The prevention effect of pulsed electromagnetic fields treatment on senile osteoporosis in vivo via improving the inflammatory bone microenvironment.

This study aimed to assess PEMF in a rat model of senile osteoporosis and its relationship with NLRP3-mediated low-grade inflammation in the bone marrow microenvironment. A total of 24 Sprague Dawley (SD) rats were included in this study. Sixteen of them were 24-month natural-aged male SD rats, which were randomly distributed into the Aged group and the PEMF group (n = 8 per group). The remaining 8 3-month -old rats were used as the Young positive control group (n = 8). Rats in the PEMF group received 12 weeks of PEMF with 40 min/day, five days per week, while the other rats received placebo PEMF intervention. Bone mineral density/microarchitecture, serum levels of CTX-1 and P1CP, and NLRP3-related signaling genes and proteins in rat bone marrow were then analyzed. The 12-week of PEMF showed significant mitigation of aging-induced bone loss and bone microarchitecture deterioration, i.e. PEMF increased the bone mineral density of the proximal femur and L5 vertebral body and improved parameters of the proximal tibia and L4 vertebral body. Further analysis showed that PEMF reversed aging-induced bone turnover, specifically, decreased serum CTX-1 and elevated serum P1CP. Furthermore, PEMF also dramatically inhibited NLRP3-mediated low-grade inflammation in the bone marrow, i.e. PEMF inhibited the levels of NLRP3, proCaspase1, cleaved Caspase1, IL-1ß, and GSDMD-N. The study demonstrated that PEMF could mitigate the aging-induced bone loss and reverses the deterioration of bone microarchitecture probably through inhibiting NLRP3-mediated low-grade chronic inflammation to improve the inflammatory bone microenvironment in aged rats.

Serial Bone Density Changes in Women Undergoing Pelvic (Chemo) Radiation: Results From the PARCER Trial.

PURPOSE: Pelvic irradiation leads to substantial dose to the pelvic girdle. However, bone density loss as a function of radiation therapy dose and time has not been investigated. This study was undertaken to evaluate such a dose-response relationship. METHODS AND MATERIALS: Women undergoing pelvic radiation therapy for cervix cancer within a phase 3 trial were included. The study necessitated 2 computed tomography imaging sets acquired at least 12 months apart in patients with no evidence of relapse. All images were transferred to the treatment planning system to determine radiation dose and Hounsfield unit (HU). Across the entire lumbopelvic region (lumbar 1-5 [L1-5] vertebrae, pubic symphysis, femur, acetabulum, greater trochanter, and anterior-superior iliac spine) multiple regions were defined to measure radiation therapy dose and HU. Bone health was categorized as normal if >130 HU, osteopenic at 110 to 130 HU, and osteoporotic <110 HU at baseline and follow-up. Univariate analysis was performed to test the effect of various factors on HU. Further interaction among radiation therapy dose, time, and HU was assessed using a linear mixed model. RESULTS: Overall, 132 of 300 patients were eligible. The median age was 49 (42-56) years. With a prescription dose of 50 Gy, the L1 and L2 vertebrae received a median dose of 1.2 and 4 Gy, respectively, and L3-5 received 10 to 50 Gy. At 24 months, median HU loss at L4-5 was 45 HU (interquartile range, 34-77 HU). Out of the 132 patients, at baseline 96% had normal bone health. However, at the last follow-up, 3% of patients had normal bone health, 12% developed osteopenia, and 85% developed osteoporosis (P < .001). There were no patient- or treatment-related factors predicted for HU loss on univariate analysis. HU loss >60 to 70 was observed at >45 Gy at L5 vertebra (60-70 HU, P < .02) and >15 Gy at L4 vertebra (33 HU; P = .04). CONCLUSIONS: Dose-response relationship is observed between radiation dose and bone mineral density loss. Prospective studies are needed to corroborate these observations and design future interventions.

Radiotherapy of bone metastases.

We present the update of the recommendations of the French society of oncological radiotherapy on bone metastases. This is a common treatment in the management of patients with cancer. It is a relatively simple treatment with proven efficacy in reducing pain or managing spinal cord compression. More complex treatments by stereotaxis can be proposed for oligometastatic patients or in case of reirradiation. In this context, increased vigilance should be given to the risks to the spinal cord.

Bone health and osteoporosis screening in gynecologic cancer survivors.

Cancer treatment-induced bone loss is a known side effect of cancer therapy that increases the risk of osteoporosis and bone fracture. Women with gynecologic cancer are at increased risk of bone loss secondary to the combined effect of oophorectomy and adjuvant therapies. Data regarding bone loss in women with gynecologic cancers are overall lacking compared to other cancer populations. Consequently, guidelines for osteoporosis screening in women with cancer are largely based on data generated among non-gynecologic cancer survivors. This article reviews current available data of bone health in women with gynecologic cancer, summarizes best-available guidelines for screening for osteoporosis in women with cancer, and provides guidance for osteoporosis screening in women with gynecologic cancers based on best available evidence.

Aumento da hiperdensidade da cortical óssea línguo-basal após radioterapia em região de cabeça e pescoço: relato de caso / Hyperdensity of the lingual-basal bone cortex incresead after radiotherapy in the head and neck region: case report

Objetivo: relatar um caso de aumento da hiperdensidade da cortical óssea línguo-basal pós-radioterapia em região de cabeça e pescoço por meio de avaliação imaginológica. Relato de caso: paciente do sexo feminino, 80 anos, procurou tratamento odontológico com a finalidade de reabilitação oral com implantes dentários. Na anamnese, relatou histórico de carcinoma espinocelular em regiões distintas da cavidade oral. No exame clínico, notou-se que a paciente era edêntula total e foi solicitado um exame de tomografia computadorizada de feixe cônico. Foi observado, na região anterior inferior, aumento da hiperdensidade da cortical óssea línguo-basal, com osso compacto mais espesso, achado incomum na literatura após radioterapia. Considerações finais: os efeitos da radioterapia em mandíbula estão relatados na literatura. No caso clínico em questão, detectou-se uma alteração pouco notada em pacientes submetidos à radioterapia, fazendo surgir novos questionamentos, sendo eles sobre o diagnóstico dessa modificação na estrutura óssea e suas repercussões. (AU)

Objective: to report a case of increased hyperdensity of the lingual-basal bone cortex after radiotherapy in the head and neck region by means of imaging evaluation. Case report: female patient, 80 years old, sought dental treatment for the purpose of oral rehabilitation with dental implants. In the anamnesis, she reported a history of squamous cell carcinoma in different regions of the oral cavity. Upon clinical examination, it was noted that the patient was total edentulous and a cone beam computed tomography examination was requested. An increase in the hyperdensity of the lingual-basal bone cortex was observed in the lower anterior region, with thicker compact bone, an unusual finding in the literature after radiotherapy. Final considerations: the effects of radiotherapy on the mandible are reported in the literature. In the clinical case in question, a little-noticed change was detected in patients undergoing radiotherapy, leading to new questions, concerning the diagnosis of this change in bone structure and its repercussions.(AU)

Assessment of irradiated socket healing in the rabbit's mandible: Experimental study.

As bone healing is altered after external radiation therapy, its evaluation is mandatory and lacks in clinical practice. The aim of the pilot study was to validate micro computed tomography (microCT) as a simple and reliable technique for assessing irradiated bone healing in the rabbit's mandible and compare with histologic findings. Nineteen rabbits (female New Zealand white) were used. The radiation protocol consisted of 5 sessions delivering 8.5 Gy each. MicroCT was performed at D0, D7, D14, D28 and D42 for the control group and D0, D28 and D42 for the irradiated group. A modified Perry's score was determined on histologic samples, and comparison between microCT and histological findings was performed. The main differences between irradiated and non-irradiated rabbits were observed at Day 28 and 42. There was a strong correlation between imaging and histologic findings. Radiation decreases bone quality and bone mineral density. As the correlation was strong between microCT and histologic findings, micro imaging could be considered as a simple and reliable technique to assess bone healing after radiation therapy and allows an easy comparison between samples, without invasive procedures. Great attention should be kept on the parameters and on the region of interest. The development of in-vivo microCT enlarges the perspectives of microCT use in experimental studies, avoiding invasive procedures, and preserving animal lives and well-being, and furthermore lead to clinical applications.

Determinants of bone health in adults Polish women: The influence of physical activity, nutrition, sun exposure and biological factors.

PURPOSE: The aim of this study was to assess the determinants of bone health in the group of women over 40 years old. Lifestyle factors such as past and present physical activity, past and present sun exposure, current dietary intake of calcium and vitamin D, nutritional status as measured by BMI, family history of osteoporosis and current hormonal status were analysed. METHODS: The study involved 500 women over 40 years old. All examined women was the same ethnicity- European origin. Methods used: densitometry method (DXA), bioelectrical impedance analysis, International Physical Activity Questionnaire, nutrition questionnaire, past and present sun exposure questionnaire. Past and present physical activity, past and present sun exposure and sufficient level of calcium in the diet proved to be the most important factors determining mineralization of bone tissue of women. In order to indicate an independent association of the correct bone tissue mineralization with individual factors, multivariate analysis was used-logistic regression. RESULTS: The norm BMD in the distal part of the forearm was strongly influenced: recommended dietary calcium intake (OR = 5.95; p = 0.003), moderately (OR = 1.88; p = 0.053) and high (OR = 14.0; p<0.001) past physical activity, sufficient (OR = 4.97; p<0.001) and high (OR = 18.9; p = 0.004) level of present physical activity, sufficient past (OR = 5.15; p<0.001) and sufficient present sun exposure (OR = 10.0; p<0.001). The chance for the BMD prox norm was also increased several times: high past physical activity (OR = 68.4; p<0.0001) and sufficient past sun exposure (OR = 10.6; p<0.001), moderate past activity (OR = 4.20; p<0.001), sufficient (OR = 6.13; p<0.001) and high (OR = 10.0; p<0.001) present physical activity, sufficient present sun exposure (OR = 9.09; p<0.0001), recommended intake of calcium (OR = 9.57; p<0.001) and vitamin D (OR = 2.68; p = 0.052). Whereas e significantly lower likelihood for the BMD prox norm was found in women with the oldest hormonal status (postmenopausal period) (OR = 0.18; p<0.001), with osteoporosis in the family (OR = 0.37; p<0.001) and living in an agglomeration (OR = 0.68; p = 0.03). CONCLUSION: Interventions to increase physical activity, especially outdoors, may help reduce risk of osteoporosis, fractures and subsequent healthcare costs.

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice.

Spaceflight is a unique environment that includes at least two factors which can negatively impact skeletal health: microgravity and ionizing radiation. We have previously shown that a diet supplemented with dried plum powder (DP) prevented radiation-induced bone loss in mice. In this study, we investigated the capacity of the DP diet to prevent bone loss in mice following exposure to simulated spaceflight, combining microgravity (by hindlimb unloading) and radiation exposure. The DP diet was effective at preventing most decrements in bone micro-architectural and mechanical properties due to hindlimb unloading alone and simulated spaceflight. Furthermore, we show that the DP diet can protect osteoprogenitors from impairments resulting from simulated microgravity. Based on our findings, a dietary supplementation with DP could be an effective countermeasure against the skeletal deficits observed in astronauts during spaceflight.

Effect of Sunlight Exposure on Vitamin D Status of Individuals Living in a Nursing Home and Their Own Homes.

INTRODUCTION/BACKGROUND: The present study was carried out to determine prevalence of vitamin D deficiency and related factors in individuals living in nursing home and their own homes. METHODOLOGY: This cross-sectional study included 72 elderly people 60 yr and older. All subjects were given a questionnaire form evaluating their individual characteristics, eating habits which affected their vitamin D status, wearing habits, and their duration of sun exposure and a Standardized Mini Mental Test evaluating their cognitive levels. Serum 25(OH)D, calcium, parathyroid hormone, alkaline phosphatase and phosphorus levels, and bone mineral density measurements were also considered. RESULTS: Vitamin D deficiency was observed in 47% of elderly people (nursing home: 64%, own home 31%, p = 0.05). Both 25(OH)D (14 ± 8 vs 27 ± 10, respectively, p < 0.001) and ultraviolet index value (0.63 ± 0.3 vs 0.92 ± 0.27, respectively, p < 0.001) were lower in people living in nursing home compared to ones living in their own homes. Parathyroid hormone level, on the other hand, was lower in people living in own homes. Vitamin D deficiency/insufficiency was more common in elderly people living in nursing home (100%) compared to those living in their own homes (64%) (p = 0.003). Osteopenia and osteoporosis incidence rates were also higher in elderly people living in nursing home (p = 0.001). No significant associations were found between vitamin D status and body mass index, smoking or dietary habits (p > 0.05). As levels of benefiting from ultraviolet index increased, significantly improvements were observed in 25(OH)D levels (p < 0.001). CONCLUSIONS: In elderly people living in nursing home, vitamin D deficiency was higher and benefitting from ultraviolet index was lower compared to elderly people living in their own homes. Vitamin D deficiency could be prevented in elderly people, especially ones living in nursing homes, through enough sun exposure with appropriate clothing.

A Mouse Model for Skeletal Structure and Function Changes Caused by Radiation Therapy and Estrogen Deficiency.

Radiation therapy and estrogen deficiency can damage healthy bone and lead to an increased fracture risk. The goal of this study is to develop a mouse model for radiation therapy using a fractionated biologically equivalent dose for cervical cancer treatment in both pre- and postmenopausal women. Thirty-two female C57BL/6 mice 13 weeks of age were divided into four groups: Sham + non-irradiated (SHAM + NR), Sham + irradiated (SHAM + IRR), ovariectomy + non-irradiated (OVX + NR) and ovariectomy + irradiated (OVX + IRR). The irradiated mice received a 6 Gy dose of X-rays to the hindlimbs at Day 2, Day 4 and Day 7 (18 Gy total). Tissues were collected at Day 35. DEXA, microCT analysis and FEA were used to quantify structural and functional changes at the proximal tibia, midshaft femur, proximal femur and L1 vertebra. There was a significant (p < 0.05) decline in proximal tibia trabecular BV/TV from (1) IRR compared to NR mice within Sham (- 46%) and OVX (- 41%); (2) OVX versus Sham within NR mice (- 36%) and IRR mice (- 30%). With homogenous material properties applied to the proximal tibia mesh using FEA, there was (1) an increase in whole bone (trabecular + cortical) structural stiffness from IRR compared to NR mice within Sham (+ 10%) and OVX (+ 15%); (2) a decrease in stiffness from OVX versus Sham within NR mice (- 18%) and IRR mice (- 14%). Fractionated irradiation and ovariectomy both had a negative effect on skeletal microarchitecture. Ovariectomy had a systemic effect, while skeletal radiation damage was largely specific to trabecular bone within the X-ray field.

Influence of radiation exposure pattern on the bone injury and osteoclastogenesis in a rat model.

Radiotherapy, one of the clinical treatments of cancer, is accompanied by a high risk of damage to healthy tissues, such as bone loss and increased risk of fractures. The aim of the present study was to establish a rat model of local and systemic bone injury by focal irradiation, in order to study the etiological mechanism and intervention. The proximal metaphyseal region of the left hindlimb of male Sprague­Dawley rats were exposed to a single 2 Gy or three 8 Gy doses delivered on days 1, 3 and 5 using a small animal irradiator, the changes in bone volume and microarchitecture were evaluated, and the mineral apposition rate (MAR) was assessed. Furthermore, bone marrow­derived macrophages (BMMs) were isolated and induced to osteoclasts. It has been demonstrated that a single dose of 2 Gy may result in a significant loss of lumbar bone density at 3 days post­irradiation, however this is restored at 30 days post­irradiation. In the 3x8 Gy irradiation rat model, there was a rapid decrease in the aBMD of lumbar spine at 3 days and at 7 days post­irradiation, and the aBMD decline persisted even at 60 days post­irradiation. In addition, microCT analysis revealed a persistent decline in bone volume and damage in microarchitecture in the 3x8 Gy irradiation model, accompanied by a decrease in MAR, index of the decline in bone­forming ability. In the cellular mechanism, a single 2 Gy local irradiation mainly manifested as an enhancement of the BMMs osteoclastogenesis potential, which was different from the osteoclastogenesis inhibition after high­dose focal irradiation (3x8 Gy). In summary, the irradiation with simulated clinical focal fractionated radiotherapy exerts short­ and long­term systemic injury on bone tissue, characterized by different osteoclastogenesis potential between the high dose mode and a single 2 Gy focal irradiation. Physicians must consider the irreversibility of bone damage in clinical radiotherapy.

Effects of ex vivo ionizing radiation on collagen structure and whole-bone mechanical properties of mouse vertebrae.

Bone can become brittle when exposed to ionizing radiation across a wide range of clinically relevant doses that span from radiotherapy (accumulative 50 Gy) to sterilization (~35,000 Gy). While irradiation-induced embrittlement has been attributed to changes in the collagen molecular structure, the relative role of collagen fragmentation versus non-enzymatic collagen crosslinking remains unclear. To better understand the effects of radiation on the bone material without cellular activity, we conducted an ex vivo x-ray radiation experiment on excised mouse lumbar vertebrae. Spinal tissue from twenty-week old, female, C57BL/6J mice were randomly assigned to a single x-ray radiation dose of either 0 (control), 50, 1000, 17,000, or 35,000 Gy. Measurements were made for collagen fragmentation, non-enzymatic collagen crosslinking, and both monotonic and cyclic-loading compressive mechanical properties. We found that the group differences for mechanical properties were more consistent with those for collagen fragmentation than for non-enzymatic collagen crosslinking. Monotonic strength at 17,000 and 35,000 Gy was lower than that of the control by 50% and 73% respectively, (p < 0.001) but at 50 and 1000 Gy was not different than the control. Consistent with those trends, collagen fragmentation only occurred at 17,000 and 35,000 Gy. By contrast, non-enzymatic collagen crosslinking was greater than control for all radiation doses (p < 0.001). All results were consistent both for monotonic and cyclic loading conditions. We conclude that the reductions in bone compressive monotonic strength and fatigue life due to ex vivo ionizing radiation are more likely caused by fragmentation of the collagen backbone than any increases in non-enzymatic collagen crosslinks.

Photobiomodulation by a 635nm Diode Laser on Peri-Implant Bone: Primary and Secondary Stability and Bone Density Analysis-A Randomized Clinical Trial.

INTRODUCTION: Various procedures in dental implantology are performed to enhance the bone healing process and implant stability. One of these methods can be a low-level laser therapy (LLLT). OBJECTIVES: The aim of our study was to evaluate the stabilization (primary and secondary) and bone density in peri-implant zone after LLLT protocol using a 635 nm diode laser. MATERIAL AND METHODS: The research included 40 implants placed in the posterior region of a mandible in 24 patients (8 women and 16 man; age: 46.7 ± 8.7 years). The patients were randomly divided into 2 groups G1 (n=12, 18 implants) and G2 (n=12, 22 implants) according to the treatment procedure; G1 (test): 635 nm laser, with handpiece diameter: 8mm, output power: 100mW, spot area: 0.5024cm2, average power density: 199.04mW/cm2, continuous mode, dose: 4J per point (8J/cm2), time: 40 sec per point, 2 points (irradiation on a buccal and a lingual side of the alveolus/implant), and total energy per session 8J; G2 (control): no laser irradiation. The G1 (test) group's implants were irradiated according to the following protocol: 1 day before surgery, immediately after the surgery and 2, 4, 7, and 14 days after. The total energy after all therapeutic sessions was 48J. The implants stability was measured employing a Periotest device (Periotest Test Value: PTV) (measured immediately after the surgery, 7 days, 2 weeks, 4 weeks, and 2 and 3 months after the surgery) and the bone density using cone-beam computed tomography (grayscale value) (measured immediately after the surgery, 4 weeks and 12 weeks after the treatment). RESULTS: The average implant stability at different time points showed lower PTV value (higher stability) at 2nd and 4th week after 635 nm laser irradiation (G1) compared with a control (G2) group (p<0.01). The secondary stability of the implants after 12 weeks observation was not significantly higher for the laser group in contrast to none-irradiated implants (p>0.05). The mean grayscale value at the apical, middle, and cervical level of the titanium implants showed the reduction of pixel grayscale value after 2 weeks and was lower for the G1 group in contrast to the G2 group (p<0.01). The value of grayscale after 12 weeks was significantly higher at the middle and apical level of the implants in the G1group in contrast to the G2 group (p<0.01). CONCLUSION: The application of the 635 nm diode laser enhanced secondary implant stability and bone density. However, to assess the impact of the LLLT on peri-implant bone with different bone densities, further well-controlled long-term trials on larger study groups are needed.

Pulsed electromagnetic fields promote bone formation by activating the sAC-cAMP-PKA-CREB signaling pathway.

The application of pulsed electromagnetic fields (PEMFs) in the prevention and treatment of osteoporosis has long been an area of interest. However, the clinical application of PEMFs remains limited because of the poor understanding of the PEMF action mechanism. Here, we report that PEMFs promote bone formation by activating soluble adenylyl cyclase (sAC), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) signaling pathways. First, it was found that 50 Hz 0.6 millitesla (mT) PEMFs promoted osteogenic differentiation of rat calvarial osteoblasts (ROBs), and that PEMFs activated cAMP-PKA-CREB signaling by increasing intracellular cAMP levels, facilitating phosphorylation of PKA and CREB, and inducing nuclear translocation of phosphorylated (p)-CREB. Blocking the signaling by adenylate cyclase (AC) and PKA inhibitors both abolished the osteogenic effect of PEMFs. Second, expression of sAC isoform was found to be increased significantly by PEMF treatment. Blocking sAC using sAC-specific inhibitor KH7 dramatically inhibited the osteogenic differentiation of ROBs. Finally, the peak bone mass of growing rats was significantly increased after 2 months of PEMF treatment with 90 min/day. The serum cAMP content, p-PKA, and p-CREB as well as the sAC protein expression levels were all increased significantly in femurs of treated rats. The current study indicated that PEMFs promote bone formation in vitro and in vivo by activating sAC-cAMP-PKA-CREB signaling pathway of osteoblasts directly or indirectly.

Denosumab versus zoledronic acid for preventing symptomatic skeletal events in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer: an outcome analyses with a mean follow-up of 3 years.

BACKGROUND: The purpose of this study was to evaluate the efficacy of denosumab or zoledronic acid (ZA) using symptomatic skeletal events (SSEs) as the primary endpoint in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer. METHODS: Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer receiving subcutaneous denosumab 120 mg Q4W, or intravenous ZA 4 mg Q4W until the primary analysis cut-off date were retrospectively analysed in the Hong Kong Practice-Based Cancer Research Center(HKCRC) from March 2011 to March 2013. The time to first on-study SSE that was assessed either clinically or through routine radiographic scans was the primary endpoint. RESULTS: 242 patients received denosumab or ZA treatment (n = 120, mean age of 64.9 years (SD 3.01) and n = 122, 65.4 years (3.44), respectively). The median times to first on-study SSE were 14.7 months (12.9-45.6) and 11.7 months (9.9-45.6) for denosumab and ZA, respectively (hazard ratio, HR 0.44, 95% CI 0.71-2.95; p = 0·0002). Compared with the ZA group, denosumab-treated patients had a significantly delayed time to first SSE (HR 0.65 [95% CI 0.29-1.45], p < 0.0001). An increased incidence of SSE was found in the 16-month follow-up with rates of 2.1 and 10.7% for denosumab and ZA, respectively (P = 0.033). The difference persisted with time with rates of 8.3 and 17.2% at the final follow-up, respectively (P < 0.05). CONCLUSION: In postmenopausal women aged ≥60 years with oestrogen-receptor-positive advanced breast cancer, denosumab significantly reduced the risk of developing SSEs compared with ZA. The findings of this pilot trial justify a larger study to determine whether the result is more generally applicable to a broader population.

Late vertebral side effects in long-term survivors of irradiated childhood brain tumor.

PURPOSE: Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. METHODS: 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. RESULTS: 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation-induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. CONCLUSION: Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.

Bone density and pain response following intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for vertebral metastases - secondary results of a randomized trial.

BACKGROUND: This was a prespecified secondary analysis of a randomized trial that analyzed bone density and pain response following fractionated intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) for palliative management of spinal metastases. METHODS/MATERIALS: Sixty patients were enrolled in the single-institutional randomized exploratory trial, randomly assigned to receive IMRT or 3DCRT (30 Gy in 10 fractions). Along with pain response (measured by the Visual Analog Scale (VAS) and Chow criteria), quantitative bone density was evaluated at baseline, 3, and 6 months in both irradiated and unirradiated spinal bodies, along with rates of pathologic fractures and vertebral compression fractures. RESULTS: Relative to baseline, bone density increased at 3 and 6 months following IMRT by a median of 24.8% and 33.8%, respectively (p < 0.01 and p = 0.048). These figures in the 3DCRT cohort were 18.5% and 48.4%, respectively (p < 0.01 for both). There were no statistical differences in bone density between IMRT and 3DCRT at 3 (p = 0.723) or 6 months (p = 0.341). Subgroup analysis of osteolytic and osteoblastic metastases showed no differences between groups; however, mixed metastases showed an increase in bone density over baseline in the IMRT (but not 3DCRT) arm. The 3-month rate of the pathological fractures was 15.0% in the IMRT arm vs. 10.5% in the 3DCRT arm. There were no differences in pathological fractures at 3 (p = 0.676) and 6 (p = 1.000) months. The IMRT arm showed improved VAS scores at 3 (p = 0.037) but not 6 months (p = 0.430). Using Chow criteria, pain response was similar at both 3 (p = 0.395) and 6 (p = 0.732) months. CONCLUSIONS: This the first prospective investigation evaluating the impact of IMRT vs. 3DCRT on bone density. Along with pain response and pathologic fracture rates, significant rises in bone density after 3 and 6 months were similar in both cohorts. Future randomized investigations with larger sample sizes are recommended. TRIAL REGISTRATION: NCT, NCT02832830 . Registered 14 July 2016.

Modeling Space Radiation Induced Bone Changes in Rat Femurs through Finite Element Analysis.

As the duration of manned missions outside of the Earth's protective shielding increase, astronauts are at risk for exposure to space radiation. Various organ systems may be damaged due to exposure. This study investigates the bone strength changes using finite element modeling of Long Evans rats (n=85) subjected to graded, head-only proton (0, 10, 25, and 100 cGy, 150 MeV/n) and 28silicon (0, 10, 25, and 50 cGy, 300 MeV/n) radiation. The strength of the femoral neck will be examined due its clinical relevance to hip fractures. It has been shown in previous studies that bone mineral density was not reduced at the site of fracture. These findings question whether measurements of bone mineral density may be used to assess risk of hip fracture. The mechanisms leading to the irregular relationship between bone density and strength are still uncertain within literature and investigated to greater extent in clinical applications. Finite element analysis within this study simulated physiological loading of the femoral neck. No significant changes in femoral neck strength were found across doses of proton or 28silicon head-only radiation. Future work includes performing mechanical testing of the bone samples. Moving from mouse to larger animal models may also provide the increased lifespan for assessing the long-term outcomes of radiation exposure.

Pulsed electromagnetic fields prevented the decrease of bone formation in hindlimb-suspended rats by activating sAC/cAMP/PKA/CREB signaling pathway.

Microgravity is one of the main threats to the health of astronauts. Pulsed electromagnetic fields (PEMFs) have been considered as one of the potential countermeasures for bone loss induced by space flight. However, the optimal therapeutic parameters of PEMFs have not been obtained and the action mechanism is still largely unknown. In this study, a set of optimal therapeutic parameters for PEMFs (50 Hz, 0.6 mT 50% duty cycle and 90 min/day) selected based on high-throughput screening with cultured osteoblasts was used to prevent bone loss in rats induced by hindlimb suspension, a commonly accepted animal model to simulate the space environment. It was found that hindlimb suspension for 4 weeks led to significant decreases in femoral and vertebral bone mineral density (BMD) and their maximal loads, severe deterioration in bone micro-structure, and decreases in levels of bone formation markers and increases in bone resorption markers. PEMF treatment prevented about 50% of the decreased BMD and maximal loads, preserved the microstructure of cancellous bone and thickness of cortical bone, and inhibited decreases in bone formation markers. Histological analyses revealed that PEMFs significantly alleviated the reduction in osteoblast number and inhibited the increase in adipocyte number in the bone marrow. PEMFs also blocked decreases in serum levels of parathyroid hormone and its downstream signal molecule cAMP, and maintained the phosphorylation levels of protein kinase A (PKA) and cAMP response element-binding protein (CREB). The expression level of soluble adenylyl cyclases (sAC) was also maintained. It therefore can be concluded that PEMFs partially prevented the bone loss induced by weightless environment by maintaining bone formation through signaling of the sAC/cAMP/PKA/CREB pathway. Bioelectromagnetics. 39:569-584, 2018. © 2018 Wiley Periodicals, Inc.

177 Lu-DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line.

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium-177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half-life and convenient production logistics. 177 Lu-DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by 177 Lu-DOTMP in MG63 cells. 177 Lu-DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of 177 Lu-DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose-dependent. Thus, 177 Lu-DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases.