The Bone-Brain Connection

First I’ll explore the effects of medications that either harm both bone and brain, or that help one but not the other. Then I’ll dive into the science of how skull bone marrow supports cognitive health, and is in turn supported by the brain.

What quietly harms both bone and brain
This section tends to surprise my patients, because some of these are medications they are taking specifically to protect their health.

• Loss of estradiol at menopause is the most important driver of bone loss in women — and a time of increased vulnerability for neuroinflammation and cognitive change. Menopausal hormone therapy is clearly beneficial for bone and fracture risk when started around the transition. Its cognitive effects are more nuanced: most large randomized trials show a neutral effect overall, with some timing-specific hints of benefit. This remains a conversation worth having with your provider.
• Anticholinergic medications — oxybutynin for bladder control, diphenhydramine (Benadryl), hydroxyzine, tricyclic antidepressants, some antipsychotics and antiemetics — have a well-documented association with worse memory and executive function, reduced brain metabolism, and higher incidence of MCI and dementia. They are not thought of as "bone drugs," but the cognitive decline they contribute to accelerates the sedentary spiral that loses bone.
• Benzodiazepines and sedative-hypnotics impair attention, reaction time, and memory, and substantially increase falls and fracture risk. They are among the most prescribed medications in older adults. From a bone-brain perspective, they are quietly devastating.
• Gabapentin, now prescribed for nerve pain, anxiety, and insomnia, is associated with neurocognitive slowing, gait instability, and emerging data linking heavier use to higher risk of MCI and dementia. Falls and fractures follow.
• SSRIs and SNRIs surprise people most. Chronic use is associated with lower bone mineral density and higher fracture risk — through direct skeletal effects, and through hyponatremia, dizziness, and falls. Some patients also experience cognitive blunting that gets attributed to depression rather than the drug.
• Aromatase inhibitors, used widely in breast cancer treatment, markedly accelerate bone loss and carry accumulating evidence of contributing to cognitive symptoms. They are a double negative for bone and brain — a fact not discussed nearly enough when they are prescribed.

When bone and brain don't agree: medications with mismatched effects
If the bone-brain axis were simple, every drug that helped bone would help the brain, and every drug that hurt bone would hurt the brain. It is not that simple.

Some of the most instructive examples are the ones that pull in opposite directions — and they deserve a closer look, especially for women navigating cancer treatment or menopause.

• Tamoxifen is perhaps the most striking mismatch. In postmenopausal women, it acts like estrogen in bone, protecting against loss and fractures. Good news for the skeleton. But multiple studies, including recent prospective work, associate tamoxifen with slower processing speed, worse verbal memory, impaired executive and motor function, and roughly double the prevalence of measurable cognitive impairment compared to controls. The bone wins; the brain pays.
• Menopausal hormone therapy with estradiol is the reverse puzzle. It is clearly beneficial for bone mass and fracture risk when started around the menopausal transition — one of the most well-established interventions we have. But its cognitive story is surprisingly flat. Large randomized trials generally show no robust protective effect on global cognition or dementia risk. Most data suggest a neutral effect overall, with some route- and timing-specific hints of better episodic memory, but no clear disease-modifying signal. Excellent for bone. Complicated for brain.
• The Alzheimer's drugs themselves are instructive in the other direction. Donepezil and memantine provide modest symptomatic benefit — slowed decline, small improvements — but effect sizes are limited and do not transform long-term outcomes. And despite treating a disease that is deeply entangled with bone pathology, they have no established positive impact on bone. Randomized trials to test whether donepezil even alters bone turnover markers are only now being designed. We have been treating the brain without asking what was happening to the skeleton.
• Anti-amyloid monoclonal antibodies — the newer, much-discussed drugs — show statistically detectable but clinically small effects on cognitive decline that often fall below conventional thresholds for meaningful change. Their impact on bone is, at this point, essentially unknown; any effect would be indirect, through improved function, fewer falls, or concomitant therapy changes.

These drugs remind us that the bone-brain axis is real, but not simple. Some agents help bone while harming cognition. Some help cognition without touching fracture risk. Very few clearly pull in the right direction for both. Which is, of course, exactly the argument for lifestyle — because the interventions that support both bone and brain simultaneously are not drugs. They are movement, sleep, nutrition, and stress reduction. They work through the shared biology rather than around it. 

How does bone and the brain support or harm each other

I have been practicing functional medicine long enough to know that when two serious diseases keep showing up together, it is not a coincidence. It is a clue.

Osteoporosis and Alzheimer's disease show up together all the time. Patients with Alzheimer's have lower bone mass, higher fracture rates, and bone marrow that looks different under the microscope. Conventional medicine has filed this under "downstream frailty" — of course people with dementia lose bone, they don't move enough, they don't eat enough, they fall. That’s enough of an explanation.

But things in the body are often more fascinating than this, and connections often go in both directions.

Two papers landed in my social media feed recently that changed how I think about both conditions. One published in Alzheimer's & Dementia in 2024, the other in Advanced Science in 2026 — both pointing toward the same conclusion: the relationship between bone and brain in Alzheimer's disease is not a side effect and not a frailty story. It is a two-way highway, and the skull sits at the center of it.

Bone is already a recognized endocrine and immune organ
Most of us were taught that bone is scaffolding. That understanding is about 40 years out of date.

Bone produces hormones. Osteocalcin, made by the cells that build bone, crosses the blood-brain barrier and influences memory. Sclerostin, FGF23, Dkk1 — these are signaling molecules made in bone that speak directly to the brain. Bone marrow is a primary immune organ, producing monocytes and macrophages that patrol the body and, it turns out, the brain.
So when bone is sick — when bone-building cells are underperforming, when marrow is generating the wrong immune cells — the brain hears about it. And the brain talks back. Alzheimer's pathology disrupts the neuroendocrine signals that regulate osteoblast and osteoclast balance, accelerating bone loss. Which then feeds back to the brain.

The skull: a privileged passage
A 2021 paper in Science showed something anatomically remarkable: the skull and vertebral bone marrow connect to the meninges and brain via tiny vascular channels — not through the general circulation, not through the blood-brain barrier, but through direct, specialized passages. The skull is not just sitting on top of the brain. It is in conversation with it, through its own private postal system.

The 2026 paper by Xiong and colleagues took this further. In Alzheimer's mouse models, osteoblastic activity in the skull bone marrow controls how many myeloid cells travel through these channels into the brain — and what kind. When osteoblastic function was impaired, the wrong immune cells flooded in, cerebral blood flow dropped, and cognition worsened. When they boosted that osteoblastic activity, blood flow partially recovered. So did behavioral outcomes.
The garden that forgets how to tend itself

Let me tell you this like the gardening story it is.
Picture a thriving ecosystem. The skull marrow is the compost heap at the heart of it. In healthy bone, the osteoblasts are active, like good earthworms turning the soil. The myeloid cells they generate are the beneficial insects: trained, purposeful, cycling up through those tiny channels into the meninges, doing their pest control, keeping the whole system in balance. Cerebral blood flow is the irrigation. The glymphatic system, working through the night, is the rain that washes the garden clean.

Then the soil starts to change. Low-grade inflammation, building over years of poor sleep, metabolic stress, and chronic overload, alters the underground chemistry. Drainage becomes sluggish. The roots of the most vulnerable plants begin to struggle. Neuroinflammation rises. The distress signals reach the skull marrow. The earthworms slow down. Osteoblastic activity declines.

This is what permaculture calls a degraded system: not one thing failing, but a loss of the feedback loops that kept everything in balance. A degraded system does not usually restore itself. It needs intervention — intentional, layered, patient.

The good news is that permaculture is also the science of restoration. You do not need to fix everything at once. You start with the soil.

What supports both bone and brain
The same interventions that protect bone tend to protect the brain. This is not a coincidence — it tells us the underlying biology is shared.

• Strength training is the most important thing I can tell you to do right now. Not just walking. Loading your skeleton with resistance. This drives osteoblastic activity, raises osteocalcin, reduces inflammatory cytokines, improves insulin sensitivity, and supports cerebral blood flow. It also builds the muscle that prevents the falls that fracture the bones that begin the final decline in far too many older adults.
• Vitamin D, optimized rather than merely "normal," plays a role in both bone mineralization and neuroprotection. Most of my patients come in deficient.
• Avoiding sarcopenia — muscle loss with aging — is inseparable from both bone health and brain health. Protein intake, resistance training, and hormonal context all matter here.
• Nutrition that provides all the vitamins and minerals and reduces inflammation supports bone density, a healthy gut microbiome, and glymphatic clearance simultaneously.
• Metabolic health: insulin resistance harms both bone and the brain.
• Sleep. The brain clears its waste at night. Bone builds at night, on a circadian rhythm. Poor sleep hurts both systems at once.
• Stress reduction. Chronic cortisol elevation is an osteoclast activator and a neurotoxin. There is no supplement that compensates for a dysregulated stress response.

Vicious cycles and virtuous cycles
What this research gives us is a new way to think about healthspan.

The vicious cycle: inflammation → neurodegeneration → disordered bone marrow → skull marrow dysfunction → more neuroinflammation and impaired cerebral perfusion → faster cognitive decline → less movement → more bone loss → more marrow dysfunction.

The virtuous cycle: strength training → osteoblast activation → better osteocalcin → improved memory support → better marrow regulation → calmer neuroinflammation → maintained cerebral blood flow → preserved cognition → continued capacity to move and train.

What I am now asking in clinic
The practical questions have shifted. I am no longer asking just "what is your DEXA score?" I want to know: What does your inflammatory profile look like? How is your sleep? What does your resistance training look like? What medications are you on that I should look at through this new lens?

The tests and trials of the future will likely co-monitor bone markers, bone imaging, and marrow immune signatures alongside cognitive and neuroimaging outcomes. The hypothesis being tested: can treating the bone modify the trajectory of Alzheimer's disease?

I think the answer will be yes. I think we are already doing it, imperfectly, every time we get a patient lifting weights and sleeping well and reducing their inflammatory load. We just did not know, until now, exactly why it was working.

References:
Liu ZT, Zhang Y, Li X, et al. Crosstalk between bone and brain in Alzheimer's disease: mechanisms, applications, and perspectives. Alzheimers Dement. 2024.pubmed.ncbi.nlm.nih.gov/38824621/

Xiong X, Sun X, Zhang L, et al. A skull bone marrow-to-brain axis links osteoblastic activity to myeloid cell trafficking, cerebral blood flow, and cognition in Alzheimer's progression. Adv Sci (Weinh). 2026. https://pubmed.ncbi.nlm.nih.gov/42107073/

Cugurra A, Mamuladze T, Rustenhoven J, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. 2021.