Liraglutide May Prevent Weight-Loss Induced Bone Loss

Generic insulin penGeneric Insulin PenWhile weight loss often leads to decreased bone mineral content and increases the risk for bone fractures, new findings suggest that the GLP-1 receptor agonist liraglutide may prevent this bone loss when used for chronic weight management, according to a report published online ahead of print in the Journal of Clinical Endocrinology & Metabolism.

“The results are intriguing and show promise that liraglutide may attenuate the loss of bone that accompanies weight loss in older patients,” commented Sue Shapses, PhD, Professor, Rutgers University, New Brunswick, NJ. “However, further study of this is warranted to extend these bone findings and report bone mineral density at clinically relevant sites. Thereafter, a long-term trial to study [the effects of liraglutide on] fracture would be indicated,” Dr. Shapses said.

Study Rationale
“GLP-1 analogues like liraglutide are today widely used in the treatment of type 2 diabetes and have been shown not to increase the risk of bone fractures, unlike other diabetes drugs. Liraglutide has just been approved for obesity treatment because of its appetite-inhibiting effects, but its effect on the bones of overweight patients who are not suffering from type 2 diabetes has so far been unknown,” said coauthor Eva Winning Jepsen, MD, Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The study involved 37 women (age 18–65 years) with a body mass index of 30 to 40 kg/m2 who underwent an 8-week weight-loss program, including a low-calorie diet (810 calories per day). The average weight loss during this program was 12.1 kg, and no significant change in bone mineral content was found.

After the 8-week program, the women were randomized to 52 weeks of liraglutide 1.2 mg/d via subcutaneous injection or to a control group that did not receive the medication. Women in both groups were given frequent dietary advice and followed the same weight loss maintenance program; and if they gained weight, they could replace up to 2 meals with a low-calorie diet product. After 1 year, both groups maintained a 12% weight loss. The control group maintained their weight by replacing 1 meal/day with a low-calorie diet meal, whereas the liraglutide group maintained their weight loss without replacing any meals with low-calorie diets.

Liraglutide Diminishes Negative Impact of Weight Loss on Bone
Measurements of total, pelvic, and arm-leg bone mineral content (BMC) did not change significantly in the liraglutide group after 1 year of treatment, but decreased significantly in the control group during weight maintenance (35.8 g; P<0.0001). The total and arm-leg BMC loss was approximately 4 times greater in the control group than in the liraglutide group (estimated difference 27g; P=0.01),

The bone formation marker N-terminal propeptide of type 1 procollagen (P1NP) increased by 16% in the liraglutide group compared with a 2% increase in the control group (P<0.05), suggesting that liraglutide may prevent weight-loss induced decreases in BMC by increasing bone formation, according to the study authors. In contrast, the bone resorption marker CTX-1 did not change significantly in either group.

Study Has Implications for Weight Loss in Menopausal Women
“Menopausal women have an increased risk of osteoporosis and bone fractures. If they try to lose weight and thus lose even more bone mass, they are at an even higher risk. The study shows that overweight women can now lose weight with liraglutide without increasing the risk of losing bone mass. At the same time, they also achieve a number of other positive effects on their sugar metabolism, which are not achieved through a diet-induced weight loss alone,” said senior author Signe Soerensen Torekov, PhD, Associate Professor, Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. The mean age in each group was approximately 45 to 46 years and 7 women in each group were postmenopausal.

“Overweight is a protective factor for osteoporosis and bone fractures, but it increases the risk of other diseases such as cardiovascular diseases and type 2 diabetes. It appears that treatment with liraglutide makes it possible to lose weight and maintain the beneficial effect on the bones, while at the same time reducing the risk of cardiovascular disease and type 2 diabetes. This may have a significant bearing on our future approach to obesity treatment,” Dr. Torekov said.

“The 12% weight loss in this study is clinically significant,” Dr. Shapses commented. “If there is attenuated bone loss with liraglutide after weight loss, this is important since studies consistently show bone loss with weight loss,1,2 and additional [bone] loss up to 2 years later after weight loss ends.3,4 Osteoporosis medications can attenuate bone loss due to weight reduction;5 however, this study is novel in that it suggests that a weight loss medication might attenuate bone loss.”

“The limitation [of these findings] is that a mechanism for this action is not clear at this time and would need to be examined,” Dr. Shapses said. “Also, a major limitation is that the study wasn’t designed to examine bone sites that are vulnerable to fracture (as acknowledged by the authors) and only BMC. It is known that bone mineral density at the hip, spine, and wrist help to define osteoporosis and fracture risk. Hence, the measurements used in this study do not inform about osteoporosis risk. It would be important to conduct a study specifically designed to examine bone and/or fracture in a future trial,” Dr. Shapses added.

August 20, 2015

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