Stop Taking Semaglutide and Tirzepatide

Your bones are in a constant state of demolition and reconstruction, and your body manages this through a two-part system where one crew tears down old bone tissue and another crew builds new bone in its place, and when those two crews stay in sync, your skeleton stays strong even as it changes.

Researchers track this balance with two blood markers. The first is something called CTX, which is a breakdown byproduct that rises when your body is actively dissolving old bone. The second is something called P1NP, which is a construction marker that rises when your body is actively laying down new bone. In a healthy skeleton, both of those move together. When CTX goes up, P1NP follows. When CTX comes down, P1NP settles too.

When you lose weight through caloric restriction alone, both markers slow down together. Your body is doing less of everything because it has less energy coming in, so demolition slows and construction slows in equal proportion, and the ratio between them stays roughly the same. That is normal and it does not threaten your bone structure in the long run.

What researchers found with semaglutide is different, and the difference is the entire problem.

In a randomized, double-blinded phase 2 trial published in eClinicalMedicine, researchers measured CTX and P1NP in adults taking once-weekly semaglutide versus a placebo group. CTX in the semaglutide group rose by 166.4 nanograms per liter compared to placebo, and that increase was statistically significant with a p-value of 0.021. But P1NP did not budge. Bone formation stayed flat while bone breakdown accelerated, and the gap between those two processes is called uncoupled remodeling, meaning the demolition crew is working overtime and the construction crew did not get the memo. The same trial also measured bone mineral density directly and found decreases at both the hip and the lumbar spine.

This is not a caloric restriction effect. When you eat less food, both crews slow down. When you take semaglutide, the demolition crew accelerates without the construction crew responding. That distinction matters because it means something about the drug itself is driving the breakdown, not just the weight loss that follows from it.

And what surgeons are seeing in the operating room is consistent with that signal.

A study presented at the American Academy of Orthopaedic Surgeons 2026 annual meeting analyzed 73,483 matched patients per group and found that GLP-1 receptor agonist users had a 29 percent higher five-year risk of osteoporosis compared to matched non-users, which translated to 4.1 percent versus 3.2 percent in absolute terms. But the sharpest signal was in a condition called osteomalacia, which is a softening of bone that happens when the mineral matrix does not harden properly, and it showed a relative risk increase of 2.55 in GLP-1 users compared to controls. So you are not only losing bone mass, the bone that remains is not mineralizing correctly, which are two separate failure modes hitting simultaneously.

Surgeons are taking this seriously enough that the AAOS issued guidance recommending patients stop GLP-1 receptor agonists at least 14 days before joint replacement surgery. The reason is that semaglutide and tirzepatide slow gastric emptying dramatically, and a three to five day hold was shown to be insufficient to normalize that effect under anesthesia, where patients were still at elevated risk of aspirating stomach contents into their lungs. The 14-day window was what it took to bring that risk back to baseline.

Now the question the video raised is whether this same pattern appears with retatrutide, which is a triple hormone receptor agonist that acts on GLP-1, GIP, and glucagon receptors simultaneously, where semaglutide acts primarily on GLP-1 and tirzepatide adds GIP but not glucagon.

The glucagon receptor component is the theoretical difference here, and this is where the explanation moves from established data into a model that has not been directly tested in bone remodeling trials yet, so it should be understood as a working hypothesis grounded in mechanism rather than a confirmed finding.

The glucagon receptor in the liver tells hepatic cells to pull stored fat and convert it into usable fuel rapidly, specifically through a process that produces something called beta-hydroxybutyrate, which is a ketone body that indicates the liver is actively oxidizing fat for energy. In the phase 2 retatrutide trial published in the New England Journal of Medicine, researchers observed dose-dependent increases in beta-hydroxybutyrate at doses of 4 milligrams and above, which is a signal that glucagon-driven fat oxidation was occurring at meaningful levels.

The theory connecting this to bone is that the bone breakdown cascade triggered by semaglutide and tirzepatide may be a downstream consequence of the body sensing an energy deficit and mobilizing calcium and phosphate from bone as part of its conservation response, and if the glucagon receptor is delivering enough hepatic energy output that the body never registers itself as being in deficit, that conservation response may never activate, which would preserve the balance between CTX and P1NP.

That mechanism is plausible and internally consistent with what we know about how the glucagon receptor functions. It has not been tested in a direct head-to-head bone remodeling trial comparing retatrutide to semaglutide, so treating it as proven would be premature.

What is not theoretical is that semaglutide produced a 166-nanogram increase in bone resorption with no corresponding rise in formation, that osteomalacia risk more than doubled in GLP-1 users across a nearly 150,000-patient analysis, and that surgeons had to extend the pre-surgical washout period to two full weeks because three to five days was not enough.

The thing about bone is that it fails quietly. You do not feel a 4 percent shift in density or a change in mineralization quality. You feel it when it fractures, and by then the remodeling imbalance has usually been accumulating for years. That is what makes the CTX-to-P1NP gap the more important number, because it tells you the direction things are moving before the structural damage is visible on a scan.

The bone you have right now is the product of years of remodeling cycles, and every cycle either adds to it or subtracts from it. A drug that tilts that ratio toward subtraction does cumulative work, compounding in one direction, invisibly, until it isn't.

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References

1. 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
2. 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%).
3. 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.
4. 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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