J Clin Endocrinol Metab. 2015 Aug;100(8):2909-17.
GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women
Eva W. Iepsen, MD1,2, Julie R. Lundgren, BSc Med1,2, Bolette Hartmann1,2, PhD, Oluf Pedersen, DMSci2, Torben Hansen, PhD2, Niklas R. Jørgensen, DMSci4,5, Jens-Erik B. Jensen, PhD3Jens J. Holst, DMSci1,2, Sten Madsbad, DMSci3 and Signe S. Torekov, PhD1,2
1 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2 The NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3 Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark.
4 Department of Diagnostics, Glostrup University Hospital, Denmark.
5 Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen Denmark.
Recent studies have shown that the gut hormone glucagon-like peptide 1 (GLP-1) regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. Therefore, the purpose of this study was to investigate the role of GLP-1 RAs on bone formation and weight loss induced reductions in bone mass. Thirty-seven healthy, but obese women with a mean BMI of 34kg/m2 and a mean age of 46 years were subjected to a low-calorie diet which led to a weight loss of 12 %. After the weight loss the women were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2mg/day) for 52 weeks. In case of weight gain, the women could replace up to two meals per day with a low-calorie diet product in order to maintain their weight loss.
After one year of weight loss maintenance we saw that the bone mineral content (BMC) in the total skeleton, pelvic area as well as the arm and leg area decreased significantly during weight maintenance in the control group, but not in the liraglutide group. Thus, the total and arm-leg BMC loss was 4 times greater in the control group compared to the liraglutide group although the 12% weight loss was equally maintained in both groups. Additionally, in the liraglutide group, the bone formation marker N-terminal pro-peptide of type 1 pro-collagen (P1NP) increased by 16 % vs a 2 % decrease in the control group. However, the bone resorption marker C-terminal telopeptide of type 1 collagen (CTX-1) did not change during the weight loss maintenance phase. From this we conclude that treatment with a long-acting GLP-1 RA increased bone formation by 16 % and prevented bone loss after weight loss obtained through a low calorie-diet, supporting its role as a safe weight-lowering agent.
It is known that patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fractures and antidiabetic agents such as thiazolidinediones may accentuate bone loss and bone fragility. Recent clinical studies have shown that treatment with a glucagon like peptide-1 receptor agonist (GLP-1 RA) does not increase the risk of fractures in T2DM patients. Additionally, liraglutide 3.0mg (Saxenda®) was recently approved as treatment for chronic weight management in obesity, but the effect of GLP-1 RAs on bone in obese non-diabetic individuals undergoing weight loss is still unknown.
The possible role of the gut hormone GLP-1 as well as its analogues on bone turnover is not very clear. However, GLP-1 receptor knock-out (KO) mice have shown cortical osteopenia and bone fragility as well as reduced cortical bone strength and bone quality. Moreover, treatment with the GLP-1 RA exendin-4 in rats with ovariectomy-induced osteoporosis has been shown to prevent osteopenia by improving bone strength, prevent deterioration of trabecular bone and increase the bone formation marker, N-terminal pro-peptide of type 1 pro-collagen (P1NP) and suppress the bone resorption marker, C-terminal telopeptide of type 1 collagen (CTX-1).
A large (and fast) weight loss is often associated with a decrease in bone mineral content (BMC) and bone mineral density (BMD), an imbalance between bone resorption and formation and, as a consequence, an increased risk of fractures. Furthermore, it has been proposed that weight loss-induced decrease in bone mass persists even if lost weight is regained. However, weight loss achieved with standard powder diets may counteract the negative impact of weight loss on bone, perhaps due to vitamin and mineral enrichment in the diet.
Thus the impact of GLP-1 RA treatment on bone metabolism and bone markers in obese non-diabetic individuals following a larger weight loss is unknown and thus the focus of this study.
Figure 1. Full body DXA scans were performed before and after weight loss in order to assess bone mineral content.
After 1 year of weight loss maintenance we saw that by providing a relatively low dose of the long-acting GLP-1 RA liraglutide (1.2 mg daily), the weight loss-induced decrease in total, pelvic and arm-leg BMC was abolished. Thus, the total BMC loss was 4 times greater in the control group compared to the liraglutide group indicating that the sustained weight loss had a negative impact on bone, but that is negative impact was diminished in the liraglutide group. Furthermore, our results suggest that it might be in the pelvic but especially in the arm and leg area that the BMC loss is prevented with GLP-1 RA treatment. As the pelvic area mainly comprises trabecular bone and the long bones of the arms and legs mainly comprise cortical bone, our data suggest that weight loss primarily leads to reductions in cortical bone mass, which may be prevented by GLP-1 RA treatment. This finding is in agreement with previous reports of cortical osteopenia and fragility in GLP-1 R KO mice. The bone formation marker P1NP increased by 16 % in the liraglutide group compared to a 2 % decrease in the control group. Interestingly, the difference between the groups regarding BMC loss was dependent on the increase in P1NP levels, suggesting that liraglutide prevents decreases in BMC by increasing bone formation.
Since weight loss is often associated with a decrease in bone mass, the effect of GLP-1 RA treatment on bone in obesity is of particular clinical interest. And interestingly, we found that liraglutide prevented BMC loss after weight loss in contrast to the control group, and propose a contributory role of GLP-1 RA on bone formation, supported by the increase in the bone formation marker P1NP with liraglutide treatment. We observed a weight loss induced decrease of total BMC of 2 % during one year in the control group which corresponds to the findings in other studies. Thus, it is likely that the observed changes in total BMC are of clinical relevance. Importantly, the observed difference in total BMC loss between the groups during the treatment period did not change when adjusting for the effect of baseline total BMC or the change in total BMC from before to after weight loss. Development of new treatment modalities for obesity management is highly important given the continued increase in the prevalence of obesity. As weight loss often is associated with bone loss and thus increased fracture risk, it is of high clinical relevance to consider the risk of bone loss when initiating treatment with weight-lowering agents in obese individuals. And the GLP-1 RAs comprise a promising candidate in this context as they not only lower weight but also, due to their gluco-regulatory profile, reduce the risk of several other obesity-related co-morbidities. With the combination of low calorie diet and GLP-1 RA treatment the beneficial effects of weight loss on cardiac events may be preserved in addition to prevention of weight loss induced bone loss, thereby providing a safe weight loss strategy.
Figure 2. Proposed model for GLP-1 function in bone metabolism.