Abstract
Most studies of combination therapy with teriparatide and a bisphosphonate have not shown greater efficacy over monotherapy. The bisphosphonate risedronate, has not been studied in this context. The purpose of this proof-of-concept study was to assess whether combination risedronate and teriparatide increases bone mineral density (BMD) more than monotherapy with either drug alone. This was a randomized, double-blinded study of risedronate (35 mg weekly plus placebo injection), teriparatide (20 μg subcutaneously daily plus placebo tablet), or both risedronate plus teriparatide (combination) for 18 months in 29 men with low BMD. The primary endpoint was percentage change in lumbar spine (LS) BMD at 18 months. Secondary outcomes included changes in bone markers and BMD at other sites and interim time-points. All therapies increased LS BMD as compared with baseline (p < 0.05), but there were no between-group differences at 18 months. Total hip (TH) BMD increased to a greater extent in the combination group (mean ± SEM, 3.86 ± 1.1 %) versus teriparatide (0.29 ± 0.95 %) or risedronate (0.82 ± 0.95 %; p < 0.05 for both). Femoral neck (FN) BMD also increased more in the combination group (8.45 ± 1.8 %) versus risedronate (0.50 ± 1.7 %; p = 0.002), but was not different from teriparatide alone. In the combination group, P1NP and CTX increased rapidly, mirroring the teriparatide-alone arm. There were no between-group differences in adverse events. Combination teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increases at the TH than monotherapy. The results suggest combination risedronate and teriparatide therapy holds promise as a treatment for osteoporosis.
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References
R. Eastell, I.T. Boyle, J. Compston, C. Cooper, I. Fogelman, R.M. Francis, D.J. Hosking, D.W. Purdie, S. Ralston, J. Reeve, D.M. Reid, R.G. Russell, J.C. Stevenson, Management of male osteoporosis: report of the UK Consensus Group. QJM 91(2), 71–92 (1998)
O. Johnell, J.A. Kanis, An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int. 17(12), 1726–1733 (2006). doi:10.1007/s00198-006-0172-4
J.R. Center, T.V. Nguyen, D. Schneider, P.N. Sambrook, J.A. Eisman, Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 353(9156), 878–882 (1999). doi:10.1016/S0140-6736(98)09075-8
J.A. Kanis, G. Bianchi, J.P. Bilezikian, J.M. Kaufman, S. Khosla, E. Orwoll, E. Seeman, Towards a diagnostic and therapeutic consensus in male osteoporosis. Osteoporos. Int. 22(11), 2789–2798 (2011). doi:10.1007/s00198-011-1632-z
E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J. Clin. Endocrinol. Metab. 85(9), 3069–3076 (2000)
E.S. Orwoll, W.H. Scheele, S. Paul, S. Adami, U. Syversen, A. Diez-Perez, J.M. Kaufman, A.D. Clancy, G.A. Gaich, The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J. Bone Miner. Res. 18(1), 9–17 (2003). doi:10.1359/jbmr.2003.18.1.9
E. Orwoll, M. Ettinger, S. Weiss, P. Miller, D. Kendler, J. Graham, S. Adami, K. Weber, R. Lorenc, P. Pietschmann, K. Vandormael, A. Lombardi, Alendronate for the treatment of osteoporosis in men. N. Engl. J. Med. 343(9), 604–610 (2000). doi:10.1056/NEJM200008313430902
S. Boonen, E.S. Orwoll, D. Wenderoth, K.J. Stoner, R. Eusebio, P.D. Delmas, Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J. Bone Miner. Res. 24(4), 719–725 (2009). doi:10.1359/jbmr.081214
E.S. Orwoll, P.D. Miller, J.D. Adachi, J. Brown, R.A. Adler, D. Kendler, C. Bucci-Rechtweg, A. Readie, P. Mesenbrink, R.S. Weinstein, Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J. Bone Miner. Res. 25(10), 2239–2250 (2010). doi:10.1002/jbmr.119
G. Mazziotti, J. Bilezikian, E. Canalis, D. Cocchi, A. Giustina, New understanding and treatments for osteoporosis. Endocrine 41(1), 58–69 (2012). doi:10.1007/s12020-011-9570-2
J.S. Finkelstein, A. Hayes, J.L. Hunzelman, J.J. Wyland, H. Lee, R.M. Neer, The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N. Engl. J. Med. 349(13), 1216–1226 (2003). doi:10.1056/NEJMoa035725NEJMoa035725
J.S. Finkelstein, B.Z. Leder, S.M. Burnett, J.J. Wyland, H. Lee, A.V. de la Paz, K. Gibson, R.M. Neer, Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men. J. Clin. Endocrinol. Metab. 91(8), 2882–2887 (2006). doi:10.1210/jc.2006-0190
J.S. Finkelstein, J.J. Wyland, H. Lee, R.M. Neer, Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 95(4), 1838–1845 (2010). doi:10.1210/jc.2009-1703
D.M. Black, S.L. Greenspan, K.E. Ensrud, L. Palermo, J.A. McGowan, T.F. Lang, P. Garnero, M.L. Bouxsein, J.P. Bilezikian, C.J. Rosen, The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349(13), 1207–1215 (2003). doi:10.1056/NEJMoa031975NEJMoa031975
J. Compston, The use of combination therapy in the treatment of postmenopausal osteoporosis. Endocrine 41(1), 11–18 (2012). doi:10.1007/s12020-011-9554-2
C. Deal, M. Omizo, E.N. Schwartz, E.F. Eriksen, P. Cantor, J. Wang, E.V. Glass, S.L. Myers, J.H. Krege, Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J. Bone Miner. Res. 20(11), 1905–1911 (2005). doi:10.1359/JBMR.050714
G.H. Nancollas, R. Tang, R.J. Phipps, Z. Henneman, S. Gulde, W. Wu, A. Mangood, R.G. Russell, F.H. Ebetino, Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38(5), 617–627 (2006). doi:10.1016/j.bone.2005.05.003
C.J. Rosen, M.C. Hochberg, S.L. Bonnick, M. McClung, P. Miller, S. Broy, R. Kagan, E. Chen, R.A. Petruschke, D.E. Thompson, A.E. de Papp, Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J. Bone Miner. Res. 20(1), 141–151 (2005). doi:10.1359/JBMR.040920
S.L. Bonnick, C.C. Johnston Jr, M. Kleerekoper, R. Lindsay, P. Miller, L. Sherwood, E. Siris, Importance of precision in bone density measurements. J Clin Densitom 4(2), 105–110 (2001)
H.K. Genant, C.Y. Wu, C. van Kuijk, M.C. Nevitt, Vertebral fracture assessment using a semiquantitative technique. J. Bone Miner. Res. 8(9), 1137–1148 (1993). doi:10.1002/jbmr.5650080915
F. Cosman, E.F. Eriksen, C. Recknor, P.D. Miller, N. Guanabens, C. Kasperk, P. Papanastasiou, A. Readie, H. Rao, J.A. Gasser, C. Bucci-Rechtweg, S. Boonen, Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26(3), 503–511 (2011). doi:10.1002/jbmr.238
R.M. Neer, C.D. Arnaud, J.R. Zanchetta, R. Prince, G.A. Gaich, J.Y. Reginster, A.B. Hodsman, E.F. Eriksen, S. Ish-Shalom, H.K. Genant, O. Wang, B.H. Mitlak, Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344(19), 1434–1441 (2001)
B. Borah, T. Dufresne, J. Nurre, R. Phipps, P. Chmielewski, L. Wagner, M. Lundy, M. Bouxsein, R. Zebaze, E. Seeman, Risedronate reduces intracortical porosity in women with osteoporosis. J. Bone Miner. Res. 25(1), 41–47 (2010). doi:10.1359/jbmr.090711
P.D. Miller, P.D. Delmas, R. Lindsay, N.B. Watts, M. Luckey, J. Adachi, K. Saag, S.L. Greenspan, E. Seeman, S. Boonen, S. Meeves, T.F. Lang, J.P. Bilezikian, Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J. Clin. Endocrinol. Metab. 93(10), 3785–3793 (2008). doi:10.1210/jc.2008-0353
D. Gatti, O. Viapiana, S. Adami, L. Idolazzi, E. Fracassi, M. Rossini, Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin. Bone 50(3), 739–742 (2012). doi:10.1016/j.bone.2011.11.028
S.A. Polyzos, A.D. Anastasilakis, C. Bratengeier, W. Woloszczuk, A. Papatheodorou, E. Terpos, Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women—the six-month effect of risedronate and teriparatide. Osteoporos. Int. 23(3), 1171–1176 (2012). doi:10.1007/s00198-010-1525-6
J.F. Griffith, H.K. Genant, New advances in imaging osteoporosis and its complications. Endocrine 42(1), 39–51 (2012). doi:10.1007/s12020-012-9691-2
Acknowledgments
This investigator-initiated study was originally funded by The Alliance for Better Bone Health (Procter and Gamble-Sanofi-Aventis) and then by Warner Chilcott and Sanofi. Study drugs were supplied by Procter and Gamble (Risedronate) and Eli Lilly (Teriparatide).
Disclosure
JPB was previously a consultant for The Alliance for Better Bone Health (Procter and Gamble-Sanofi-Aventis) and Warner Chilcott; JPB is a consultant for Amgen, Eli Lilly, Merck, Novartis, NPS Pharmaceuticals, and Radius. JPB receives research support from Amgen, NPS Pharmaceuticals and Warner Chilcott. No conflicts of interest reported for the remaining authors.
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Walker, M.D., Cusano, N.E., Sliney, J. et al. Combination therapy with risedronate and teriparatide in male osteoporosis. Endocrine 44, 237–246 (2013). https://doi.org/10.1007/s12020-012-9819-4
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DOI: https://doi.org/10.1007/s12020-012-9819-4