N-terminal propeptide of type III procollagen as a biomarker of anabolic response to recombinant human GH and testosterone

Abstract

Context: Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH.

Design: Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 microg recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16. LBM and appendicular skeletal muscle mass (ASM) were measured by dual-energy x-ray absorptiometry.

Results: One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 +/- 2.14 vs. 4.51 +/- 1.05, P < 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r = 0.26, P = 0.007; r = 0.53, P < 0.001) and ASM (r = 0.17, P = 0.07; r = 0.40, P < 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r = 0.20, P = 0.056 and r = 0.36, P = 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models.

Conclusion: Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomarker of anabolic response to GH and testosterone.

Figure 1

A, Regression plot of change in total lean body mass (kilograms) from baseline to wk 16 relative to change in serum P3NP concentrations (nanograms per milliliter) from baseline to wk 16. B, Change in appendicular lean mass (kilograms) from baseline to wk 16 was plotted against change in serum P3NP concentrations (nanograms per milliliter) from baseline to wk 16. C, Change in lean body mass (kilograms) from baseline to wk 16 was plotted against change in serum P3NP concentrations (nanograms per milliliter) from baseline to wk 4 (n = 106 for all three panels).

Figure 2

Figure shows regression plots of the changes in serum P3NP after 16 wk relative to changes in serum testosterone (A) and serum IGF-I (B) after 16 wk of therapy.

Figure 3

To determine the magnitude of change in P3NP concentrations that was associated with changes in lean mass, we used the boot strapping method in which each bootstrap sample set contained 90% of the original sample randomly drawn from the original 106 samples without replacement. A and B, Histograms show the distribution of the slopes (change in P3NP for each kilogram change in total LBM from baseline to wk 16). A, Each kilogram change in LBM was associated with 0.93 ng/ml (95% CI 0.83–1.02) change in P3NP concentration from baseline to wk 16. B, Each kilogram change in LBM was associated with 0.28 ng/ml (95% CI 0.22–0.36) change in P3NP from baseline to wk 4. C and D, Histograms show the distribution of the slopes (change in P3NP for each 0.5 kg change in ASM). C, Each 0.5 kg change in ASM was associated with 0.57 ng/ml (95% CI 0.57, 0.57) change in P3NP from baseline to wk 16. D, Each 0.5 kg change in ASM was associated with 0.15 ng/ml (95% CI 0.15, 0.16) change in P3NP from baseline to wk 4.