial crises ; Financial markets ; Federal Reserve System

Biomarkers in WNT1 and PLS3 Osteoporosis : Altered Concentrations of DKK1 and FGF23

Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/beta-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p <.001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. (c) 2020 American Society for Bone and Mineral Research.Peer reviewe

Zoledronic acid in vivo increases in vitro proliferation of rat mesenchymal stromal cells

Background and purpose-Bisphosphonates are widely used in the treatment of bone loss, but they might also have positive effects on osteoblastic cells and bone formation. We evaluated the effect of in vivo zoledronic acid (ZA) treatment and possible concomitant effects of ZA and fracture on the ex vivo osteogenic capacity of rat mesenchymal stromal cells (MSCs). Methods-A closed femoral fracture model was used in adult female rats and ZA was administered as a single bolus or as weekly doses up to 8 weeks. Bone marrow MSCs were isolated and cultured for in vitro analyses. Fracture healing was evaluated by radiography, micro -computed tomography (mu CT), and histology. Results-Both bolus and weekly ZA increased fracture-site bone mineral content and volume. MSCs from weekly ZA-treated animals showed increased ex vivo proliferative capacity, while no substantial effect on osteoblastic differentiation was observed. Fracture itself did not have any substantial effect on cell proliferation or differentiation at 8 weeks. Serum biochemical markers showed higher levels of bone formation in animals with fracture than in intact animals, while no difference in bone resorption was observed. Interestingly, ex vivo osteoblastic differentiation of MSCs was found to correlate with in vivo serum bone markers. Interpretation-Our data show that in vivo zoledronic acid treatment can influence ex vivo proliferation of MSCs, indicating that bisphosphonates can have sustainable effects on cells of the osteoblastic lineage. Further research is needed to investigate the mechanisms.Peer reviewe

Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice

Recent studies suggest health benefits including protection from cancer after eating fermented foods such as probiotic yogurt, though the mechanisms are not well understood. Here we tested mechanistic hypotheses using two different animal models: the first model studied development of mammary cancer when eating a Westernized diet, and the second studied animals with a genetic predilection to breast cancer. For the first model, outbred Swiss mice were fed a Westernized chow putting them at increased risk for development of mammary tumors. In this Westernized diet model, mammary carcinogenesis was inhibited by routine exposure to Lactobacillus reuteri ATCC-PTA-6475 in drinking water. The second model was FVB strain erbB2 (HER2) mutant mice, genetically susceptible to mammary tumors mimicking breast cancers in humans, being fed a regular (non-Westernized) chow diet. We found that oral supplement with these purified lactic acid bacteria alone was sufficient to inhibit features of mammary neoplasia in both models. The protective mechanism was determined to be microbially-triggered CD4+CD25+ lymphocytes. When isolated and transplanted into other subjects, these L. reuteri-stimulated lymphocytes were sufficient to convey transplantable anti-cancer protection in the cell recipient animals. These data demonstrate that host immune responses to environmental microbes significantly impact and inhibit cancer progression in distal tissues such as mammary glands, even in genetically susceptible mice. This leads us to conclude that consuming fermentative microbes such as L. reuteri may offer a tractable public health approach to help counteract the accumulated dietary and genetic carcinogenic events integral in the Westernized diet and lifestyle.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant RO1CA108854)National Institutes of Health (U.S.) (Grant U01 CA164337

Good stability of a cementless, anatomically designed femoral stem in aging women: a 9-year RSA study of 32 patients

Background and purpose — We previously reported a transient, bone mineral density (BMD)-dependent early migration of anatomically designed hydroxyapatite-coated femoral stems with ceramic–ceramic bearing surfaces (ABG-II) in aging osteoarthritic women undergoing cementless total hip arthroplasty. To evaluate the clinical significance of the finding, we performed a follow-up study for repeated radiostereometric analysis (RSA) 9 years after surgery.Patients and methods — Of the 53 female patients examined at 2 years post-surgery in the original study, 32 were able to undergo repeated RSA of femoral stem migration at a median of 9 years (7.8–9.3) after surgery. Standard hip radiographs were obtained, and the subjects completed the Harris Hip Score and Western Ontario and McMaster Universities Osteoarthritis Index outcome questionnaires.Results — Paired comparisons revealed no statistically significant migration of the femoral stems between 2 and 9 years post-surgery. 1 patient exhibited minor but progressive RSA stem migration. All radiographs exhibited uniform stem osseointegration. No stem was revised for mechanical loosening. The clinical outcome scores were similar between 2 and 9 years post-surgery.Interpretation — Despite the BMD-related early migration observed during the first 3 postoperative months, the anatomically designed femoral stems in aging women are osseointegrated, as evaluated by RSA and radiographs, and exhibit good clinical function at 9 years.</div

New Insights Into Monogenic Causes of Osteoporosis

Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I¬ collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.Peer reviewe

Radiostereometric analysis of the initial stability of internally fixed femoral neck fractures under differential loading

We examined the feasibility of radiostereometric analysis (RSA) in the assessment of the initial stability of internally fixed femoral neck fractures. The study included 16 patients (mean age 73 years). During surgery, multiple RSA‐beads were inserted on both sides of the fracture. Radiographs for RSA were taken in the supine position within the first 3 days and 6, 12, 24, and 52 weeks after surgery. To detect any inducible motion at the fracture‐site, radiographs for RSA were taken with the patient resting or applying a load through the fracture. Fracture loading was achieved by the patient pressing the ipsilateral foot as much as tolerated on a force plate while providing a counterforce through both hands. Micromotion exceeding the precision values of RSA (≥0.3 mm for the translation vector and/or ≥1.2 degrees for the rotation vector) was considered significant. Permanent three‐dimensional fracture‐site displacement was also recorded. Voluntary loading induced fracture‐site micromotion, which exhibited a dichotomous distribution. In patients with uncomplicated fracture union, inducible micromotion was detectable only at baseline—if at all. Conversely, fractures that developed a nonunion were characterized by the continuation of inducible micromotion beyond baseline. Permanent fracture‐site displacement was, on average, nearly an order of magnitude greater than the inducible micromotion. Fracture unions were characterized by the cessation of permanent fracture‐site displacement by 12 weeks. Nonunions presented as outliers in permanent fracture‐site displacement. Large‐scale studies are warranted to evaluate whether the detection of inducible micromotion beyond baseline could serve as an indicator of insufficient fixation stability.</p

Dietary Microbes Modulate Transgenerational Cancer Risk

Environmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet-associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer.National Institutes of Health (U.S.) (RO1CA108854)National Institutes of Health (U.S.) (U01 CA164337)National Institutes of Health (U.S.) (P30-ES002109