Osteoporosis International

, Volume 29, Issue 7, pp 1477–1491 | Cite as

Understanding osteoporotic pain and its pharmacological treatment

  • R. Vellucci
  • R. Terenzi
  • J. A Kanis
  • H. G. Kress
  • R. D. Mediati
  • J.-Y. Reginster
  • R. Rizzoli
  • M. L. Brandi


Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. The aim of this paper is to summarize the pathogenesis and systemic treatment of osteoporotic pain. This narrative review summarizes the main pathogenetic aspects of osteoporotic pain and the cornerstones of its treatment. Osteoporotic fractures induce both acute and chronic nociceptive and neuropathic pain. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and non-pharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post-fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients.


Analgesic treatment Chronic pain Opioids Osteoporotic fracture pain Osteoporotic pain mechanism Osteoporotic pain treatment 



We acknowledge Fondazione F.I.R.M.O. for the support given in the preparation of the manuscript.

Compliance with ethical standards

Conflicts of interest

Renato Vellucci, Riccardo Terenzi, Rocco Domenico Mediati, Jean-Yves Reginster, René Rizzoli and Maria Luisa Brandi declare that they have no conflict of interest. John A. Kanis reports grants from Amgen, grants from Lilly, grants from Radius Health, other from Meda, grants and other from UCB, outside the submitted work; and John A. Kanis is a member of the National Osteoporosis Guideline Group (NOGG) and the principal architect of FRAX but derives no financial benefit. Hans G. Kress received speaker’s and/or consultancy honoraria from the following pharmaceutical companies: Abbott, Astellas, bene-Arzneimittel, Berlin-Chemie/Menarini, Bionorica SE, Boehringer Ingelheim, Boston Scientific, CSC Pharmaceuticals, Grünenthal GmbH, IBSA, Linde Group, Medtronic, Mundipharma International, Nevro, Pfizer, Teva ratiopharm and Trigal Pharma.


  1. 1.
    Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994; 843:1–129Google Scholar
  2. 2.
    Hernlund E, Svedbom A, Ivergard M, Compston J, Cooper C, Stenmark J, McCloskey EV, Jonsson B, Kanis JA (2013) Osteoporosis in the European Union: medical management, epidemiology and economic burden: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 8:136CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Iwamoto J, Makita K, Sato Y, Takeda T, Matsumoto H (2011) Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis. Osteoporos Int 22:2735–2742. CrossRefPubMedGoogle Scholar
  4. 4.
    Ohtori S, Akazawa T, Murata Y, Kinoshita T, Yamashita M, Nakagawa K, Inoue G, Nakamura J, Orita S, Ochiai N, Kishida S, Takaso M, Eguchi Y, Yamauchi K, Suzuki M, Aoki Y, Takahashi K (2010) Risedronate decreases bone resorption and improves low back pain in postmenopausal osteoporosis patients without vertebral fractures. J Clin Neurosci 17:209–213. CrossRefPubMedGoogle Scholar
  5. 5.
    Sambrook PN, Silverman SL, Cauley JA, Recknor C, Olson M, Su G, Boonen S, Black D, Adachi JD, HORIZON Pivotal Fracture Trial (2011) Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT. Bone 48:1298–1304. CrossRefPubMedGoogle Scholar
  6. 6.
    Tetsunaga T, Tetsunaga T, Nishida K, Tanaka M, Sugimoto Y, Takigawa T, Takei Y, Ozaki T (2017) Denosumab and alendronate treatment in patients with back pain due to fresh osteoporotic vertebral fractures. J Orthop Sci 22(2):230–236CrossRefPubMedGoogle Scholar
  7. 7.
    Petranova T, Sheytanov I, Monov S, Nestorova R, Rashkov R (2014) Denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment. Biotechnol Biotechnol Equip 28(6):1127–1137CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Scharla S, Oertel H, Helsberg K, Kessler F, Langer F, Nickelsen T (2006) Skeletal pain in postmenopausal women with osteoporosis: prevalence and course during raloxifene treatment in a prospective observational study of 6 months duration. Curr Med Res Opin 22:2393–2402CrossRefPubMedGoogle Scholar
  9. 9.
    Fujita T, Fujii Y, Munezane H, Ohue M, Takagi Y (2010) Analgesic effect of raloxifene on back and knee pain in postmenopausal women with osteoporosis and/or osteoarthritis. J Bone Miner Metab 28:477–484. CrossRefPubMedGoogle Scholar
  10. 10.
    Genant HK, Halse J, Briney WG, Xie L, Glass EV, Krege JH (2005) The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis. Curr Med Res Opin 21:1027–1034CrossRefPubMedGoogle Scholar
  11. 11.
    Jakob F, Oertel H, Langdahl B, Ljunggren O, Barrett A, Karras D, Walsh JB, Fahrleitner-Pammer A, Rajzbaum G, Barker C, Lems WF, Marin F (2012) Effects of teriparatide in postmenopausal women with osteoporosis pre-treated with bisphosphonates: 36-month results from the European Forsteo Observational Study. Eur J. Endocrinol 166(1):87–97Google Scholar
  12. 12.
    Jimenez-Andrade JM, Mantyh WG, Bloom AP, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW (2010) The effect of aging on the density of the sensory nerve fiber innervation of bone and acute skeletal pain. Neurobiol Aging 33:921–932CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vellucci R, Mediati RD, Ballerini G (2014) Use of opioids for treatment of osteoporotic pain. Clin Cases Miner Bone Metab 11(3):173–176PubMedPubMedCentralGoogle Scholar
  14. 14.
    Old JL, Calvert M (2004) Vertebral compression fractures in the elderly. Am Fam Physician 69:111–115PubMedGoogle Scholar
  15. 15.
    Davidovitch Z, Nicolay O, Ngan PW, Shanfeld JL (1988) Neurotransmitters cytochines, and die control of alveolar bone remodelling in orthodontìcs. Dent Clin N Am 32:411–435PubMedGoogle Scholar
  16. 16.
    Bjurholm A, Kreicbergs A, Terenius L, Goldstein M, Schultzberg M (1988) Neuropeptide Y tyrosine hydroxylase and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J Auton Nerv Syst 25(2–3):119–125CrossRefPubMedGoogle Scholar
  17. 17.
    Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25CrossRefPubMedGoogle Scholar
  18. 18.
    Asmus SE, Parsons S, Landis SC (2000) Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum. J Neurosci 20(4):1495–1504CrossRefPubMedGoogle Scholar
  19. 19.
    Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638PubMedGoogle Scholar
  20. 20.
    Bataille C, Mauprivez C, Hay E, Baroukh B, Brun A, Chaussain C, Marie PJ, Saffar JL, Cherruau M (2012) Different sympathetic pathways control the metabolism of distinct bone envelopes. Bone 50:1162–1172CrossRefPubMedGoogle Scholar
  21. 21.
    Eimar H, Tamimi I, Murshed M, Tamimi F (2013) Cholinergic regulation of bone. J Musculoskelet Neuronal Interact 13:124–132PubMedGoogle Scholar
  22. 22.
    He JY, Jiang LS, Dai LY (2011) The roles of the sympathetic nervous system in osteoporotic diseases: a review of experimental and clinical studies. Ageing Res Rev 10:253–263CrossRefPubMedGoogle Scholar
  23. 23.
    Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413(6852):203–210CrossRefPubMedGoogle Scholar
  24. 24.
    Nagae M, Hiraga T, Wakabayashi H, Wang L, Iwata K, Yoneda T (2006) Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone 39(5):1107–1115CrossRefPubMedGoogle Scholar
  25. 25.
    Lerner UH, Persson E (2008) Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. J Musculoskelet Neuronal Interact 8(2):154–165PubMedGoogle Scholar
  26. 26.
    Abdelaziz DM, Abdullah S, Magnussen C, Ribeiro-da-Silva A, Komarova SV, Rauch F, Stone LS (2015) Behavioral signs of pain and functional impairment in a mouse model of osteogenesis imperfecta. Bone 81:400–406CrossRefPubMedGoogle Scholar
  27. 27.
    Eide PK (2000) Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 4(1):5–15CrossRefPubMedGoogle Scholar
  28. 28.
    Hansen RR, Vacca V, Pitcher T, Clark AK, Malcangio M (2016) Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain. Pain 157(3):666–676CrossRefPubMedGoogle Scholar
  29. 29.
    Sezer O, Heider U, Zavrski I, Kühne CA, Hofbauer LC (2003) RANK ligand and osteoprotegerin in myeloma bone disease. Blood 101(6):2094–2098CrossRefPubMedGoogle Scholar
  30. 30.
    Standal T, Seidel C, Hjertner Ø, Plesner T, Sanderson RD, Waage A, Borset M, Sundan A (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100(8):3002–3007CrossRefPubMedGoogle Scholar
  31. 31.
    Lipton A, Ali SM, Leitzel K, Chinchilli V, Witters L, Engle L, Holloway D, Bekker P, Dunstan CR (2002) Serum osteoprotegerin levels in healthy controls and cancer patients. Clin Cancer Res 8(7):2306–2310PubMedGoogle Scholar
  32. 32.
    Seidel C, Hjertner Ø, Abildgaard N, Heickendorff L, Hjorth M, Westin J, Nielsen JL, Hjorth-Hansen H, Waage A, Sundan A, Børset M (2001) Nordic Myeloma Study Group. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 98(7):2269–2271CrossRefPubMedGoogle Scholar
  33. 33.
    Mantyh PW (2014) The neurobiology of skeletal pain. Eur J Neurosci 39(3):508–519. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bennett GJ (2000) Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manag 19(1 Suppl):S2–S6CrossRefGoogle Scholar
  35. 35.
    Ortiz-Romero J, Bermudez-Soto I, Torres-González R (2017) Factors associated with complex regional pain syndrome in surgically trated distal radius fracture. Acta Ortop Bras 25(5):194–196CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lipman MD, Hess DE, Werner BC (2017) Fibromyalgia as a predictor of complex regional pain syndrome after distal radius fracture. Hand (N Y).
  37. 37.
    Wang W, Wang W, Mei X, Huang J, Wei Y, Wang Y, Wu S, Li Y (2009) Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One 4(9):e6973CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15CrossRefPubMedGoogle Scholar
  39. 39.
    Vellucci R (2012) Heterogeneity of chronic pain. Clin Drug Investig 32(Suppl 1):3–10CrossRefPubMedGoogle Scholar
  40. 40.
    Nees F, Becker S (2017) Psychological processes in chronic pain: influences of reward and fear learning as key mechanisms—behavioral evidence, neural circuits, and maladaptive changes. Neuroscience.
  41. 41.
    Valet M, Gündel H, Sprenger T, Sorg C, Mühlau M, Zimmer C, Henningsen P, Tölle TR (2009 Jan) Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study. Psychosom Med 71(1):49–56CrossRefPubMedGoogle Scholar
  42. 42.
    Institute for Clinical Systems Improvement (ICSI). Health Care Guideline: assessment and management of chronic pain (fourth edition) 2009: Available from:
  43. 43.
    Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24(1):23–57CrossRefPubMedGoogle Scholar
  44. 44.
    Wells G, Cranney A, Shea B, Tugwell P (1997) Responsiveness of endpoints in osteoporosis clinical trials. J Rheumatol 24:1230–1233PubMedGoogle Scholar
  45. 45.
    Knopp-Sihota JA, Newburn-Cook CV, Homik J, Cummings GG, Voaklander D (2012) Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis. Osteoporos Int 23:17–38. CrossRefPubMedGoogle Scholar
  46. 46.
    Gennari C (2002) Analgesic effect of calcitonin in osteoporosis. Bone 30:67S–70SCrossRefPubMedGoogle Scholar
  47. 47.
    Franceschini R, Cataldi A, Barreca T, Salvemini M, Rolandi E (1989) Plasma beta-endorphin, ACTH and cortisol secretion in man after nasal spray administration of calcitonin. Eur J Clin Pharmacol 37:341–343CrossRefPubMedGoogle Scholar
  48. 48.
    Fujita T, Ohue M, Nakajima M, Fujii Y, Miyauchi A, Takagi Y (2011) Comparison of the effects of elcatonin and risedronate on back and knee pain by electroalgometry using fall of skin impedance and quality of life assessment using SF-36. J Bone Miner Metab 29:588–597. CrossRefPubMedGoogle Scholar
  49. 49.
    Tschopp FA, Henke H, Petermann JB, Tobler PH, Janzer R, Hökfelt T, Lundberg JM, Cuello C, Fischer JA (1985) Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary. Proc Natl Acad Sci U S A 82:248–252CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C, FREEDOM Trial (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765. CrossRefPubMedGoogle Scholar
  51. 51.
    Martin-Broto J, Cleeland CS, Glare PA, Engellau J, Skubitz KM, Blum RH, Ganjoo KN, Staddon A, Dominkus M, Feng A, Qian Y, Braun A, Jacobs I, Chung K, Atchison C (2014) Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study. Acta Oncol 53:1173–1179. CrossRefPubMedGoogle Scholar
  52. 52.
    Pantano F, Zoccoli A, Iuliani M, Lanzetta G, Vincenzi B, Tonini G, Santini D (2011) New targets, new drugs for metastatic bone pain: a new philosophy. Expert Opin Emerg Drugs 16:403–405. CrossRefPubMedGoogle Scholar
  53. 53.
    Cleeland CS, Body JJ, Stopeck A, von Moos R, Fallowfield L, Mathias SD, Patrick DL, Clemons M, Tonkin K, Masuda N, Lipton A, de Boer R, Salvagni S, Oliveira CT, Qian Y, Jiang Q, Dansey R, Braun A, Chung K Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer 119:832–838.
  54. 54.
    Benhamou J, Gensburger D, Chapurlat R (2014) Transient improvement of severe pain from fibrous dysplasia of bone with denosumab treatment. Joint Bone Spine 81:549–550. CrossRefPubMedGoogle Scholar
  55. 55.
    Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Glüer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) 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 282:637–645 Erratum in: JAMA 1999 Dec 8;282(22):2124CrossRefPubMedGoogle Scholar
  56. 56.
    Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA (2008) Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23:1923–1934. CrossRefPubMedGoogle Scholar
  57. 57.
    Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441CrossRefPubMedGoogle Scholar
  58. 58.
    Nevitt MC, Chen P, Dore RK, Reginster JY, Kiel DP, Zanchetta JR, Glass EV, Krege JH (2006) Reduced risk of back pain following teriparatide treatment: a meta-analysis. Osteoporos Int 17:273–280CrossRefPubMedGoogle Scholar
  59. 59.
    Miller PD, Delmas PD, Lindsay R, Watts NB, Luckey M, Adachi J, Saag K, Greenspan SL, Seeman E, Boonen S, Meeves S, Lang TF, Bilezikian JP, Open-label Study to Determine How Prior Therapy with Alendronate or Risedronate in Postmenopausal Women with Osteoporosis Influences the Clinical Effectiveness of Teriparatide Investigators (2008) Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J Clin Endocrinol Metab 93:3785–3793. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082CrossRefPubMedGoogle Scholar
  61. 61.
    Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541CrossRefPubMedGoogle Scholar
  62. 62.
    Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443CrossRefPubMedGoogle Scholar
  63. 63.
    Bannuru RRDU, McAlindon TE (2010) Reassessing the role of acetaminophen in osteoarthritis: systematic review and meta-analysis. Osteoarthritis Research Society International World Congress; 2010 Sep 23e26; Brussels, Belgium. Osteoarthr Cartil 18(Suppl 2):S250CrossRefGoogle Scholar
  64. 64.
    Kress HG, Untersteiner G (2017) Clinical update on benefit versus risks of oral paracetamol alone or with codeine: still a good option? Curr Med Res Opin 33(2):289–304CrossRefPubMedGoogle Scholar
  65. 65.
    Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A et al (2013) Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382(9894):769–779CrossRefGoogle Scholar
  66. 66.
    Kress HG, Baltov A, Basiński A, Berghea F, Castellsague J, Codreanu C, Copaciu E, Giamberardino MA, Hakl M, Hrazdira L, Kokavec M, Lejčko J, Nachtnebl L, Stančík R, Švec A, Tóth T, Vlaskovska MV, Woroń J (2016) Acute pain: a multifaceted challenge—the role of nimesulide. Curr Med Res Opin 32(1):23–36CrossRefPubMedGoogle Scholar
  67. 67.
    Su B, O’Connor JP (2013) NSAID therapy effects on healing of bone, tendon, and the enthesis. J Appl Physiol (1985) 115(6):892–899CrossRefGoogle Scholar
  68. 68.
    Liu B, Liu R, Wang L (2017) A meta-analysis of the preoperative use of gabapentinoids for the treatment of acute postoperative pain following spinal surgery. Medicine (Baltimore) 96(37):e8031CrossRefGoogle Scholar
  69. 69.
    Kanda J, Izumo N, Kobayashi Y (2017) Effects of the antiepileptic drugs Phenytoin, Gabapentin, and Levetiracetam on bone strength, bone mass, and bone turnover in rats. Biol Pharm Bull 40:1934–1940CrossRefPubMedGoogle Scholar
  70. 70.
    Bruyère O, Reginster JY (2015) Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome. Endocrine 48(1):65–68CrossRefPubMedGoogle Scholar
  71. 71.
    Klotz U (2003) Tramadol—the impact of its pharmacokinetic and pharmacodynamics properties on the clinical management of pain. Arzneimittelforschung Drug Res 53:681–687Google Scholar
  72. 72.
    Dhillon S (2010) Tramadol/paracetamol fixed-dose combination: a review of its use in the management of moderate to severe pain. Clin Drug Investig 30:711–738CrossRefPubMedGoogle Scholar
  73. 73.
    Kress HG, Koch ED, Kosturski H, Steup A, Karcher K, Dogan C, Etropolski M, Eerdekens M (2016) Direct conversion from tramadol to tapentadol prolonged release for moderate to severe chronic malignant tumour-related pain. Eur J Pain 20:1513–1518CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, Kress HG, Langford R, Likar R, Raffa RB, Sacerdote P (2008) Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract 8(4):287–313CrossRefPubMedGoogle Scholar
  75. 75.
    O'Brien T, Christrup LL, Drewes AM, Fallon MT, Kress HG, McQuay HJ, Mikus G, Morlion BJ, Perez-Cajaraville J, Pogatzki-Zahn E, Varrassi G, Wells JC (2017) European Pain Federation position paper on appropriate opioid use in chronic pain management. Eur J Pain 21(1):3–19CrossRefPubMedGoogle Scholar
  76. 76.
    Vargas-Schaffer G (2010) Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician 56(6):514–517PubMedPubMedCentralGoogle Scholar
  77. 77.
    Kress HG (2010) Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon? Eur J Pain 14(8):781–783CrossRefPubMedGoogle Scholar
  78. 78.
    Baron R, Eberhart L, Kern KU, Regner S, Rolke R, Simanski C, Tölle T (2016) Tapentadol prolonged release for chronic pain: a review of clinical trials and 5 years of routine clinical practice data. Pain Pract 17:678–700CrossRefPubMedGoogle Scholar
  79. 79.
    Steigerwald I, Müller M, Davies A, Samper D, Sabatowski R, Baron R, Rozenberg S, Szczepanska-Szerej A, Gatti A, Kress HG (2012) Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study. Curr Med Res Opin 28(6):911–936CrossRefPubMedGoogle Scholar
  80. 80.
    Pergolizzi J, Alon E, Baron R, Bonezzi C, Dobrogowski J, Gálvez R, Jensen T, Kress HG, Marcus MA, Morlion B, Perrot S, Treede RD (2011) Tapentadol in the management of chronic low back pain: a novel approach to a complex condition? J Pain Res 4:203–210PubMedPubMedCentralGoogle Scholar
  81. 81.
    Barbosa J, Faria J et al (2016) Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 48(4):577–592CrossRefPubMedGoogle Scholar
  82. 82.
    Kress HG, Koch ED, Kosturski H, Steup A, Karcher K, Lange B, Dogan C, Etropolski MS, Eerdekens M (2014) Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Phys 17(4):329–343Google Scholar
  83. 83.
    Buyenak R, Rappaport SA et al (2015) Long-term safety and efficacy of Tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther 37(11):2420–2438CrossRefGoogle Scholar
  84. 84.
    Baron R, Jansen JP et al (2016) Tolerability, safety, and quality of life with Tapentadol prolonged release (PR) compared with oxycodone/naloxone PR in patients with severe chronic low back pain with a neuropathic component: a randomized, controlled, open-label, phase 3b/4 trial. Pain Pract 16(5):600–619CrossRefPubMedGoogle Scholar
  85. 85.
    Wiffen PJ, Derry S et al (2015) Oral tapentadol for cancer pain. Cochrane Database Syst Rev 9:CD011460Google Scholar
  86. 86.
    Lutfy K, Cowan A (2004) Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol 2(4):395–402CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Kress HG (2009) Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 13(3):219–230CrossRefPubMedGoogle Scholar
  88. 88.
    Strain EC, Preston K, Liebson I, Bigelow G (1995) Buprenorphine effects in methadone-maintained volunteers: effect at two hours after methadone. J Pharmacol Exp Ther 272:628–638PubMedGoogle Scholar
  89. 89.
    Pérez-Castrillón JL, Olmos JM, Gómez JJ, Barrallo A, Riancho JA, Perera L, Valero C, Amado JA, González-Macías J (2000) Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells. Neuroendocrinology 72(3):187–194CrossRefPubMedGoogle Scholar
  90. 90.
    Coluzzi F, Pergolizzi J et al (2015) The unsolved case of “bone-impairing analgesics”: the endocrine effects of opioids on bone metabolism. Ther Clin Risk Manag 11:515–523CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Rico H, Costales C, Cabranes JA, Escudero M (1990) Lower serum osteocalcin levels in pregnant drug users and their newborns at the time of delivery. Obstet Gynecol 75(6):998–1000PubMedGoogle Scholar
  92. 92.
    Aloisi AM, Aurilio C, Bachiocco V, Biasi G, Fiorenzani P, Pace MC, Paci V, Pari G, Passavanti G, Ravaioli L, Sindaco G, Vellucci R, Ceccarelli I (2009) Endocrine consequences of opioid therapy. Psychoneuroendocrinology 34(Suppl 1):S162–S168CrossRefPubMedGoogle Scholar
  93. 93.
    Daniell HW (2006) DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid induced inhibition of adrenal androgen production. J Pain 7:901–907CrossRefPubMedGoogle Scholar
  94. 94.
    Fraser LA, Morrison D, Morley-Forster P, Paul TL, Tokmakejian S, Larry Nicholson R, Bureau Y, Friedman TC, van Uum S (2009) Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes 117(1):38–43CrossRefPubMedGoogle Scholar
  95. 95.
    Smith HS, Elliott JA (2012) Opioid-induced androgen deficiency (OPIAD). Pain Phys 15(3 Suppl):ES145–ES156Google Scholar
  96. 96.
    Oltmanns K, Fehm H, Peters A (2005) Chronic fentanyl application induces adrenocortical insufficiency. J Intern Med 257:478–480CrossRefPubMedGoogle Scholar
  97. 97.
    Eichenbaum G, Göhler K, Etropolski M et al (2015) Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. J Opioid Manag 11(3):211–227CrossRefPubMedGoogle Scholar
  98. 98.
    Siemionow K, Lieberman IH (2007) Vertebral augmentation in osteoporosis and bone metastasis. Curr Opin Support Palliat Care 1(4):323–327CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • R. Vellucci
    • 1
  • R. Terenzi
    • 2
  • J. A Kanis
    • 3
    • 4
  • H. G. Kress
    • 5
  • R. D. Mediati
    • 1
  • J.-Y. Reginster
    • 6
  • R. Rizzoli
    • 7
  • M. L. Brandi
    • 2
  1. 1.Palliative Care and Pain Therapy UnitUniversity Hospital of CareggiFlorenceItaly
  2. 2.Department of Surgery and Translational MedicineUniversity of FlorenceFlorenceItaly
  3. 3.Centre for Metabolic Bone DiseasesUniversity of Sheffield Medical SchoolSheffieldUK
  4. 4.Institute for Health and AgeingCatholic University of AustraliaMelbourneAustralia
  5. 5.Department of Special Anaesthesia and Pain MedicineMedical University/AKH of ViennaViennaAustria
  6. 6.University of LiègeLiègeBelgium
  7. 7.Service of Bone DiseasesGeneva University Hospitals and Faculty of MedicineGeneva 14Switzerland

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