Anti-Obesity Drugs Put to the Test: How Weight Loss Drugs Affect Bones

A new critical review published in Diabetes, Obesity and Metabolism summarizes the current evidence on the effects of leading anti-obesity drugs on bone metabolism in overweight and obese individuals. The authors note that along with the loss of fat mass, muscle and bone tissue are inevitably lost during weight loss, making the study of the effects of anti-obesity drugs on skeletal health particularly relevant.

Background and significance of the problem

Pharmacological treatment of obesity has made significant progress in recent years with the development of highly effective drugs, but along with the reduction of fat mass, muscle and bone tissue inevitably suffer. Bone loss increases the risk of osteopenia and fractures, which is especially relevant for obese people seeking long-term weight loss. The aim of a new review is to critically evaluate the available data on the effects of the main anti-obesity agents on bone metabolism, including bone turnover markers (BTMs), bone mineral density (BMD) and fracture risk.

1. GLP-1R agonists

Glucagon-like peptide-1 receptor (GLP-1R) agonists, including liroglutide and semaglutide, stimulate osteoblasts and reduce osteoclast activity in preclinical studies, potentially protecting bone. However, in clinical trials, bone turnover markers and BMD are typically neutral or only slightly reduced, and these changes do not reach clinically significant levels. Meta-analyses and randomized controlled trials have found no statistically significant increase in fracture risk with therapeutic doses of GLP-1R agonists.

2. Dual and triple incretin analogues

Novel combinations of incretin receptor agonists have shown potential positive effects on bone tissue in preclinical models.

• GLP-1R/GIPR agonists (tizepatide) and GLP-1R/GCGR agonists stimulate osteoblast formation and inhibit bone resorption, as confirmed in studies in animal models of obesity.
• Triple agonists (GLP-1R/GIPR/GCGR) also show a favourable balance between anticatabolic and anabolic effects on bone tissue in preclinical data, but clinical data on the effect on BMD and fracture risk are currently lacking.

3. Amylin analogues

Initial preclinical studies of amylin analogues (eg, pramlintide) show stimulation of osteogenesis and suppression of bone resorption in cell cultures and rodent models. Clinical studies of the effect of amylin drugs on bone mass are not yet available, which requires further study.

4. Activin receptor type II antagonists (ActRII)

ActRII blockers (e.g., bimagrumab) are a particularly promising group—they not only promote fat loss, but also preserve or even increase muscle and bone mass. In preclinical studies in mice, the combination of an ActRII antagonist and semaglutide resulted in significant weight loss and simultaneous muscle mass gain without loss of BMD. These findings make ActRII inhibitors a promising complement to incretin drugs to minimize skeletal side effects.

5. Other groups of drugs

• Opioid receptors and setmelanotide: There are almost no data on the effects on bone tissue, which does not allow an assessment of skeletal safety.
• Phentermine/topiramate combination: Based on mechanistic considerations and limited data, a negative effect on BMD and an increase in osteoclastic activity is suggested, but no specific clinical studies are available.
• Orlistat: Very limited clinical data suggest a neutral effect on bone turnover markers and BMD, but long-term randomized studies are underpowered to draw definitive conclusions.

Clinical findings and recommendations

1. Bone health monitoring: For all patients initiating anti-obesity therapy, especially long-term, BMD and bone turnover markers (BTMs) should be assessed regularly.
2. Optimization of therapy: in the presence of a risk of osteopenia and risk factors for fractures, it is advisable to consider combinations of ActRII antagonists with incretin drugs or add specific osteoprotective therapy (bisphosphonates, denosumab).
3. Further research: Multicenter clinical trials of at least 2–3 years duration are needed to evaluate the effects of dual and triple incretins, amylin analogues, and ActRII blockers on the tipping point and long-term BMD dynamics.

Below are the key comments and recommendations from the review authors:

• Prof. A. D. Anastassilakis (lead author):
  “Monitoring of bone metabolism parameters and bone mineral density should be an integral part of pharmacological weight loss programs. We recommend that clinicians assess BMD before initiating therapy and repeat the assessment at least annually in patients at high risk of fracture.”

• Assoc. Prof. E. V. Marinis:
  “Although preclinical data on dual and triple incretin agonists look very encouraging, we need long-term clinical trials to confirm their safety for the skeleton and to understand the mechanisms of interaction with bone cells.”

• Prof. K. L. Phillips:
  "ActRII blockers represent a revolutionary approach: simultaneously reducing fat mass while preserving muscle and bone tissue. In our animal experiments, combining these drugs with semaglutide has produced impressive results - we hope to see similar effects in the clinic."

• Assoc. Prof. M. G. Rakhman:
  “The lack of data on setmelanotide and opioid receptor antagonists is a blind spot in our picture. We encourage colleagues to conduct special studies to determine whether it makes sense to include these drugs in therapeutic algorithms for patients at risk of osteopenia.”

• Prof. P. I. Smirnov:
  "It is important to remember about the comprehensive approach: weight loss is effective only in combination with monitoring by an endocrinologist, nutritionist and bone metabolism specialist. Only in this way can we minimize side effects and ensure long-term health of patients."

Thus, despite the overall neutral or slightly negative effect of most new anti-obesity drugs on bone tissue, proper combination selection and monitoring can significantly reduce the risk of skeletal complications in obese patients.