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Promising drug target for treating osteoporosis

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Osteoporosis is a skeletal condition that leads to the weakening of bones, making them porous, fragile, and prone to breakage. A massive 8.9 million fractures are caused by osteoporosis annually, with one fracture occurring every three seconds.

The ageing population is the most vulnerable to primary osteoporosis, given, their frailty, and often, requires long-term therapy and support. Advances in healthcare and the corresponding rise in the aging population have put a strain on available resources, underscoring the need for effective therapies against osteoporosis.

Induction of parathyroid hormone (PTH) signalling using the PTH-derived peptide – teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialised cells responsible for bone resorption.

Although, bone remodelling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signalling in bone remodelling are not well understood.

To bridge this gap, Professor Tadayoshi Hayata and Ms. Chisato Sampei, from Tokyo University of Science, along with their colleagues, conducted a series of experiments to identify druggable target genes downstream of PTH signalling in osteoblasts.

Explaining the rationale behind their study published in the Journal of Cellular Physiology, corresponding author, Professor Hayata commented: “In Japan, it is estimated that 12.8 million people, or one in ten people, suffer from osteoporosis, which can significantly deteriorate their quality of life. Teriparatide is classified as a drug that promotes bone formation, but it also promotes bone resorption, which may limit bone formation. However, the full scope of its pharmacological action remains unknown.”

The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene – ‘Gprc5a’, encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.

PTH induction has been known to activate the cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC) signalling pathways. Interestingly, the team found that in addition to PTH induction, activation of cAMP and PKC also resulted in overexpression of Gprc5a, albeit to a lesser extent, underscoring the potential involvement of other molecular pathways. Notably, upregulation of Gprc5a was suppressed upon inhibition of transcription, but, remained unaffected upon suppressing protein synthesis, suggesting that Gprc5a could be transcribed early on in response to PTH signalling and serves as a direct target gene.

Furthermore, the researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation.

Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3) – a bone morphogenetic protein (BMP) signalling pathway receptor, as an interacting partner of Gprc5a. In line with their speculation, overexpression of Gprc5a indeed, led to suppression of BMP signalling via receptors including ALK3.

Overall, these findings reveal that Gprc5a – a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation, by partially suppressing BMP signalling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis. The study sheds light on the complex process of bone remodelling and explains the bone-promoting and bone-resorbing effects of PTH signalling.

“Our study shows Gprc5a may function as a negative feedback factor for the bone formation promoting effect of teriparatide. Suppressing Gprc5a function may, therefore, increase the effectiveness of teriparatide in non-responding patients. In the future, we hope that our research will lead to improved quality of life and healthy longevity for people suffering from osteoporosis,” concluded Hayata.

Mobility

A new way forward for managing obesity in older adults?

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A new seven-point strategy for better managing obesity in the care of older adults has been set out by the Gerontological Society of America (GSA).

Their aim is to remove the barriers to quality care caused by obesity; with education, attention to language usage and focus on the care environment among the areas covered.

The GSA outlined the recommendations at its annual summit in Washington this week, and in a new publication, “Bringing Obesity Management to the Forefront of Care for Older Adults.”

GSA member John A. Batsis, from the University of North Carolina, said: “Obesity is now recognised as a chronic disease requiring lifelong therapy to correct abnormalities in a complex interplay of genetics, gastrointestinal and pancreatic hormones, gut-brain signaling, the environment, and socioeconomic factors.”

Moreover, he added that older adults are particularly vulnerable to the negative consequences of overweight and obesity.

Fellow GSA member Kathryn N. Porter Starr, from Duke University, said: “Older adults should be cared for by an inter-professional team during the weight loss process to ensure that the clinical goals are achieved without compromising overall health or other conditions.

“Patients may need long-term contact with registered dietitians, exercise physiologists, physical and/or occupational therapists, social workers, pharmacists, and other involved members of the health care team.”

The seven strategies to address barriers to quality obesity care for older adults are:

  1. Inform and educate about obesity as a chronic disease, requiring care across the lifespan.
  2. Address weight bias and stigma among health providers and the public.
  3. Use person-first language when referring to someone who has obesity.
  4. Respect and honor cultural considerations about body size.
  5. Engineer environments of care to accommodate people of all body sizes.
  6. Ensure access to the full range of care for older adults with obesity: diet, exercise, behavioral modification, and medical and surgical interventions.
  7. Incorporate an inter-professional, evidence-based approach to caring for older adults who have obesity.

The GSA summit was attended by researchers, clinicians, and representatives from a variety of communities of interest including advocacy organisations and professional societies.

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Mobility

Videoconferencing gets older adults moving

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An Osaka Metropolitan University-led research team has been exploring how videoconferencing can improve the health of older adults living in the countryside.

The COVID-19 pandemic made videoconferencing software commonplace in businesses and even schools, but this communication tool has the potential to offer benefits beyond the office or classroom.

OMU Associate Professor Kazuki Uemura of the Graduate School of Rehabilitation Science and colleagues devised a 12-week health education programme conducted using the videoconferencing software Zoom, with the aim of having participants engage in active learning. A control group was provided a similar 12-week programme by email, with attached pdf files giving health instructions in a passive learning format.

The researchers assessed the participants before and after the 12 weeks, then performed a follow-up at 36 weeks. Their results showed that compared to the control group the videoconferencing group tended to follow the health advice and showed some improvement in the amount of time spent doing physical activities as opposed to sedentary behaviour.

“This study proposes a new health education programme that is not dependent on location or distance and takes sustainable behavioural changes into consideration,” Professor Uemura suggested. “In the future, by expanding the implementation scale and conducting further verification, we aim to popularize such health programmes that everyone, everywhere can participate in.”

The findings were published in the Journal of Aging and Physical Activity.

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Independence

NHS health records help predict risk of falling

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Patients’ risk of falling in the next 12 months could be predicted from their NHS data using a newly developed calculator.

eFalls is a falls prediction model which uses routinely available primary care electronic health record data, the first of its kind in the world.

Developed and tested by researchers from the University of Leeds, the University of Birmingham, and a team of collaborators*, with funding from the National Institute for Health and Care Research (NIHR), it can be used to help identify people at risk of hospitalisation or emergency department attendance after a fall over the next 12 months. This means these people can be provided with interventions to prevent falls taking place.

A research paper outlining the findings is published in Age and Ageing

Falls are common among people aged over 65 and can be devastating for people’s personal independence. The risks are multifactorial and include conditions that affect mobility or balance; medications, and home hazards. A history of falls is the strongest risk factor. The incidence of falls is also projected to rise in line with the global ageing demographic.

The findings help proactive identification of people who are at risk of experiencing a fall in the next 12 months. eFalls uses existing primary care data, reducing the need for intensive clinical falls assessment, saving doctors and nurses valuable time. Once identified as at risk of falling, people can be referred on to a specialist falls prevention service for assessment and treatment to prevent future falls.

The National Institute for Health and Care Excellence (NICE) estimates that 40% to 60% of falls result in major lacerations, traumatic brain injuries, or fractures. Other complications of falls include distress, pain, loss of self-confidence, reduced quality of life, loss of independence, and mortality.

Principal Investigator Andrew Clegg, Professor of Geriatric Medicine in the University of Leeds School of Medicine, said: “Falls are a global health problem of major importance to health and social care systems. Currently, people’s fall risk is usually only assessed when they have already experienced a fall, which means that they might have already experienced a major injury such as a hip fracture.

“Our eFalls calculator means that, for the first time, it is possible to proactively identify a person’s risk of future falls which means that they can be referred to specialist falls prevention services, reducing the risk of a fall from happening. The ability to put plans in place to protect those at risk is invaluable to the patient and their loved ones.

“The benefit to the health service is that it reduces the need for treatment and care in hospital and in the community, and the associated costs to the NHS of that treatment. We hope that eFalls will be widely adopted across the NHS to prevent falls from taking place.”

Lead author Lucinda Archer, Assistant Professor in Biostatistics at the University of Birmingham, said: “The eFalls calculator can be used to predict a person’s risk of a fall, based on information that is already included in their GP records. The accuracy of the tool has been thoroughly tested in two large datasets, containing routinely recorded information on patients from Wales and England, which has shown promising results.

“If this accuracy is consistent across the wider population, the use of eFalls to target those who would benefit from specialist assessment could vastly improve the way that falls prevention services are provided in the UK.”

Health Minister Andrew Stephenson said: “Suffering from a fall can be traumatic for both the individual and their family but innovations such as eFalls could provide a fantastic solution to prevent such incidents, saving people from a lot of pain, as well as time and resource for the NHS.

“Our ongoing work to ensure people get the right care at the right time includes giving people access to local falls services and rehabilitations services, but I’m proud that the UK is at the forefront of developing further solutions to such a widespread issue, through co-funding the development of this technology.”

The team set out to produce and assess a robust and reliable method to proactively identify people for falls prevention interventions, due to the currently limited availability of such systems.

The team developed the eFalls tool using data from more than 750,000 healthcare records. Of these almost 35,000 people experienced a fall or a fracture resulting in A&E attendance or hospitalisation within 12 months.

The researchers now hope the eFalls prediction model to be successfully integrated into UK primary care electronic patient record systems and are keen to work with UK policymakers to explore how eFalls could be used to inform health policy.

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