Impacto de las fracturas por fragilidad en mujeres españolas con osteoporosis posmenopáusica / Impact of fragility fractures in postmenopausal Spanish women with osteoporosis

Objetivo: dada la repercusión que tienen las fracturas por fragilidad y sus secuelas en la vida de las mujeres con osteoporosis posmenopáusica (OPM), el objetivo de este estudio es describir y analizar su impacto en esta población. Material y métodos: se realizó una encuesta a mujeres posmenopáusicas con fractura por fragilidad en un diseño observacional transversal. Se recogieron variables sociodemográficas, impacto de la fractura (necesidad de cuidados, productividad laboral), calidad de vida relacionada con la salud (CVRS, mediante cuestionario QUALEFFO-31) y disposición a pagar (DAP) por recuperarla. Resultados: participaron 120 mujeres, promedio de edad 62 ± 7 años. Las fracturas más frecuentes fueron las de radio distal (29,9 %) y las vertebrales (21,3 %). Un 53,3 % necesitó cuidados durante su recuperación (76,5 % informales; 24,9 % formales) y un 4,2 % tuvo que ingresar en un centro/residencia sociosanitaria. De aquellas que trabajaban cuando se produjo la fractura (62,5 %), el 56 % vio su vida laboral afectada (69,3 % incapacidad temporal; 17,3 % incapacidad permanente; 10,7 % reducción de jornada; 10,7 % abandono laboral; 5,3 % permiso/excedencia; 3,6 % prejubilación). El impacto de la fractura se debió principalmente al dolor (71,7 %), dificultad para realizar actividades cotidianas (48,3 %), problemas de movilidad (46,7 %) y estado emocional (41,7 %). La mayor DAP se ofreció por recuperar la capacidad para realizar actividades cotidianas y el estado emocional. La puntuación total QUALEFFO-31 (0-100) fue 49,9 ± 10,8 (función mental: 68,3 ± 7,3; dolor: 56 ± 22,6; función física: 39,3 ± 15,5). Conclusiones: las fracturas por fragilidad tienen un alto impacto en la calidad de vida de las mujeres con OPM. Resulta fundamental poner en valor aquellos aspectos que más les preocupan para optimizar su abordaje. (AU)

Objective: Given the impact of fragility fractures and their consequences on the lives of women with postmenopausal osteoporosis (PMO), the objective of this study is to describe and analyze the impact of this kind of fractures on this population. Materials and methods: A survey was conducted among postmenopausal women with fragility fractures in a cross-sectional observational design. Sociodemographic variables, fracture impact (need for care, work productivity), and data on health-related quality of life (HRQoL, assessed using the QUALEFFO-31 questionnaire), and willingness to pay (WTP) to regain HRQoL were collected. Results: A total of 120 women participated, with a mean age of 62 ± 7 years. The most frequent fractures described were distal radius fractures (29.9 %), followed by vertebral fractures (21.3 %). A total of 53.3 % required care during their recovery (76.5 %, informal; 24.9 %, formal), and 4.2 % had to be admitted to a health care or nursing home. Among those who were working when the fracture occurred (62.5 %), 56 % had their working life affected (69.3 %, temporary disability; 17.3 %, permanent disability; 10.7 %, reduced working hours; 10.7 %, quit their jobs; 5.3 %, leave of absence; and 3.6 %, early retirement). The impact of the fracture was primarily due to pain (71.7 %), difficulty performing activities of daily living (48.3 %), mobility problems (46.7 %), and emotional state (41.7 %). The highest WTP was offered to regain the ability to perform activities of daily living and improve the emotional state. The overall QUALEFFO-31 score (0-100) was 49.9 ± 10.8 (mental function, 68.3 ± 7.3; pain, 56 ± 22.6; physical function, 39.3 ± 15.5). Conclusions: Fragility fractures play a significant role on the quality of life of women with PMO. It is of paramount importance to value the aspects that concern them the most to optimize their management. (AU)

Quantitative PET tracking of intra-articularly administered 89Zr-peptide-decorated nanoemulsions.

Intra-articular (IA) administration of drugs for the treatment of diseases such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis is a common strategy; however, the rapid clearance from the synovial fluid restricts their effectivity due to the limited retention time. Drug Delivery Systems (DDS) are currently being developed to increase their joint retention time. This study compares the biodistribution and retention time of a senolytic peptide (PEP), with potential application in osteoarthritis disease, and this senolytic peptide encapsulated in a DDS based on a lipid nanoemulsion (PEPNE) by using positron emission tomography (PET) imaging. To this aim, the PEP was conjugated with a chelating agent (DFO) and radiolabeled with zirconium-89 (89Zr). Then, [89Zr]-PEP was encapsulated in a novel nanoemulsion formulation, composed by vitamin E, sphingomyelin, and a lipid-PEG. Afterward, healthy rats were administered with either the [89Zr]-PEP or the [89Zr]-PEP-NE via IA injection and underwent PET scans at 0.5-, 24-, 48-, 72-, 168-, 240- and 336 h post-injection. To assess the biodistribution of both radiotracers, several volume-of-interest were manually drawn in different organs of the rat body and the %ID/organ was calculated. The [89Zr]-PEP was successfully encapsulated in the NE and their physicochemical properties were minimally affected by the radiolabeling buffer. Adequate stability of both [89Zr]-PEP and [89Zr]-PEP-NE was found in synovial fluid over 72 h. Quantitative data from PET images revealed a significantly higher [89Zr]-PEP-NE retention in the injected knee than with [89Zr]-PEP in all follow-up PET scans. The [89Zr]-PEP %ID/organ values in the liver and kidney were significantly higher than those from [89Zr]-PEP-NE, which might indicate a faster elimination of the [89Zr]-PEP. Therefore, the study highlights the higher retention time on the target site of the [89Zr]-PEP-NE which may improve the therapeutic effects of the peptide. Thereby, the novel nanoemulsion formulation seems to be a successful DDS for IA injection. In addition, these results represent the first study that evaluates the distribution of a PET-guided DDS after its IA administration.

Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression.

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

Multiple vertebral fractures after suspension of denosumab. A series of 56 cases.

BACKGROUND: Denosumab is a monoclonal antibody approved for the treatment of postmenopausal osteoporosis. The withdrawal of denosumab produces an abrupt loss of bone mineral density and may cause multiple vertebral fractures (MVF). OBJECTIVE: The objective of this study is to study the clinical, biochemical, and densitometric characteristics in a large series of postmenopausal women who suffered MVF after denosumab withdrawal. Likewise, we try to identify those factors related to the presence of a greater number of vertebral fractures (VF). PATIENTS AND METHODS: Fifty-six patients (54 women) who suffered MVF after receiving denosumab at least for three consecutive years and abruptly suspended it. A clinical examination was carried out. Biochemical bone remodelling markers (BBRM) and bone densitometry at the lumbar spine and proximal femur were measured. VF were diagnosed by magnetic resonance imaging MRI, X-ray, or both at dorsal and lumbar spine. RESULTS: Fifty-six patients presented a total of 192 VF. 41 patients (73.2%) had not previously suffered VF. After discontinuation of the drug, a statistically significant increase in the BBRM was observed. In the multivariate analysis, only the time that denosumab was previously received was associated with the presence of a greater number of VF (P = .04). CONCLUSIONS: We present the series with the largest number of patients collected to date. 56 patients accumulated 192 new VF. After the suspension of denosumab and the production of MVF, there was an increase in the serum values of the BBRM. The time of denosumab use was the only parameter associated with a greater number of fractures.

Orthogeriatric Management: Improvements in Outcomes during Hospital Admission Due to Hip Fracture.

Hip fractures are an important socio-economic problem in western countries. Over the past 60 years orthogeriatric care has improved the management of older patients admitted to hospital after suffering hip fractures. Quality of care in orthogeriatric co-management units has increased, reducing adverse events during acute admission, length of stay, both in-hospital and mid-term mortality, as well as healthcare and social costs. Nevertheless, a large number of areas of controversy regarding the clinical management of older adults admitted due to hip fracture remain to be clarified. This narrative review, centered in the last 5 years, combined the search terms "hip fracture", "geriatric assessment", "second hip fracture", "surgery", "perioperative management" and "orthogeriatric care", in order to summarise the state of the art of some questions such as the optimum analgesic protocol, the best approach for treating anemia, the surgical options recommendable for each type of fracture and the efficiency of orthogeriatric co-management and functional recovery.

Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment in osteoarthritis.

Articular cartilage and synovial tissue from patients with osteoarthritis (OA) show an overactivity of connexin43 (Cx43) and accumulation of senescent cells associated with disrupted tissue regeneration and disease progression. The aim of this study was to determine the effect of oleuropein on Cx43 and cellular senescence for tissue engineering and regenerative medicine strategies for OA treatment. Oleuropein regulates Cx43 promoter activity and enhances the propensity of hMSCs to differentiate into chondrocytes and bone cells, reducing adipogenesis. This small molecule reduce Cx43 levels and decrease Twist-1 activity in osteoarthritic chondrocytes (OACs), leading to redifferentiation, restoring the synthesis of cartilage ECM components (Col2A1 and proteoglycans), and reducing the inflammatory and catabolic factors mediated by NF-kB (IL-1ß, IL-6, COX-2 and MMP-3), in addition to lowering cellular senescence in OACs, synovial and bone cells. Our in vitro results demonstrate the use of olive-derived polyphenols, such as oleuropein, as potentially effective therapeutic agents to improve chondrogenesis of hMSCs, to induce chondrocyte re-differentiation in OACs and clearing out senescent cells in joint tissues in order to prevent or stop the progression of the disease.

Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis.

Osteoarthritis (OA), a chronic disease characterized by articular cartilage degeneration, is a leading cause of disability and pain worldwide. In OA, chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring disease progression. Similar to other wound-healing disorders, chondrocytes from OA patients show a chronic increase in the gap junction channel protein connexin43 (Cx43), which regulates signal transduction through the exchange of elements or recruitment/release of signalling factors. Although immature or stem-like cells are present in cartilage from OA patients, their origin and role in disease progression are unknown. In this study, we found that Cx43 acts as a positive regulator of chondrocyte-mesenchymal transition. Overactive Cx43 largely maintains the immature phenotype by increasing nuclear translocation of Twist-1 and tissue remodelling and proinflammatory agents, such as MMPs and IL-1ß, which in turn cause cellular senescence through upregulation of p53, p16INK4a and NF-κB, contributing to the senescence-associated secretory phenotype (SASP). Downregulation of either Cx43 by CRISPR/Cas9 or Cx43-mediated gap junctional intercellular communication (GJIC) by carbenoxolone treatment triggered rediferentiation of osteoarthritic chondrocytes into a more differentiated state, associated with decreased synthesis of MMPs and proinflammatory factors, and reduced senescence. We have identified causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation, redifferentiation and senescence. We propose that chondrocytes undergo chondrocyte-mesenchymal transition where increased Cx43-mediated GJIC during OA facilitates Twist-1 nuclear translocation as a novel mechanism involved in OA progression. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration.

Numerical Modelling of Femur Fracture and Experimental Validation Using Bone Simulant.

Bone fracture pattern prediction is still a challenge and an active field of research. The main goal of this article is to present a combined methodology (experimental and numerical) for femur fracture onset analysis. Experimental work includes the characterization of the mechanical properties and fracture testing on a bone simulant. The numerical work focuses on the development of a model whose material properties are provided by the characterization tests. The fracture location and the early stages of the crack propagation are modelled using the extended finite element method and the model is validated by fracture tests developed in the experimental work. It is shown that the accuracy of the numerical results strongly depends on a proper bone behaviour characterization.

Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78-Week Randomized Clinical Trial.

We present final results of a study comparing teriparatide 20 µg every day (QD) with risedronate 35 mg once per week (QW) started within 2 weeks after surgery for a pertrochanteric hip fracture. Patients with BMD T-score ≤ -2.0 and 25OHD ≥9.2 ng/mL were randomized to receive 26-week double-dummy treatment plus calcium and vitamin D, followed by 52-week open-label treatment with the same assigned active drug. Primary endpoint was change from baseline in lumbar spine (LS) BMD at 78 weeks. Secondary and exploratory endpoints were change in BMD at the proximal femur, function, hip pain (Charnley score and 100 mm Visual Analog Scale [VAS]), quality of life (Short Form-36), radiology outcomes, and safety. Data were analyzed with mixed models for repeated measures (MMRM) and logistic regression. Totally, 224 patients were randomized; 171 (teriparatide: 86) contributed to the efficacy analyses (mean ± SD age: 77 ± 7.7 years, 77% females). Mean baseline LS, femoral neck (FN), and total hip (TH) T-scores were -2.16, -2.63, and -2.51, respectively. At 78 weeks, BMD increased significantly more with teriparatide compared to risedronate at the LS (+11.08% versus +6.45%; p < 0.001) and FN (+1.96% versus -1.19%; p = 0.003), with no significant between-group difference in TH BMD. Timed up-and-go (TUG) test was significantly faster with teriparatide at 6, 12, 18, and 26 weeks (differences: -3.2 to -5.9 s; p = 0.045 for overall difference). Hip pain during TUG test by 100 mm VAS was significantly lower with teriparatide at 18 weeks (adjusted difference: -11.3 mm, p = 0.033; -10.0 and -9.3 mm at 12 and 26 weeks, respectively; p = 0.079 for overall difference). Other secondary and exploratory outcomes were not different. Teriparatide group showed two new hip fractures versus seven with risedronate (p = 0.171) and more frequent hypercalcemia and hyperuricemia. In conclusion, 78-week treatment with teriparatide showed significantly greater increases in LS and FN BMD, less pain, and a faster TUG test versus risedronate. © 2016 American Society for Bone and Mineral Research.

Burden of First Osteoporotic Hip Fracture in Spain: A Prospective, 12-Month, Observational Study.

The purpose of this study was to estimate the burden of osteoporotic fractures beyond the hospitalization period covering up to the first year after the fracture. This was a prospective, 12-month, observational study including patients aged ≥65 years hospitalized due to a first low-trauma hip fracture, in six Spanish regions. Health resource utilization (HRU), quality of life (QoL) and autonomy were collected and total costs calculated. Four hundred and eighty seven patients (mean ± SD age 83 ± 7 years, 77 % women) were included. Twenty-two percent of patients reported a prior non-hip low-trauma fracture, 16 % were receiving osteoporotic treatment at baseline, and 3 % had densitometry performed (1.8 % T-score ≤-2.5). Sixteen percent of patients died (women 14 %; men 25 %; p = 0.0011) during the first year. Mean hospital stay was 11.8 ± 7.9 days and 95.1 % of patients underwent surgery. Other relevant HRUs were: outpatient visits in 78 % of patients (mean 9.2 ± 9.7); walking aids, 58.7 %; rehabilitation facilities, 35.5 % (28.7 ± 41.2 sessions); and formal and informal home care, 22.2 % (49.6 ± 72.2 days) and 53.4 % (77.1 ± 101.0 h), respectively. Mean direct cost was €9690 (95 % confidence interval: 9184-10,197) in women and €9019 (8079-9958) in men. Main cost drivers were: first hospitalization episode (women €7067 [73 %]; men €7196 [80 %]); outpatient visits (€1323 [14 %]; €997 [11 %]); and home care (€905 [9 %]; €767 [9 %]). QoL and autonomy showed a marked decrease during hospitalization, not entirely recovered at 12 months (p < 0.05 vs. baseline for EQ-5D, Harris hip score and modified Barthel index). In a Spanish setting, osteoporotic hip fractures incur a high societal and economic cost, mainly due to the first hospitalization HRU, but also due to subsequent outpatient visits and home care.

Effects of Teriparatide Compared with Risedronate on Recovery After Pertrochanteric Hip Fracture: Results of a Randomized, Active-Controlled, Double-Blind Clinical Trial at 26 Weeks.

BACKGROUND: Osteoporosis drugs might affect fracture-healing. We therefore studied the effects of teriparatide in comparison with risedronate on recovery after pertrochanteric hip fractures. METHODS: The study was a randomized, multicenter, active-controlled, 78-week trial comparing teriparatide (20 µg/day) with risedronate (35 mg/week) initiated within 2 weeks after fixation of a low-trauma pertrochanteric hip fracture (AO/OTA 31-A1 or 31-A2). The main inclusion criteria were a bone mineral density T-score of ≤-2.0 and 25-OH-vitamin D of ≥9.2 ng/mL. During the first 26 weeks, patients received study medication with oral or injectable placebo plus calcium and vitamin D in a double-blinded fashion. Secondary (Timed Up-and-Go [TUG] test, hip pain, Short Form [SF]-36 health status, and safety) and exploratory (radiographic outcomes and ability to walk) 26-week end points are reported. RESULTS: Of the 224 patients who were randomized, 171 (86 teriparatide, 85 risedronate) were included in the analysis. The mean age was 77 ± 8 years, 77% were female, and 26% had a prior history of low-trauma fracture. The teriparatide group completed the TUG test in a shorter time at 6, 12, 18, and 26 weeks (differences of -5.7, -4.4, -3.1, and -3.1 seconds, respectively; p = 0.021 for the overall difference). They also reported less pain on a visual analog scale immediately after the TUG test at 12 and 18 weeks (adjusted absolute differences of 10.6 and 11.9 mm, respectively; p < 0.05). There were no significant between-group differences in the SF-36 score, Charnley hip pain score, ability to walk, or use of walking aids during follow-up. Radiographic healing at 6, 12, and 26 weeks, mechanical failure of the implant (teriparatide, 7; risedronate, 8), loss of reduction (teriparatide, 2; risedronate, 4), and nonunion (0 cases) were not significantly different. Mild hypercalcemia and hyperuricemia were more frequent with teriparatide. CONCLUSIONS: Teriparatide was associated with less pain and a shorter time to complete the TUG test between 6 and 26 weeks compared with risedronate. Other fracture-recovery outcomes were similar. The results should be interpreted with caution as these were secondary end points. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Effects of diacerein on cartilage and subchondral bone in early stages of osteoarthritis in a rabbit model.

BACKGROUND: Osteoarthritis is thought to be the most prevalent chronic and disabling joint disease in animals and humans. At present, there is no ideal treatment option. The aim of this study was to assess the effects of the treatment with oral diacerein on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of osteoarthritis by micro-CT evaluation and histological analysis. To this purpose, osteoarthritis was surgically induced on one knee of 16 rabbits using the contralateral knee as healthy controls. Treatment was started three weeks later and lasted eight weeks. Animals were divided into two groups for treatment: Placebo (treated daily with oral saline) and diacerein (treated orally with 1.5 mg/kg/day of diacerein). RESULTS: Sample analysis revealed that this model induced osteoarthritis in the operated knee joint. Osteoarthritis placebo group showed a significant increase in non-calcified cartilage thickness and volume with respect to the control placebo group and important changes in the synovial membrane; whereas the parameters measured in subchondral bone remained unchanged. In the osteoarthritis diacerein-treated group the results showed an improvement with respect to the OA placebo group in all parameters, although the results were not statistically significant. CONCLUSION: The results of this animal study suggested that the diacerein treatment for OA may be able to ameliorate the swelling and surface alterations of the cartilage and exert an anti-inflammatory effect on the synovial membrane, which might contribute to OA improvement, as well as an anabolic effect on subchondral trabecular bone.

Comparison of various SYSADOA for the osteoarthritis treatment: an experimental study in rabbits.

BACKGROUND: Osteoarthritis is thought to be the most prevalent chronic and disabling joint disease in animals and humans and its treatment is a major orthopaedic challenge because there is no ideal drug treatment to preserve joint structure and function, as well as to ameliorate the symptomatology of the disease. The aim of the present study was to assess, using histology, histomorphometry and micro-CT, the effects of the treatment with several drugs of the SYSADOA group and a bisphosphonate in a model of early osteoarthritis, comparing all the results obtained. METHODS: Osteoarthritis was surgically induced by anterior cruciate ligament transection and partial meniscectomy on one knee of 56 rabbits; treatment was started three weeks after surgery and lasted 8 weeks; at the end of this period, the animals were sacrificed. Animals were divided into seven groups (8 animals each), one for each regimen of treatment (glucosamine sulfate, chondroitin sulfate, hyaluronic acid, diacerein, risedronate and a combination of risedronate and glucosamine) and one for the control (placebo-treated) group. Following sacrifice, femoral osteochondral cylinders and synovial membrane samples were obtained for their evaluation by qualitative and quantitative histology and micro-CT. RESULTS: The model induced osteoarthritic changes in the knee joints and none of the treatments showed a significantly better efficacy over the others. Regarding cartilage thickness and volume, all the treatments achieved scores halfway between control groups, without statistical differences. Regarding the synovial membrane, diacerein and risedronate showed the best anti-inflammatory profile, whereas glucosamine and chondroitin did not present any effect standing the hyaluronic acid results between the others. Regarding the subchondral bone, there were no differences in thickness or volume, but risedronate, diacerein and hyaluronic acid seemed to have considerably modified the orientation of the trabecular lattice. CONCLUSIONS: Out of the different drugs evaluated in the study for OA treatment, diacerein and risedronate showed, in all the parameters measured, a better profile of effectiveness; hyaluronic acid ameliorated cartilage swelling and promoted bone formation, but with a poor synovial effect; and finally, chondroitin and glucosamine sulfate prevented cartilage swelling in a similar way to the others, but had no effect on cartilage surface, synovial membrane or subchondral bone.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats.

The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on bone mass, femoral microstructure, femoral biomechanical properties, and bone remodeling in healthy adult male rats. Forty-eight 5-month-old male Wistar rats were used. CsA (2 mg/kg/day), FK-506 (3 mg/kg/day), RAPA (1.25 mg/kg/day), or water (0.5 ml/rat/day, control group) were administered orally for 3 months. After sacrifice, mean values of immunosuppressants in blood were: CsA (670.4 ng/ml), FK-506 (19.2 ng/ml), and RAPA (4.8 ng/ml). Levels of biochemical parameters were normal in all groups. Femoral BMD was decreased in FK-506 and RAPA groups and lumbar BMD in FK-506 group. Trabecular volume fraction (BV/TV) decreased only in FK-506 group. RAPA and CsA affected femoral cortical structure, but FK-506 did not. FK-506 produced an increase in bone remodeling, and CsA a decrease. FK-506 group showed a decrease in biomechanical parameters relative to all groups. RAPA group showed a decrease in ultimate stress vs control group, and CsA group presented an increase in biomechanical parameters versus control group. We found that administration of both RAPA and FK-506 as monotherapy for healthy rats produced osteopenia. CsA treatment only produces slight damages in the cortical zone of the femur.

Impact of estrogens on atherosclerosis and bone in the apolipoprotein E-deficient mouse model.

OBJECTIVE: The common inflammatory pathophysiology has nourished the hypothesis of a relationship between osteoporosis and cardiovascular disease. Estrogens are key agents in the modulation of both processes. We investigated whether induction of atherosclerosis affects bone and whether estrogens modulate both processes. METHODS: Female apolipoprotein E-deficient mice (a well-established model of atherogenesis) were ovariectomized or falsely operated and fed either standard diet or high-fat diet (HFD). Six animals were included in each of the four groups. To clarify mechanisms, we treated preosteoblastic MC3T3-E1 cells with mouse serum. RESULTS: Physiological levels of estrogens in falsely operated mice limited atherosclerotic burden in the thoracic aorta, but not in the aortic arch. Bone resorption, as assessed by C-telopeptides, was increased by ovariectomy in animals fed standard diet, but not in animals fed HFD. Bone microstructural properties at the distal femur showed deteriorated trabecular architecture in bone volumetric fraction and trabecular number after ovariectomy, but trabecular pattern factor, trabecular thickness, trabecular spacing, or the structural model index remained unchanged. Changes in cortical parameters were not significant. Volumetric bone mineral density was reduced in trabecular bone, but not in cortical bone, in ovariectomized mice fed standard diet. Preosteoblastic MC3T3-E1 cells exhibited increased cellular proliferation and viability and alkaline phosphatase activity after treatment with sera from animals fed HFD. CONCLUSIONS: Endogenous estrogens partially reduce atherogenic burden in female apolipoprotein E-deficient mice. Ovariectomy increases bone resorption, but not under exacerbated proatherogenic conditions induced by HFD. The absence of apolipoprotein E might have an influence on the asymmetric responses of atherogenesis and bone resorption.

Complications of hip fractures: A review.

Nowadays, fracture surgery represents a big part of the orthopedic surgeon workload, and usually has associated major clinical and social cost implications. These fractures have several complications. Some of these are medical, and other related to the surgical treatment itself. Medical complications may affect around 20% of patients with hip fracture. Cognitive and neurological alterations, cardiopulmonary affections (alone or combined), venous thromboembolism, gastrointestinal tract bleeding, urinary tract complications, perioperative anemia, electrolytic and metabolic disorders, and pressure scars are the most important medical complications after hip surgery in terms of frequency, increase of length of stay and perioperative mortality. Complications arising from hip fracture surgery are fairly common, and vary depending on whether the fracture is intracapsular or extracapsular. The main problems in intracapsular fractures are biological: vascularization of the femoral head, and lack of periosteum -a major contributor to fracture healing- in the femoral neck. In extracapsular fractures, by contrast, the problem is mechanical, and relates to load-bearing. Early surgical fixation, the role of anti-thromboembolic and anti-infective prophylaxis, good pain control at the perioperative, detection and management of delirium, correct urinary tract management, avoidance of malnutrition, vitamin D supplementation, osteoporosis treatment and advancement of early mobilization to improve functional recovery and falls prevention are basic recommendations for an optimal maintenance of hip fractured patients.

Effects of glucosamine and risedronate alone or in combination in an experimental rabbit model of osteoarthritis.

BACKGROUND: The osteoarthritis (OA) treatment in humans and in animals is a major orthopaedic challenge because there is not an ideal drug for preserving the joint structure and function. The aim of this study was to assess the effects of the treatment with oral glucosamine and risedronate alone or in combination on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of OA. Osteoarthritis was surgically induced on one knee of 32 New Zealand White rabbits using the contralateral as healthy controls. Three weeks later treatments were started and lasted 8 weeks. Animal were divided in four groups of oral treatment: the first group received only saline, the second 21.5 mg/kg/day of glucosamine sulfate, the third 0.07 mg/kg/day of risedronate; and the fourth group both drugs simultaneously at the same dosages. Following sacrifice femurs were removed and osteochondral cylinders and synovial membrane were obtained for its histological and micro-CT evaluation. RESULTS: Sample analysis revealed that the model induced osteoarthritic changes in operated knees. OA placebo group showed a significant increase in cartilage thickness respect to the control and inflammatory changes in synovial membrane; whereas subchondral bone structure and volumetric bone mineral density remained unchanged. All the treated animals showed an improvement of the cartilage swelling independent of the drug used. Treatment with glucosamine alone seemed to have no effect in the progression of cartilage pathology while risedronate treatment had better results in superficial fibrillation and in resolving the inflammatory changes of the tissues, as well as modifying the orientation of trabecular lattice. The combination of both compounds seemed to have additive effects showing better results than those treated with only one drug. CONCLUSIONS: The results of this animal study suggested that glucosamine sulfate and risedronate treatment alone or in combination may be able to stop cartilage swelling. The risedronate treatment could partially stop the fibrillation and the inflammation of synovial membrane as well as modify the orientation of trabeculae in healthy and in osteoarthritic knees.

Effects of PTH (1-84) on bone quality in a validated model of osteoporosis due to androgenic deprivation.

AIM: The purpose of this study was to evaluate the effect of parathyroid hormone (PTH) (1-84) in a model of male osteoporosis induced by orchidectomy in rats. METHODS: Six-month-old Wistar rats were used as follows: SHAM (simulated orchidectomy), orchidectomized (ORX), ORX + PTH1 (ORX and treated with 10 µg/Kg/d of PTH 1-84) and ORX + PTH2 (ORX and treated with 50 µg/Kg/d of PTH 1-84) over 3 months, with treatment beginning three months after orchidectomy. RESULTS: Orchidectomy resulted in a decreased of femoral and lumbar bone mineral density (BMD), a worsening of trabecular and cortical microarchitecture and a decrease in biomechanical properties. Both doses of PTH (1-84) partially (low dose) or totally (high dose) restored the ORX-induced changes. Serum C-telopeptide of type I collagen/5b isoenzyme of tartrate-resistant acid phosphatase (CTX/TRAP) resorption index increased after orchidectomy. Osteocalcin (bone Gla protein; BGP) levels were not affected by orchidectomy. PTH (1-84) treatment did not produce any changes in the levels of CTX/TRAP with respect to the ORX group. BGP levels increased with PTH treatment. CONCLUSION: PTH (1-84) is able to restore the adverse effects of orchidectomy on bone as measured by BMD, microstructural and biomechanical properties and bone remodeling markers.

Effects of kalsis, a dietary supplement, on bone metabolism in the ovariectomized rats.

We studied the ability of Kalsis, a food supplement that contains selenium, citric acid, and vitamin E, to prevent the effects of ovariectomy on bone loss. Six-month-old, Wistar female rats were studied. Groups (n = 12): SHAM: sham-operated rats; OVX: ovariectomized rats, treated with vehicle; OVX + Kalsis: ovariectomized rats treated with Kalsis (25 mg/kg/day) for 3 months. Bone mineral density (BMD) was determined by DXA in lumbar spine and femur. Computerized microtomography (µCT) in femur and serum osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), ß-isomer of carboxyterminal telopeptide of collagen I (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase (TRAP) were performed. Treatment with Kalsis prevented BMD loss in OVX group. µCT showed a decrease in BV/TV, and trabecular number, and an increase in trabecular separation in OVX rats. Kalsis administration attenuated partially bone loss observed by µCT due to ovariectomy. BGP, PINP, and the resorption index (CTX/TRAP) were increased in OVX group. Treatment with Kalsis maintained this increase. The mechanism of action of this supplement is not through a decrease in bone remodelling rate. The antioxidant action of this food supplement, due to the synergism of all its components, as a cause of its beneficial effect is suggested.