Bone Deep
The Surprising Link Between Osteoporosis & Alzheimer’s.
Roughly 13 years ago, Dr. Minghao Zheng saw a situation unfold in his own family that is unfortunately all too familiar to health professionals who specialize in aging. “My mom suffered a first vertebral fracture because of age-related osteoporosis,” said Dr. Zheng, a professor of orthopaedic research at the University of Western Australia (UWA) and a researcher at the Perron Institute for Neurological and Translational Science in Perth, Australia.
Afterward, I could see her cognitive function deteriorate. And about ten months later, she had another fracture, and we identified that she had cognitive impairment.
Traditionally, the fact that it’s not uncommon for people with osteoporosis to develop dementia and vice versa was thought to be simply due to the fact both are age-related diseases, Dr. Zheng noted. But he began to wonder if there might be biological links between the two conditions, too.
“If you look at the development of an embryo to become a human being, bone formation and brain development share a very similar pathway,” explained Dr. Zheng. For the past ten years, he has led a team of researchers that is investigating the connection between these two systems, and today, is head of the Bone and Brain Axis Research Group at the Perron Institute and UWA.
EPIDEMIOLOGICAL CONNECTIONS
As well, over the past decade, population studies by other research groups have “been looking at whether bone density may be a marker of cognitive function and decline,” noted Dr. Angela Cheung, a senior scientist and Founding Director of the Osteoporosis Program at University Health Network and a professor of medicine at the University of Toronto.
WHILE THE RESULTS OF THESE STUDIES HAVE BEEN MIXED, SOME HAVE SUGGESTED THAT PEOPLE WITH OSTEOPOROSIS MAY INDEED BE MORE LIKELY TO DEVELOP COGNITIVE DECLINE OR DEMENTIA IN FUTURE THAN THOSE WITH NO HISTORY OF THE BONE-WEAKENING DISEASE.
(It’s also worth noting that other research indicates that the reverse is also true: that the risk of developing osteoporosis is higher among individuals with cognitive impairment and dementia compared to the general population.) However, these types of observational studies can only point to associations – they can’t prove cause and effect.
For example, could the relationship between the two diseases be due to shared risk factors, such as low physical activity? Or might changes in behaviour due to early symptoms of one disease contribute to the other?
For instance, low physical activity and poor nutrition, which are more common among people who develop dementia, can increase bone loss. This would not entirely explain the association, though, since the increase in risk has also been found in studies with participants who were cognitively intact upon enrolment.
Some researchers have designed observational studies to try and get closer to answering such questions. A study published in Neurology in March 2023 measured the bone mineral density (BMD) of 3,651 people aged 70 and older who were dementia-free at the start of the study and followed them for an average of 11 years.
A total of 688 participants (19%) ultimately developed dementia. Of the 1,211 with the highest BMD, 68 developed dementia within ten years, versus 90 among the 1,211 with the lowest BMD. After adjusting for factors including age, sex, and a family history of dementia, participants with the lowest BMD were 42% more likely to develop dementia compared to the group with the highest BMD.
UNDERSTANDING BONE METABOLISM
On yet another research front, over the past roughly 20 years, scientists have learned that specific bone cells produce certain proteins that are involved in the constant tearing down and rebuilding of bone that continues across our lifetimes.
“A lot of people think of the skeleton as being static, but bone is quite a metabolically active organ,” explained Dr. Christine Lary, a biostatistician, epidemiologist, and research associate professor at the Roux Institute at Northeastern University in Portland, Maine. “There are osteoblasts, which are bone-building cells, and osteoclasts, which are bone-resorbing cells,” she added.
What happens in osteoporosis, and to some extent in normal aging, is that this process gets out of balance and the osteoclasts are working more quickly than the osteoblasts.
“That’s what governs bone density changes as you get older, roughly speaking, and there are a lot of molecular mechanisms that govern that.”
Certain bone cells secrete proteins that are involved in regulating this process, known as bone metabolism. Mature bone cells called osteocytes, which are embedded in the mineralized component of bone, produce sclerostin, which inhibits bone formation.
Bone-building osteoblast cells produce osteocalcin, which binds calcium to bone and is also released into the bloodstream. And osteopontin, which is mostly made by osteoblasts, contributes to bone remodelling by promoting the development of osteoclasts and osteoclast activity.
BONE AS A SIGNALLING HUB
When Dr. Zheng and his colleagues began digging into the scientific literature in a bid to better understand the connections between the brain and bone and whether some of these proteins might also play a role in dementia, “we found that in some ways, bone is like a signalling hub,” said Dr. Jun Yuan, a postdoctoral research associate at the Bone and Brain Axis Research Group.
For example, by the mid-2010s, research established that bone is an endocrine organ, meaning it releases hormones. And as it turns out, both osteocalcin and sclerostin act as hormones. For example, in addition to its role in bone formation, osteocalcin functions as a hormone that, among other things, stimulates insulin secretion. And, “as early as 2013, a paper was published in Cell, which found that a protein mainly produced by bone, osteocalcin, has a function in mediating embryonic brain development and adult cognition,” Dr. Yuan said.
He and Dr. Zheng later proposed that sclerostin “might be another candidate involved in the progression of dementia,” he added. This belief was based in part on the knowledge that sclerostin inhibits the function of a cellular “communication channel” called the Wnt (pronounced “wint”) signalling pathway, which plays crucial roles in both bone and brain development.
Data scientists have been using other methods to try and learn more about how osteoporosis and dementia might be related.
APPLYING DATA SCIENCE
Dr. Marina Sirota arrived at this area of research somewhat indirectly. Dr. Sirota, professor and Acting Director of the Bakar Computational Health Sciences Institute (BCHSI) at the University of California, San Francisco (UCSF), and her lab have access to de-identified records from across the UCSF health system.
The researchers initially wanted to find out if, using this data, they could learn whether certain conditions were more prevalent among people with Alzheimer’s disease (AD) versus individuals matched by such factors as age, sex, and ethnicity, who didn’t have AD. Unsurprisingly, mild cognitive impairment and early dementia were more common among people later diagnosed with dementia.
“But we also saw things that were more interesting, like hyperlipidemia,” or high LDL blood cholesterol, Dr. Sirota said. This study was published in Nature Communications in February 2022.
In a follow-up study, a graduate student in Dr. Sirota’s lab, Dr. Alice Tang, built predictive models using machine learning and the same data “to understand if we can identify patients who are at a higher risk for Alzheimer’s from the electronic medical records before any diagnosis is made,” Dr. Sirota explained.
The research team found that “even seven years out, we could predict, not incredibly well, but we could predict whether somebody was more likely to get Alzheimer’s disease.” Next, they looked at men and women separately.
“We saw that we could predict in both groups with roughly equal accuracy, but while some of the clinical features predictive of the diagnosis were the same, some were different,” Dr. Sirota said.
Osteoporosis was predictive of Alzheimer’s in women but not in men. That’s what brought me to the bone-brain axis.
They then took what they’d learned from these studies and applied it to a resource called SPOKE that maps relationships between a huge number of different biomedical factors, such as clinical symptoms, diseases, genes, and drugs. First, they looked at high LDL cholesterol, “and the gene that arose as a link between hyperlipidemia and Alzheimer’s was APOE4,” said Dr. Sirota.
Since this gene variant, which is the largest genetic risk factor for AD, was already known to be associated with an increased risk of hyperlipidemia, “we thought OK, there might be something to this approach,” Dr. Sirota said.
“So then we took that approach and layered it on top of the osteoporosis and Alzheimer’s link. And we saw there were a lot of immune genes that were coming up. That doesn’t give you causality or mechanism, but it tells you maybe you should dig deeper.”
Since genetics data wasn’t available for the same set of patients for whom the team had clinical data, they turned to the public domain. “We looked at a study that measured genetic associations with heel bone mineral density, which is a measure of bone density, and a separate study that looked at Alzheimer’s disease,” said Dr. Sirota.
“We wanted to see if there are any common genes” across low BMD and AD.
Indeed, there was a significant correlation between the two traits and one gene, called MS4A6A, but only in women.
This work was published in February 2024, in Nature Aging.
Dr. Sirota would like to see future research probing these relationships. “Ideally, we would find a patient population that has both, and maybe investigate some single cell signals,” she said. “At the same time, I would look to studies in animal models of both diseases to see whether we could explore (MS4A6A) as either a diagnostic marker, or a therapeutic target.”
BONE PROTEIN’S ROLE IN AD
After homing in on sclerostin, the Wnt inhibitor, as playing a possible role in AD, Dr. Yuan did a study that found that levels of the protein, which rise in normal aging, were even higher in people who had deposits of abnormal beta amyloid in the brain, which are a hallmark of AD. “We thought there was something there,” said Dr. Zheng. Could the sclerostin be somehow promoting the formation of beta amyloid plaques? At the time, there was no way to know.
However, one year later, a group of researchers in China, led by Professor Qing Jiang at Nanjing University, a former colleague of Dr. Zheng’s, “found sclerostin gets through the blood-brain barrier,” Dr. Zheng explained. “At the same time, they found this molecule does two things. One, it inhibits neurogenesis (the formation of new brain cells). The second: it causes beta amyloid deposition.” The work was published in Nature Metabolism in March 2024.
Research by Dr. Lary and her colleagues at Northeastern University – published in The Journals of Gerontology: Series A in 2024 – using genetic data, implicated the possible role of sclerostin from a different direction. Using data from participants enrolled in two long-term studies, Dr. Lary’s team searched for any common gene expression patterns in both low BMD and AD.
“The big one we found was Wnt signalling. It’s a pretty well-known pathway of importance in bone health and brain health, but to find it connected to both in one study was kind of novel,” Dr. Lary said. Sclerostin’s influence on bone acts via this pathway. By inhibiting Wnt signalling, it reduces osteoblast activity, and thus, bone formation.
PROMISING PATH TO NEW TREATMENTS
What makes this avenue of research exciting is that an existing drug for treating osteoporosis, a monoclonal antibody called romosozumab (EvenityTM), works by blocking the activity of sclerostin. “When we have more data from more people using this drug, we can look from the clinical perspective to see whether they have a lower risk of developing AD in future,” noted Dr. Yuan.
This could potentially lead to a repurposing of the drug “to prevent or postpone the onset of AD,” he explained. (Dr. Zheng added that his team is also working on developing a new molecular therapy for preventing or delaying both osteoporosis and AD by targeting sclerostin.)
A number of ongoing clinical trials are investigating whether other older osteoporosis medications affect future dementia risk. Dr. Lary is hoping to get funding for a study to look at whether one of the first-line treatments for osteoporosis, which belongs to a group of drugs called bisphosphonates, “is associated with a delay in the onset of dementia,” she said.
If existing osteoporosis drugs do turn out to show such a benefit, they won’t have to go through as lengthy a testing and approval process as entirely new therapies. “You already have an established safety profile for some these drugs in a very similar patient population – older adults,” noted Dr. Lary.
The developments detailed above could one day lead to advances such as improved understanding of the benefits of exercise for both bone and brain health, potential screening strategies for early identification of elevated risk of AD, and effective therapies for preventing or delaying the onset of the disease.
In the meantime, such discoveries haven’t changed expert guidelines on how to protect your bone health. “If you have a fracture after age 40, you need to be assessed for osteoporosis,” Dr. Cheung said.
If you do require medication to treat osteoporosis, you could potentially be helping your brain health – although this research is still in its early days.
Evidence-backed lifestyle strategies for preserving your bone strength include avoiding excess alcohol consumption, engaging in regular exercise including resistance and balance training, and eating a healthy diet that includes adequate amounts of calcium, vitamin D, and protein, and minimal amounts of processed foods. Most of these habits give you double the benefit for your efforts, since they’re linked with a lower risk of dementia, as well.
“We have to keep both organs – your bone and your brain – active,” said Dr. Zheng. “If you have better bone health, you’re likely to have better brain health, so better bone, better brain.”
Source: Mind Over Matter V21