Investigational anabolic agents for the treatment of osteoporosis: an update on recent developments

References

• Osteoporosis facts and statistics. [cited 2017 May 13]. Available from: https://www.iofbonehealth.org/
   Google Scholar
• Papapoulos SE. Use of bisphosphonates in the management of postmenopausal osteoporosis. Ann N Y Acad Sci. 2011 Feb;1218:15–32. DOI:10.1111/j.1749-6632.2010.05767.x
   PubMed Web of Science ®Google Scholar
• Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016 Jan;31(1):16–35. DOI:10.1002/jbmr.2708
   PubMed Web of Science ®Google Scholar
• Cummings SR, San Martin J, McClung MR, et al.; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20; 361: 8. 756–765. DOI:10.1056/NEJMoa0809493
   PubMed Web of Science ®Google Scholar
• Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513–523. DOI:10.1016/S2213-8587(17)30138-9
   PubMed Web of Science ®Google Scholar
• Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 2017 Jun;32(6):1291–1296. DOI:10.1002/jbmr.3110
   PubMed Web of Science ®Google Scholar
• Toulis KA, Anastasilakis AD, Polyzos SA, et al. Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis. Hormones (Athens). 2011 Jul-Sep;10(3):174–195.
   PubMedGoogle Scholar
• Lewiecki EM, Miller PD. Skeletal effects of primary hyperparathyroidism: bone mineral density and fracture risk. J Clin Densitom. 2013 Jan-Mar;16(1):28–32. DOI:10.1016/j.jocd.2012.11.013
   PubMed Web of Science ®Google Scholar
• Silva BC, Costa AG, Cusano NE, et al. Catabolic and anabolic actions of parathyroid hormone on the skeleton. J Endocrinol Invest. 2011 Nov; 34(10):801–810. DOI:10.3275/7925
   PubMed Web of Science ®Google Scholar
• McCudden CR, Hains MD, Kimple RJ, et al. G-protein signaling: back to the future. Cell Mol Life Sci. 2005;62(5):551–577.
   PubMed Web of Science ®Google Scholar
• Lee SK, Lorenzo JA. Regulation of receptor activator of nuclear factor-kappa B ligand and osteoprotegerin mRNA expression by parathyroid hormone is predominantly mediated by the protein kinase a pathway in murine bone marrow cultures. Bone. 2002;31(1):252–259.
   PubMed Web of Science ®Google Scholar
• Anastasilakis AD, Goulis DG, Polyzos SA, et al. Acute changes in serum osteoprotegerin and receptor activator for nuclear factor-kappaB ligand levels in women with established osteoporosis treated with teriparatide. Eur J Endocrinol. 2008 Mar;158(3):411–415. DOI:10.1530/EJE-07-0528
   PubMed Web of Science ®Google Scholar
• Bellido T, Ali AA, Plotkin LI, et al. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem. 2003;278(50):50259–50272.
   PubMed Web of Science ®Google Scholar
• Ogata N, Shinoda Y, Wettschureck N, et al. G{alpha}q signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone. J Biol Chem. 2011;286:13733–13740.
   PubMed Web of Science ®Google Scholar
• Datta NS, Abou-Samra AB. PTH and PTHrP signaling in osteoblasts. Cell Signal. 2009;21:1245–1254.
   PubMed Web of Science ®Google Scholar
• Polyzos SA, Makras P, Efstathiadou Z, et al. Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis. Expert Opin Investig Drugs. 2015 Feb;24(2):145–157. DOI:10.1517/13543784.2015.973021
   PubMed Web of Science ®Google Scholar
• Anastasilakis AD, Polyzos SA, Toulis KA. Role of wingless tail signaling pathway in osteoporosis: an update of current knowledge. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):383–388. DOI:10.1097/MED.0b013e32834afff2
   PubMed Web of Science ®Google Scholar
• Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. NatMed. 2013;19(2):179–192.
   PubMed Web of Science ®Google Scholar
• Hoeppner LH, Secreto FJ, Westendorf JJ. Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets. 2009 Apr;13(4):485–496. DOI:10.1517/14728220902841961
   PubMed Web of Science ®Google Scholar
• Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007 Jun;148(6):2635–2643.
   PubMed Web of Science ®Google Scholar
• MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009 Jul;17(1):9–26. DOI:10.1016/j.devcel.2009.06.016
   PubMed Web of Science ®Google Scholar
• Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002 May 16;346(20):1513–1521.
   PubMed Web of Science ®Google Scholar
• Semenov MV, He X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem. 2006 Dec 15;281(50):38276–38284.
   PubMed Web of Science ®Google Scholar
• van Lierop AH, Appelman-Dijkstra NM, Papapoulos SE. Sclerostin deficiency in humans. Bone. 2017 Mar;96:51–62. DOI:10.1016/j.bone.2016.10.010
   PubMed Web of Science ®Google Scholar
• Makras P, Delaroudis S, Anastasilakis AD. Novel therapies for osteoporosis. Metabolism. 2015 Oct;64(10):1199–1214. DOI:10.1016/j.metabol.2015.07.011
   PubMed Web of Science ®Google Scholar
• Miller PD, Hattersley G, Riis BJ, et al.; ACTIVE Study Investigators. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. Jama. 2016 Aug 16;316(7):722–733. DOI:10.1001/jama.2016.11136.
   PubMed Web of Science ®Google Scholar
• Cosman F, Hattersley G, Hu MY, et al. Effects of abaloparatide-SC on fractures and bone mineral density in subgroups of postmenopausal women with osteoporosis and varying baseline risk factors. J Bone Miner Res. 2017 Jan;32(1):17–23. DOI:10.1002/jbmr.2991
   PubMed Web of Science ®Google Scholar
• McCloskey EV, Johansson H, Oden A, et al. The effect of abaloparatide-SC on fracture risk is independent of baseline FRAX fracture probability: a post hoc analysis of the ACTIVE study. J Bone Miner Res. 2017 May;5. DOI:10.1002/jbmr.3163
   Web of Science ®Google Scholar
• Cosman F, Miller PD, Williams GC, et al. Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: results of the ACTIVExtend trial. Mayo Clin Proc. 2017 Feb;92(2):200–210. DOI:10.1016/j.mayocp.2016.10.009
   PubMed Web of Science ®Google Scholar
• Jolette J, Attalla B, Varela A, et al. Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34). Regul Toxicol Pharmacol. 2017 Apr 4;86: 356–365. DOI:10.1016/j.yrtph.2017.04.001
   PubMed Web of Science ®Google Scholar
• Yates J, Miller PD, Bolognese MA, et al. OR22-4: a transdermal patch delivering the PTHrP1-34 analog, abaloparatide (BA058), dose-dependently increases spine and hip BMD compared to placebo; Endocrine Society’s 96th Annual Meeting and Expo; 2014 June 21–24; Chicago
   Google Scholar
• Whitfield JF, Morley P, Willick GE, et al. Stimulation of the growth of femoral trabecular bone in ovariectomized rats by the novel parathyroid hormone fragment, hPTH-(1-31)NH2 (Ostabolin). Calcif Tissue Int. 1996 Feb;58(2):81–87.
   PubMed Web of Science ®Google Scholar
• Fraher LJ, Avram R, Watson PH, et al. Comparison of the biochemical responses to human parathyroid hormone-(1-31)NH2 and hPTH-(1-34) in healthy humans. J Clin Endocrinol Metab. 1999 Aug;84(8):2739–2743.
   PubMed Web of Science ®Google Scholar
• Henriksen K, Andersen JR, Riis BJ, et al. Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis. Bone. 2013 Mar;53(1):160–166. DOI:10.1016/j.bone.2012.11.045
   PubMed Web of Science ®Google Scholar
• Hodsman A, Bone H, Gallagher C, et al. Ostabolin-C increases lumbar spine and hip BMD after 1 year of therapy: results of a phase II clinical trial. Annu Meet Am Soc Bone Mineral Res (ASBMR) Presentation. 2007;1130.
   Google Scholar
• Horwitz MJ, Tedesco MB, Gundberg C, et al. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2003;88:569–575.
   PubMed Web of Science ®Google Scholar
• Horwitz MJ, Augustine M, Khan L, et al. A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study. J Bone Miner Res. 2013 Nov;28(11):2266–2276. DOI:10.1002/jbmr.1978
   PubMed Web of Science ®Google Scholar
• Matsumoto T, Shiraki M, Hagino H, et al. Daily nasal spray of hPTH(1-34) for 3 months increases bone mass in osteoporotic subjects: a pilot study. Osteoporos Int. 2006 Oct;17(10):1532–1538.
   PubMed Web of Science ®Google Scholar
• Hämmerle SP, Mindeholm L, Launonen A, et al. The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women. Bone. 2012 Apr;50(4):965–973. DOI:10.1016/j.bone.2012.01.009
   PubMed Web of Science ®Google Scholar
• Kenan Y, Kochba E, Shahar M, et al. Comparison of transdermal and subcutaneous teriparatide effect on markers of bone turnover and safety in postmenopausal women; OC47 presented at 37th European Symposium on Calcified Tissues; 2010 June; Bone.Vol 47, Sup 1, Page S49. DOI: 10.1016/j.bone.2010.04.090
   Google Scholar
• Cosman F, Lane NE, Bolognese MA, et al. Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2010 Jan;95(1):151–158. DOI:10.1210/jc.2009-0358
   PubMed Web of Science ®Google Scholar
• [ Cited 2017 June 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004368/WC500216057.pdf
   Google Scholar
• [ cited 2017 June 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003916/WC500223888.pdf
   Google Scholar
• Neerup TS, Stahlhut M, Petersen JS, et al. ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats. Bone. 2011 Jun 1;48(6):1319–1327. DOI:10.1016/j.bone.2011.02.019
   PubMed Web of Science ®Google Scholar
• Vickery BH, Avnur Z, Cheng Y, et al. RS-66271, a C-terminally substituted analog of human parathyroid hormone-related protein (1-34), increases trabecular and cortical bone in ovariectomized, osteopenic rats. J Bone Miner Res. 1996 Dec;11(12):1943–1951.
   PubMed Web of Science ®Google Scholar
• Frolik CA, Cain RL, Sato M, et al. Comparison of recombinant human PTH(1-34) (LY333334) with a C-terminally substituted analog of human PTH-related protein(1-34) (RS-66271): in vitro activity and in vivo pharmacological effects in rats. J Bone Miner Res. 1999 Feb;14(2):163–172.
   PubMed Web of Science ®Google Scholar
• Thomsen JS, Mosekilde LI, Gasser JA. Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone analog SDZ PTS 893 and bone maintenance in retired breeder rats. Bone. 1999 Nov;25(5):561–569.
   PubMed Web of Science ®Google Scholar
• Kneissel M, Boyde A, Gasser JA. Bone tissue and its mineralization in aged estrogen-depleted rats after long-term intermittent treatment with parathyroid hormone (PTH) analog SDZ PTS 893 or human PTH(1-34). Bone. 2001 Mar;28(3):237–250.
   PubMed Web of Science ®Google Scholar
• Cornish J, Callon KE, Nicholson GC, et al. Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo. Endocrinology. 1997 Mar;138(3):1299–1304.
   PubMed Web of Science ®Google Scholar
• de Castro LF, Lozano D, Portal-Núñez S, et al. Comparison of the skeletal effects induced by daily administration of PTHrP (1-36) and PTHrP (107-139) to ovariectomized mice. J Cell Physiol. 2012 Apr;227(4):1752–1760. DOI:10.1002/jcp.22902
   PubMed Web of Science ®Google Scholar
• Fenton AJ, Kemp BE, Hammonds RG Jr, et al. A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111]. Endocrinology. 1991 Dec;129(6):3424–3426.
   PubMed Web of Science ®Google Scholar
• Bohinc BN, Gesty-Palmer D. β-Arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption. Endocr Metab Immune Disord Drug Targets. 2011 Jun;11(2):112–119.
   PubMedGoogle Scholar
• Gesty-Palmer D, Flannery P, Yuan L, et al. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med. 2009 Oct 7;1(1):1ra1–1ra1. DOI:10.1126/scitranslmed.3000071
   PubMed Web of Science ®Google Scholar
• Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016 Oct 20; 375(16):1532–1543.
   PubMed Web of Science ®Google Scholar
• Lewiecki E, Horlait S, Blicharski T, et al. Results of a phase 3 clinical trial to evaluate the efficacy and safety of romosozumab in men with osteoporosis [abstract]. Arthritis Rheumatol. 2016 cited Jun 3;68(suppl 10). Available from: http://acrabstracts.org/abstract/results-of-a-phase-3-clinical-trial-to-evaluate-the-efficacy-and-safety-of-romosozumab-in-men-with-osteoporosis/
   Google Scholar
• Amgen and UCB announce top-line phase 3 data from active-comparator study of EVENITY™ (Romosozumab) in postmenopausal women with osteoporosis. Available from: http://www.amgen.com/media/news-releases/2017/05/amgen-and-ucb-announce-topline-phase-3-data-from-activecomparator-study-of-evenity-romosozumab-in-postmenopausal-women-withosteoporosis/
   Google Scholar
• Recker RR, Benson CT, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res. 2015 Feb;30(2):216–224. DOI:10.1002/jbmr.2351
   PubMed Web of Science ®Google Scholar
• Tournis S, Dede AD. Osteogenesis imperfecta – a clinical update. Metabolism. 2017 Jun 8; pii: S0026-0495(17)30158-0. DOI:10.1016/j.metabol.2017.06.001
   PubMedGoogle Scholar
• Boschert V, Frisch C, Back JW, et al. The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin’s binding site for the Wnt co-receptor LRP6. Open Biol. 2016 Aug;6(8):pii: 160120. DOI:10.1098/rsob.160120
   PubMed Web of Science ®Google Scholar
• Li X, Grisanti M, Fan W, et al. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res. 2011 Nov;26(11):2610–2621. DOI:10.1002/jbmr.472
   PubMed Web of Science ®Google Scholar
• Florio M, Gunasekaran K, Stolina M, et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun. 2016 May 27;7: 11505. DOI:10.1038/ncomms11505
   PubMed Web of Science ®Google Scholar
• Agholme F, Isaksson H, Kuhstoss S, et al. The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions. Bone. 2011 May 1;48(5):988–996. DOI:10.1016/j.bone.2011.02.008
   PubMed Web of Science ®Google Scholar
• Kimura S, Nakagawa T, Matsuo Y, et al. JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats. Eur J Pharmacol. 2011 Oct 1;668(1–2):331–336. DOI:10.1016/j.ejphar.2011.07.015
   PubMed Web of Science ®Google Scholar
• John MR, Widler L, Gamse R, et al. ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone. 2011 Aug;49(2):233–241. DOI:10.1016/j.bone.2011.04.007
   PubMed Web of Science ®Google Scholar
• Kumar S, Matheny CJ, Hoffman SJ, et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone. 2010 Feb;46(2):534–542. DOI:10.1016/j.bone.2009.09.028
   PubMed Web of Science ®Google Scholar
• Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab. 2011 Aug;96(8):2441–2449. DOI:10.1210/jc.2010-2855
   PubMed Web of Science ®Google Scholar
• Halse J, Greenspan S, Cosman F, et al. A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2014 Nov;99(11):E2207–E2215. DOI:10.1210/jc.2013-4009
   PubMed Web of Science ®Google Scholar
• Cosman F, Gilchrist N, McClung M, et al. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates. Osteoporos Int. 2016 Jan;27(1):377–386. DOI:10.1007/s00198-015-3392-7
   PubMed Web of Science ®Google Scholar
• John MR, Harfst E, Loeffler J, et al. AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014 Jul;64:204–210. DOI:10.1016/j.bone.2014.04.015
   PubMed Web of Science ®Google Scholar