Yes, Ozempic, Mounjaro, and similar medications are making headlines again for weight loss- recently for their effect on squashing demand for bariatric surgery. These medications belong to a family of drugs known as GLP-1 receptor agonists (GLP-1RAs), designed to mimic hormones in our body that control blood sugar levels and appetite. Technically, tirzepatide (the active ingredient in Mounjaro/Zepbound) and future injectable weight loss medications work as GLP-1RA as well as on other related pathways, but mechanistically they are all similar enough to warrant including them in the same discussion. While these drugs have drawn attention for their effectiveness in weight loss, they offer other unexpected benefits for people with painful joints, especially those considering joint replacement surgery. Here’s how they may be some of the most important medications for joint replacement prehab that we’ve got:

Anyone carrying extra bodyweight on an arthritic joint could likely benefit from weight loss by any mechanism. These medications increase the likelihood and magnitude of meaningful weight loss. Through their mechanism of mimicking hormones in the body that also regulate blood sugar, GLP-1RAs control elevated blood sugar immediately; then, as the individual loses more weight, the physiologic changes begin to reverse the factors contributing to metabolic disease.

These medications are not cure-alls, nor without risks. With both their popularity and increasingly bipolar news coverage as magic drugs or dangerous shortcuts, we need to understand their rightful place in the prehab toolbox.

1. Direct Benefits in Orthopedic Prehab

As suggested above, these medications can support impressive weight loss. The SURMOUNT-4 trial* showed that individuals who were on tirzepatide therapy for 88 weeks lost an average of 25% of their total bodyweight. Let’s put this in context for someone trying to qualify for a knee replacement. An adult male of average height (5’ 9”) with a BMI of 50 would weigh approximately 335 lbs. 25% weight loss would be 84 pounds in 88 weeks or, on average just under a pound per week assuming the rate of weight loss doesn’t change over time. In reality, it would likely start quicker, but let’s keep this estimate conservative.

To qualify for joint replacement, the most relaxed BMI cutoff is typically 45 for someone without other significant health issues; for the person in our example, this means getting weight under 305 pounds (30 pound weight loss). So, the average person may be able to start at a BMI of 50 and qualify for joint replacement in about 6 months, all else held equal. But why would we hold all else equal?

The premise of prehab is that a hands on, comprehensive program that “pulls all the levers” of exercise, nutritional and sleep optimization, anti-obesity medications, and others can potentially accelerate “typical” outcomes. This may be possible because of the effects that pain relief can have in facilitating increased physical activity. Or, this program that addresses poor sleep and nudges nutrition in the right direction can tip the scales (pun not intended, I promise) in your favor.

Injectable weight loss medications offer one interesting benefit in the orthopedic population. As most joint replacements swap out joints with painful osteoarthritis, medications that may directly slow the arthritis itself may theoretically show pain reducing benefits earlier than what weight loss alone will produce. In practice, this is exactly what we see*, and we have a decent understanding of the mechanisms.

The medical community used to generally regard osteoarthritis (OA) as a “wear and tear” disease, in contrast with rheumatoid and other autoimmune arthritis conditions which are considered “inflammatory.” If OA were strictly caused by wear and tear, then physical activity would increase the impact on the joints and someone with a high BMI but no other health-related impacts (“metabolically healthy obesity”or “MOH) should still have roughly the same risk of OA as someone with the same BMI and complications like diabetes. We now understand this is not the case.Exercise, even in the presence of arthritis, tends to improve pain and slow progression over the long term*, and diabetes is an independent risk factor forOA.

These weight-independent benefits are conferred through at least two known mechanisms. Ongoing research has identified the same GLP-1 receptors in the brain and gastrointestinal tract that the medications target for weight loss within joints. Early research in animal models suggests that injections of GLP-1RA medications directly into arthritic joints may improve joint health-

-but, please do not inject Ozempic into your knees. In fact, don’t do anything based on these blog posts; this is all just for educational purposes.-  

Trials of these medications also show improvement of whole-body inflammation, beyond what would be expected just by better controlling diabetes.* I describe inflammation and pain like this: when you’re coming down with a nasty viral infection, joint/muscle aches and pains that are typically minor suddenly become much more painful. The inflammation just “turns the heat up” on pain that is already simmering. In the case of these medications, for someone with an exquisitely painful hip or knee, less “heat” means less pain and better tolerance of exercise. Exercise then can further reduce pain.

2. How Prehab Programs Offset CertainRisks of Injectable Weight Loss Medications

After the initial honeymoon period during which the world was fawning over these wonder drugs, reports started coming out of concerning side effects. While addressing each side effect and complication is impossible, we can treat some using standard prehab practices. For example, individuals with clinically-relevant low muscle mass(sarcopenia) are at risk of losing even more muscle any time they lose weight, regardless of the medication. As multimodal programs prioritize protein maximization and resistance training, this inherently protects muscle mass during weight loss.

Other, more immediate, side effects of these medications relate to intolerance of the nausea, constipation, etc. that these medications cause by design. One way these medications work is by slowing the passage of food through the stomach and intestines. Slow this passage and the body feels fuller, longer. This effect is potentiated by signaling that occurs in the brain. Besides the nutritional management in prehab, these programs are built on a foundation of patient empowerment and education. Typically, this refers to thorough expectation management of surgical outcomes and postoperative pain, which then makes minor complications and setbacks less alarming for patients. By receiving these medications from a trained provider- instead of a faceless individual on the internet after a 5 minute conversation- patients understand what effects are normal and temporary and what effects indicate something more serious. This creates a better experience with greater adherence to medications, resulting in successful weight loss and pain improvements.

3. Are They Forever?

“But aren’t I just going to regain the weight the minute I stop?” This is a common and understandable concern. The short answer is- probably. Most people regain some of the weight they lost when they stop potent medications like these. Is this really a reason to avoid them?

Obesity is a disease- it is heritable (genes predispose you to it), it is chronic, and if left untreated, it is progressive. 

I personally have elevated cholesterol, despite maintaining a healthy bodyweight.It, too, is heritable… thanks Dad. Fortunately, we have effective, affordable medications to control levels in the body, because even with a good diet and active lifestyle, many cannot steer their cholesterol to their target level. For now, I can maintain healthy behaviors to lower my LDL-cholesterol, but I still add a low dose statin on top to really move the needle. Obesity is very similar to this relationship. Just like I’d expect my cholesterol to rise if I stopped myrosuvastatin, I’d expect weight to increase if someone stopped their anti-obesity medication. Note, there is ongoing debate over the true causal relationship between LDL-cholesterol and blood vessel disease, and I am not trying to poke that hornet’s nest here. This was just to prove a point.

This does not mean individuals with obesity are doomed to a lifetime of high dose medications with uncertain longterm effects. After achieving weight loss with a sustainable strategy of increased exercise/activity, nutritional changes, sleep improvement, etc., the weight regain may be minimal or at least manageable. Ongoing research looks to determine if a step-down approach to lower doses of current medications or to transition to less “intense” medications may adequately maintain successful weight loss. Other individuals may sustain weight loss through their lifestyle changes alone or by addressing any adaptive hormonal changes that occur when the body attempts to slow metabolic activity such as by suppressing thyroid hormone activity. This does not occur in everyone, and adding thyroid medications for anyone indiscriminately to support weight loss is not necessary. Some may sustain weight loss easier than anticipated due to improvements in testosterone (and related hormone) levels that occur with resolution of insulin resistance.  

Existing medications already afford individuals with obesity a chance to lose weight, improve diabetes, and reduce acute/chronic pain. As this family of medications has become major blockbusters for manufacturers, other pharmaceutical companies are hot in pursuit with their own versions of these medications. The forthcoming generation of these medications also work down synergistic pathways that may have fewer/less intense side effects, increased potency, or other benefits. On top of that, other medications in development may pair well with these to support muscle building while simultaneously losing weight- medications like a novel infusion called bimagrumab.

Allin all, this is the most exciting time in medicine to be treating obesity and weight-related conditions. There are no easy fixes, but we are steadily building an arsenal of increasingly effective treatments and an understanding of how they work, when they are best, and who may benefit.

Again, don’t inject your medications into your knees. Be well.

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