Review article: Biomedical intelligence
Vol. 142 No. 2930 (2012)
The future of osteoporosis treatment – a research update
Summary
Osteoporosis is characterised by a progressive loss of bone mass and microarchitecture which leads to increased fracture risk. Some of the drugs available to date have shown reductions in vertebral and non-vertebral fracture risk. However, in the ageing population of industrialised countries, still more fractures happen today than are avoided, which highlights the large medical need for new treatment options, models, and strategies. Recent insights into bone biology, have led to a better understanding of bone cell functions and crosstalk between osteoblasts, osteoclasts, and osteocytes at the molecular level. In the future, the armamentarium against osteoporotic fractures will likely be enriched by (1.) new bone anabolic substances such as antibodies directed against the endogenous inhibitors of bone formation sclerostin and dickkopf-1, PTH and PTHrp analogues, and possibly calcilytics; (2.) new inhibitors of bone resorption such as cathepsin K inhibitors which may suppress osteoclast function without impairing osteoclast viability and thus maintain bone formation by preserving the osteoclast-osteoblast crosstalk, and denosumab, an already widely available antibody against RANKL which inhibits osteoclast formation, function, and survival; and (3.) new therapeutic strategies based on an extended understanding of the pathophysiology of osteoporosis which may include sequential therapies with two or more bone active substances aimed at optimising the management of bone capital acquired during adolescence and maintained during adulthood in terms of both quantity and quality. Finally, one of the future challenges will be to identify those patients and patient populations expected to benefit the most from a given drug therapy or regimen. The WHO fracture risk assessment tool FRAX® and improved access to bone mineral density measurements by DXA will play a key role in this regard.
References
- Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646–50.
- Bundesamt für Statistik: Mortality and Life Expectancy tables. http://www.bfs.admin.ch/bfs/portal/de/index/themen/01/06/blank/key/04.html. Last visited February 20, 2010.
- Bundesamt für Statistik. Szenarien zur Bevölkerungsentwicklung der Schweiz 2005–2050. http://www.bfs.admin.ch/bfs/portal/de/index/news/publikationen.Document.83713.pdf. Last visited May 14, 2008.
- Lippuner K, Grifone S, Schwenkglenks M, Schwab P, Popp AW, Senn C, Perrelet R. (2011) Comparative trends in hospitalizations for osteoporotic fractures and other frequent diseases between 2000 and 2008. Osteoporos Int
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.
- Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85:4118–24.
- Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077–82.
- McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333–40.
- Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344–52.
- Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–38.
- Rizzoli R, Burlet N, Cahall D, et al. Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone. 2008;42:841–7.
- Rizzoli R, Akesson K, Bouxsein M, Kanis JA, Napoli N, Papapoulos S, et al. Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int. 2011;22:373–90.
- Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267–94.
- Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637–45.
- Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:1751–61.
- Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.
- Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727–41.
- Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.
- Terpos E, Dimopoulos MA. Interaction between the skeletal and immune systems in cancer: mechanisms and clinical implications. Cancer immunology, immunotherapy: CII 2011;60:305–17.
- Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int. 2010;21:1963–4.
- Compston J. Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int. 2011;22:2951–61.
- Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: Results from the first two years of the FREEDOM extension. J Bone Miner Res 2011.
- Kyrgidis A, Toulis KA. Denosumab-related osteonecrosis of the jaws. Osteoporos Int. 2011;22:369–70.
- Saad F, Brown JE, Van Poznak C, et al. (2011) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol
- Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48:677–92.
- Greenspan SL, Bone HG, Ettinger MP, Hanley DA, Lindsay R, Zanchetta JR, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326–39.
- Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–441.
- Saag KG, Shane E, Boonen S, Marin F, Donley DW, Taylor KA, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357:2028–39.
- Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115–37.
- Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest. 1999;104:439–46.
- Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993;366:575–80.
- Steddon SJ, Cunningham J. Calcimimetics and calcilytics – fooling the calcium receptor. Lancet. 2005;365:2237–9.
- Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.
- Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, et al. Wnt signaling and stem cell control. Cold Spring Harbor symposia on quantitative biology 2008;73:59–66.
- Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.
- Rey JP, Ellies DL. Wnt modulators in the biotech pipeline. Developmental dynamics: an official publication of the American Association of Anatomists 2010;239:102–14.
- Noble BS. The osteocyte lineage. Arch Biochem Biophys. 2008;473:106–11.
- van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CW. SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev. 2005;16:319–27.
- Martin RB. Toward a unifying theory of bone remodeling. Bone. 2000;26:1–6.
- Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866–75.
- Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res. 2009;24:1651–61.
- Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–42.
- McClung MR. Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Curr Osteoporos Rep. 2006;4:28–33.
- Vaananen HK, Laitala-Leinonen T. Osteoclast lineage and function. Arch Biochem Biophys. 2008;473:132–8.
- Bromme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs. 2009;18:585–600.
- Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996;273:1236–8.
- Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A 1998;95:13453–8.
- Rizzoli R, Kraenzlin M, Krieg MA, Mellinghoff HU, Lamy O, Lippuner K. Indications to teriparatide treatment in patients with osteoporosis. Swiss Med Wkly. 2011;141:w13297.
- Daddona PE, Matriano JA, Mandema J, Maa YF. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharmaceutical research. 2011;28:159–65.
- Cosman F, Lane NE, Bolognese MA, Zanchetta JR, Garcia-Hernandez PA, Sees K, et al. Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2010;95:151–8.
- Lippuner K, Zehnder HJ, Casez JP, Takkinen R, Jaeger P. PTH-related protein is released into the mother’s bloodstream during location: evidence for beneficial effects on maternal calcium-phosphate metabolism. J Bone Miner Res. 1996;11:1394–9.
- Casez J, Pfammatter R, Nguyen Q, Lippuner K, Jaeger P. Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements. Eur J Intern Med. 2001;12:344–9.
- Rosenblatt M. When two keys fit one lock, surprises follow. Nat Chem Biol. 2009;5:707–8.
- Martin TJ. Osteoblast-derived PTHrP is a physiological regulator of bone formation. J Clin Invest. 2005;115:2322–4.
- Kimura S, Nakagawa T, Matsuo Y, Ishida Y, Okamoto Y, Hayashi M. JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats. Eur J Pharmacol. 2011;668:331–6.
- 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;46:534–42.
- Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68:577–89.
- Balemans W, Ebeling M, Patel N, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43.
- Papapoulos SE. Targeting sclerostin as potential treatment of osteoporosis. Ann Rheum Dis. 2011;70(Suppl 1):i119–22.
- Beighton P, Durr L, Hamersma H. The clinical features of sclerosteosis. A review of the manifestations in twenty-five affected individuals. Ann Intern Med. 1976;84:393–7.
- Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clinical genetics. 2003;63:192–7.
- Moester MJ, Papapoulos SE, Lowik CW, van Bezooijen RL. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int. 2010;87:99–107.
- Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Lowik CW, Hamersma H, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab. 2005;90:6392–5.
- Vanhoenacker FM, Balemans W, Tan GJ, Dikkers FG, De Schepper AM, Mathysen DG, et al. Van Buchem disease: lifetime evolution of radioclinical features. Skeletal Radiol. 2003;32:708–18.
- Van Hul W, Balemans W, Van Hul E, Dikkers FG, Obee H, Stokroos RJ, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet. 1998;62:391–9.
- Jacobs P. Van Buchem disease. Postgrad Med J. 1977;53:497–506.
- Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res. 2010;25:948–59.
- Li X, Warmington KS, Niu QT, et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J Bone Miner Res. 2010;25:2647–56.
- Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26:19–26.
- Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–94.
- Butler JS, Murray DW, Hurson CJ, O’Brien J, Doran PP, O’Byrne JM. The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res. 2011;29:414–8.
- Anastasilakis AD, Polyzos SA, Avramidis A, Toulis KA, Papatheodorou A, Terpos E. The effect of teriparatide on serum Dickkopf-1 levels in postmenopausal women with established osteoporosis. Clin Endocrinol. (Oxf) 2010;72:752–7.
- Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab. 2011;96:1555–9.
- (2010) National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. http://www.nof.org/professionals/clinical-guidelines.
- Compston J, Cooper A, Cooper C, Francis R, Kanis JA, Marsh D, et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas. 2009;62:105–8.
- Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19:399–428.
- Enders GH. Wnt therapy for bone loss: golden goose or Trojan horse? J Clin Invest. 2009;119:758–60.
- Kansara M, Tsang M, Kodjabachian L, et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest. 2009;119:837–51.
- Boonen S, Adachi JD, Man Z, et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96:1727–36.
- (2011) Prescribing information of Prolia® (denosumab) approved by the FDA. Last revision 09/2011. Available under http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125320s5s6lbl.pdf. Last accessed February 22, 2012.
- Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer. J Clin Oncol (2008).
- Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745–55.
- (2011) Safety, pharmacokinetics and efficacy of anti-RANKL Nanobody®ALX-0141 in healthy postmenopausal women. Presentation at the EULAR 2011. Available under http://www.ablynx.com/wp-content/uploads/2011/05/2011-05-27-ALX-0141-EULAR_final.pdf. Last accessed February 22, 2012.
- Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorganic & medicinal chemistry letters. 2008;18:923–8.
- Runger TM, Adami S, Benhamou CL, Czerwinski E, Farrerons J, Kendler DL, et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2012;66:e89–96.
- Stoch SA, Zajic S, Stone J, et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther. 2009;86:175–82.
- Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25:937–47.
- Perez-Castrillon JL, Pinacho F, De Luis D, Lopez-Menendez M, Duenas Laita A. (2010) Odanacatib, a new drug for the treatment of osteoporosis: review of the results in postmenopausal women. Journal of osteoporosis 2010:
- Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377:1276–87.
- Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel D, Scott BB, et al. (2011) Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res
- Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res. 2011;26:1303–12.
- Suhm N, Lamy O, Lippuner K. Management of fragility fractures in Switzerland: results of a nationwide survey. Swiss Med Wkly. 2008;138:674–83.
- Lippuner K, Johansson H, Kanis JA, Rizzoli R. Remaining lifetime and absolute 10-year probabilities of osteoporotic fracture in Swiss men and women. Osteoporos Int. 2009;20:1131–40.
- Lippuner K, Johansson H, Kanis JA, Rizzoli R. FRAX assessment of osteoporotic fracture probability in Switzerland. Osteoporos Int. 2010;21:381–9.
- Kanis JA, Hans D, Cooper C, et al. Interpretation and use of FRAX in clinical practice. Osteoporos Int. 2011;22:2395–411.
- Lippuner K, Johansson H, Borgstrom F, Kanis JA, Rizzoli R. (2012) Cost-effective intervention thresholds against osteoporotic fractures based on FRAX(R) in Switzerland. Osteoporos Int
- Tosteson AN, Melton LJ, 3rd, Dawson-Hughes B, Baim S, Favus MJ, Khosla S, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int. 2008;19:437–47.