According to research reviewed by Gram, a liver-made protein called LEAP2 appears linked to heel bone density, but it is not proven to cause weak bones. In a 60-person hospital study, people with osteoporosis had lower blood LEAP2 levels, about 5.3 versus 8.2 ng/mL, than people without the condition. Further research is needed.
Bones get weaker as we age, and scientists are looking beyond bones for clues. This study looked at proteins made by the liver and found one, called LEAP2, that appears connected to heel bone density. The heel measurement used in this research relies on ultrasound, not the standard X-ray scan. In a small hospital group of 60 people, those with osteoporosis had lower blood LEAP2 levels than those without it. Mice fed a high-fat diet or after the removal of the testes also showed weaker bones and lower LEAP2. According to research reviewed by Gram, these results are promising but early. The study did not prove that LEAP2 causes bone loss, and it cannot yet be used as a test for osteoporosis. Researchers see LEAP2 as a good candidate for future studies.
Key Statistics
A 2026 exploratory study published in Frontiers in Endocrinology found that people with osteoporosis had lower blood levels of the liver protein LEAP2 than people without it, with median levels of 5.336 ng/mL versus 8.153 ng/mL among 60 hospital participants.
A 2026 genetic analysis in Frontiers in Endocrinology tested 1,414 liver-signal and bone-outcome combinations and found that the LEAP2 and heel bone density link stayed statistically significant after strict correction, with an adjusted p-value below 0.0001.
A 2026 mouse study reported that a high-fat diet and testes removal were each associated with weaker trabecular bone and lower liver Leap2 and circulating LEAP2 levels.
The Quick Take
- What they studied: Can a protein made mainly in the liver, called LEAP2, help explain why some people have weaker bones?
- Who participated: The main human group had 60 adults from a hospital setting: 30 with osteoporosis (thin, fragile bones) and 30 without it. Their average ages differed, which makes the comparison less certain. The study also used genetic data from large public databases and laboratory mice.
- Key finding: People with osteoporosis had lower blood LEAP2 levels, with a typical value of about 5.3 ng/mL compared with about 8.2 ng/mL in people without it. In genetic analysis, LEAP2 was linked to heel bone density after strict statistical correction, but the evidence for a direct cause-and-effect chain was not strong enough to confirm.
- What it means for you: This research is a starting point, not a health recommendation. It does not mean you should change your diet or take supplements because of LEAP2. Bone health is still best supported by proven habits such as weight-bearing exercise, enough calcium and vitamin D, and regular checkups with your doctor.
The Research Details
The researchers used several methods to explore whether a liver-made protein might be connected to bone strength. First, they screened 168 proteins made by the liver against seven measures of bone health, using genetic data from large population studies. This type of genetic analysis, called Mendelian randomization, uses natural differences in people’s genes to look for possible cause-and-effect links, which helps reduce the influence of lifestyle and other outside factors.
Next, the team examined where LEAP2 is produced in the body by looking at detailed laboratory maps of human liver cells and bone tissue. They then measured LEAP2 in blood samples from the 60-person hospital group. Finally, they ran an experiment in mice that were fed either a high-fat diet, had their testes removed, or both, and then compared their bones and LEAP2 levels.
The team also used a safety check called a confirmatory screen, which was designed to be strict. Much of the work was labeled exploratory, meaning it was meant to generate ideas for future testing rather than to prove them.
Using several approaches together makes the findings more trustworthy than a single test would be. Genetic analysis helps show whether a protein might play a role in bone strength, while blood tests and mouse experiments show whether that protein changes alongside bone problems. Because each method has blind spots, combining them helps researchers see whether the pattern holds up from different angles.
The study was careful about its limits. The strict confirmatory screen found no clear result, and the authors clearly state they did not claim proof of cause. The main human blood comparison was small, with only 60 people, and the two groups differed in age. Age and metabolic factors such as blood sugar and body weight were not fully accounted for, so the blood result cannot be fully separated from those influences. The heel bone measure is an ultrasound estimate, not the X-ray scan (DXA) most often used to diagnose osteoporosis. The journal, Frontiers in Endocrinology, is a peer-reviewed publication with a moderate impact factor, which means its articles are reviewed by outside experts before publication.
What the Results Show
The strongest signal in the exploratory analysis was a link between LEAP2 and heel bone density. Among 1,414 combinations of liver signals and bone outcomes tested, this link remained statistical significant after a strict correction for multiple comparisons, meaning it was unlikely to be a chance finding within that particular analysis. The researchers reported an adjusted p-value below 0.0001 for this association.
However, the team was careful about what this result means. When they tested how strongly the genetic signals overlapped, the result changed depending on how strict the cutoff was. Under a more conservative setting, the overlap became much weaker. Because of this, the authors did not claim that LEAP2 and bone density share a single, confirmed genetic cause. A genetic link in the liver to a protein in the blood was also too uncertain to analyze fully.
The cell-level data pointed to liver cells, specifically hepatocytes, as the main source of LEAP2 in all three datasets examined. This suggests the protein is mostly made in the liver and released into the bloodstream, although the study did not show that it directly signals to bone cells.
In the hospital blood samples, LEAP2 levels were lower in people with osteoporosis, with a median of 5.336 ng/mL (middle range 3.780 to 6.083), compared with 8.153 ng/mL (middle range 7.015 to 9.458) in people without osteoporosis. Mice fed a high-fat diet or after testes removal also had weaker trabecular bone, the spongy inner bone, along with lower liver Leap2 and lower circulating LEAP2.
The mouse experiment added supporting detail. Both the high-fat diet and the removal of the testes were linked to changes in the spongy inner part of bone, and both were also linked to lower Leap2 in the liver and lower LEAP2 in the blood. This pattern fits with the idea that metabolism and hormones may influence both the liver and bone, but mice are not people, so the results cannot be applied directly to humans.
Another notable point is that the researchers did not claim LEAP2 could diagnose osteoporosis. Blood levels differed between groups on average, but individual people overlap widely, so a single blood reading would not reliably tell someone whether they have osteoporosis.
Scientists have long known that bone health is shaped by more than calcium and exercise. Hormones, metabolism, and signals from organs such as the liver all play roles. Research on the liver’s role in bone is still emerging, and LEAP2 is a relatively new subject in bone science. This study builds on the growing idea that organs beyond bone may send messages that affect skeletal strength, but it is one of the early steps rather than a final answer.
The most important limitation is that the study cannot show cause and effect. LEAP2 may be a marker that changes alongside bone loss rather than a driver of it. The confirmatory genetic test was negative, and the more exploratory results depended on the strictness of the statistical cutoff. The human blood group was small, included only 60 people, and was not perfectly matched for age. Important factors such as metabolic health were not fully measured. The bone measure used for the genetic analysis was an ultrasound estimate, which differs from the standard DXA scan used in clinics. Finally, mouse research does not always translate directly to people, so the mouse findings are best viewed as supporting clues.
The Bottom Line
Based on this study alone, no change in medical care or personal habits is supported for LEAP2. Confidence is low that LEAP2 plays a direct role in bone strength, and the authors themselves describe it as a candidate for further research. Proven bone-protecting habits remain well supported with high confidence: regular weight-bearing and resistance exercise, adequate calcium and vitamin D from food or supplements as advised by a doctor, not smoking, and limiting heavy alcohol use.
Researchers studying bone disease, liver metabolism, and hormone-related bone loss should pay close attention, since the study points to specific questions to test. People at higher risk of osteoporosis, such as older adults, postmenopausal women, and men with low testosterone, may find the topic interesting, but they should not change their care based on these early findings. Anyone with a bone health concern should talk with a doctor about standard tests such as DXA scans.
Any real-world benefit from this line of research is likely years away. The next steps would include larger human studies, tests that show whether LEAP2 changes before bone loss occurs, and experiments showing whether changing LEAP2 alters bone strength. Clinical use would require much more evidence, so there is no near-term timeline for LEAP2 testing or treatment.
Frequently Asked Questions
What is LEAP2 and does it affect bone health?
LEAP2 is a protein made mainly in the liver that enters the bloodstream. A 2026 study found it is linked to heel bone density, but researchers have not proven it causes bone loss. Its role in bone health remains an open question for future research.
Can a LEAP2 blood test diagnose osteoporosis?
No single LEAP2 blood test is recommended for diagnosing osteoporosis. A 2026 study of 60 people found lower average levels in those with osteoporosis, but the groups overlapped widely. Bone density scans such as DXA remain the standard diagnostic tool.
What can I do now to protect my bones?
Weight-bearing and strength exercise, adequate calcium and vitamin D, not smoking, and limiting heavy alcohol are well supported for bone health. Aim for about 150 minutes of moderate activity weekly plus two strength sessions, and talk with a doctor about your personal needs.
Does a high-fat diet affect bones through the liver?
A 2026 mouse study found that high-fat diets were linked to weaker trabecular bone and lower liver Leap2 and blood LEAP2. Because this was done in mice, the results do not confirm the same effect in humans, and more research is needed.
Want to Apply This Research?
- Track the proven bone-supporting habits that are measurable in daily life: minutes of weight-bearing or resistance exercise per week (target at least 150 minutes of moderate activity plus two strength sessions, per general guidelines), daily calcium intake in milligrams, and days per week of strength training. Log these in the app with a weekly summary.
- Encourage users to add one short strength or weight-bearing activity, such as brisk walking, stair climbing, or bodyweight squats, three times per week. Pair it with a simple reminder to include a calcium-rich food at one meal each day, such as yogurt, fortified plant milk, or leafy greens.
- Use the app for long-term habit tracking rather than disease prediction. Review exercise and nutrition trends every three months, and encourage users to bring their logs to routine checkups. Include a note that LEAP2 is not a tested or recommended measure, and that bone density should be assessed with a doctor-ordered scan when risk factors are present.
This article summarizes an early, exploratory research study and is for general information only. The findings do not show that LEAP2 causes or can diagnose osteoporosis, and they should not be used to make decisions about diet, supplements, or medical treatment. Mouse research and small human studies do not always apply to everyone. Please talk with a doctor or qualified health professional about bone health, osteoporosis screening, and any concerns about your own risk.
This research translation is published by Gram Research, the science division of Gram, an AI-powered nutrition tracking app.