Combat-related injuries to bone are common in military personnel and can lead to pain and disability. Results from a new study in the Journal of Bone and Mineral Research suggest that amputations for such injuries may negatively affect bone mass.
Traumatic amputation from combat injuries has the potential to lead to osteoporosis through not only systemic inflammation and hormonal changes but also altered loading. Although a documented long-term complication of lower limb amputation is osteoporosis, this is often observed in older less active subjects with comorbidities, thus it is unknown whether this is secondary to systemic changes or changes to the loading environment.
In the study of 575 male adult UK military personnel with combat-related traumatic injuries and 562 without such injuries, veterans who sustained traumatic amputations often had low bone density in the hip region. Changes in bone health appeared to be mechanically driven rather than systemic and were only evident in those with lower limb amputations.
“We hope these results will drive further research into ways to reverse bone mineral density changes,” said co-author Group Captain Alex Bennett, Defence Professor of Rehabilitation, Defence Medical Rehabilitation Centre. “We need to investigate the role of prosthetics and exercise in reversing bone mineral density loss to reduce the longer-term risk of hip fracture. Because systemic treatments like bisphosphonates are not indicated in this young population with bone mineral density loss, it is important to understand other ways to reduce their hip fracture risk.”
Van Andel Institute scientists have pinpointed a key driver of low bone density, a discovery that may lead to improved treatments with fewer side effects for women with osteoporosis. Their findings appear in the journal Science Advances.
Their research reveals that loss of an epigenetic modulator, KDM5C, preserves bone mass in mice. KDM5C works by altering epigenetic ‘marks’, switches that ensure the instructions written in DNA are read in the right time and place.
Several medications are approved to treat osteoporosis but fears of rare, severe side effects often are a barrier for their use. Treatments that leverage the hormone oestrogen also are available, but are only recommended for low-dose, short-term use due in part to associations with cancer risk.
It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age.
To figure out why this happens, VAI Associate Professors Connie M. Krawczyk, PhD, and Tao Yang, PhD, and their teams looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on osteoclasts, which help maintain bone health by breaking down and recycling old bone.
“Osteoporosis is a common disease that can have debilitating outcomes,” Yang said. “KDM5C is a promising target to treat low bone mass in women because it is highly specific. We’re hopeful that our findings will contribute to improved therapies.”
The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down the recycling process and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males.
“Lowering KDM5C levels is like flipping a switch to stop an overactive recycling process. The result is more bone mass, which ultimately means stronger bones,” Krawczyk said. “We’re very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis.”
New research published in the Journal of Food and Medicine reports that daily prunes consumption protects bone health in men over 50. This study is the first of its kind to examine the beneficial prune effect on bones in men.
Some 2 million men are estimated to be battling osteoporosis and another 16.1 million men have osteopenia, or low bone mass. Despite these numbers, bone disease in men is often overlooked.
“We’ve already seen significant evidence that prunes have a positive effect on bone health in women, so it’s particularly exciting to find that prunes can also play a beneficial role in men’s bone health. We look forward to continuing to study the ‘prune effect’ on bone and other health outcomes in men,” said lead researcher Professor Shirin Hooshmand at San Diego State University.
In this study, 57 healthy men aged 50-79 years old were randomised to either consume 100 grams of prunes every day or no prunes for twelve months. After a year, the prune consumers showed significant decreases in biomarkers of bone breakdown, while no changes were observed in the control group. The study authors also reported the men who ate prunes showed improvements in bone geometry indicating greater bone strength.
Historically, research has focused on osteoporosis and bone health in women, already indicating a favorable bone response to prunes specifically among postmenopausal women. Several studies have suggested that eating 50 to 100 grams of prunes everyday could lead to increased bone mass and decreased bone breakdown. Moreover, a recent case study earlier this year reported that total bone mineral density increased in a postmenopausal woman with osteopenia after she consumed 50 grams of prunes daily for 16 months.
“Bone health is not just a concern for women. Men need to think about how to protect their bones as well,” said Leslie Bonci, MPH, RDN and consultant with the California Prune Board. “Prunes are a shelf-stable and nutrient-packed food that provide a preventive, proactive, palatable option for men to optimize their bone health.”
While San Diego State University’s newest research is an exciting addition to existing prune-focused literature, more work on the effect of prunes on human bone health is currently underway. An upcoming study from Pennsylvania State University examines how consuming different amounts of prunes affects health outcomes in postmenopausal women over a one-year period. The study not only explores the impact of prunes on bone health, but it will also look at the prune-effect on inflammation and gut health.
A new discovery about a signalling function in osteoclasts suggests a potential treatment target for osteoporosis and for bone loss from rheumatoid arthritis.
The findings from University of Virginia School of Medicine researchers and their collaborators help us understand why osteoclastsbegin to break down more bone than the body replaces.
“Bone degradation and subsequent repair are fine-tuned through complex interactions between the cells that degrade the bone – osteoclasts – and those that produce new bone matrix. Simple elimination of osteoclasts is, therefore, not always the best approach to treat pathologic bone loss. Instead, we found a ‘signalling node’ in osteoclasts that regulates their function in degrading the bone, but doesn’t reduce osteoclast numbers,” said researcher Sanja Arandjelovic of UVA’s Department of Medicine and UVA’s Carter Immunology Center.
With further research, it may be possible for scientists to one day be able to develop drugs that target the signalling node to prevent or treat bone loss. This discovery also helps explain why some previous attempts to develop osteoporosis treatments produced disappointing results. Researcher Kodi Ravichandran, chair of UVA’s Department of Microbiology, Immunology and Cancer Biology and director of UVA’s Center for Cell Clearance, noted the potential of the findings to inform efforts to develop better treatments for osteoporosis: “In this study,” he said, “we identified previously unappreciated factors that contribute to osteoclast function that are truly exciting and open up new avenues to pursue.”
The researchers have found an important contributor, a cellular protein called ELMO1, which promotes the activity of the bone-removing osteoclasts. Osteoclasts are critical for bone health, as they normally remove just enough to stimulate new bone growth. The problem arises when the osteoclasts become too aggressive and remove more bone than the body makes, resulting in bone mass loss.
This excessive bone degradation is likely influenced by genetic factors, the researchers say. They note that many of the genes and proteins linked to ELMO1 have been previously associated with bone disorders and osteoclast function.
Encouragingly, the researchers were able to prevent bone loss in lab mice by blocking ELMO1, including in two different models of rheumatoid arthritis. That suggests clinicians may be able to target the protein in people as a way to treat or prevent bone loss caused by osteoporosis and rheumatoid arthritis, the researchers say.
They note that prior efforts to treat osteoporosis by targeting osteoclasts have had only mixed success, and they offer a potential explanation for why: Osteoclasts not only remove bone, but play a role in calling in other cells to do bone replacement. As such, targeting ELMO1 may offer a better option than simply waging war on the osteoclasts.
“We used a peptide to target ELMO1 activity and were able to inhibit degradation of the bone matrix in cultured osteoclasts without affecting their numbers,” Ravichandran said. “We hope that these new osteoclast regulators identified in our study can be developed into future treatments for conditions of excessive bone loss such as osteoporosis and arthritis.”
Researchers have found that a substance derived from Saussurea controversa, a member of the thistle family, may have significant potential in recovering lost bone mass.
Metabolic bone diseases such as osteoporosis are called the silent epidemic of the 21st century. A person may only become aware of their condition by sustaining a hip or spine fracture.
According to statistics, every third woman and every fifth man after 50 have osteoporosis. Thus, it is promising to search for and obtain substances and materials for implants that have osteoinductive properties and are capable of initiating the processes of transformation of stem cells into bone.
Certain trace elements, such as calcium and magnesium, influence the processes of bone regeneration and the maintenance of their normal structure. Organic molecules that can bind to them provide an improvement in the selectivity of their therapeutic action – the resulting complexes play a significant role in bone formation and development. From this point of view, salts of chelidonic acid have great potential, for example, from the Saussurea controversa known since ancient times for its healing properties.
Researchers from the Immanuel Kant Baltic Federal University, Siberian State Medical University, and Tomsk Polytechnic University had previously discovered that calcium chelidonate is a promising drug for bone volume restoration.
In their latest work, they obtained this substance in a semisynthetic way: extracts from Saussurea controversa were the source of the chelidonic acid, to which an alkali solution and calcium chloride were added.
“The content of this substance differs in the samples of raw material and, most likely, its biosynthesis depends on the amount of calcium in the soil. For pharmaceutical purposes, it is advisable to use calcium chelidonate obtained by a semisynthetic method,” explained Elena Avdeeva, candidate of pharmaceutical sciences, researcher, Siberian State Medical University
An X-ray analysis confirmed that the substance has a structure identical to a natural compound. Researchers tested the effect of the substance in vitro and in vivo: it promoted the conversion of human stem cells derived from adipose tissue (hAMMSC) and mouse mesenchymal stromal cells into osteoblasts respectively.
Calcium chelidonate is non-toxic and promotes bone regeneration: in vitro studies have shown that a dose of only 10mg/L increases the number of viable stem cells. Titanium implants coated with calcium phosphate and bearing autologous bone marrow were introduced into mice. The researchers found that calcium chelidonate stimulated the growth of new bone on the surface of the implant with daily administration of the drug for 35 days.
“The use of substances with osteoprotective properties, in particular, calcium chelidonate, is promising for the treatment of several diseases associated with bone defects or bone metabolism disorders. We are considering the development of a pharmaceutical form of the substance and its introduction into practical medicine,” concluded Larisa Litvinova, Doctor of Medicine, professor, head of the laboratory of immunology and cellular biotechnology at the IKBFU.
Journal information: Avdeeva, E., et al. (2021) Calcium Chelidonate: Semi-Synthesis, Crystallography, and Osteoinductive Activity In Vitro and In Vivo. Pharmaceuticals. doi.org/10.3390/ph14060579.
Researchers have discovered some new insights into how bone mass is maintained and how physical load stimulates bone growth.
Researchers from the National Cerebral and Cardiovascular Center Research Institute in Japan have revealed that the expression of the peptide osteocrin (OSTN) is influenced by load – decreasing when load is reduced, and increasing when it is added. Their study was published in Cell Reports.
Bones and skeletal muscles are strengthened by loads produced in exercise, preventing bone and muscle atrophy, and maintaining bone and muscle strength is important for maintaining physical activity. The growth of long bones, such as the femur and tibia, is a very complex process controlled by genetic and environmental factors, such as exercise and gravity.
Understanding bone loss would help retain bone density and strength in people who are unable to exercise due to immobility, the elderly, as well as astronauts in spaceflight.
Study lead author Haruko Watanabe-Takano said, “Not much is known about how mechanical force initiates biochemical signals to control bone growth. We investigated how load is related to the metabolic balance adjustment of bone maintenance.”
Bone mass and strength is maintained by the balanced activities of two types of cells – the bone-genearting osteoblasts, and the bone-dissolving osteoclasts – and is thought to be made in response to load demand. Specifically, the team investigated the expression of OSTN, a peptide produced by osteoblasts, in mice. OSTN is critical to the regulation of bone growth, as well as physical endurance.
The researchers found that OSTN was very strongly expressed in bones such as the tibia, radius, and ulna, and in regions experiencing load. They determined that OSTN was secreted by the periosteal osteoblasts in these bones. The periosteum is a fibrous membrane that covers nearly every bone in the body, except for the joints of the long bones. This tissue has a major role in bone growth and bone repair and has an impact on the blood supply of bone as well as skeletal muscle. Despite its importance, it has received little attention in the literature and in some ways is not well understood.
“We also found that OSTN expression decreased when load was reduced, and was increased by load stimulation,” says Watanabe-Takano. “Moreover, when we genetically engineered mice lacking OSTN, we found that they had reduced bone mass compared with normal mice and lacked load-induced recovery of bone mass after prolonged load reduction. Thus, we concluded that OSTN makes bone in response to stimulation by load, promoting bone formation.”
The team found that to create this effect, OSTN increases levels of another peptide, called C natriuretic peptide, which in turn drives bone-forming osteoblasts to multiply, mature, and become functional.
The findings have implications for treatments for bed-ridden patients and others at risk of bone loss, such as the elderly. Further studies will explore issues such as how periosteal cells detect load stimulation.
Researchers at Nanyang Technological University, Singapore (NTU Singapore) have developed a new biomaterial made entirely from discarded bullfrog skin and fish scales that could help in bone repair.
The porous biomaterial, which contains the same compounds that are predominant in bones, acts as a scaffold for osteoblasts, or bone-forming cells, to adhere to and multiply, leading to new bone formation. Bone-forming cells successfully latched onto the biomaterial and started growing, and it was found to have a low inflammatory risk.
This kind of scaffold could help regenerate bone tissue lost to disease or injury, such as jaw defects from trauma or cancer surgery. It could also assist bone growth around surgical implants such as dental implants.
The current standard practice of using a patient’s own tissues means extra surgery is needed for bone extraction. The biomaterial used, frog skin and fish scales, are a significant waste stream produced by Singapore’s aquaculture industry and using them helps repurpose this waste.
‘Waste-to-resource’
“We took the ‘waste-to-resource’ approach in our study and turned discards into a high-value material with biomedical applications, closing the waste loop in the process,” said Dalton Tay, Assistant Professor, Nanyang Technological University. “Our lab studies showed that the biomaterial we have engineered could be a promising option that helps with bone repair. The potential for this biomaterial is very broad, ranging from repairing bone defects due to injury or ageing, to dental applications for aesthetics. Our research builds on NTU’s body of work in the area of sustainability and is in line with Singapore’s circular economy approach towards a zero-waste nation.”
To make the biomaterial, the team first extracted Type 1 tropocollagen (many molecules of which form collagen fibres) from the discarded skins of the American bullfrog and hydroxyapatite (a calcium-phosphate compound) from the scales of snakehead fish, commonly known as the Toman fish.
Collagen and hydroxyapatite (HA) are two predominant components found in bones, thus conferring on the biomaterial a structure, composition, and ability to promote cell attachment similar to bone, as well as toughness.
The scientists removed all impurities from the bullfrog skin, then blended it to form a thick collagenous paste that is diluted with water, from which collagen was extracted. “Using this approach, we were able to obtain the highest ever reported yield of collagen of approximately 70 per cent from frog skin, thus making this approach commercially viable,” said Asst Prof Tay, who is also from the NTU School of Biological Sciences (SBS).
HA was harvested from discarded fish scales through calcination – a purification process that requires high heat – to remove the organic matter, and then air-dried.
The biomaterial was synthesised by adding HA powder to the extracted collagen, then cast into a mould to make a 3D porous scaffold — a two-week process which the team believes can be shortened.
Testing the biomaterial
To assess the biological performance of the porous biomaterial scaffold for bone repair, the scientists seeded bone-forming cells onto the scaffold.
The cells proliferated, and after a week, the cells were uniformly distributed across the scaffold – an indicator that the scaffold could promote proper cellular activities and eventually lead to tissue formation. The scientists also found that the presence of HA in the biomaterial significantly enhanced bone formation.
The biomaterial was also tested for its tendency to cause an inflammatory response, which is common after a biomaterial is implanted in the body.
Using real-time polymerase chain reaction, the scientists found that the expression of pro-inflammatory genes in human immune cells exposed to the biomaterial stayed “relatively modest” compared to a control exposed to endotoxins, a compound known to stimulate immune response, said Asst Prof Tay.
For instance, the expression of the gene IL6 in the biomaterial group was negligible and at least 50 times lower than that of the endotoxins-exposed immune cells. This suggests that the risk of the NTU-developed biomaterial to trigger an excessive acute inflammatory response is low.
The team is now further evaluating the long-term safety and efficacy of the biomaterial as dental products. Further research would involve studying how the body responds to this biomaterial in the long term, as well its use in other applications such as skin wounds, along with further development of the waste-to-resource pipeline.
A preprint copy of the article is available as a PDF for download.
Pioneering new research has charted the unique genetic profile of the skeleton’s ‘master regulator’ cells, known as osteocytes.
The study led by the Garvan Institute of Medical Research was published in Nature Communications. The study describes the genes that are switched on or off in osteocytes, a multifunctional type of bone cell that regulates how bone material is grown or broken down in order to maintain healthy skeletons.
“This new information provides a kind of genetic shortlist we can look to when diagnosing bone diseases that have a genetic component,” said the study’s first author Dr Scott Youlten, Research Officer in the Bone Biology Lab. “Identifying this unique genetic pattern will also help us find new therapies for bone disease and better understand the impacts of current therapies on the skeleton.”
Far from static, the skeleton is a highly dynamic structure that is constantly remodelled throughout a person’s life. Though osteocytes are the most common cell type in bone, they have been hard to study as they are embedded within the skeleton’s hard mineral structure.
Osteocytes form a network inside bones on a scale and complexity which mirrors the neurons in the brain (42 billion osteocytes with over 23 trillion connections between them), which monitors bone health and responds to ageing and damage by signalling other cells to either add more bone or break down old bone. Osteoporosis, rare genetic skeletal disorders and other bone diseases arise from an imbalance in these processes.
To understand what genes are involved in controlling bone build-up or breakdown, the researchers isolated bone samples from different skeletal sites of experimental models in order to measure the average gene activity in osteocytes. In so doing, they found an osteocyte ‘signature’ of 1239 genes that are switched on. Of these genes, 77% had no previously known role in the skeleton, and many were completely novel and unique to osteocytes.
“Many of the genes we saw enriched in osteocytes are also found in neurons, which is interesting given these cells share similar physical characteristics and may suggest they are more closely related than we previously thought,” explained Dr Youlten.
Comparing the osteocyte signature genes with human genetic association studies of osteoporosis could identify new genes that may be associated with susceptibility to this common skeleton disease. Additionally, a number of these osteocyte genes were also shown to be responsible for rare bone diseases.
“Mapping the osteocyte transcriptome could help clinicians and researchers more easily establish whether a rare bone disease has a genetic cause, by looking through the ‘shortlist’ of genes known to play an active role in controlling the skeleton,” said Dr Youlten.
Co-senior author Professor Peter Croucher, Deputy Director of the Garvan Institute and Head of the Bone Biology Lab, said that “the osteocyte transcriptome map gives researchers a picture of the whole landscape of genes that are switched on in osteocytes for the first time, rather than just a small glimpse”.
“The majority of genes that we’ve found to be active within osteocytes had no previously known role in bones. This discovery will help us understand what controls the skeleton, which genes are important in rare and common skeletal diseases and help us identify new treatments that can stop development of bone disease and also restore lost bone.”
Osteoporosis is present in Almost one in five American women aged 50 and older, according to data from the National Health and Nutrition Examination Survey (NHANES), and the osteoporosis rates are increasing.
Neda Sarafrazi, PhD, of the National Center for Health Statistics (NCHS) in Hyattsville, Maryland, and colleagues reported the findings in an NCHS Data Brief.
Osteoporosis is defined as bone mineral density (BMD) value at least 2.5 standard deviations below young-adult average at the femoral neck or lumbar spine was present, and was measured in NHANES with dual x-ray absorption dosimetry.
In cross-sectional survey data from 2017-2018, 19.6% of women 50 and older had osteoporosis at the femoral neck, lumbar spine, or both. In men, the age-adjusted prevalence was only 4.4% of men 50 and older.
All in all, osteoporosis was present in 12.6% of all American adults 50 and older, which was defined as a bone mineral density (BMD) value at least 2.5 standard deviations below the average for young adults at the femoral neck or lumbar spine.
Osteoporosis, as to be expected, was far more common among older adults, affecting 17.7% of all men and women 65 and older, versus 8.4% of those ages 50-64. In women ages 65 and older, the prevalence was 27% and at ages 50-64 was 13.1%. In men, prevalence values were 5.7% in those 65 and older and 3.3% for those 50-64.
Sarafrazi’s team found that osteoporosis had become slightly more prevalent over the years. In 2007-2008, 9.4% of Americans 50 and older had osteoporosis. While rates remained steady throughout for men, a big uptick of 5 percentage points was seen for women.
“Monitoring the prevalence of osteoporosis and low bone mass may inform public health programs that focus on reducing or preventing osteoporosis and its consequences,” suggested Sarafrazi’s group. “Healthy People 2020 has a goal of 5.3% or less for the prevalence of osteoporosis at the femur neck for adults aged 50 and over.”
“In the United States, the prevalence of osteoporosis among adults aged 50 and over at the femur neck only was 6.3% and has not met the 2020 goal,” they stressed.
The data also revealed high rates of low bone mass, a precursor of osteoporosis, defined as BMD of 1 to 2.5 standard deviations below the average for young adults.
Among all adults ages 50 and older, 43.1% had low bone mass at the femoral neck, lumbar spine, or both. Among women, prevalence was 51.5% and among men 33.5% .
The overall rate reached 47.5% in those 65 and older. However, older age seemed to be less of a factor for women, with almost no difference between the 50-64 and 65-plus age groups.
However, the prevalence rates of low bone mass in both sexes held steady during the decade between 2007-2008 and 2017-2018.
The US space agency NASA has awarded a US$750 000 grant to conduct research into how bone weakening in the absence of mechanical loading, as in zero gravity, can be reduced.
Dr Meghan E McGee-Lawrence, biomedical engineer in the Department of Cellular Biology and Anatomy at the Medical College of Georgia, the recipient of the grant, will use the money to better understand how bone loss occurs in space from lack of gravity and also from disuse here on Earth.
“It’s a problem for the astronauts who are on the International Space Station for long periods of time, and it’s going to continue to be a problem for eventually trying to send astronauts to Mars,” Dr McGee-Lawrence said. It is also a problem in patients with spinal cord injuries, undergoing prolonged bedrest or physical inactivity.
“If we can find a way to make bone more sensitive to mechanical loading, then we would be able to increase bone mass with less effort. That is a long-term goal,” she says.
Her focus is the natural sensors of mechanical loading on the bone called osteocytes, and her lab found that tears, called plasma membrane disruptions, occur in osteocytes from mechanical loading, resulting in repair. They showed that these disruptions from loads happen in under a minute, and set off changes like letting in extra calcium, influencing osteoblast and osteoclast activity. If there are few tears from mechanical loading, osteoblasts are not needed and so osteoclasts will resorb some bone matrix. Even walking around has been shown to cause plasma membrane disruptions, something not possible for bedrest patients or astronauts in space.
With this in mind she posed the question, “can we do anything to reverse those processes. Can we do something to the osteocytes to make them either more likely to experience tears or more likely to repair those tears and then, accordingly, make it so there is less bone loss during disuse.”
Fewer tears seem to be not good, and she and her team want to further investigate what happens to the repair rate with disuse. They also want to know the best healing rate; slow for better osteocyte survival, or does osteocyte survival enable faster repair?
“The good news is we can dial it in either direction,” she says. However, they believe faster repair is not better because the calcium influx is linked to the cell’s response.
“Think of a membrane disruption as a doorway into the cell. If you slam the door too quickly, then there is not enough time for the cell to sense that tear and initiate the signaling to respond,” she explained.
She believes that proteins involved in repairing membrane tears, like PRKD1, are logical targets for genetic and pharmacological methods to either increase tears or speed up repair.
“The ultimate goal is can we come up with a way, whether it’s a drug therapy or a different type of regimen that can make these processes work better in astronauts and people on earth who are subjected to disuse as well,” she said.
Even with resistive exercises, astronauts lose bone mass in space. Bisphosphonates are only really effective with age-related bone loss and not loss from inactivity or lack of gravity. With the current most advanced exercise device on the International Space Station, astronauts come back to Earth fitter than when they left but still lose some bone mass. On a three-year voyage to Mars, many astronauts could return with osteoporosis. “That is really a problem. Not only are they losing bone actively while they are in space, at some point they have to come back to gravity… and then what happens?” she says. Recovering bone strength on Earth is a long and difficult process for astronauts. She and her research team are also finding that osteocytes are less likely to repair and survive tears after a long period of disuse.
There are effective therapies, like bisphosphonates, that can help age-related bone loss, but they have not been shown to be effective when disuse is the primary driver. “That is why we need to come up with better targets, more effective targets, to try to prevent disuse-induced bone loss,” she said. While it has long been clear that mechanical load also translates to stronger bones, just how remains a question, she says. She suspects the plasma membrane tears are key.
“We think the formation of these tears is important for how the bone cells know they are being exposed to that level of loading,” she said, with high-impact loading from running and jumping being particularly important. “Cells need a way to know what is going on outside their cell membrane. This is one way to do that.”
