Tag Archives: #boneloss

A Compound That Slows Bone Loss, and a Resource for Developing Treatments to Slow Aging (Biology)

A compound that extends lifespan in a tiny nematode worm slows bone loss in aging mice. That surprising result comes from a longitudinal and functional study of 700 aging mice at the Buck Institute, a project that provides a treasure trove of data for researchers aiming to develop therapeutics to slow aging and age-related diseases.  The study is currently online in the Journal of Bone and Mineral Research Plus.

The project, which involved five Buck labs and took several years to complete, involved serially profiling the individual mice as they aged while testing several therapeutics that extended lifespan in simple model organisms or reduced neurological disease in mice. Researchers established rates of change for clinically significant parameters in untreated mice including kyphosis, blood glucose, body composition, activity, metabolic measures and detailed parameters of skeletal aging in bone.  The study involved collecting and analyzing terabytes of data over several years.

The online application is available at https://danielevanslab.shinyapps.io/buckMouseAging/

Simon Belov © Buck Institute

“This is a unique resource that comes from a study of multiple phenotypes of aging that had never been looked at before,” said Buck professor Simon Melov, PhD, senior author of the paper. “Our hope is that our data will enable those working on pre-clinical studies to essentially model experiments virtually, in order to provide a starting point for testing other interventions in mice.” 

Benzoxazole, the compound that slowed bone aging by up to 31% over the course of a year’s treatment in the mice, was first identified as one of five compounds that extended nematode lifespan in the Lithgow lab in a study that appeared in Nature in 2011.  “If you have a therapeutic that extends lifespan in a simple animal that has no bone whatsoever, you certainly wouldn’t predict that it would slow the rate of bone aging in a mammal,” said Gordon Lithgow, PhD, Buck professor and Vice President. “It’s obvious that aging-related pathways have been conserved during evolution. This new finding is a great example of the utility of screening compounds in simple animals as the starting point to look for unexpected and surprising benefits in mammals.” In the Nature article, benzoxazole appeared to suppress age-related protein aggregation.  The mechanism of action in mouse bone is still under study, although researchers say the compound appears to slow the reabsorption of osteoclasts, bone cells that are active during growth and healing.

Gordon Lithgow © Buck Institute

Melov says the findings in the large study are relevant to humans, especially in regards to pre-clinical phenotypes. “The metrics we used are all directly applicable to aging in humans. They literally have direct clinical correlates to the types of things you would measure in humans.” For example, for the first time researchers witnessed spontaneous fractures in aging mouse femurs.  Melov says they occurred in 2.5% of the mouse population, not dissimilar to the 1 -2.7% incidence of hip fractures in people over the age of 65.  He also notes that they developed a new unbiased method for evaluating kyphosis, an age-related curvature of the spine, and may pave the way for testing new interventions.

“We think using this new database could save substantial resources for those wanting to do pre-clinical studies of interventions,” said Melov.  “If someone wants to test a compound against a particular aging phenotype this database could provide information about how many mice are needed for the experiments and how long it would likely take to see results.”

This work was supported by grants from the Larry L. Hillblom Foundation; The American Foundation for Aging Research; NIH Grants U19AG023122,  U24AG051129, AG055822, AG061879, AG051129, UL1DE019608, AG038688 & AG045835, and AR56679; the Glenn Foundation for Medical Research; the Ellison Medical Foundation; and family and friends of Catherine Munson.

Featured image: Kyphosis: Green = Young mice; Red = Old mice

Reference: Evans, D.S., O’Leary, M.N., Murphy, R., Schmidt, M., Koenig, K., Presley, M., Garrett, B., Kim, H.‐N., Han, L., Academia, E.C., Laye, M.J., Edgar, D., Zambataro, C.A., Barhydt, T., Dewey, C.M., Mayfield, J., Wilson, J., Alavez, S., Lucanic, M., Kennedy, B.K., Almeida, M., Andersen, J.K., Kapahi, P., Lithgow, G.J. and Melov, S. (2021), Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs. JBMR Plus. Accepted Author Manuscript e10466. https://doi.org/10.1002/jbm4.10466

Provided by Buck Institute

Anorexia Nervosa Treatment: Patients Tolerate Rapid Weight Gain With Meal-Based Behavioral Support (Medicine)

A new study by Johns Hopkins Medicine researchers of adults hospitalized for the eating disorder anorexia nervosa has strengthened the case for promoting rapid weight gain as part of overall efforts for a comprehensive treatment plan. The study findings, after analyzing data regarding 149 adult inpatients with anorexia nervosa in the Johns Hopkins Eating Disorders Program, stand in contrast to long held beliefs that patients would not tolerate a faster weight gain plan because it would be too traumatic.

Credit: Getty Images

In a report on the work published online Oct. 7 in the International Journal of Eating Disorders, researchers say a majority of patients not only tolerated the regimen, they also met their weight gain goals in weeks rather than months, they would recommend the program to others and they would be willing to repeat it, if needed.

A form of self-starvation, anorexia nervosa is a serious psychiatric disorder in which people feel fat or fear gaining weight despite being very underweight. Over time, people with anorexia experience physical, psychological and social complications with a high risk of long-term consequences that can include heart, kidney and liver damage, bone loss, depression and self-harm. Anorexia has one of the highest mortality rates of any psychiatric condition.

The investigators say their findings also suggest that inpatient eating disorder programs that focus on rapid weight gain can minimize a patient’s time away from home, work and family, help curb treatment costs by reducing lengths of stay in a hospital or residential treatment program and be rated helpful by most patients.

“Treating anorexia is expensive due to the high cost of inpatient and residential treatment, and the cost of health care is important to both patients and health systems,” says Angela Guarda, M.D., director of the Eating Disorders Program at The Johns Hopkins Hospital. Guarda is also the Stephen and Jean Robinson Associate Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. “Our findings suggest that a meal-based nutritional approach that emphasizes faster weight gain coupled with different types of behavioral therapy and meal support is well tolerated and achieves weight restoration in a majority of patients.”

Earlier work by Guarda and others countered the belief that patients with anorexia need to gain weight slowly to avoid a potentially life threatening condition called re-feeding syndrome, which is a metabolic imbalance that can occur when severely malnourished people take in too much food or drink. Despite these safety studies, clinicians are still reluctant to implement rapid re-feeding strategies, combined with behavioral treatment approaches, because they fear that patients won’t endure them. With the new study, Guarda and her team sought the patients’ perception of the Johns Hopkins rapid re-feeding program.

For the study, researchers analyzed information gathered on 134 women and 15 men, averaging 35 years of age, who were treated and discharged from the integrated inpatient-partial hospitalization eating disorders program at The Johns Hopkins Hospital between February 2014 and June 2017. They were underweight when admitted to the program and placed on a regimen emphasizing faster weight gain, balanced meals and behavioral therapies designed to prevent relapses. The program aims to normalize eating and weight control behaviors, encourage healthier eating habits and help patients overcome their anxieties about eating a variety of foods.

More than 70% of the patients in the study reached a healthy body mass index (BMI). BMI is a measure of body fat based on height and weight. For most adults, a healthy BMI is between 18.5 and 24.9. Patients in the study achieved an average BMI of at least 19, which is within the healthy range, compared to an average of 16.1 at the beginning of the program. The average hospital stay was just 39 days, and patients gained 4 pounds per week on average — “close to twice what many intensive treatment programs achieve, which means half as much hospital time is needed to reach a healthy weight,” says Guarda.

Upon hospital discharge, patients were invited to complete an anonymous questionnaire to rate their satisfaction with the treatment. Some 107 participants (72%) completed the questionnaire. Overall, 71% of respondents said they would come back if they needed help with their eating disorder in the future, while 83% would recommend the program to others.

Like faster weight gain, Guarda explains, behavioral management is often criticized by clinicians as poorly tolerable by patients. However, the program’s focus on behavior change was rated good or very good by 83% of the patients.

Participants also rated the degree to which they felt included in the treatment (78%), and their level of satisfaction with staff members (clinical nurses: 96%, occupational therapists: 99%, dietitians: 45%, social workers: 75%). Satisfaction with intervention factors (group therapies: 79%, family meetings and education: 63%) and environmental factors (comfort of units: 50%, presentation/taste of food: 36%) was also assessed.

“Our program is solely meal-based and does not employ tube feeding,” says Guarda. Occupational therapists and nursing and dietician staff members assist patients in preparing and portioning meals, and in eating food prepared by others in cafeteria and restaurant settings. “We want to help our patients translate what they’re learning here to a more real world environment so they can stay healthy once back at home.”

According to Guarda, most patients go to inpatient programs like the one at Johns Hopkins under pressure from family members, employers or a significant other, and they are often anxious and apprehensive about entering treatment. “At the beginning, they often don’t see the need to be here,” she says, “but these results show that for most patients, their overall perception is positive by the end of treatment.”

Guarda says she’s encouraged that the field of anorexia nervosa is gradually moving toward greater and more uniform accountability about outcomes. “The standard of care should be based on evidence. Uniform, transparent reporting of weight and behavioral outcomes by treatment programs is needed so that patients, their families and referring clinicians can be more informed about treatment programs,” she says.

According to the National Eating Disorders Association, 0.9% of women and 0.3% of men will develop anorexia during their lifetime.

Additional authors on the study include Marita Cooper, Allisyn Pletch, Lori Laddaran, Graham Redgrave and Colleen Schreyer. The authors have no conflicts to declare.

This research was supported in part by the Stephen and Jean Robinson Fund.

Provided by Johns Hopkins Medicine

Targeting Myostatin/Activin A Protects Against Skeletal Muscle And Bone Loss During Spaceflight (Astronomy)

Among the major health challenges for astronauts during prolonged space travel are loss of muscle mass and loss of bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. In the recent study, Emily Lee and colleagues investigated the effects of targeting the signaling pathway mediated by the secreted signaling molecules, myostatin and activin A, in mice sent to the International Space Station.

Mice without the gene for myostatin, a protein that limits muscle growth, retained more bone and muscle mass during spaceflight than normal mice that do carry the gene. The larger of the two mice pictured here has been genetically modified to lack myostatin and, as a result, has larger muscles. (Image: © Se-Jin Lee)

They found that 24 of the 40 mice were normal, eight of them were missing the myostatin gene and eight others were treated with a molecule that suppressed both myostatin and a protein known as activin A, which has similar effects on muscle as myostatin.

Normal mice — those that carried the myostatin gene and received no protein-inhibiting treatments — lost significant muscle and bone mass during the 33 days spent in microgravity. In contrast, mice that were missing the myostatin gene and had a muscle mass about twice that of a regular mouse, largely retained their muscles during spaceflight. 

This graphic shows how effective the treatments were at mitigating the bone loss that mice experience in microgravity, with micro-computed tomography (micro-CT) images of femurs and vertebrae of mice that received or did not receive the treatment, both on Earth and at the International Space Station.  (Image credit: Se-Jin Lee)

Also, systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice.

They concluded that targeting this signaling pathway (MSTN/activin A) has significant beneficial effects in protecting against both muscle and bone loss in microgravity, suggesting that this strategy may be effective in preventing or treating muscle and bone loss not only in astronauts on prolonged missions but also in people with disuse atrophy on Earth, such as in older adults or in individuals who are bedridden or wheelchair-bound from illness.

References: Se-Jin Lee, Adam Lehar, Jessica U. Meir, Christina Koch, Andrew Morgan, Lara E. Warren, Renata Rydzik,  Daniel W. Youngstrom, Harshpreet Chandok, Joshy George, Joseph Gogain, Michael Michaud, Thomas A. Stoklasek, Yewei Liu, and  Emily L. Germain-Lee, “Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight”, PNAS, 2020, doi: https://doi.org/10.1073/pnas.2014716117