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Part 1: What Are P1NP and CTX, and Why Do They Matter?
The basics: bone is always remodeling Your skeleton is not a fixed structure. It's in a constant state of turnover — old or damaged bone is removed by cells called osteoclasts, and new bone is laid down by osteoblasts. In a healthy adult, these processes are roughly balanced. In states of net bone loss — whether from aging, hormonal changes, poor nutrition, or disuse — resorption outpaces formation. Over years, that imbalance is what leads to structural fragility and fracture. Bone remodeling (turnover) markers (BTMs) are proteins released into the bloodstream during this process. They give us a window into the rate and direction of remodeling right now, which a static measure like DEXA bone density cannot (Schini et al., 2023). P1NP: the formation marker P1NP — the N-terminal propeptide of type I procollagen — is released when new collagen is incorporated into bone matrix. It's a direct byproduct of osteoblast activity. Higher P1NP generally means more active bone building. A typical reference range for women aged 50–69 is roughly 15–75 µg/L, though lab-specific ranges vary (Jenkins et al., 2013). The International Osteoporosis Foundation and IFCC have designated serum P1NP as the reference formation marker — the one to use when you want comparable, standardized data across studies and clinical settings (Szulc et al., 2017). CTX: the resorption marker CTX — the C-terminal telopeptide of type I collagen — is released during degradation of mature collagen. It's a byproduct of osteoclast activity. Higher CTX means more active bone breakdown. A common reference interval is 100–700 pg/mL in women over 50, though lab ranges differ (Jenkins et al., 2013; Yuan et al., 2026). CTX is more sensitive to diurnal variation and feeding state than P1NP — a fasting, early-morning draw is required for reliable results (Szulc et al., 2017). It's also the marker most responsive to antiresorptive medications like bisphosphonates, often falling substantially within weeks of starting treatment (Naylor et al., 2016). Why the ratio matters Looking at P1NP and CTX together gives you a sense of whether the skeleton is in a net building or net breakdown state. Research in orthogeriatric patients found that a P1NP/CTX ratio below 100 was independently associated with nonvertebral fractures, even after accounting for bone density (Fisher et al., 2017). A subsequent classification paper used P1NP 32 µg/L, CTX 0.250 µg/L, and a P1NP/CTX ratio of 100 to define bone turnover subtypes, noting that lower ratios indicated accelerated resorption (Fisher et al., 2018). Using markers clinically Current guidelines allow clinicians to use a 3-month change in CTX or P1NP as an alternative to repeat DEXA to assess treatment response or identify non-adherence (Schini et al., 2023). A fall of 25% or more in CTX by 3–6 months is generally considered an adequate response to antiresorptive therapy. For anabolic therapies, a rise of 40% or more in P1NP signals a meaningful response, with 100–200% considered excellent (Schini et al., 2023). Higher baseline BTMs also predict fracture risk independently of BMD — so knowing where a patient starts provides useful prognostic information beyond the density number (Schini et al., 2023). Part 2: What Moves the Markers? Resistance and impact training Exercise is one of the best-studied lifestyle levers for bone markers. The signal isn't uniform across all exercise types — it's specific to load and impact. An acute crossover trial in younger and older adults found that both strength and endurance sessions temporarily shifted the P1NP/CTX ratio toward formation in the hours after exercise — though this transient effect was largely gone by 24 hours and was blunted in older participants, suggesting single sessions are insufficient and repeated loading over weeks to months is needed to see lasting BTM changes (Stunes et al., 2022). Over training blocks, the effects are more durable. A 12-week study in older adults with low bone mass found that resistance training significantly changed CTX compared with walking, which had no effect — underscoring that load matters, not just movement (Gombos et al., 2016). A separate RCT on high-impact exercise confirmed that this type of training increases P1NP without substantially changing CTX, pointing to a formation-dominant response with appropriate loading protocols (Hilkens et al., 2023). A narrative review further summarizes that high-strain, odd-impact, and resistance protocols can produce measurable shifts in BTMs — usually an increase in P1NP with stable or reduced CTX — across weeks to months, though protocols and populations vary widely (Aini Sahrir & Kiew Ooi, 2018). Sleep and circadian disruption A controlled laboratory study combining three weeks of sleep restriction with circadian misalignment in healthy men found a significant decline in P1NP with no meaningful change in CTX (Swanson et al., 2017). The authors interpret this as a suppression of bone formation — not an acceleration of breakdown — as the primary mechanism by which sleep disruption affects the skeleton. The implication is that chronic sleep disruption could quietly tip the P1NP/CTX ratio toward net bone loss over time, without a clear resorption signal to catch it. Protein and calcium Adequate protein supports bone matrix synthesis and promotes IGF-1, a growth factor important for osteoblast function. A large cluster-randomized trial in over 7,000 older adults in residential care showed that increasing dietary calcium and protein via dairy foods over two years produced a 33% reduction in fractures and 46% fewer hip fractures — a striking clinical outcome, though this trial measured fractures and BMD rather than P1NP and CTX directly (Schini et al., 2023). On the resorption side, calcium from food has a notable acute effect on CTX. Mechanistic work has shown that calcium-fortified foods can reduce CTX by roughly 20% within an hour and sustain a lower level over weeks (Schini et al., 2023). This gives clinicians a dietary tool that is trackable via a morning CTX draw. Vitamin D Vitamin D deficiency drives secondary hyperparathyroidism — elevated PTH that accelerates resorption. Many vitamin D RCTs have primarily measured PTH and BMD rather than P1NP/CTX directly, but reviews suggest modest decreases in resorption markers with supplementation, particularly when baseline status is low (Schini et al., 2023). Testing 25-OH vitamin D and intact PTH alongside CTX and P1NP gives a fuller picture of the calcium-regulation context. The gut microbiome Cross-sectional data in postmenopausal women show that gut microbiome composition correlates with BTM levels — certain bacterial taxa are significantly associated with lower CTX, suggesting the microbial community may influence resorption tone even at baseline (Chen et al., 2021). Reviews have further characterized the gut-bone relationship, with some taxa identified as potentially protective via lower resorption (Lyu et al., 2023; Hwang et al., 2025). Probiotic intervention trials have produced mixed but encouraging results. A double-blind RCT in postmenopausal women with osteopenia found a significant decrease in CTX after 12 weeks of multi-species probiotic supplementation versus placebo (Yumol et al., 2025). A 2025 meta-analysis found a standardized mean difference of approximately -0.35 for CTX — modest, but directionally consistent across trials — and an average P1NP increase of about 8.4 µg/L, a small-to-moderate formation signal (Yuan et al., 2026). The proposed mechanism centers on short-chain fatty acids, particularly butyrate, produced by gut bacteria from fermented fiber. Butyrate appears to promote regulatory T cell expansion, which in turn supports osteoblast activity via Wnt signaling in the bone marrow (Hernandez et al., 2016). Mathematical modeling of the gut-bone axis supports the idea that changes in SCFA production and immune signaling can shift resorption versus formation in ways that predict changes in CTX and P1NP, though most direct data remain preclinical (Islam et al., 2021). What "optimal" looks like There is no single target number that fits everyone. Clinically, the goal is directional: move CTX downward from an elevated baseline into a lower-turnover zone without over-suppressing it. Keep P1NP in a range consistent with active but not excessive formation. Watch the ratio. And re-test with the same lab, same assay, and same draw conditions — because the signal you're tracking is change over time, not any single absolute value. References
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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.
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.
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.
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. The most highly respected experts are finally reaching some consensus. Here's what the evidence actually says — and what it means for your muscles, kidneys, and bones.
This post used as a starting point a major 2026 review that brought together some of the most respected researchers in nutrition and aging to ask a simple question: how much protein do people actually need, and what happens if they get too little — or too much? The answer has real consequences for how you age, how strong you stay, and how well your kidneys and bones hold up. Here's my take on what it means in practice — including the parts the review didn’t mention. How much protein do you actually need? The best evidence now supports a target closer to 1.2 g/kg/day for most adults, and up to 1.6 g/kg/day for older adults, people losing weight, or anyone trying to build or maintain muscle. For that same 70 kg person, that's 84–112 grams a day — meaningfully more than the old recommendation. The number isn't enough on its own Total daily protein matters, but so does how you distribute it. Spreading protein evenly across three meals — rather than eating most of it at dinner — significantly improves how well your body uses it. A bowl of oatmeal and fruit for breakfast followed by a light lunch and a large protein dinner is a common pattern that undermines the whole effort. Aim for at least 25–30 grams of quality protein at each meal. Are you eating as much protein as you think? Most people overestimate their protein intake. This is especially true for people eating plant-based diets. Plants contain protein, but the amount and quality vary enormously — and not in the way most people assume. Animal proteins (meat, fish, eggs, dairy) are “complete:” they contain all the essential amino acids your body needs in the right proportions, and they're highly absorbable. Most plant proteins are not — they're lower in one or more essential amino acids, and some are significantly less absorbable. A note on plant protein quality This isn't an argument against plant-based eating. It's an argument for eating it thoughtfully. Varied plant sources — legumes, lentils, tofu, edamame, whole grains, nuts — can together provide all essential amino acids. But "I eat plants" is not the same as "I'm getting enough protein." If you eat a plant-based diet, it's worth actually tracking your intake for a week, not just assuming it's fine. If you're relying heavily on one or two plant sources, or if your meals skew toward grains and vegetables with minimal legumes or soy, there's a good chance your protein intake is lower — and lower quality — than you think. This is something worth discussing with your doctor or dietitian. Beware of people with agendas: I’ve seen people argue that rice is all you need, and people argue that steak is all you need. What about your kidneys? If your kidneys are healthy, eating more protein will not cause kidney disease. Full stop. Higher protein increases the workload on your kidneys, similar to how exercise increases the workload on your heart — and in a healthy person, that's not a problem. The picture is more complicated if you already have kidney disease (CKD). In that case, very high protein may accelerate decline in kidney function — but here's what most people aren't told: restricting protein in that context has its own costs. You lose muscle. You become weaker. You become frail. And frailty — not kidney disease — is often what actually kills older adults first, even the ones with renal insufficiency. The risk nobody talks about Cohort data show that older adults — including those with mild-to-moderate kidney disease — have lower death rates at protein intakes of 1.2–1.4 g/kg/day compared to lower intakes. Blanket protein restriction in someone who is already losing muscle is not a safe recommendation. It carries its own mortality signal. If your doctor is recommending low protein because of kidney disease, ask them to measure your muscle mass and functional strength — not just your kidney numbers. A word on kidney testing Standard kidney function tests (eGFR based on creatinine) can be misleading in people with low muscle mass — because creatinine is a waste product of muscle metabolism. A sarcopenic person can have a falsely reassuring eGFR. A more accurate measure is cystatin-C, which is not affected by muscle mass. If you have borderline kidney function and low muscle mass, it's worth asking whether a cystatin-C-based test has been done. If it turns out you have renal insufficiency, there are several ways you can prevent further decline in kidney function,. What about your bones? Higher protein increases the amount of calcium lost through urine. This sounds alarming, but it's only half the story. Higher protein also improves how much calcium your gut absorbs. When your calcium intake is adequate, these two effects roughly cancel out — and several studies suggest higher protein is actually modestly beneficial for bone density. The catch is that word "adequate." Most older adults, especially women, are not getting anywhere near enough dietary calcium. The recommendation is at least 1,000 mg per day for adults over 50, and 1,200 mg for women over 51. Many people are getting half that. So the reassuring statement that "higher protein is fine for bones" comes with a condition most people don't meet. If you're increasing your protein intake without also ensuring your calcium is sufficient, you may be quietly accelerating bone loss. The plant-based calcium trap If you don't eat dairy, getting enough calcium from food is genuinely difficult. Many plant foods contain calcium on paper, but most of it is poorly absorbed — bound to compounds called oxalates or phytates that your gut can't break down effectively. Spinach, for example, is high in calcium but almost none of it is bioavailable. The realistic options for dairy-free calcium are: calcium-set tofu (check the label — the coagulant must be calcium sulfate or calcium chloride), fortified plant milks, and supplements. If none of those are regular parts of your diet, your calcium intake is almost certainly inadequate. How to estimate your calcium intake A rough screen: one serving of dairy (a cup of milk or yogurt, or 30g of hard cheese) provides roughly 300 mg of calcium. Two to three servings a day gets most people to their target. If you're dairy-free, one cup of fortified plant milk provides a similar amount — but check the label, as amounts vary. If you can't reliably account for 1,000 mg from food sources, talk to your doctor about supplementation. None of this works as well without strength training Protein is not enough for muscle building (as you get older). It works by giving your muscles the building blocks they need to repair and grow — but only if there's a signal telling them to do so. That signal is resistance exercise. Without strength training, higher protein has a fraction of the effect on muscle mass. With it, the combination is one of the most powerful tools we have for maintaining function, independence, and quality of life as you age. This isn't a nice-to-have. It's the other half of the prescription. If you are not currently doing some form of resistance training — weights, resistance bands, bodyweight exercises — this is the single most important thing you can add to your routine, regardless of your age or current fitness level. The evidence for benefit starts at any age and continues well into your 80s and beyond. Six questions worth asking at your next appointment Bring these to your doctor or dietitian 1. What protein target is right for me specifically — given my age, muscle mass, kidney function, and activity level? 2. Has my muscle strength been measured? A grip strength test or 30-second sit-to-stand test takes two minutes and tells you something a blood test can't. 3. Am I getting enough calcium? Don't assume. If you're on a protein-optimization plan without confirmed adequate calcium, you may be trading bone for muscle. 4. If I have kidney disease — has my muscle mass been factored into the protein recommendation? Has cystatin-C been measured? 5. If I eat plant-based — has anyone actually looked at whether my protein intake is sufficient and varied enough? 6. What's the plan for resistance training? Any protein conversation that doesn't include this is incomplete. My starting point: Kanter MM, Aaron S, Austad SN, Brown AW, et al. Examining widely held propositions on human dietary protein needs and benefits: a critical review of the science that shapes both the data and our understanding of an essential macronutrient. Crit Rev Food Sci Nutr. 2026;64(6):ePub ahead of print. https://doi.org/10.1080/10408398.2024.2410236 |
Blog AuthorDr. Myrto Ashe MD, MPH is a functional medicine family physician. Archives
May 2026
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