Stop Taking Semaglutide and Tirzepatide

Your skeleton is not a fixed structure. It is a living tissue that your body is constantly dismantling and rebuilding, and it does this through a process called bone remodeling, which is essentially a two-part cycle where specialized cells break down old bone and other specialized cells lay down new bone in its place.

Your body tracks this cycle with two measurable proteins. The first is something called CTX, which stands for C-telopeptide, and it rises in your blood when bone is being broken down because it is a fragment that gets released during that breakdown process. The second is something called P1NP, which is a marker of bone formation and it rises when your body is actively building new bone. Under normal conditions, these two markers move together, because bone breakdown and bone formation are supposed to be coupled, meaning one triggers the other in a balanced sequence.

When you diet and lose weight the conventional way, both markers slow down together. The rate of breakdown drops and the rate of formation drops to match it, and the ratio between them stays roughly intact. This is normal. It is not ideal, but the system stays balanced and your bones are not being depleted.

What researchers found in people taking semaglutide and tirzepatide is different, and the numbers make this concrete. In a randomized double-blinded phase 2 trial published in eClinicalMedicine in 2024, semaglutide increased CTX by 166.4 ng/L compared to placebo, meaning bone breakdown accelerated meaningfully and significantly. P1NP did not move. Bone formation stayed flat while breakdown sped up, and when that happens the two sides of the cycle are no longer synchronized.

Researchers call this uncoupled remodeling, which means the breakdown half of the cycle is running faster than the formation half, so the cycle is producing a net loss of bone tissue with every turn.

This is not what happens when you just eat less food. It appears to be something specific to how these drugs interact with the biological systems that govern bone turnover, and the mechanism behind it is still being worked out, but the signal in the data is there.

The same trial also measured bone mineral density directly and found decreases at both the hip and lumbar spine in the semaglutide group. And independent of that trial, a large observational study presented at the American Academy of Orthopaedic Surgeons annual meeting in 2026 tracked 73,483 matched patients per group over five years and found that GLP-1 receptor agonist users had a 29% increased risk of developing osteoporosis compared to non-users, which translated to 4.1% versus 3.2% in absolute terms.

But the finding that drew the most attention from surgeons was not the osteoporosis number. It was the osteomalacia number.

Osteomalacia is a condition where bone fails to mineralize properly, meaning the structural matrix is being laid down but it is not hardening the way it should, so the bone itself becomes softer than normal. In the AAOS data, patients on GLP-1 receptor agonists had a relative risk of 2.55 for osteomalacia compared to matched controls, which was the largest relative increase of any musculoskeletal outcome in the study. The absolute numbers were small, 0.2% versus 0.1%, but a more than doubling of the risk of a condition that makes bone physically softer is the kind of finding that orthopedic surgeons take seriously because they feel it in the operating room.

Several surgeons have now reported independently that bone in patients on these drugs feels softer than expected during procedures, which aligns with what the osteomalacia finding predicts.

So the picture that is building is this: the bone remodeling cycle becomes uncoupled, with breakdown outpacing formation, and at the same time the bone that remains is mineralizing less completely, and both of those processes are silent because you cannot feel bone density changing or bone tissue softening, and both compound over time with continued use.

The surgical community has also moved on a separate but related concern. Because semaglutide and tirzepatide slow gastric emptying so significantly, patients on these drugs retain stomach contents for much longer than normal, and when someone goes under general anesthesia, that retained material creates a real aspiration risk. Research presented at the 2025 AAOS annual meeting found that a three to five day hold before surgery was not sufficient to normalize that risk, and that a 14-day discontinuation was required to bring aspiration pneumonitis risk back to baseline levels. Many surgical centers have now adopted that protocol.

The question of whether this bone remodeling pattern occurs with retatrutide, a newer triple hormone receptor agonist, is worth addressing directly because the mechanism of that drug is structurally different. Retatrutide activates three receptors rather than two, and the third is the glucagon receptor, which semaglutide and tirzepatide do not activate meaningfully.

When the glucagon receptor is activated, it signals the liver to pull stored fat and convert it into usable energy rapidly, so rapidly that the body's energy availability stays high even while caloric intake is reduced. Retatrutide's phase 2 trial published in the New England Journal of Medicine in 2023 showed meaningful increases in beta-hydroxybutyrate at doses of 4mg and above, which is a direct marker of hepatic fat oxidation and confirms that glucagon-driven fat burning is actually occurring.

The theory, and it is a theory based on the available research rather than a proven conclusion, is that the bone breakdown cascade is triggered by the body detecting an energy deficit and entering conservation mode, and that semaglutide and tirzepatide produce that state because they primarily reduce food intake without providing an alternative energy source, while retatrutide's glucagon component replaces where the energy is coming from so the body never registers the deficit in the same way.

There is no long-term bone remodeling data on retatrutide yet, so this remains a mechanistic argument rather than a confirmed finding. But the mechanistic argument is grounded in how the glucagon receptor functions and what the energy metabolism data from the phase 2 trial actually shows.

The drugs that are being prescribed most widely right now are the ones that take food away without addressing where the body will source energy instead, and the bone data suggests that the body is answering that question on its own in a way that may carry a cost that does not show up for years.

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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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