Search

Objective: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by 188 Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with 188 Re in prostate carcinoma cell lines., Materials and Methods: The cytotoxic effects of single and combined treatment with taxanes and 188 Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model., Results: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and 188 Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect., Conclusions: This proof-of-mechanism study exploring radiosensitization by combining 188 Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and 188 Re-HEDP.

Mechanical loading plays an essential role in maintaining skeletal integrity. Mechanical stimulation leads to increased bone formation. However, the cellular and molecular mechanisms that are involved in the translation of mechanical stimuli into bone formation, are not completely understood. Growth factors and osteocytes, which act as mechanosensors, play a key role during the bone formation after mechanical stimulation. The aim of this study was to characterize the role of IGF-I in the translation of mechanical stimuli into bone formation locally in rat tibiae. Fifteen female Wistar rats were randomly assigned to three groups (n = 5): load, sham-loaded, and control. The four-point bending model of Forwood and Turner was used to induce a single period of mechanical loading on the tibia shaft. The effects of mechanical loading on IGF-I mRNA expression were determined with non-radioactive in situ hybridization on decalcified tibiae sections, 6 h after the loading session. Endogenous IGF-I mRNA was expressed in trabecular and cortical osteoblasts, some trabecular and sub-endocortical osteocytes, intracortical endothelial cells of blood vessels, and periosteum. Megakaryocytes, macrophages, and myeloid cells also expressed IGF-I mRNA. In the growth plate, IGF-I mRNA was located in proliferative and hypertrophic chondrocytes. Mechanical loading did not affect the IGF-I mRNA expression in osteoblasts, bone marrow cells, and chondrocytes, but the osteocytes at the endosteal side of the shaft showed a twofold increase of IGF-I mRNA expression. The proportion of IGF-I mRNA positive osteocytes in loaded tibiae was 29.3 +/- 12.9% (mean +/- s.d.; n = 5), whereas sham-loaded and contra-lateral control tibiae exhibited 16.7 +/- 4.4% (n = 5) and 14.7 +/- 4.2% (n = 10) respectively (P < 0.05). Lamellar bone formation after a single mechanical loading session was observed at the endosteal side of the shaft. In conclusion, a single loading session results in a twofold up-regulation of IGF-I mRNA synthesis in osteocytes which are present in multiple layers extending into the cortical bone of mechanically stimulated tibia shaft 6 h after loading. This supports the hypothesis that IGF-I, which is located in osteocytes, is involved in the translation of mechanical stimuli into bone formation.

Mechanical loading and estrogen play important roles in bone homeostasis. The aim of this study was to evaluate the effects of mechanical loading on trabecular bone in the proximal femur of ovariectomized rats. We hypothesized that mechanical loading suppresses bone resorption and increases bone formation, which differs from the suppressive effects of estrogen on both resorption and formation. Furthermore, we expected to find changes in trabecular architecture elicited by the effects of mechanical loading and estrogen deficiency. Sixty female Wistar rats, 12 weeks old, were assigned to either the sedentary groups sham surgery (SED), ovariectomy (SED+OVX), and ovariectomy with estrogen replacement (SED+OVX+E2) or to the exercise groups EX, EX+OVX, EX+OVX+E2. Following ovariectomy, 5 microg 17beta-estradiol was given once weekly to the estrogen replacement groups. Exercise consisted of running with a backpack (load +/-20% of body weight) for 15 minutes/day, 5 days/week, for 19 weeks. Dual-energy X-ray absorptiometry (DXA) scans were performed before (T0), during (T6), and after (T19) the exercise period to obtain bone mineral content (BMC) and bone mineral density (BMD) data. After the exercise program, all rats were killed and right and left femora were dissected and prepared for micro-CT scanning and histomorphometric analysis of the proximal femoral metaphysis. After 19 weeks, increases in BMC (P = 0.010) and BMD (P = 0.031) were significant. At T19, mechanical loading had a significant effect on BMC (P = 0.025) and BMD (P = 0.010), and an interaction between mechanical loading and estrogen (P = 0.023) was observed. Bone volume and trabecular number decreased significantly after ovariectomy, while trabecular separation, mineralizing surface, bone formation rate, osteoclast surface, degree of anisotropy, and structure model index increased significantly after ovariectomy (P < 0.05). Trabecular bone turnover and structural parameters in the proximal femur were not affected by exercise. Estrogen deficiency resulted in a less dense and more oriented trabecular bone structure with increased marrow cavity and a decreased number of trabeculae. In conclusion, mechanical loading has beneficial effects on BMC and BMD of the ovariectomized rat. This indicates that the load in the backpack was high enough to elicit an osteogenic response sufficient to compensate for the ovariectomy-induced bone loss. The results confirm that estrogen suppresses both bone resorption and bone formation in the proximal metaphysis in the femoral head of our rat-with-backpack model. The effects of mechanical loading on the trabecular bone of the femoral head were not significant. This study suggests that the effect of mechanical loading in the rat-with-backpack model mainly occurs at cortical bone sites.

This large prospective cohort study was undertaken to construct a fall-risk model for elderly. The emphasis of the study rests on easily measurable predictors for any falls and recurrent falls. The occurrence of falls among 1285 community-dwelling elderly aged 65 years and over was followed during 1 year by means of a "fall calendar." Physical, cognitive, emotional and social functioning preceding the registration of falls were studied as potential predictors of fall-risk. Previous falls, visual impairment, urinary incontinence and use of benzodiazepines were the strongest predictors identified in the risk profile model for any falls (area under the curve [AUC] = 0.65), whereas previous falls, visual impairment, urinary incontinence and functional limitations proved to be the strongest predictors in the model for recurrent falls (AUC = 0.71). The probability of recurrent falls for subsequent scores of the screening test ranged from 4.7% (95% Confidence Interval [CI]: 4.0-5.4%) to 46.8% (95% CI: 43.0-50.6%). Our study provides a fall-risk screening test based on four easily measurable predictors that can be used for fall-risk stratification in community-dwelling elderly.

The objectives of this study were to ascertain the prevalence of the number and severity of vertebral deformities in elderly people and determine the extent to which these are associated with several aspects of functioning. The study was conducted in a subsample of the Longitudinal Aging Study Amsterdam (LASA) consisting of 527 participants (260 men and 267 women), aged 65 years or over. Lateral radiographs of the spine (T4-L5) were made of each participant and a semiquantitative method was used to assess the number and degree of vertebral deformities. The prevalence of having at least one vertebral deformity was 39% in both men and women. Six percent of the men and 5% of the women had at least three vertebral deformities. For severe deformities, the prevalence was 8% in men and 12% in women. The number of vertebral deformities was significantly associated with a height loss of more than 5 cm, difficulties in activities of daily living, poor performance, more than 3 days in bed and more than 3 days with limited activities because of health problems in the past month, and poor self-perceived health. For most of these outcome measures, associations were strongest when three or more deformities were present. The presence of a severe deformity was associated with a height loss of more than 5 cm, poor performance, more than 3 days with limited activities in the past month, and poor self-perceived health. None of the associations between number and severity of vertebral deformities and the level of functioning was modified by sex. We can conclude that vertebral deformities are very common in both older men and older women and that vertebral deformities, even if they are not clinically manifest, have a substantial impact on the level of functioning and well-being of older people.

The properties of impacted morsellised bone graft (MBG) in revision total knee arthroplasty (TKA) were studied in 12 horses. The left hind metatarsophalangeal joint was replaced by a human TKA. The horses were then randomly divided into graft and control groups. In the graft group, a unicondylar, lateral uncontained defect was created in the third metatarsal bone and reconstructed using autologous MBG before cementing the TKA. In the control group, a cemented TKA was implanted without the bone resection and grafting procedure. After four to eight months, the animals were killed and a biomechanical loading test was performed with a cyclic load equivalent to the horse's body-weight to study mechanical stability. After removal of the prosthesis, the distal third metatarsal bone was studied radiologically, histologically and by quantitative and micro CT. Biomechanical testing showed that the differences in deformation between the graft and the control condyles were not significant for either elastic or time-dependent deformations. The differences in bone mineral density (BMD) between the graft and the control condyles were not significant. The BMD of the MBG was significantly lower than that in the other regions in the same limb. Micro CT showed a significant difference in the degree of anisotropy between the graft and host bone, even although the structure of the area of the MBG had trabecular orientation in the direction of the axial load. Histological analysis revealed that all the grafts were revascularised and completely incorporated into a new trabecular structure with few or no remnants of graft. Our study provides a basis for the clinical application of this technique with MBG in revision TKA.

In a prospective study of 348 apparently healthy women, aged 70 years and over (mean 80.3 years), we examined bone mineral density (BMD), biochemical markers of bone metabolism, and some easily measurable predictors in relation to hip and osteoporotic fractures. In addition, we constructed risk profiles for hip and osteoporotic fractures. At baseline, BMD at both hips, using dual-energy X-ray absorptiometry, body height and body weight were measured. At the same time, serum and urine samples were obtained for biochemical analysis. Serum samples were analyzed for vitamin D metabolites, sex hormone binding globulin, serum intact parathyroid hormone, osteocalcin, alkaline phosphatase, phosphate, albumin, calcium and creatinine. In 2 h fasting urine, hydroxyproline, type I collagen crosslinked N-telopeptide (NTx) and calcium excretion were measured. Furthermore, easily measurable predictors, such as previous fracture, body mass index (BMI) and mobility were assessed. During the follow-up period (mean duration 5.0 years), hip and any osteoporotic fracture (wrist, humerus or hip fracture) occurred in 16 and 33 participants, respectively. Data were analyzed using Cox regression analysis. BMD of the trochanter (per 1 SD decrease) and previous fracture were most strongly associated with hip fractures (adjusted relative risk (RR) = 3.0, 95% confidence interval (CI): 1.4-6.6; RR = 4.2, 95% CI: 1.5-11.6, respectively) and osteoporotic fractures (RR = 1.8, 95% CI: 1.1-2.8; RR = 2.9, 95% CI: 1.5-5.7, respectively). Previous fracture, BMI and mobility were identified as easily measurable predictors for hip fractures, whereas previous fracture, use of loop diuretics and age were predictors for osteoporotic fractures in the risk profile model. The risk of fractures can be predicted with three easily measurable predictors. This study confirms the importance of previous fracture as a predictor for hip fractures and other fractures. It also shows that the use of loop diuretics is a predictor for osteoporotic fractures.

The performance of quantitative ultrasound (QUS) measurements of the tibia and calcaneus was studied in 109 elderly people (age range 65-87 years). Broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured at the calcaneus and SOS was assessed at the tibia. Short-term precision of tibial QUS was studied in 16 volunteers. The coefficient of variation (CV) was 0.4% and the standardized CV (sCV) was 4.4%. We compared the calcaneal and tibial QUS measurements with bone mineral density (BMD) measurements of the lumbar spine, femoral neck, trochanter and total body assessed by dual-energy X-ray absorptiometry (DXA). Calcaneal QUS correlated better with BMD at various skeletal sites than tibial QUS. Calcaneal BUA showed higher correlations with BMD values of the lumbar spine, femoral neck, trochanter and total body than calcaneal and tibial SOS (r = 0.48-0.64, r = 0.30-0.47, r = 0.35-0.47, respectively; p < 0.001). Body weight modified the relationships between calcaneal and tibial QUS and BMD measurements of the hip. Higher body weight was associated with higher BMD values at the femoral neck and trochanter for the same calcaneal and tibial QUS values. After adjustments for body weight correlations of tibial and calcaneal QUS with BMD improved and were very similar. This suggests that correction for body weight is important and could add to the predictive value of QUS measurements.

The objective of this study was to identify easily measurable predictors for falls, recurrent falls, and fractures using a population-based prospective cohort study of 1469 elderly, born before 1931, in three regions of the Netherlands. The baseline at-home interview was in 1992. In 1995, falls experienced in the preceding year and fractures over the preceding 38-month period were registered. In a period of 1 year, 32% of the participants fell at least once, and 15% fell two or more times. The rate of recurrent falls was similar in men and women up until the age of 75 years. The total number of fractures was 85, including 23 wrist fractures, 12 hip fractures, and 9 humerus fractures. The incidence density per 1000 person-years for any fracture was 25.1 (95% confidence interval [CI], 18.9-31.4) for women and 8.2 (95% CI, 4.5-12.0) for men, respectively. Multiple logistic regression identified urinary incontinence, impaired mobility, use of analgetics, and use of antiepileptic drugs as the predictors most strongly associated with recurrent falls. Female gender, living alone, past fractures, inactivity, body height, and use of analgetics proved to be the predictors most strongly associated with fractures. The probabilities of recurrent falls were 4.7% (95% CI, 2.9-7.5%) to 59. 2% (95% CI, 24.1-86.9%) with zero to four predictors, respectively. The probability of fractures ranged from 0.0% (95% CI, 0.0-0.4%) without any of the identified predictors to 12.9% (95% CI, 4.4-32. 2%) with all six predictors present. Our study shows that the risk of recurrent falls and of fractures can be predicted using up to, respectively, four and six easily measurable predictors. This study emphasizes the importance of impaired mobility and inactivity as predictors for falls and fractures.

Intravenous fluid therapy is often the only effective treatment of severely dehydrated calves. In farm animal practice, application of IV fluid therapy is still comparatively rare. A protocol for treatment of dehydration and acidosis in the field is described, along with the rationale behind each fluid used. Even without the support of sophisticated laboratory analysis, an estimated 50% of calves that are expected to die of dehydration recover after IV fluid therapy is given.