Table 2.
Median concentrations and interquartile range (IQR) of serum biomarkers at baseline, one month and one year according to intervention (zoledronic acid (ZA) or placebo infusion). P1 shows the significance of the change in each respective biomarker concentration from baseline to one month or from baseline to one year. P2 shows the significance of the difference in change from baseline to one month or from baseline to one year in the concentration of each biomarker between the ZA and placebo groups. Significant p-values are in bold.
| Serum Biomarkers | Baseline Median (IQR) | 1-Month Median (IQR) | P1 | P2 | 1-Year Median (IQR) | P1 | P2 |
|---|---|---|---|---|---|---|---|
| Bone panel | |||||||
| AFOS (U/L) | 0.554 | <0.001 * | |||||
| Placebo | 64 (53, 76) | 63 (58, 77) | 0.480 | 61 (55, 82) | 0.528 | ||
| ZA | 71 (58, 80) | 67 (62, 78) | 0.826 | 57 (49, 68) | <0.001 | ||
| RANKL (pg/mL) | 0.369 | 0.724 | |||||
| Placebo | 11.3 (0.0, 49.2) | 14.6 (0.0, 67.2) | 0.470 | 11.3 (0.0, 59.6) | 0.520 | ||
| ZA | 13.0 (0.0, 37.0) | 0.0 (0.0, 41.3) | 0.891 | 14.4 (0.0, 48.5) | 0.853 | ||
| iPINP (ng/mL) | 0.018 | <0.001 * | |||||
| Placebo | 35 (27, 40) | 36 (23, 42) | 0.729 | 38 (26, 45) | 0.123 | ||
| ZA | 36 (27, 49) | 29 (20, 33) | 0.004 | 15 (13, 18) | <0.001 | ||
| CTX-1 (pg/mL) | 0.009 | 0.211 | |||||
| Placebo | 0.2 (0.1, 0.4) | 0.2 (0.1, 0.6) | 0.546 | 0.3 (0.2, 0.4) | 0.189 | ||
| ZA | 0.3 (0.2, 0.5) | 0.0 (0.0, 0.0) | 0.154 | 0.2 (0.1, 5.4) | 0.927 | ||
| Chemokine panel | |||||||
| Eotaxin-1 (pg/mL) | 0.841 | 0.398 | |||||
| Placebo | 214 (136, 263) | 202 (151, 258) | 0.956 | 193 (149, 239) | 0.622 | ||
| ZA | 163 (146, 201) | 167 (140, 224) | 0.841 | 180 (144, 232) | 0.546 | ||
| Eotaxin-3 (pg/mL) | 0.565 | 0.862 | |||||
| Placebo | 17.9 (10.5, 22.7) | 16.0 (10.4, 19.6) | 0.245 | 13.9 (11.9, 19.9) | 0.261 | ||
| ZA | 20.2 (12.2, 31.6) | 18.3 (11.5, 27.6) | 0.076 | 22.3 (12.9, 31.7) | 0.388 | ||
| IP-10 (pg/mL) | 0.056 | 0.005 * | |||||
| Placebo | 265 (199, 349) | 240 (204, 351) | 0.756 | 248 (171, 305) | 0.177 | ||
| ZA | 253 (187, 305) | 282 (231, 423) | 0.036 | 316 (240, 420) | 0.015 | ||
| MIP-1A (pg/mL) | 0.518 | 0.817 | |||||
| Placebo | 13.5 (5.3, 21.7) | 16.7 (5.3, 21.5) | 0.818 | 16.7 (5.3, 19.1) | 0.804 | ||
| ZA | 5.3 (5.3, 16.3) | 5.3 (5.3, 15.7) | 0.945 | 5.3 (5.3, 17.5) | 0.719 | ||
| MIP-1B (pg/mL) | 0.883 | 0.091 | |||||
| Placebo | 126 (79, 156) | 102 (91, 161) | 0.729 | 106 (83, 158) | 0.177 | ||
| ZA | 85 (58, 144) | 87 (63, 136) | 0.330 | 85 (66, 156) | 0.277 | ||
| MCP-1 (pg/mL) | 0.327 | 0.174 | |||||
| Placebo | 276 (226, 337) | 286 (249, 332) | 0.812 | 267 (222, 346) | 0.756 | ||
| ZA | 237 (207, 281) | 265 (207, 313) | 0.040 | 279 (206, 326) | 0.133 | ||
| MCP-4 (pg/mL) | 0.925 | 0.429 | |||||
| Placebo | 158 (108, 189) | 140 (111, 190) | 0.674 | 135 (109, 164) | 0.701 | ||
| ZA | 136 (105, 172) | 133 (115, 180) | 0.571 | 136 (108, 193) | 0.330 | ||
| MDC-1 (ng/mL) | 0.445 | 0.925 | |||||
| Placebo | 1.1 (0.8, 1.4) | 1.1 (0.8, 1.4) | 0.498 | 1.1 (0.7, 1.4) | 0.546 | ||
| ZA | 1.1 (0.9, 1.3) | 1.0 (0.9, 1.2) | 0.571 | 1.0 (0.9, 1.2) | 0.701 | ||
| RANTES (ng/mL) | 0.529 | 0.968 | |||||
| Placebo | 78 (48, 168) | 85 (52, 116) | 0.245 | 81 (62, 126) | 0.261 | ||
| ZA | 72 (50, 163) | 80 (41, 126) | 0.097 | 81 (54, 113) | 0.648 | ||
| TARC (pg/mL) | 0.157 | 0.512 | |||||
| Placebo | 295 (197, 391) | 326 (229, 438) | 0.216 | 329 (198, 411) | 0.231 | ||
| ZA | 202 (179, 391) | 241 (169, 344) | 0.409 | 269 (161, 383) | 0.812 | ||
| MIG-1 (pg/mL) | 0.908 | 0.122 | |||||
| Placebo | 72 (65, 118) | 72 (37, 154) | 0.880 | 72 (33, 118) | 0.446 | ||
| ZA | 69 (28, 132) | 78 (33, 118) | 0.939 | 69 (47, 134) | 0.262 | ||
| Cytokine panel | |||||||
| IL-7 (pg/mL) | 0.738 | 0.445 | |||||
| Placebo | 18.0 (14.0, 22.8) | 15.8 (11.1, 20.9) | 0.452 | 14.4 (11.4, 17.7) | 0.133 | ||
| ZA | 19.3 (15.2, 23.7) | 16.2 (13.9, 20.1) | 0.154 | 18.7 (13.9, 21.0) | 0.064 | ||
| IL-12/23p40 (pg/mL) | 0.341 | 0.758 | |||||
| Placebo | 122 (92, 157) | 113 (87, 185) | 0.571 | 116 (94, 154) | 0.898 | ||
| ZA | 102 (77, 145) | 97 (84, 134) | 0.546 | 100 (84, 135) | >0.999 | ||
| IL-15 (pg/mL) | 0.134 | 0.678 | |||||
| Placebo | 2.8 (2.3, 3.4) | 2.6 (2.4, 3.3) | 0.985 | 2.8 (2.5, 3.2) | 0.869 | ||
| ZA | 3.0 (2.5, 3.2) | 3.1 (2.6, 3.4) | 0.123 | 3.0 (2.7, 3.3) | 0.312 | ||
| IL-16 (pg/mL) | 0.301 | 0.035 | |||||
| Placebo | 191 (151, 246) | 194 (167, 213) | 0.515 | 172 (156, 200) | 0.027 | ||
| ZA | 173 (151, 223) | 205 (174, 220) | 0.349 | 207 (167, 248) | 0.245 | ||
| IL-17A (pg/mL) | 0.201 | 0.841 | |||||
| Placebo | 2.3 (1.7, 3.3) | 2.6 (1.5, 3.3) | 0.177 | 2.6 (1.5, 3.5) | 0.869 | ||
| ZA | 2.2 (1.5, 3.3) | 2.3 (1.6, 2.9) | 0.622 | 2.2 (1.4, 3.4) | 0.829 | ||
| TNF-B (pg/mL) | 0.175 | 0.636 | |||||
| Placebo | 0.4 (0.1, 0.5) | 0.4 (0.1, 0.5) | 0.761 | 0.3 (0.1, 0.5) | 0.940 | ||
| ZA | 0.1 (0.1, 0.4) | 0.1 (0.1, 0.4) | 0.240 | 0.3 (0.1, 0.4) | 0.588 | ||
| Anti-inflammatory panel | |||||||
| IL-1sRII (ng/mL) | 0.989 | 0.391 | |||||
| Placebo | 22.1 (18.8, 28.1) | 23 (15, 26) | 0.515 | 23 (16, 27) | 0.651 | ||
| ZA | 24.7 (20.5, 28.0) | 22 (19, 28) | 0.522 | 25 (21, 27) | 0.181 | ||
| Pro-inflammatory panel | |||||||
| IFN-A (pg/mL) | 0.329 | 0.267 | |||||
| Placebo | 71 (55, 91) | 66 (47, 87) | 0.806 | 66 (55, 95) | 0.924 | ||
| ZA | 61 (55, 78) | 66 (55, 78) | 0.070 | 71 (58, 79) | 0.032 | ||
| IFN-G (pg/mL) | 0.820 | 0.445 | |||||
| Placebo | 5.6 (4.3, 9.3) | 4.7 (3.2, 9.6) | 0.498 | 4.6 (3.7, 8.0) | 0.245 | ||
| ZA | 4.5 (3.3, 7.1) | 5.5 (3.2, 8.8) | 0.898 | 5.3 (3.1, 8.3) | 0.756 | ||
| IL-2R (pg/mL) | 0.425 | 0.625 | |||||
| Placebo | 144 (95, 229) | 164 (109, 214) | 0.225 | 123 (89, 193) | 0.671 | ||
| ZA | 117 (97, 163) | 117 (90, 161) | 0.588 | 125 (97, 150) | 0.899 | ||
| IL-6 (pg/mL) | 0.445 | 0.192 | |||||
| Placebo | 0.8 (0.5, 1.1) | 0.6 (0.5, 1.1) | 0.648 | 0.7 (0.4, 0.8) | 0.105 | ||
| ZA | 0.7 (0.4, 0.9) | 0.6 (0.5, 1.0) | 0.674 | 0.6 (0.5, 0.9) | 0.522 | ||
| IL-8 (pg/mL) | 0.583 | 0.659 | |||||
| Placebo | 11.1 (7.5, 14.9) | 10.2 (7.9, 11.6) | 0.040 | 9.2 (6.8, 12.2) | 0.165 | ||
| ZA | 9.7 (7.5, 11.7) | 9.7 (7.4, 14.2) | 0.294 | 10.0 (7.6, 13.7) | 0.546 | ||
| TNF-A (pg/mL) | 0.512 | 0.049 | |||||
| Placebo | 2.0 (1.6, 2.3) | 2.0 (1.7, 2.2) | 0.231 | 1.8 (1.4, 2.2) | 0.294 | ||
| ZA | 1.6 (1.2, 2.2) | 1.7 (1.3, 2.3) | 0.956 | 1.7 (1.2, 2.5) | 0.202 | ||
| Angiogenesis panel | |||||||
| VEGF-A (pg/mL) | 0.758 | 0.947 | |||||
| Placebo | 249 (110, 388) | 198 (125, 320) | 0.596 | 182 (111, 406) | 0.729 | ||
| ZA | 380 (167, 530) | 348 (178, 502) | 0.189 | 412 (170, 497) | 0.841 | ||
| VEGF-C (pg/mL) | 0.947 | 0.369 | |||||
| Placebo | 417 (342, 498) | 459 (288, 510) | 0.812 | 432 (330, 548) | 0.245 | ||
| ZA | 392 (382, 506) | 399 (369, 501) | 0.596 | 403 (346, 514) | 0.869 | ||
| VEGF-D (ng/mL) | 0.529 | 0.495 | |||||
| Placebo | 0.7 (0.6, 1.0) | 0.8 (0.6, 1.0) | 0.349 | 0.8 (0.6, 0.9) | 0.105 | ||
| ZA | 0.7 (0.6, 0.9) | 0.7 (0.6, 0.8) | 0.596 | 0.7 (0.6, 0.9) | 0.571 | ||
| Tie-2 (ng/mL) | 0.529 | 0.314 | |||||
| Placebo | 4.6 (4.0, 5.2) | 4.7 (3.7, 5.5) | 0.869 | 4.5 (3.9, 5.1) | 0.701 | ||
| ZA | 4.4 (4.0, 5.3) | 4.4 (3.7, 5.1) | 0.245 | 4.3 (3.5, 4.9) | 0.019 | ||
| Flt-1 (pg/mL) | 0.925 | 0.989 | |||||
| Placebo | 88 (77, 97) | 91 (63, 126) | 0.812 | 90 (80, 99) | 0.756 | ||
| ZA | 91 (75, 98) | 83 (76, 93) | 0.349 | 82 (78, 99) | 0.756 | ||
| bFGF (pg/mL) | 0.659 | 0.659 | |||||
| Placebo | 3.4 (1.9, 5.1) | 3.2 (2.3, 5.3) | 0.869 | 3.5 (1.9, 8.0) | 0.123 | ||
| ZA | 5.2 (2.7, 7.3) | 3.7 (2.9, 7.1) | 0.522 | 4.5 (3.8, 8.3) | 0.522 | ||
| HGF-1 (pg/mL) | 0.974 | 0.201 | |||||
| Placebo | 205 (110, 263) | 184 (115, 248) | 0.874 | 157 (84, 248) | 0.245 | ||
| ZA | 146 (89, 219) | 143 (67, 193) | 0.374 | 171 (89, 248) | 0.430 | ||
| Vascular injury panel | |||||||
| hs-CRP (mg/L) | 0.176 | 0.551 | |||||
| Placebo | 1.2 (0.4, 2.6) | 0.9 (0.6, 1.9) | 0.936 | 0.9 (0.6, 2.0) | 0.157 | ||
| ZA | 0.9 (0.5, 1.2) | 1.3 (0.4, 2.2) | 0.042 | 0.8 (0.4, 1.3) | 0.652 | ||
| ICAM-1 (µg/mL) | 0.341 | 0.773 | |||||
| Placebo | 0.4 (0.4, 0.5) | 0.4 (0.3, 0.5) | 0.368 | 0.4 (0.3, 0.5) | 0.196 | ||
| ZA | 0.4 (0.3, 0.5) | 0.4 (0.3, 0.5) | 0.622 | 0.3 (0.3, 0.4) | 0.073 | ||
| VCAM-1 (µg/mL) | 0.547 | 0.603 | |||||
| Placebo | 0.6 (0.6, 0.8) | 0.6 (0.5, 0.7) | 0.409 | 0.6 (0.5, 0.7) | 0.096 | ||
| ZA | 0.6 (0.5, 0.7) | 0.5 (0.5, 0.7) | 0.841 | 0.5 (0.5, 0.7) | 0.369 | ||
| SAA (µg/mL) | 0.512 | 0.954 | |||||
| Placebo | 1.8 (1.1, 4.1) | 1.9 (1.2, 4.2) | 0.452 | 1.7 (1.3, 2.5) | 0.595 | ||
| ZA | 1.7 (0.8, 2.2) | 1.9 (1.0, 4.3) | 0.048 | 1.5 (0.6, 2.8) | 0.922 |
1 Significance in Wilcoxon signed rank test, 2 Significance in Mann–Whitney’s test; * significant after B–H correction; AFOS = alkaline phosphatase; bFGF = basic fibroblast growth factor beta; CTX1 = C telopeptide of type I collagen; Flt = fms related tyrosine kinase (=VEGFR1); HGF = hepatocyte growth factor; hs-CRP = high-sensitive C-reactive protein; ICAM = intercellular adhesion molecule; IL = interleukin; IFN = interferon; IP = interferon-γ-inducible protein; iPINP = intact procollagen I N-terminal propeptide; MCP = monocyte chemotactic protein; MDC = macrophage derived chemokine; MIG = monokine induced by gamma-interferon; MIP = macrophage inflammatory protein; RANKL = receptor activator of NF-κB ligand; RANTES = regulated upon activation, normally T-expressed, and presumably secreted; SAA = serum amyloid A; TARC = thymus and activation-regulated chemokine; Tie = TEK receptor tyrosine kinase; TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule; VEGF = vascular endothelial growth factor.