Stop Taking Semaglutide and Tirzepatide

Your skeleton is not static. It is alive in the same way your muscles are alive, constantly being torn down and rebuilt in a process called bone remodeling, which is your body's way of replacing old or damaged bone tissue with fresh, mineralized bone.

To track whether that process is working properly, researchers measure two markers in the blood. One is called CTX, which stands for C-terminal telopeptide, and it measures how fast bone is being broken down. The other is called P1NP, which stands for procollagen type 1 N-terminal propeptide, and it measures how fast new bone is being built. Think of these as the demolition crew and the construction crew for your skeleton. Under normal circumstances, when one speeds up, the other does too, and the balance holds.

That balance is exactly what gets disrupted when you go on semaglutide or tirzepatide.

Before getting into what the drugs do, it helps to understand what normal weight loss does, because people often assume any change in bone during weight loss is just a side effect of dieting. When you restrict calories and lose weight, both CTX and P1NP slow down together. The demolition crew slows down, the construction crew slows down by roughly the same amount, and the net effect on bone is fairly neutral. The balance stays intact. That is the baseline you need to hold in your head.

Now here is where semaglutide and tirzepatide diverge from that pattern.

In a randomized, double-blinded phase 2 trial published in eClinicalMedicine, researchers measured bone remodeling markers in people taking once-weekly semaglutide versus placebo. CTX, the breakdown marker, increased by 166.4 ng/L in the semaglutide group compared to placebo. That is a statistically significant jump, with a p-value of 0.021. P1NP, the formation marker, did not move to compensate. The demolition crew accelerated. The construction crew stayed home. And the result is what researchers call uncoupled remodeling, where breakdown and formation no longer track together.

This is not a measurement artifact. The same trial also found decreased bone mineral density at both the hip and lumbar spine, which means the uncoupled remodeling is translating into actual structural bone loss.

The orthopedic surgery world has been noticing something adjacent to this from a completely different angle. At the 2026 American Academy of Orthopaedic Surgeons annual meeting, a study drawing on 73,483 matched patients per group found that GLP-1 receptor agonist users had a 29 percent higher five-year risk of osteoporosis compared to non-users, with rates of 4.1 percent versus 3.2 percent. But the finding that stood out most was osteomalacia, a condition where bone tissue forms but fails to mineralize properly, meaning the bone exists but it is soft and structurally weak the way green wood is weak compared to dry hardwood. GLP-1 users had a relative risk of 2.55 for osteomalacia compared to matched controls. That is a 155 percent increase in relative risk.

So you have two separate problems happening simultaneously. The total amount of bone is decreasing because remodeling is uncoupled, and the bone that remains is failing to mineralize properly. Neither problem produces symptoms you can feel. You cannot sense your CTX rising. You cannot feel your hip BMD declining. The damage accumulates silently until something breaks.

The surgical community has already responded to one of the other bone-adjacent effects of these drugs. A study presented at the 2025 AAOS annual meeting found that a three-to-five day drug hold before total joint replacement surgery was not enough to normalize aspiration risk under anesthesia, because semaglutide and tirzepatide slow gastric emptying so significantly that food and liquid remain in the stomach far longer than expected. The recommendation that came out of that research was a fourteen-day discontinuation before surgery. Surgeons are already building this into their protocols.

Now the reasonable question is whether this bone problem is specific to the GLP-1 mechanism or whether it is just a byproduct of rapid weight loss itself.

The retatrutide data points toward it being mechanism-specific. Retatrutide is a triple agonist, meaning it activates three receptors instead of two: GLP-1, GIP, and glucagon. The glucagon receptor component is what makes it structurally different from semaglutide and tirzepatide, which do not have meaningful glucagon activity. When glucagon receptors in the liver are activated, they signal the liver to convert stored fat into usable energy through a process called hepatic fat oxidation, and you can measure this happening because it produces beta-hydroxybutyrate, which is a ketone body your tissues can burn as fuel.

In the phase 2 retatrutide trial published in the New England Journal of Medicine, participants on doses of 4 mg or higher showed measurable increases in beta-hydroxybutyrate, which is a signal that hepatic fat oxidation was actively occurring. The theoretical implication is that when the body has a continuous internal fuel source being mobilized from stored fat, it never registers a true energy deficit the way it does on semaglutide or tirzepatide, which primarily reduce caloric intake without replacing that energy from an internal source. If the deficit signal is what triggers the bone breakdown cascade, then a drug that prevents the deficit signal from ever fully firing might preserve the balance between CTX and P1NP.

That is a theory, not a proven conclusion. The bone remodeling markers have not been formally compared head to head between retatrutide and semaglutide in a controlled trial. But the mechanistic logic is coherent, the ketone data from the phase 2 trial supports that the glucagon component is doing something metabolically distinct, and it is a signal worth watching as the longer-term retatrutide data comes in.

What we can say with confidence right now is that semaglutide and tirzepatide produce a pattern of uncoupled bone remodeling that is measurably different from what happens during ordinary caloric restriction, that this pattern is associated with both bone density loss and impaired bone mineralization, and that these changes happen without any symptoms while the drugs are working exactly as intended on every other metric.

The weight on the scale is going down. The bone that holds you up is going with it.

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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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