Stop Taking Semaglutide and Tirzepatide
Your bones are doing something right now that most people do not know about. They are tearing themselves down and rebuilding, continuously, in a process that your body runs like a construction crew operating on a schedule, where the demolition team and the building team are supposed to stay coordinated so you never end up with a structural deficit.
That coordination is the whole system. And something about semaglutide and tirzepatide appears to be breaking it.
To understand why that matters, you need the full map first.
Bone is not static tissue. It is living material that your body constantly replaces, and it does this through two types of cells working in opposition. Osteoclasts are the demolition crew, breaking down old bone tissue. Osteoblasts are the builders, laying down new mineralized bone to replace what was removed. Under normal conditions these two teams are coupled, meaning they move together, and the net result is that your skeleton renews itself without losing density.
Researchers can track this process in real time using two blood markers. The first is something called CTX, which stands for C-terminal telopeptide, and it measures how fast osteoclasts are chewing through old bone. The second is something called P1NP, which stands for procollagen type 1 N-terminal propeptide, and it measures how fast osteoblasts are laying down new bone. When both go up together, bone is turning over quickly but the balance holds. When both go down together, which is what happens during ordinary caloric restriction and weight loss, the whole system simply slows down in tandem and the balance still holds.
That second scenario is what researchers expected to see in people taking semaglutide and tirzepatide, because these drugs cause significant caloric restriction and weight loss, and weight loss is known to reduce bone turnover markers proportionally.
That is not what they found.
In a randomized, double-blinded phase 2 trial published in eClinicalMedicine, researchers measured these markers in adults taking once-weekly semaglutide versus placebo. CTX increased by 166.4 nanograms per liter compared to placebo, which was statistically significant at p equals 0.021, meaning bone resorption was accelerating. But P1NP showed no compensatory increase. The demolition was speeding up and the construction crew did not show up to match it. That mismatch is what researchers call uncoupled remodeling, and it is the opposite of what happens when someone simply eats less food and loses weight.
When remodeling uncouples, bone does not just turn over faster. It turns over in the wrong direction, and the deficit compounds over time.
This finding from the bone marker data now connects to something orthopedic surgeons have been reporting independently. In an analysis of 73,483 matched patients per group presented at the American Academy of Orthopaedic Surgeons annual meeting in 2026, GLP-1 receptor agonist users showed a 29 percent increased five-year risk of osteoporosis compared to matched controls, with rates of 4.1 percent versus 3.2 percent. But the number that stands out more is the relative risk for osteomalacia, which came in at 2.55, meaning more than double the rate in matched controls.
Osteomalacia is a condition that is worth understanding separately, because it is not the same as osteoporosis. Osteoporosis means you have lost bone density, which is a quantity problem. Osteomalacia means the bone you do have is not mineralizing correctly, which is a quality problem. The bone matrix is laid down but it does not harden the way it should. Surgeons who operate on patients with osteomalacia describe the bone as softer than expected, which is a clinical observation, not just a number on a scan.
Both of these problems can be happening at the same time. You can be losing bone mass through uncoupled remodeling while the bone that remains is failing to mineralize correctly. And neither one produces a symptom you would notice until the damage is already significant.
The surgical risk from these drugs has become pressing enough that recommendations have now changed around perioperative management. A study presented at the 2025 AAOS annual meeting found that a three to five day hold on GLP-1 receptor agonists before surgery was insufficient. A 14-day discontinuation was required to normalize aspiration pneumonitis risk under general anesthesia, because these drugs slow gastric emptying so substantially that food and gastric contents remain in the stomach far longer than the normal fasting window accounts for. Patients were aspirating under anesthesia even after following standard pre-surgical fasting protocols, and 14 days off the drug was what it took to resolve that risk.
The bone question and the surgical question are different mechanisms, but they point to the same underlying reality about what these drugs do to physiology beyond appetite suppression.
Which raises the obvious comparison to retatrutide.
Retatrutide is a triple receptor agonist, meaning it activates three hormone receptors rather than one or two, and the third receptor it hits is the glucagon receptor, which semaglutide and tirzepatide do not activate. That distinction may matter for bone specifically, and here is the proposed mechanism, offered as a theory grounded in current research rather than a proven conclusion.
When glucagon receptor activation is added to the equation, it signals the liver to convert stored body fat into usable energy through a process called beta-oxidation, which produces ketone bodies as a byproduct. In the phase 2 retatrutide trial published in the New England Journal of Medicine, beta-hydroxybutyrate, which is the primary ketone body and a direct marker of hepatic fat oxidation, increased in a dose-dependent fashion at doses of 4 milligrams and above. This indicates the glucagon component is actively driving the liver to generate energy from stored fat.
The implication for bone is that when the liver is rapidly converting stored fat into fuel, the body's energy availability does not drop the way it does when you simply suppress appetite and restrict calories. The theory is that semaglutide and tirzepatide create a state where energy intake falls significantly but endogenous energy production does not compensate fast enough, and the body reads that as a deficit severe enough to trigger the conservation response that drives uncoupled bone remodeling. Retatrutide, by adding the glucagon signal, may be replacing the energy source fast enough that the body never registers the same deficit and never initiates that cascade.
The bone data specifically comparing retatrutide to semaglutide and tirzepatide has not yet been published at the scale needed to confirm this. But the mechanistic difference is real, and the glucagon receptor is not a minor addition to the pharmacology.
The practical takeaway right now, before the comparative data matures, is that if you are on semaglutide or tirzepatide, the bone remodeling signal is strong enough to warrant monitoring your CTX and P1NP levels, not just your weight or blood sugar. These markers give you visibility into something a scale and a DEXA scan alone will not catch early enough to matter.
The drugs suppress appetite effectively. What they may also be suppressing is your skeleton's ability to keep rebuilding itself, and the two effects do not show up in the same place or on the same timeline.
References
- Hansen MS, Wolfel EM, Jeromdesella S, et al. 2024. Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial. eClinicalMedicine The Lancet. Finding: Semaglutide increased bone resorption marker CTX by 166.4 ng/L vs placebo p=0.021 with no compensatory increase in bone formation marker P1NP, demonstrating uncoupled bone remodeling. Also decreased areal BMD at hip and lumbar spine. Source
- Wajahath M, et al. (2026). GLP-1 Receptor Agonist Use and Long-Term Musculoskeletal Health. Presented at American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting, March 2-6, 2026, New Orleans. Finding: In 73,483 matched patients per group, GLP-1 RA users had 29% increased 5-year osteoporosis risk (4.1% vs 3.2%) and osteomalacia showed the greatest relative risk increase (RR 2.55, 0.2% vs 0.1%).
- AAOS 2025 Annual Meeting. New Study Recommends Stopping GLP-1 Agonists 14 Days Before Total Joint Arthroplasty to Reduce Anesthesia Risks. Finding: 3-5 day hold was insufficient; 14-day discontinuation normalized aspiration pneumonitis risk under anesthesia due to GLP-1-mediated delayed gastric emptying.
- Jastreboff AM, Kaplan LM, Frias JP, et al. 2023. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. Finding: Retatrutide produced dose-dependent weight loss with beta-hydroxybutyrate increases at 4mg+ doses indicating glucagon-driven hepatic fat oxidation. Source
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