Stop Taking Semaglutide and Tirzepatide

Your skeleton is not a fixed structure. It is a living system that is constantly dismantling itself and rebuilding, and the balance between those two processes is what keeps your bones strong across a lifetime.

Researchers track that balance with two markers. The first is something called CTX, which is a fragment of broken-down collagen that shows up in your blood when bone is being resorbed, meaning dissolved and cleared away. The higher your CTX, the faster your skeleton is tearing itself down. The second is something called P1NP, which is a protein released by the cells that build new bone, so it tells you how fast construction is happening. In a healthy system, those two markers move together. Breakdown goes up, formation follows. Breakdown slows, formation slows with it. The ratio stays balanced, and your net bone mass holds steady.

When you lose weight through calorie restriction, both markers drop. Your body is doing less of everything, including bone turnover, and that is completely normal. The ratio stays intact, which means the bone you have continues to be replaced at roughly the same proportion it is removed.

That is not what is happening on semaglutide and tirzepatide.

In a randomized, double-blinded phase 2 trial published in eClinicalMedicine, researchers measured those same two markers in adults on once-weekly semaglutide versus placebo. CTX increased by 166.4 nanograms per liter in the semaglutide group compared to placebo, and that result was statistically significant. P1NP did not increase to match it. Bone breakdown accelerated and bone formation stayed flat, and that imbalance has a name: something called uncoupled remodeling, which means the demolition crew showed up but the construction crew did not.

The same trial also measured areal bone mineral density at the hip and lumbar spine and found decreases in both. So the uncoupled remodeling is not a lab artifact. It is showing up in the actual density of the tissue.

Now you might expect the orthopedic community to be the last place you would find signal on a metabolic drug, but that is exactly where the next piece of evidence emerged. At the 2026 American Academy of Orthopaedic Surgeons annual meeting, researchers presented data from 73,483 matched patients per group, which is a large enough sample to detect relatively rare outcomes. GLP-1 receptor agonist users had a 29 percent higher five-year risk of osteoporosis compared to matched non-users, 4.1 percent versus 3.2 percent. But the number that stands out is the relative risk for osteomalacia, which came in at 2.55, meaning users were about two and a half times as likely to develop that condition.

Osteomalacia is worth understanding separately from osteoporosis because they are different problems. Osteoporosis means you have less bone. Osteomalacia means the bone you have is not mineralizing correctly, so the structural matrix is there but it is not hardening the way it should. Surgeons operating on patients who use these drugs have been noting that bone tissue feels softer than expected for the patient's age and weight, and the AAOS data gives that clinical observation a quantitative context.

Those are two distinct mechanisms running simultaneously. You are losing bone volume through uncoupled remodeling and you are losing bone quality through impaired mineralization, and neither one produces a symptom you can feel until something breaks.

The aspiration risk during surgery is a separate issue but it points to the same underlying pharmacology. Semaglutide and tirzepatide slow gastric emptying significantly enough that even a patient who has fasted according to standard pre-operative protocol may still have stomach contents when they go under anesthesia. The 2025 AAOS recommendation moved from a three to five day hold to a fourteen day discontinuation specifically because the shorter window was not enough to normalize aspiration pneumonitis risk. The fact that surgeons need two weeks of washout to consider a patient's stomach behavior safe tells you something about how persistently these drugs alter baseline physiology.

The question the video raises about retatrutide is worth addressing carefully, because the mechanism is different and the distinction matters, but the clinical evidence is not yet at the same level.

Retatrutide is a triple agonist, meaning it activates three receptors: GLP-1, GIP, and the glucagon receptor. The glucagon receptor is the piece that semaglutide and tirzepatide do not have. Glucagon signaling tells the liver to oxidize stored fat aggressively and convert it into ketone bodies for fuel, and the phase 2 trial published in the New England Journal of Medicine showed that retatrutide produced measurable increases in beta-hydroxybutyrate, which is a ketone body, at doses of 4 milligrams and above, and that increase was dose-dependent. Beta-hydroxybutyrate rising in the blood is direct evidence that the liver is running fat oxidation at an elevated rate.

The theory is that this glucagon-driven fat mobilization keeps circulating energy supply high enough that the body never registers a true energy deficit, and the bone remodeling cascade that appears to be triggered by that deficit never gets initiated. Semaglutide and tirzepatide suppress appetite and reduce food intake, but they do not have a parallel mechanism accelerating the use of stored fuel. The body may interpret that as a shortage rather than a substitution, and the conservation response to shortage includes pulling resources from bone.

That is a mechanistically coherent theory, and the retatrutide phase 2 data is consistent with it, but bone remodeling markers were not the primary endpoints in that trial and the long-term skeletal data on retatrutide does not yet exist at the scale the AAOS dataset provides for GLP-1 agonists.

What the existing evidence does establish clearly is that the bone effects of semaglutide and tirzepatide are not explained by weight loss alone, because the pattern of uncoupled remodeling is distinct from what dieting produces, and because orthopedic surgeons are seeing tissue changes that correspond to a drug mechanism, not just a lower number on the scale.

The distinction between losing weight and losing the energy that was stored as fat turns out to matter at the level of skeletal biology, and that is not a distinction most people are thinking about when they start one of these medications.

---

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

---

Join the free community:
Men: Iron Forge Brotherhood
Women: Powerhouse Fitness