Stop Taking Semaglutide and Tirzepatide

Your skeleton is not a static structure. It is a living tissue that is constantly being torn down and rebuilt in a process that runs every day of your life, and the body maintains that process through a careful balance between two types of cells. Osteoclasts break old bone down, and osteoblasts build new bone up. When those two sides stay in sync, your skeleton stays strong. When they fall out of sync, you lose bone faster than you can replace it, and that is when real structural damage begins.

Researchers track this balance using two markers in the blood. The first is something called CTX, which is a fragment released into your bloodstream every time osteoclasts digest old bone tissue, so a high CTX reading means your body is breaking bone down quickly. The second is something called P1NP, which is a protein released when osteoblasts are actively laying down new bone, so a high P1NP reading means your body is building bone quickly. In a healthy skeleton, these two numbers move together. When one goes up, the other follows. When one slows down, the other slows down with it.

Normal weight loss, the kind that happens when someone just eats less food, actually slows both markers down. Bone turnover decreases across the board, the ratio stays intact, and the architecture of the skeleton stays balanced even as body weight drops. This is well established and it is not considered harmful.

What researchers found when they measured these same markers in people taking semaglutide is different in a specific and important way.

In a randomized, double-blind, phase 2 trial published in eClinicalMedicine, participants on semaglutide showed a 166.4 ng/L increase in CTX compared to placebo, and that result was statistically significant with a p-value of 0.021. Bone breakdown accelerated. But P1NP, the formation marker, showed no compensatory increase. The osteoblasts did not respond. So the body was tearing old bone down faster than before and not replacing any of it, and that specific pattern is called something called uncoupled remodeling, which means the two sides of the process have stopped communicating properly. The same trial also found decreased bone mineral density at both the hip and the lumbar spine, which is what you would expect to see downstream of that imbalance.

This is not what happens when you just eat less. The uncoupling is the signal that something beyond caloric restriction is driving the bone resorption.

That finding from the trial maps onto something orthopedic surgeons have been observing independently. In a dataset of 73,483 matched patients per group presented at the American Academy of Orthopaedic Surgeons Annual Meeting, GLP-1 receptor agonist users showed a 29 percent increased risk of osteoporosis over five years compared to matched controls, translating to an event rate of 4.1 percent versus 3.2 percent. But the finding that stood out was osteomalacia, which is a condition where bone fails to mineralize properly so the existing structure becomes soft rather than simply thin. Osteomalacia showed the greatest relative risk increase of any musculoskeletal outcome in that dataset, with a relative risk of 2.55 and event rates of 0.2 percent versus 0.1 percent. Surgeons operating on these patients are reporting that the bone feels softer than expected for the patient's age and weight, which is consistent with a mineralization problem on top of a resorption problem.

That is two separate mechanisms compounding at the same time, and neither one produces any symptom you can feel until something breaks.

The same surgical community has raised a separate concern that is unrelated to bone but reflects how broadly these drugs affect physiology. GLP-1 receptor agonists slow gastric emptying significantly, and when patients on these drugs undergo general anesthesia, the stomach is not emptying at the rate physicians expect, which creates a real aspiration risk. A study 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 the recommendation shifted to a fourteen day discontinuation before total joint arthroplasty.

Now the question worth asking is whether this bone remodeling pattern shows up across all GLP-1 receptor agonists, or whether it is specific to how semaglutide and tirzepatide work.

Retatrutide is a triple receptor agonist, meaning it activates three receptors rather than two. It activates the GLP-1 receptor and the GIP receptor the same way tirzepatide does, but it adds activation of something called the glucagon receptor, which is a receptor that signals the liver to convert stored fat into usable energy directly. In the phase 2 trial of retatrutide published in the New England Journal of Medicine, participants at the 4mg dose and above showed measurable increases in beta-hydroxybutyrate, which is a ketone body that your liver produces specifically when it is pulling fat out of storage and oxidizing it for fuel. That is a direct indicator of glucagon-driven hepatic fat mobilization.

The theory, and it is worth being clear that this is mechanistic reasoning applied to available data rather than a proven causal chain, is that semaglutide and tirzepatide create a state where the body perceives an energy deficit because food intake drops sharply and the liver is not rapidly compensating by pulling from fat stores. In that perceived deficit state, the body activates conservation strategies that include accelerating bone resorption, because bone is a metabolic reservoir and the body treats it as one under stress. The uncoupled remodeling pattern would then be a downstream consequence of that perceived deficit signal.

Retatrutide's glucagon component may prevent that state from occurring because the liver is actively converting stored body fat into circulating energy fast enough that the body never registers a deficit to begin with. The fuel source changes before the conservation cascade can start.

Whether that mechanism fully explains the difference in bone outcomes will require head-to-head trials with bone marker endpoints, and those do not yet exist. But the biological pathway is coherent and the signal from the existing semaglutide data is strong enough to take seriously now, not after the longer-term fracture data accumulates.

Most people think of bone density as something that declines slowly with age and becomes a concern in your seventies. What this data suggests is that a drug can accelerate that process in a specific and measurable way within a timeframe that a clinical trial can capture, and it can do it through a mechanism that is distinct from anything produced by weight loss alone. The bone you have right now is the product of decades of remodeling, and the process rebuilding it today is the one that determines what you have left in ten years.

---

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