Recent studies indicate that glucagon-like peptide (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.
To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction.
Randomized control study.
Outpatient research hospital clinic.
Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m2 and age 46 ± 2 years.
After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss.
Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment.
Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5–48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 μg/L) vs a 2% (−1 ± 4 μg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase.
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.
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fractures (1, 2). Furthermore, antidiabetic agents such as thiazolidinediones may accentuate bone loss and bone fragility (3–5). Recent clinical studies have reported that treatment with a glucagon-like peptide (GLP)-1 receptor agonist (GLP-1 RA) does not increase the risk of fractures in T2DM patients (6–8). The GLP-1 RAs potentiate glucose-induced insulin secretion, inhibit glucagon release, delay gastric emptying, and reduce appetite, thereby inducing weight loss (9–12). Thus, GLP-1 RAs are now widely used in the treatment of T2DM (13, 14), and their potential in preventing diabetes in prediabetic individuals is being intensively investigated (12, 15–17). Both the US Food and Drug Administration and the European Medicines Agency recently approved liraglutide 3.0 mg (Saxenda; Novo Nordisk) as treatment for chronic weight management in obesity (18, 19), but the effect of GLP-1 RAs on bone in obese nondiabetic individuals undergoing weight loss is unknown.
Although several studies support the hypothesis that the gut hormones glucose-dependent insulinotropic peptide and GLP-2 are modulators of bone growth (20–22) and remodeling (23–25), the possible role of the gut hormone GLP-1 and its analogs on bone turnover is less clear (26). However, cortical osteopenia and bone fragility (27), as well as reduced cortical bone strength and bone quality (28), have been demonstrated in GLP-1 receptor knockout mice. So far, studies have failed to demonstrate the presence of GLP-1 receptors on osteoblasts (28, 29), but it has been suggested that GLP-1 may interact with osteoblastic cells through a glycosylphosphatidylinositol/inositolphosphoglycan-coupled receptor (30).
Treatment with the GLP-1 RA exendin-4 in rats with ovariectomy-induced osteoporosis has been shown to prevent osteopenia by improving bone strength; to prevent deterioration of trabecular bone; to increase the bone formation marker, N-terminal propeptide of type 1 procollagen (P1NP); and to suppress the bone resorption marker, C-terminal telopeptide of type 1 collagen (CTX-1) (31). Furthermore, 3 days of continuous exendin-4 treatment in insulin-resistant and type 2 diabetic rats induced osteogenic effects (32).
Weight loss is often associated with a decrease in bone mineral content (BMC) and bone mineral density (BMD) (33, 34) and an imbalance between bone resorption and formation (35); as a consequence, there is an increased risk of fractures (36). Furthermore, it has been proposed that weight loss-induced decrease in bone mass persists even if lost weight is regained (35, 37). The mechanism whereby weight loss increases bone may include mechanical alterations due to unloading of the skeleton as a result of weight loss (38) as well as hormonal changes (36, 39). Insufficient intake of calcium and 25(OH) vitamin D during caloric restriction may further promote bone resorption (40). However, weight loss achieved with standard powder diets may counteract the negative impact of weight loss on bone due to vitamin and mineral enrichment (34, 41). Previously, it has been shown that GLP-1 RA treatment did not change BMD in T2DM patients with moderate weight loss (6%) during 44 weeks of treatment (42). However, the impact of GLP-1 RA treatment on bone metabolism and bone markers in obese nondiabetic individuals after a larger weight loss is unknown, although the question is highly relevant given the new release of the first GLP-1 RA for the treatment of obesity.
We therefore assessed total body, central (pelvic), and peripheral (arm-leg) BMC as well as clinical biomarkers of bone resorption (CTX-1) and bone formation (P1NP) in 37 obese glucose-tolerant women who, after an 8-week weight loss period with a very-low-calorie powder diet, were randomized to a group receiving the GLP-1 RA liraglutide for 1 year or to a control group.
Subjects and Methods
Study participants
Fifty-eight obese glucose-tolerant individuals (body mass index [BMI], 30–40 kg/m2) aged 18–65 years were recruited for the study by advertising in local newspapers. Participants suffering from acute or chronic illnesses (including diabetes) or those taking any form for medical treatment with known effects on glucose metabolism, lipid metabolism, and bone metabolism were excluded before entering the study.
Of the 58 participants entering the study, 37 women (nonpregnant and nonlactating) and 6 men completed the 8-week weight loss program and the 52-week weight maintenance follow-up period (12).
Because there was only one man in the control group who completed the study, and due to the known effect of gender on bone loss (43), the present study was performed in the 37 women only. Randomization was as follows: 18 women in the liraglutide group (mean age, 46 y), and 19 women in the control group (mean age, 45 y). Seven subjects in each group were postmenopausal.
Weight loss program with low-calorie diet
The study participants were instructed by a clinical dietician how to conduct a low-calorie powder diet of 810 cal (3402 kJ) per day for 8 weeks. Products were provided by the Cambridge Diet (Cambridge Weight Plan) (44). The low-calorie diet program consisted of a powdered formula mixture dissolved in skimmed milk or water. The program met all recommendations for daily intake of essential amino acids, fatty acids, vitamins, and minerals. Daily intake of vitamin D was 7.3 μg; B12 vitamin, 6.4 μg; iron, 19 mg; and calcium, 2146 mg. Daily intake of protein was at least 43.2 g; essential fatty acids and linoleic acid were 3.0 g and 0.4 g, respectively. Dietary fiber intake was 7.2 g per day at minimum. During the 8-week weight loss phase, the participants had individual meetings with a dietician every week with the objective to achieve a weight loss of at least 7.5% of their initial body weight.
Randomization and weight maintenance program
After 8 weeks on the very-low-calorie diet, the study participants were randomized into two groups: one receiving the GLP-1 RA liraglutide 1.2 mg/d, and the other serving as the control group. Liraglutide was administered using FlexPen devices (Victoza; Novo Nordisk A/S) by sc injections in the abdomen or thigh. Throughout the 52 weeks, both groups followed the Cambridge Weight Loss Maintenance Program with Cambridge Weight Plan products. Study participants were instructed to calculate their restricted calorie intake by subtracting 600 kcal from their estimated daily energy need. They received education on diet and lifestyle changes. In case of weight gain, up to two meals a day during the weight maintenance period were allowed to be replaced by Cambridge Weight Plan products aiming at a stable maintenance of weight loss. Both groups maintained the weight loss with no significant difference between the groups at 12 months, but the control group replaced one meal per day with a low-calorie diet meal in contrast to no meal replacements in the liraglutide group (12).
Outcome measures
Total body, central (pelvic), and peripheral (arm-leg) BMC and BMD were assessed by dual-energy x-ray absorptiometry scan (Hologic Discovery A) at screening (before weight loss), at baseline (after weight loss), and after 52 weeks of weight maintenance. Fasting clinical biochemical bone markers were measured by a fully automated immunoassay system (iSYS; Immunodiagnostic Systems Ltd); plasma CTX-1 (bone resorption) and intact P1NP (bone formation) were measured by a chemiluminescence method. Two other bone markers were also measured: osteocalcin by a chemiluminescence method, and serum bone-specific alkaline phosphatase (bone ALP) by a photometric method. However, the clinical relevance of these two bone formation markers is not fully understood according to the official guidelines of clinical studies on bone metabolism (45). The samples were analyzed in a single run with the same batch of the reagents/assay. The coefficient of variation ranged from 8 to 10%.
Fasting ionized plasma calcium, 25(OH) vitamin D, and intact PTH levels were measured at screening, at baseline, and at week 52. Ionized plasma calcium levels were measured using a Konelab Prime 30 Clinical Chemistry Analyzer (Thermo Fisher Scientific, Inc). Plasma intact PTH and 25(OH) vitamin D were measured with an electrochemiluminescence immunoassay (Elecsys 2010; Roche Diagnostics International Ltd).
Serum calcitonin was measured with a sandwich chemiluminescence immunometric method (Immulite 2000; Siemens). For this assay, the upper normal range is 1.46 pmol/L for women, and the lower limit of quantification is 0.6 pmol/L.
Ethical issues
The project and the associated bio-bank were approved by the ethical committee in Copenhagen (reference no. H-4-2010-134), and the study was performed in accordance with the Helsinki Declaration II. Participation was voluntary, and the individuals could at any time retract their consent to participate.
Statistics
Changes from screening to baseline and baseline to week 52 were analyzed with paired t tests. There were no outliers in the data. Delta changes in variables were analyzed using a general linear model contrasting the liraglutide treated group vs the control group with weight change and age as covariates (SPSS version 22; IBM Corporation). The data are shown as mean ± SEM. A P value <.05 was considered significant.
Statistical power assessment
The primary endpoint was change in BMC at week 52 from baseline. Based on previous studies of weight loss and BMC (34, 46), we hypothesized a difference of at least 25 g between groups. With a difference of BMC loss of 27 ± 7 g between 18 experimental subjects and 19 control subjects, we have a power >0.8 (PS: Power and Sample Size Calculation).
Results
Weight loss phase
During the weight loss phase, the women achieved an average weight loss of 12.1 kg with no significant change in BMC (P > .05) (Table 1). BMD increased from screening to baseline (mean difference, 0.014 g/cm2 [95% CI, 0.007–0.021]; P < .001) due to a decrease in bone area (mean difference, −11.8 cm2 [−1.2 to −22.4]; P = .03).
Subject Characteristics From Screening to Baseline
| Screening | Baseline | Mean Difference (95% CI) | P Value | |
|---|---|---|---|---|
| Weight, kg | 97.3 ± 1.7 | 85.2 ± 1.5 | −12.1 (−13.0 to −11.2) | <.001 |
| BMI, kg/m2 | 34.4 ± 0.5 | 30.2 ± 0.43 | −4.22 (−4.5 to −3.9) | <.001 |
| BMC, g | 2561 ± 50.0 | 2574.4 ± 50.6 | 13.3 (−0.17 to 26.3) | .1 |
| BMD, g/cm2 | 1.0320 ± 0.09 | 1.0370 ± 0.099 | 0.014 (0.007 to 0.021) | <.001 |
| Serum bone ALP, μg/mL | 13.6 ± 5.3 | 12.8 ± 4.6 | −0.78 (−0.29 to 1.8) | .1 |
| Plasma CTX-1, ng/mL | 0.47 ± 0.04 | 0.53 ± 0.04 | 0.06 (0.009 to 0.1) | .02 |
| Plasma osteocalcin, ng/L | 15.9 ± 6.5 | 14.5 ± 5.3 | −1.4 (−2.5 to −0.2) | .02 |
| Plasma P1NP, μg/L | 46.7 ± 2.5 | 46.7 ± 2.8 | −0.1 (−3.2 to 3.0) | .95 |
| Plasma ionized calcium, mmol/L | 1.18 ± 0.03 | 1.19 ± 0.03 | 0.01 (0.10 to 0.08) | .8 |
| Plasma 1,25(OH) vitamin D, nmol/L | 47 ± 3 | 67 ± 3 | 20 (15 to 25) | <.001 |
| Plasma PTH, pmol/L | 5.7 ± 0.2 | 5.7 ± 1.5 | 0.02 (0.46 to 0.42) | .9 |
| Serum calcitonin, pmol/La | <0.06 | <0.06 |
| Screening | Baseline | Mean Difference (95% CI) | P Value | |
|---|---|---|---|---|
| Weight, kg | 97.3 ± 1.7 | 85.2 ± 1.5 | −12.1 (−13.0 to −11.2) | <.001 |
| BMI, kg/m2 | 34.4 ± 0.5 | 30.2 ± 0.43 | −4.22 (−4.5 to −3.9) | <.001 |
| BMC, g | 2561 ± 50.0 | 2574.4 ± 50.6 | 13.3 (−0.17 to 26.3) | .1 |
| BMD, g/cm2 | 1.0320 ± 0.09 | 1.0370 ± 0.099 | 0.014 (0.007 to 0.021) | <.001 |
| Serum bone ALP, μg/mL | 13.6 ± 5.3 | 12.8 ± 4.6 | −0.78 (−0.29 to 1.8) | .1 |
| Plasma CTX-1, ng/mL | 0.47 ± 0.04 | 0.53 ± 0.04 | 0.06 (0.009 to 0.1) | .02 |
| Plasma osteocalcin, ng/L | 15.9 ± 6.5 | 14.5 ± 5.3 | −1.4 (−2.5 to −0.2) | .02 |
| Plasma P1NP, μg/L | 46.7 ± 2.5 | 46.7 ± 2.8 | −0.1 (−3.2 to 3.0) | .95 |
| Plasma ionized calcium, mmol/L | 1.18 ± 0.03 | 1.19 ± 0.03 | 0.01 (0.10 to 0.08) | .8 |
| Plasma 1,25(OH) vitamin D, nmol/L | 47 ± 3 | 67 ± 3 | 20 (15 to 25) | <.001 |
| Plasma PTH, pmol/L | 5.7 ± 0.2 | 5.7 ± 1.5 | 0.02 (0.46 to 0.42) | .9 |
| Serum calcitonin, pmol/La | <0.06 | <0.06 |
Data are shown as mean ± SEM or difference (95% CI). n = 37 women, age 46 years.
All samples were below the detection limit of 0.6 pmol/L, so mean difference and P value could not be applied.
Subject Characteristics From Screening to Baseline
| Screening | Baseline | Mean Difference (95% CI) | P Value | |
|---|---|---|---|---|
| Weight, kg | 97.3 ± 1.7 | 85.2 ± 1.5 | −12.1 (−13.0 to −11.2) | <.001 |
| BMI, kg/m2 | 34.4 ± 0.5 | 30.2 ± 0.43 | −4.22 (−4.5 to −3.9) | <.001 |
| BMC, g | 2561 ± 50.0 | 2574.4 ± 50.6 | 13.3 (−0.17 to 26.3) | .1 |
| BMD, g/cm2 | 1.0320 ± 0.09 | 1.0370 ± 0.099 | 0.014 (0.007 to 0.021) | <.001 |
| Serum bone ALP, μg/mL | 13.6 ± 5.3 | 12.8 ± 4.6 | −0.78 (−0.29 to 1.8) | .1 |
| Plasma CTX-1, ng/mL | 0.47 ± 0.04 | 0.53 ± 0.04 | 0.06 (0.009 to 0.1) | .02 |
| Plasma osteocalcin, ng/L | 15.9 ± 6.5 | 14.5 ± 5.3 | −1.4 (−2.5 to −0.2) | .02 |
| Plasma P1NP, μg/L | 46.7 ± 2.5 | 46.7 ± 2.8 | −0.1 (−3.2 to 3.0) | .95 |
| Plasma ionized calcium, mmol/L | 1.18 ± 0.03 | 1.19 ± 0.03 | 0.01 (0.10 to 0.08) | .8 |
| Plasma 1,25(OH) vitamin D, nmol/L | 47 ± 3 | 67 ± 3 | 20 (15 to 25) | <.001 |
| Plasma PTH, pmol/L | 5.7 ± 0.2 | 5.7 ± 1.5 | 0.02 (0.46 to 0.42) | .9 |
| Serum calcitonin, pmol/La | <0.06 | <0.06 |
| Screening | Baseline | Mean Difference (95% CI) | P Value | |
|---|---|---|---|---|
| Weight, kg | 97.3 ± 1.7 | 85.2 ± 1.5 | −12.1 (−13.0 to −11.2) | <.001 |
| BMI, kg/m2 | 34.4 ± 0.5 | 30.2 ± 0.43 | −4.22 (−4.5 to −3.9) | <.001 |
| BMC, g | 2561 ± 50.0 | 2574.4 ± 50.6 | 13.3 (−0.17 to 26.3) | .1 |
| BMD, g/cm2 | 1.0320 ± 0.09 | 1.0370 ± 0.099 | 0.014 (0.007 to 0.021) | <.001 |
| Serum bone ALP, μg/mL | 13.6 ± 5.3 | 12.8 ± 4.6 | −0.78 (−0.29 to 1.8) | .1 |
| Plasma CTX-1, ng/mL | 0.47 ± 0.04 | 0.53 ± 0.04 | 0.06 (0.009 to 0.1) | .02 |
| Plasma osteocalcin, ng/L | 15.9 ± 6.5 | 14.5 ± 5.3 | −1.4 (−2.5 to −0.2) | .02 |
| Plasma P1NP, μg/L | 46.7 ± 2.5 | 46.7 ± 2.8 | −0.1 (−3.2 to 3.0) | .95 |
| Plasma ionized calcium, mmol/L | 1.18 ± 0.03 | 1.19 ± 0.03 | 0.01 (0.10 to 0.08) | .8 |
| Plasma 1,25(OH) vitamin D, nmol/L | 47 ± 3 | 67 ± 3 | 20 (15 to 25) | <.001 |
| Plasma PTH, pmol/L | 5.7 ± 0.2 | 5.7 ± 1.5 | 0.02 (0.46 to 0.42) | .9 |
| Serum calcitonin, pmol/La | <0.06 | <0.06 |
Data are shown as mean ± SEM or difference (95% CI). n = 37 women, age 46 years.
All samples were below the detection limit of 0.6 pmol/L, so mean difference and P value could not be applied.
There was an increase in plasma levels of the bone resorption marker CTX-1 (0.06 ng/mL; 95% confidence interval [CI], 0.009–0.1; P = .02). Plasma levels of the bone formation marker osteocalcin decreased (−1.36 ng/L; 95% CI, −0.19 to −2.53; P = .02). Serum bone-specific ALP and plasma P1NP levels remained unchanged during the weight loss phase (Table 1).
Plasma 25(OH) vitamin D levels increased during the very-low-calorie diet (20 nmol/L; 95% CI, 15–25; P < .001). Levels of ionized plasma calcium and plasma PTH remained unchanged during the weight loss phase (Table 1).
All serum calcitonin values were below the detection value (<0.6 pmol/L) before and after weight loss.
There were no significant differences on the above-mentioned variables between the groups from screening to baseline (Supplemental Table 1).
Weight maintenance phase
Both groups maintained the weight loss for 52 weeks, with no significant weight difference between the groups (Table 2). Total BMC decreased significantly in the control group during the weight maintenance period by 35.8 ± 7.3 g (P < .0001), in contrast to a nonsignificant decrease of 9.2 ± 7.5 g in the liraglutide group (P = .2), with an estimated difference of 26.6 g (95% CI, 5–48; P = .016; Figure 1). The observed difference in total BMC loss between the groups did not change when adjusting for the effect of baseline total BMC or Δ total BMC from screening to baseline level (P < .05).
Estimated Differences Between Liraglutide and Control Group From Baseline to Week 52
| Liraglutide 1.2 mg (n = 18, Age 46 ± 2 y) | Control (n = 19, Age 45 ± 2 y) | Difference Between Groups | ||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Wk 52 | Mean of Differences | Baseline | Wk 52 | Mean of Differences | Estimated Difference Between Group Means | P Value | |
| Weight, kg | 86.4 ± 2.8 | 86.2 ± 3.4 | −0.2 ± 1.7 | 82.4 ± 1.7 | 84.1 ± 2.2 | 1.7 ± 1.6 | 1.9 (−2.8 to 6.7) | .4 |
| BMI, kg/m2 | 31.4 ± 0.8 | 31.2 ± 1.0 | −0.1 ± 0.6 | 29.0 ± 0.5 | 29.7 ± 0.6 | 0.7 ± 0.5 | 0.8 (−0.9 to 2.6) | .3 |
| Total BMC, g | 2524.6 ± 82.9 | 2515 ± 81.8 | −9.2 ± 7.5 | 2615 ± 71.8 | 2579 ± 74.1 | −35.8 ± 7.3c | 26.6 (5.2 to 47.9) | .01 |
| Central (pelvic bone) BMC, g | 264.8 ± 13.5 | 256.5 ± 14.8 | −8.3 ± 5.1 | 298.2 ± 17.8 | 283.9 ± 16.3 | −14.2 ± 4.6b | 5.9 (−8.2 to 20.1) | .3 |
| Peripheral (arm-leg bone) BMC, g | 646.2 ± 20.4 | 642.9 ± 21.9 | −3.3 ± 3.5 | 661.8 ± 20.6 | 649.2 ± 21.5 | −12.6 ± 3.7b | 9.3 (0.9 to 19.6) | .03 |
| Total BMD, g/cm2 | 1.23 ± 0.02 | 1.23 ± 0.02 | −0.004 | 1.24 ± 0.02 | 1.23 ± 0.02 | −0.005 ± 0.272 | 0.0025 (−0.013 to 0.013) | .9 |
| Central (pelvic bone) BMD, g/cm2 | 1.31 ± 0.03 | 1.28 ± 0.03 | −0.03 ± 0.01b | 1.39 ± 0.05 | 1.37 ± 0.05 | −0.02 ± 0.008a | 0.014 (−0.013 to 0.04) | .3 |
| Peripheral (arm-leg bone) BMD, g/cm2 | 2.06 ± 0.03 | 2.06 ± 0.04 | 0.005 ± 0.01 | 2.04 ± 0.03 | 2.02 ± 0.03 | 0.015 ± 0.01 | 0.021 (−0.013 to 0.054) | .2 |
| Plasma P1NP, μg/L | 40.7 ± 3.0 | 46.6 ± 3.5 | 6.5 ± 2.6a | 50.4 ± 4.9 | 49.6 ± 5.3 | −0.8 ± 3.7 | 7 (1 to 13) | .04 |
| Plasma CTX-1, ng/mL | 0.46 ± 0.06 | 0.52 ± 0.04 | 0.06 ± 0.04 | 0.58 ± 0.06 | 0.54 ± 0.05 | 0.03 ± 0.03 | 0.1 (−0.003 to 0.206) | .2 |
| Serum bone ALP, μg/L | 13.4 ± 0.9 | 12.6 ± 0.8 | −0.7 ± 0.7 | 11.2 ± 0.8 | 12.7 ± 1.0 | 1.5 ± 0.6 | 2.2 (−0.2 to 4.0) | .1 |
| Plasma osteocalcin, ng/L | 13.1 ± 0.9 | 14.6 ± 1.1 | 1.5 ± 0.7a | 14.9 ± 1.3 | 16.7 ± 1.3 | 1.7 ± 1.0 | 0.2 (−2.2 to 2.6) | .8 |
| Plasma ionized calcium, mmol/L | 1.22 ± 0.008 | 1.23 ± 0.008 | 0.001 ± 0.01 | 1.17 ± 0.065 | 1.23 ± 0.005 | 0.06 ± 0.007 | 0.064 (−0.9 to 0.22) | .4 |
| Plasma PTH, pmol/L | 5.9 ± 0.4 | 5.7 ± 0.5 | −0.2 ± 0.3 | 5.5 ± 0.4 | 5.9 ± 0.36 | 0.5 ± 0.3 | 0.7 (−0.3 to 1.6) | .2 |
| Plasma 25(OH) vitamin D, nmol/L | 66.9 ± 3.9 | 62.0 ± 4.0 | −4.8 ± 3.7 | 71.7 ± 19.7 | 55.0 ± 3.8 | −16.7 ± 2.8c | 11.8 (2.3 to 21.3) | .05 |
| Serum calcitonin, pmol/Ld | <0.6 | <0.6 | <0.6 | <0.6 | ||||
| Liraglutide 1.2 mg (n = 18, Age 46 ± 2 y) | Control (n = 19, Age 45 ± 2 y) | Difference Between Groups | ||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Wk 52 | Mean of Differences | Baseline | Wk 52 | Mean of Differences | Estimated Difference Between Group Means | P Value | |
| Weight, kg | 86.4 ± 2.8 | 86.2 ± 3.4 | −0.2 ± 1.7 | 82.4 ± 1.7 | 84.1 ± 2.2 | 1.7 ± 1.6 | 1.9 (−2.8 to 6.7) | .4 |
| BMI, kg/m2 | 31.4 ± 0.8 | 31.2 ± 1.0 | −0.1 ± 0.6 | 29.0 ± 0.5 | 29.7 ± 0.6 | 0.7 ± 0.5 | 0.8 (−0.9 to 2.6) | .3 |
| Total BMC, g | 2524.6 ± 82.9 | 2515 ± 81.8 | −9.2 ± 7.5 | 2615 ± 71.8 | 2579 ± 74.1 | −35.8 ± 7.3c | 26.6 (5.2 to 47.9) | .01 |
| Central (pelvic bone) BMC, g | 264.8 ± 13.5 | 256.5 ± 14.8 | −8.3 ± 5.1 | 298.2 ± 17.8 | 283.9 ± 16.3 | −14.2 ± 4.6b | 5.9 (−8.2 to 20.1) | .3 |
| Peripheral (arm-leg bone) BMC, g | 646.2 ± 20.4 | 642.9 ± 21.9 | −3.3 ± 3.5 | 661.8 ± 20.6 | 649.2 ± 21.5 | −12.6 ± 3.7b | 9.3 (0.9 to 19.6) | .03 |
| Total BMD, g/cm2 | 1.23 ± 0.02 | 1.23 ± 0.02 | −0.004 | 1.24 ± 0.02 | 1.23 ± 0.02 | −0.005 ± 0.272 | 0.0025 (−0.013 to 0.013) | .9 |
| Central (pelvic bone) BMD, g/cm2 | 1.31 ± 0.03 | 1.28 ± 0.03 | −0.03 ± 0.01b | 1.39 ± 0.05 | 1.37 ± 0.05 | −0.02 ± 0.008a | 0.014 (−0.013 to 0.04) | .3 |
| Peripheral (arm-leg bone) BMD, g/cm2 | 2.06 ± 0.03 | 2.06 ± 0.04 | 0.005 ± 0.01 | 2.04 ± 0.03 | 2.02 ± 0.03 | 0.015 ± 0.01 | 0.021 (−0.013 to 0.054) | .2 |
| Plasma P1NP, μg/L | 40.7 ± 3.0 | 46.6 ± 3.5 | 6.5 ± 2.6a | 50.4 ± 4.9 | 49.6 ± 5.3 | −0.8 ± 3.7 | 7 (1 to 13) | .04 |
| Plasma CTX-1, ng/mL | 0.46 ± 0.06 | 0.52 ± 0.04 | 0.06 ± 0.04 | 0.58 ± 0.06 | 0.54 ± 0.05 | 0.03 ± 0.03 | 0.1 (−0.003 to 0.206) | .2 |
| Serum bone ALP, μg/L | 13.4 ± 0.9 | 12.6 ± 0.8 | −0.7 ± 0.7 | 11.2 ± 0.8 | 12.7 ± 1.0 | 1.5 ± 0.6 | 2.2 (−0.2 to 4.0) | .1 |
| Plasma osteocalcin, ng/L | 13.1 ± 0.9 | 14.6 ± 1.1 | 1.5 ± 0.7a | 14.9 ± 1.3 | 16.7 ± 1.3 | 1.7 ± 1.0 | 0.2 (−2.2 to 2.6) | .8 |
| Plasma ionized calcium, mmol/L | 1.22 ± 0.008 | 1.23 ± 0.008 | 0.001 ± 0.01 | 1.17 ± 0.065 | 1.23 ± 0.005 | 0.06 ± 0.007 | 0.064 (−0.9 to 0.22) | .4 |
| Plasma PTH, pmol/L | 5.9 ± 0.4 | 5.7 ± 0.5 | −0.2 ± 0.3 | 5.5 ± 0.4 | 5.9 ± 0.36 | 0.5 ± 0.3 | 0.7 (−0.3 to 1.6) | .2 |
| Plasma 25(OH) vitamin D, nmol/L | 66.9 ± 3.9 | 62.0 ± 4.0 | −4.8 ± 3.7 | 71.7 ± 19.7 | 55.0 ± 3.8 | −16.7 ± 2.8c | 11.8 (2.3 to 21.3) | .05 |
| Serum calcitonin, pmol/Ld | <0.6 | <0.6 | <0.6 | <0.6 | ||||
Data are shown as mean ± SEM or difference (95% CI).
P < .05;
P < .01;
P < .0001. P values are corrected for age.
All samples were below the detection limit of 0.6 pmol/L, so mean difference and P value could not be applied.
Estimated Differences Between Liraglutide and Control Group From Baseline to Week 52
| Liraglutide 1.2 mg (n = 18, Age 46 ± 2 y) | Control (n = 19, Age 45 ± 2 y) | Difference Between Groups | ||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Wk 52 | Mean of Differences | Baseline | Wk 52 | Mean of Differences | Estimated Difference Between Group Means | P Value | |
| Weight, kg | 86.4 ± 2.8 | 86.2 ± 3.4 | −0.2 ± 1.7 | 82.4 ± 1.7 | 84.1 ± 2.2 | 1.7 ± 1.6 | 1.9 (−2.8 to 6.7) | .4 |
| BMI, kg/m2 | 31.4 ± 0.8 | 31.2 ± 1.0 | −0.1 ± 0.6 | 29.0 ± 0.5 | 29.7 ± 0.6 | 0.7 ± 0.5 | 0.8 (−0.9 to 2.6) | .3 |
| Total BMC, g | 2524.6 ± 82.9 | 2515 ± 81.8 | −9.2 ± 7.5 | 2615 ± 71.8 | 2579 ± 74.1 | −35.8 ± 7.3c | 26.6 (5.2 to 47.9) | .01 |
| Central (pelvic bone) BMC, g | 264.8 ± 13.5 | 256.5 ± 14.8 | −8.3 ± 5.1 | 298.2 ± 17.8 | 283.9 ± 16.3 | −14.2 ± 4.6b | 5.9 (−8.2 to 20.1) | .3 |
| Peripheral (arm-leg bone) BMC, g | 646.2 ± 20.4 | 642.9 ± 21.9 | −3.3 ± 3.5 | 661.8 ± 20.6 | 649.2 ± 21.5 | −12.6 ± 3.7b | 9.3 (0.9 to 19.6) | .03 |
| Total BMD, g/cm2 | 1.23 ± 0.02 | 1.23 ± 0.02 | −0.004 | 1.24 ± 0.02 | 1.23 ± 0.02 | −0.005 ± 0.272 | 0.0025 (−0.013 to 0.013) | .9 |
| Central (pelvic bone) BMD, g/cm2 | 1.31 ± 0.03 | 1.28 ± 0.03 | −0.03 ± 0.01b | 1.39 ± 0.05 | 1.37 ± 0.05 | −0.02 ± 0.008a | 0.014 (−0.013 to 0.04) | .3 |
| Peripheral (arm-leg bone) BMD, g/cm2 | 2.06 ± 0.03 | 2.06 ± 0.04 | 0.005 ± 0.01 | 2.04 ± 0.03 | 2.02 ± 0.03 | 0.015 ± 0.01 | 0.021 (−0.013 to 0.054) | .2 |
| Plasma P1NP, μg/L | 40.7 ± 3.0 | 46.6 ± 3.5 | 6.5 ± 2.6a | 50.4 ± 4.9 | 49.6 ± 5.3 | −0.8 ± 3.7 | 7 (1 to 13) | .04 |
| Plasma CTX-1, ng/mL | 0.46 ± 0.06 | 0.52 ± 0.04 | 0.06 ± 0.04 | 0.58 ± 0.06 | 0.54 ± 0.05 | 0.03 ± 0.03 | 0.1 (−0.003 to 0.206) | .2 |
| Serum bone ALP, μg/L | 13.4 ± 0.9 | 12.6 ± 0.8 | −0.7 ± 0.7 | 11.2 ± 0.8 | 12.7 ± 1.0 | 1.5 ± 0.6 | 2.2 (−0.2 to 4.0) | .1 |
| Plasma osteocalcin, ng/L | 13.1 ± 0.9 | 14.6 ± 1.1 | 1.5 ± 0.7a | 14.9 ± 1.3 | 16.7 ± 1.3 | 1.7 ± 1.0 | 0.2 (−2.2 to 2.6) | .8 |
| Plasma ionized calcium, mmol/L | 1.22 ± 0.008 | 1.23 ± 0.008 | 0.001 ± 0.01 | 1.17 ± 0.065 | 1.23 ± 0.005 | 0.06 ± 0.007 | 0.064 (−0.9 to 0.22) | .4 |
| Plasma PTH, pmol/L | 5.9 ± 0.4 | 5.7 ± 0.5 | −0.2 ± 0.3 | 5.5 ± 0.4 | 5.9 ± 0.36 | 0.5 ± 0.3 | 0.7 (−0.3 to 1.6) | .2 |
| Plasma 25(OH) vitamin D, nmol/L | 66.9 ± 3.9 | 62.0 ± 4.0 | −4.8 ± 3.7 | 71.7 ± 19.7 | 55.0 ± 3.8 | −16.7 ± 2.8c | 11.8 (2.3 to 21.3) | .05 |
| Serum calcitonin, pmol/Ld | <0.6 | <0.6 | <0.6 | <0.6 | ||||
| Liraglutide 1.2 mg (n = 18, Age 46 ± 2 y) | Control (n = 19, Age 45 ± 2 y) | Difference Between Groups | ||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | Wk 52 | Mean of Differences | Baseline | Wk 52 | Mean of Differences | Estimated Difference Between Group Means | P Value | |
| Weight, kg | 86.4 ± 2.8 | 86.2 ± 3.4 | −0.2 ± 1.7 | 82.4 ± 1.7 | 84.1 ± 2.2 | 1.7 ± 1.6 | 1.9 (−2.8 to 6.7) | .4 |
| BMI, kg/m2 | 31.4 ± 0.8 | 31.2 ± 1.0 | −0.1 ± 0.6 | 29.0 ± 0.5 | 29.7 ± 0.6 | 0.7 ± 0.5 | 0.8 (−0.9 to 2.6) | .3 |
| Total BMC, g | 2524.6 ± 82.9 | 2515 ± 81.8 | −9.2 ± 7.5 | 2615 ± 71.8 | 2579 ± 74.1 | −35.8 ± 7.3c | 26.6 (5.2 to 47.9) | .01 |
| Central (pelvic bone) BMC, g | 264.8 ± 13.5 | 256.5 ± 14.8 | −8.3 ± 5.1 | 298.2 ± 17.8 | 283.9 ± 16.3 | −14.2 ± 4.6b | 5.9 (−8.2 to 20.1) | .3 |
| Peripheral (arm-leg bone) BMC, g | 646.2 ± 20.4 | 642.9 ± 21.9 | −3.3 ± 3.5 | 661.8 ± 20.6 | 649.2 ± 21.5 | −12.6 ± 3.7b | 9.3 (0.9 to 19.6) | .03 |
| Total BMD, g/cm2 | 1.23 ± 0.02 | 1.23 ± 0.02 | −0.004 | 1.24 ± 0.02 | 1.23 ± 0.02 | −0.005 ± 0.272 | 0.0025 (−0.013 to 0.013) | .9 |
| Central (pelvic bone) BMD, g/cm2 | 1.31 ± 0.03 | 1.28 ± 0.03 | −0.03 ± 0.01b | 1.39 ± 0.05 | 1.37 ± 0.05 | −0.02 ± 0.008a | 0.014 (−0.013 to 0.04) | .3 |
| Peripheral (arm-leg bone) BMD, g/cm2 | 2.06 ± 0.03 | 2.06 ± 0.04 | 0.005 ± 0.01 | 2.04 ± 0.03 | 2.02 ± 0.03 | 0.015 ± 0.01 | 0.021 (−0.013 to 0.054) | .2 |
| Plasma P1NP, μg/L | 40.7 ± 3.0 | 46.6 ± 3.5 | 6.5 ± 2.6a | 50.4 ± 4.9 | 49.6 ± 5.3 | −0.8 ± 3.7 | 7 (1 to 13) | .04 |
| Plasma CTX-1, ng/mL | 0.46 ± 0.06 | 0.52 ± 0.04 | 0.06 ± 0.04 | 0.58 ± 0.06 | 0.54 ± 0.05 | 0.03 ± 0.03 | 0.1 (−0.003 to 0.206) | .2 |
| Serum bone ALP, μg/L | 13.4 ± 0.9 | 12.6 ± 0.8 | −0.7 ± 0.7 | 11.2 ± 0.8 | 12.7 ± 1.0 | 1.5 ± 0.6 | 2.2 (−0.2 to 4.0) | .1 |
| Plasma osteocalcin, ng/L | 13.1 ± 0.9 | 14.6 ± 1.1 | 1.5 ± 0.7a | 14.9 ± 1.3 | 16.7 ± 1.3 | 1.7 ± 1.0 | 0.2 (−2.2 to 2.6) | .8 |
| Plasma ionized calcium, mmol/L | 1.22 ± 0.008 | 1.23 ± 0.008 | 0.001 ± 0.01 | 1.17 ± 0.065 | 1.23 ± 0.005 | 0.06 ± 0.007 | 0.064 (−0.9 to 0.22) | .4 |
| Plasma PTH, pmol/L | 5.9 ± 0.4 | 5.7 ± 0.5 | −0.2 ± 0.3 | 5.5 ± 0.4 | 5.9 ± 0.36 | 0.5 ± 0.3 | 0.7 (−0.3 to 1.6) | .2 |
| Plasma 25(OH) vitamin D, nmol/L | 66.9 ± 3.9 | 62.0 ± 4.0 | −4.8 ± 3.7 | 71.7 ± 19.7 | 55.0 ± 3.8 | −16.7 ± 2.8c | 11.8 (2.3 to 21.3) | .05 |
| Serum calcitonin, pmol/Ld | <0.6 | <0.6 | <0.6 | <0.6 | ||||
Data are shown as mean ± SEM or difference (95% CI).
P < .05;
P < .01;
P < .0001. P values are corrected for age.
All samples were below the detection limit of 0.6 pmol/L, so mean difference and P value could not be applied.
Total BMC change from baseline to week 52 in the liraglutide group was −9.2 ± 7.5 g (P = .2), and in the control group was −35.8 ± 7.3 g (P < .0001).
Estimated difference between means was 26.6 g (95% CI, 5.2 to 47.9; P = .016). Arm-leg BMC change from baseline to week 52 in the liraglutide group was −3.3 ± 3.5 g, and in the control group was −12.6 ± 3.7 g (P = .003). Estimated difference between means was 9.3 g (0.9 to 19.6; P = .03). Pelvic BMC change from baseline to week 52 in the liraglutide group was −8.3 ± 5.1 g, and in the control group was −14.2 ± 4.6 g (P = .006). Estimated difference between means was 5.9 g (−8.2 to 20.1; P = .38). White bars, Control group; black bars, liraglutide group. Difference between means was 0.1 ng/mL (955 CI, −0.003 to 0.21; P = .2). *, P < .05; **, P < .01; ***, P < .0001.
The control group had a significant decrease in BMC in the arm-leg region of −12.6 ± 3.7 g (P = .003), in contrast to a nonsignificant decrease in the liraglutide group of −3.3 ± 3.5 g (P = .35) (estimated difference between groups of 9.3 g; 95% CI, 0.9 to 19.6; P = .03). Furthermore, the control group had a significant decrease in BMC in the pelvic region of 14.2 g ± 4.6 (P = .006), in contrast to a nonsignificant decrease in the liraglutide group of 8.3 ± 5.1 g (P = .124) (estimated difference between groups of 5.9 g; 95% CI, −8.2 to 20.1; P = .38). Total body BMD did not change in any of the groups during the weight maintenance period (Table 2).
Plasma levels of P1NP increased significantly by 16% (6.5 ± 2.6 μg/L; P = .02) during liraglutide treatment, in contrast to a nonsignificant decrease of 2% (−0.8 ± 3.7 μg/L) in the control group (P = .8), with a significant estimated difference between the groups of 7 μg/L (95% CI, 1–13; P = .048; Figure 2A). Levels of plasma osteocalcin increased significantly by 11% (1.5 ± 0.7 ng/L) with liraglutide treatment (P = .048) in contrast to a nonsignificant increase in the control group of 1.7 ± 0.9 ng/L (P = .1).
A, Mean changes in P1NP levels from baseline to week 52 were 6.5 ± 2.6 μg/L (P = .02) in the liraglutide group and −0.8 ± 3.7 μg/L (P = .8) in the control group. Difference between means was 7 μg/L (95% CI, 1 to 13; P = .048). B, Mean changes in CTX-1 levels from baseline to week 52 were 0.06 ± 0.04 ng/mL (P = .1) in the liraglutide group, and −0.003 ± 0.03 ng/mL (P = .2) in the control group. Difference between means was 0.1 ng/mL (95% CI, −0.003 to 0.21; P = .2). *, P < .05; **, P < .01; ***, P < .0001.
Bone ALP and CTX-1 did not change significantly in any of the two groups during the weight maintenance phase (Table 2 and Figure 2B). The observed difference in bone markers between the groups did not change when adjusting for the effect of baseline bone marker levels.
25(OH) Vitamin D levels decreased significantly in the control group (−17 ± 3.0 nmol/L; P < .0001) in contrast to a nonsignificant decrease in the liraglutide group (−5 ± 4.0 nmol/L; P = .2), with an estimated difference of 12 nmol/L (95% CI, 2–21; P = .05) between the groups. The BMC loss was still significantly smaller in the liraglutide group when adjusting for the effect of 25(OH) vitamin D changes (P = .04).
The difference in total BMC loss between the groups did not change when adjusting for the effect of any difference in peak insulin levels between groups (P < .05). Insulin data have previously been published (12). However, when adjusting the difference in total BMC between the groups for differences in P1NP changes, the total BMC change became nonsignificant (P = .2). Plasma ionized calcium and PTH levels did not change significantly in the two groups during the weight maintenance phase. All serum calcitonin values were below the detection value (<0.6 pmol/L) after weight loss and after 52 weeks of weight maintenance.
Discussion
We demonstrate here that by providing a relatively low dose of the long-acting GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks, the weight loss-induced decrease in total, pelvic, and arm-leg BMC was abolished. Thus, the total BMC loss was four times greater in the control group compared to the liraglutide group, indicating that the sustained weight loss had a negative impact on bone that was diminished in the liraglutide group. Furthermore, our results suggest that it might be in the pelvic area, but especially in the arm-leg area, that the BMC loss is prevented with GLP-1 RA treatment. Because the pelvic area mainly comprises trabecular bone and the long bones of the arms and legs mainly comprise cortical bone (47), our data suggest that weight loss primarily leads to reductions in cortical bone mass, which is be prevented by GLP-1 RA treatment. This finding is in agreement with previous reports of cortical osteopenia and fragility in GLP-1 receptor knockout mice (27, 28). 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.
Weight loss phase
Total body BMC did not change significantly during the 8-week weight loss period, whereas BMD values increased. BMD reflects the ratio of BMC to bone area, and as the bone area decreased in this period, BMD values increased. However, this may not represent an actual increase in bone mass, but is most likely due to variations of area measurements (48).With weight loss, the amount of soft tissue (fat) changes, which may affect the edge detection and definition of the region of interest and thereby the area.
Furthermore, an acute weight loss generated in the course of 8 weeks would not be expected to result in visible changes on a dual-energy x-ray absorptiometry scan (34). Markers of bone remodeling, on the other hand, reflect acute changes (49). In alignment with this, we report increased CTX-1 levels (bone resorption) and decreased osteocalcin levels (bone formation) after the very-low-calorie diet, supporting that the low-calorie diet has had a catabolic effect on bone.
Weight maintenance phase
Bone markers and GLP-1 RA treatment
In agreement with studies conducted in exendin-4-treated rodents, we found that the bone formation markers P1NP and osteocalcin increased with GLP-1 RA treatment (8, 31, 32). In contrast to a rodent study, we did not see any change in levels of the bone resorption marker CTX-1 (31). However, this is in agreement with a previous study demonstrating that GLP-1 administration in humans did not result in changes of CTX-1 levels (23). This suggests that GLP-1 may not be important for bone resorption in humans as opposed to rodents and that the main effects of GLP-1 on bone, at least in humans, are anabolic in nature.
Levels of bone-specific ALP were not affected by weight maintenance or GLP-1 RA treatment. However, bone ALP is considered a questionable marker of bone formation because it is not clear which step in the bone formation processes it reflects (50), and cross-reactivity in the ALP assays with liver ALP has been reported (51). Accordingly, The International Federation of Clinical Chemistry and The International Osteoporosis Foundation recommend that P1NP and CTX-1 are preferred as bone turnover markers in clinical trials on osteoporosis because they have the least variability and they best reflect bone formation and resorption, respectively (45).
Mechanisms of GLP-1 RA treatment on bone
Nuche-Berenguer et al (32) demonstrated impaired activation of the osteogenic Wnt-signaling pathway in diabetic and insulin-resistant male Wistar rats, which was reverted with exendin-4 treatment. Also, exendin-4 treatment of old ovariectomized rats as well as type 2 diabetic and insulin-resistant rats has been shown to induce antiosteoporotic effects (31, 32), without interaction of postprandial insulin response (8). In accordance, the difference in BMC loss did not differ between the groups when adjusting for differences in peak insulin levels between groups. This supports the notion that up to 1 year of GLP-1 RA treatment exerts insulin-independent actions on bone.
When correcting for a potential influence of 25(OH) vitamin D on BMC change, the effect of liraglutide on preserving BMC remained. In contrast, when correcting for a potential influence of P1NP on BMC, the significant difference in BMC change disappeared. This indicates that liraglutide-induced increase in bone formation is independent of 25(OH) vitamin D but, interestingly, dependent on P1NP.
Finally, we found no evidence of increased serum calcitonin levels during weight loss or with GLP-1 RA treatment in accordance with previous findings of GLP-1 RA treatment in T2DM patients (52).
Clinical relevance of GLP-1 RA treatment on bone
Because weight loss is often associated with a decrease in bone mass (33, 34), the effect of GLP-1 RA treatment on bone in obesity is of particular clinical interest. Interestingly, we found that liraglutide prevented BMC loss after weight loss, in contrast to the control group, and we 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 1 year in the control group, which corresponds to the findings in other studies (34, 46). Thus, Hinton et al (34) reported significant changes of 1.2% in total BMC after a weight loss of 11% and a 1-year subsequent weight loss maintenance, and Riedt et al (46) report similar changes of 1.2% in total BMC after a weight loss of 9%, followed by 6 months of weight loss maintenance. Thus, the observed changes in total BMC are likely of clinical relevance.
Bone strength and resistance to fractures depend not only on BMC, but also on the collagen matrix. Thus, reduced collagen matrix maturity has been demonstrated in GLP-1 receptor knockout mice, whereas mineral quality and quantity were not significantly different from wild-type mice (28). In this study, the preserved BMC level, as well as the increased levels of P1NP with liraglutide treatment, suggests higher calcium content in the bone matrix and a higher degree of maturation of bone matrix, and thus a positive effect on bone quality with GLP-1 RA treatment.
Development of new treatment modalities for obesity management is highly important, given the continued increase in the prevalence of obesity. Because 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. The GLP-1 RAs comprise promising candidates in this context because they not only lower weight but also, due to their glucoregulatory profile, presumably reduce the risk of several other obesity-related comorbidities (12). Interestingly, a new study of 10 568 T2DM patients shows that being overweight compared to normal weight was associated with higher rates of cardiac events but with lower mortality, which was suggested to be due to protection against osteoporosis and thereby fractures that increase mortality (53). With the combination of a 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.
Strengths and limitations
The strength of the study is that we were able to successfully maintain a 12% weight loss in both groups during the 52-week follow-up, allowing us to determine the effect of the long-acting GLP-1 RA liraglutide independent of weight loss on bone metabolism. A limitation of the study is that we were not allowed to buy or obtain placebo Victoza pens from the production company (Novo Nordisk); however, we hold it unlikely that there would be a significant placebo effect on bone metabolism. Also, a limitation to the study was that site-specific hip, spine, and forearm measurements were not performed, which is unfortunate because these areas comprise a more precise estimation of trabecular and cortical bone mass than arm, leg, and pelvic area. However, data from the pelvic and arm-leg regions support our finding of prevention of BMC loss during GLP-1 RA treatment.
Conclusion
In this study, we report a positive effect of GLP-1 RA treatment on bone formation and prevention of bone loss, supporting the notion of a role for GLP-1 in bone metabolism. Thus, we provide evidence that treatment with the GLP-1 RA liraglutide prevents bone loss in weight-reduced obese women, further emphasizing its potential as a clinically relevant and safe antiobesity drug.
Acknowledgments
We thank the study participants, dieticians Jane Hjort and Stine Rasmussen, Hvidovre Hospital, and lab technician Lene Albæk, University of Copenhagen.
The project including purchase of Victoza pens was supported by funding from The Danish Research Council for Health and Disease (reference no. 11-107683) and the University Investment Capital (UNIK): Food, Fitness & Pharma for Health and Disease from the Danish Ministry of Science, Technology and Innovation and the Danish Diabetes Academy. Cambridge Weight Plan products were donated from Cambridge Weight Plan. The funding sponsors were not involved in study design, conduct of the study, data analysis or approval of manuscript.
Trial Registration: Clinicaltrials.gov NCT02094183.
Author Contributions: S.S.T., J.J.H., S.M., J.-E.B.J., O.P., and T.H. designed the study. E.W.I. and J.R.L. conducted the study and collected data. E.W.I. wrote manuscript and analyzed data. J.R.L., N.R.J. J.-E.B.J., O.P., T.H., J.J.H., S.M., B.H., and S.S.T. contributed to discussion, reviewed/edited the manuscript, and approved the final version. The corresponding author, E.W.I., confirms full access to data and final responsibility for the decision to submit for publication.
Disclosure Summary: S.M. and J.J.H. have performed consultant services for Novo Nordisk. O.P. and S.S.T. hold stocks in Novo Nordisk. E.W.I., J.R.L., N.R.J., J.-E.B.J., T.H., and B.H. have no relevant conflict of interest for this study.
Abbreviations
- ALP
alkaline phosphatase
- BMC
bone mineral content
- BMD
bone mineral density
- BMI
body mass index
- CI
confidence interval
- CTX-1
C-terminal telopeptide of type 1 collagen
- GLP-1
glucagon-like peptide-1
- GLP-1 RA
GLP-1 receptor agonist
- P1NP
N-terminal propeptide of type 1 procollagen
- T2DM
type 2 diabetes mellitus.
References
