Osteoporosis International

, Volume 23, Issue 4, pp 1255–1265 | Cite as

Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS)

  • P. Vestergaard
  • P. Hermann
  • J.-E. B. Jensen
  • P. Eiken
  • L. Mosekilde
Original Article



Pain medication has been associated with fractures. We found higher weight in paracetamol and non-steroidal anti-inflammatory drugs (NSAID) users and lower vitamin D levels in opioid and acetylsalicylic acid users. None of the pain medications influenced bone mineral density or loss. NSAID were associated with an increased fracture risk.


To study the effects of use of paracetamol, non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), and opioids on bone mineral density (BMD) and risk of fractures.


Two-thousand sixteen perimenopausal women followed for 10 years as part of a partly randomised comprehensive cohort study on hormone therapy (HT). BMD was measured at baseline and after 10 years by DXA (Hologic).


Paracetamol users were heavier (70.4 ± 13.4 vs. 67.7 ± 11.9 kg, 2p < 0.01) than non-users. NSAID users were heavier (71.6 ± 15.6 vs. 67.8 ± 11.9 kg, 2p = 0.04) than non-users. ASA users had lower 25-hydroxy-vitamin D (25OHD) levels (21.9 ± 9.3 vs. 25.3 ± 12.4 ng/ml, 2p < 0.01) than non-users. Opioid users had lower 25OHD (21.4 ± 8.4 vs. 25.2 ± 12.3 ng/ml) and lower intake of vitamin D (2.2 ± 1.1 vs. 3.1 ± 3.0 μg/day, 2p < 0.01) than non-users. Despite these differences, no baseline differences were present in spine, hip, forearm or whole body BMD. Over 10 years, no differences were present in BMD alterations except a small trend towards a higher BMD gain in the spine in users of paracetamol, NSAID, ASA, and opioids compared to non-exposed. After adjustment, NSAID exposed sustained more fractures (HR = 1.44, 95% CI 1.07–1.93) than non-users. For users of paracetamol and opioids, a non-significant trend towards more fractures was present after adjustment. For ASA users, no excess risk of fractures was present.


Significant differences exist between subjects exposed to pain medications and non-users. Despite an absence of an effect over time on BMD, users of NSAID experienced more fractures than expected. The reasons for this have to be explored in further studies.


Acetylsalicylic acid Bone mineral Fracture Non-steroidal anti-inflammatory drugs Opioid Paracetamol 


Financial support

The study was made possible through financial support from the A.P. Møller Foundation (Fonden til Lægevidenskabens Fremme), and by Karen Elise Jensen’s Foundation, the Danish Medical Research Council. Novo Nordisk Denmark, Novartis Denmark, and Leo Denmark provided the study medication free of charge. None of these had any influence on study design and conduct.

Conflicts of interest



  1. 1.
    Kinjo M, Setoguchi S, Schneeweiss S, Solomon D (2005) Bone mineral density in subjects using central nervous system-active medications. Am J Med 118:1414.e7–1414.e12CrossRefGoogle Scholar
  2. 2.
    Daniell H (2002) Hypogonadism in men consuming sustained-action oral opioids. J Pain 3:377–384CrossRefPubMedGoogle Scholar
  3. 3.
    Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, Attia J (2009) Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl 32:131–139CrossRefPubMedGoogle Scholar
  4. 4.
    Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture risk associated with use of morphine and opiates. J Intern Med 260:76–87CrossRefPubMedGoogle Scholar
  5. 5.
    Bauer D, Orwoll E, Fox K, Vogt T, Lane N, Hochberg M, Stone K, Nevitt M (1996) Aspirin and NSAID use in older women: effect on bone mineral density and fracture risk Study of Osteoporotic Fractures Research Group. J Bone Miner Res 11:29–35CrossRefPubMedGoogle Scholar
  6. 6.
    Carbone L, Tylavsky F, Cauley J, Harris T, Lang T, Bauer D, Barrow K, Kritchevsky S (2003) Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity. J Bone Miner Res 18:1795–1802CrossRefPubMedGoogle Scholar
  7. 7.
    Raisz L (1995) Physiologic and pathologic roles of prostaglandins and other eicosanoids in bone metabolism. J Nutr 125:2024S–2027SPubMedGoogle Scholar
  8. 8.
    Raisz L (1999) Prostaglandins and bone: physiology and pathophysiology. Osteoarthritis Cartilage 7:419–421CrossRefPubMedGoogle Scholar
  9. 9.
    Raisz L (2001) Potential impact of selective cyclooxygenase-2 inhibitors on bone metabolism in health and disease. Am J Med 110(Suppl 3A):43S–45SCrossRefPubMedGoogle Scholar
  10. 10.
    van Staa T, Leufkens H, Cooper C (2000) Use of nonsteroidal anti-inflammatory drugs and risk of fractures. Bone 27:563–568CrossRefPubMedGoogle Scholar
  11. 11.
    Vestergaard P, Rejnmark L, Mosekilde L (2006) Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 79:84–94CrossRefPubMedGoogle Scholar
  12. 12.
    Aisen P, Schafer K, Grundman M, Pfeiffer E, Sano M, Davis K, Farlow M, Jin S, Thomas R, Thal L (2003) Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289:2819–2826CrossRefPubMedGoogle Scholar
  13. 13.
    Bannwarth B, Treves R, Euller-Ziegler L, Rolland D, Ravaud P, Dougados M (2003) Adverse events associated with rofecoxib therapy: results of a large study in community-derived osteoarthritic patients. Drug Saf 26:49–54CrossRefPubMedGoogle Scholar
  14. 14.
    Silberstein S, Tepper S, Brandes J, Diamond M, Goldstein J, Winner P, Venkatraman S, Vrijens F, Malbecq W, Lines C, Visser W, Reines S, Yuen E (2004) Randomized, placebo-controlled trial of rofecoxib in the acute treatment of migraine. Neurology 62:1552–1557PubMedGoogle Scholar
  15. 15.
    Walker PC, Alrawi A, Mitchell JF, Regal RE, Khanderia U (2005) Medication use as a risk factor for falls among hospitalized elderly patients. Am J Health Syst Pharm 62:2495–2499CrossRefPubMedGoogle Scholar
  16. 16.
    Barden J, Edwards J, Moore R, McQuay H (2004) Single dose oral diclofenac for postoperative pain. Cochrane Database Syst Rev (2):CD004768.Google Scholar
  17. 17.
    Hegeman J, van den Bemt BJF, Duysens J, van Limbeek J (2009) NSAIDs and the risk of accidental falls in the elderly: a systematic review. Drug Saf 32:489–498CrossRefPubMedGoogle Scholar
  18. 18.
    Hegeman J, Nienhuis B, van den Bemt B, Weerdesteyn V, van Limbeek J, Duysens J (2010) The effect of a non-steroidal anti-inflammatory drug on two important predictors for accidental falls: postural balance and manual reaction time. A randomized, controlled pilot study. Hum Mov Sci 30:384–395CrossRefPubMedGoogle Scholar
  19. 19.
    García-Martínez O, Díaz-Rodríguez L, Rodríguez-Pérez L, De Luna-Bertos E, Botella CR, Ruiz CC (2010) Effect of acetaminophen, ibuprofen and methylprednisolone on different parameters of human osteoblast-like cells. Arch Oral Biol 56:317–323CrossRefPubMedGoogle Scholar
  20. 20.
    Díaz-Rodríguez L, García-Martínez O, Arroyo-Morales M, Rubio-Ruiz B, Ruiz C (2010) Effect of acetaminophen (paracetamol) on human osteosarcoma cell line MG63. Acta Pharmacol Sin 31:1495–1499CrossRefPubMedGoogle Scholar
  21. 21.
    Mosekilde L, Hermann A, Beck-Nielsen H, Charles P, Nielsen S, Sørensen O (1999) The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2016 normal perimenopausal women. Maturitas 31:207–219CrossRefPubMedGoogle Scholar
  22. 22.
    Mosekilde L, Beck-Nielsen H, Sørensen O, Nielsen S, Charles P, Vestergaard P, Hermann A, Gram J, Hansen T, Abrahamsen B, Ebbesen E, Stilgren L, Jensen L, Brot C, Hansen B, Tofteng C, Eiken P, Kolthoff N (2000) Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas 36:181–193CrossRefPubMedGoogle Scholar
  23. 23.
    Brixen K, Nielsen HK, Eriksen EF, Charles P, Mosekilde L (1989) Efficacy of wheat germ lectin-precipitated alkaline phosphatase in serum as an estimator of bone mineralization rate: comparison to serum total alkaline phosphatase and serum bone Gla-protein. Calcif Tissue Int 44:93–98CrossRefPubMedGoogle Scholar
  24. 24.
    Lund B, Sorensen O (1979) Measurement of 25-hydroxyvitamin D in serum and its relation to sunshine, age and vitamin D intake in the Danish population. Scand J Clin Lab Invest 39:23–30CrossRefPubMedGoogle Scholar
  25. 25.
    Abrahamsen B, Gram J, Hansen T, Beck-Nielsen H (1995) Cross-calibration of QDR-2000 and QDR-1000 dual energy X-ray densitometers for bone mineral and soft tissue measurements. Bone 16:385–391CrossRefPubMedGoogle Scholar
  26. 26.
    De Laet C, Kanis J, Oden A, Johanson H, Johnell O, Delmas P, Eisman J, Kroger H, Fujiwara S, Garnero P, McCloskey E, Mellstrom D, Melton LJ III, Meunier P, Pols H, Reeve J, Silman A, Tenenhouse A (2005) Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporosis Int 16:1330–1338CrossRefGoogle Scholar
  27. 27.
    Lovell S, Taira T, Rodriguez E, Wackett A, Gulla J, Singer A (2004) Comparison of valdecoxib and an oxycodone-acetaminophen combination for acute musculoskeletal pain in the emergency department: a randomized controlled trial. Acad Emerg Med 11:1278–1282PubMedGoogle Scholar
  28. 28.
    Vestergaard P (2008) Pain-relief medication and risk of fractures. Curr Drug Saf 3:199–203CrossRefPubMedGoogle Scholar
  29. 29.
    Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259CrossRefPubMedGoogle Scholar
  30. 30.
    Dimmen S, Nordsletten L, Engebretsen L, Steen H, Madsen JE (2008) Negative effect of parecoxib on bone mineral during fracture healing in rats. Acta Orthop 79:438–444CrossRefPubMedGoogle Scholar
  31. 31.
    Dimmen S, Nordsletten L, Madsen JE (2009) Parecoxib and indomethacin delay early fracture healing: a study in rats. Clin Orthop Relat Res 467:1992–1999CrossRefPubMedGoogle Scholar
  32. 32.
    Bischoff H, Stahelin H, Urscheler N, Ehrsam R, Vonthein R, Perrig-Chiello P, Tyndall A, Theiler R (1999) Muscle strength in the elderly: its relation to vitamin D metabolites. Arch Phys Med Rehabil 80:54–58CrossRefPubMedGoogle Scholar
  33. 33.
    Bischoff H, St. helin H, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew R, Conzelmann M (2003) Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 18:343–351CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2011

Authors and Affiliations

  • P. Vestergaard
    • 1
    • 5
  • P. Hermann
    • 2
  • J.-E. B. Jensen
    • 3
  • P. Eiken
    • 4
  • L. Mosekilde
    • 1
  1. 1.Department of Endocrinology and Internal Medicine (MEA)Aarhus University HospitalAarhusDenmark
  2. 2.Department of Endocrinology MOdense University HospitalOdenseDenmark
  3. 3.Department of EndocrinologyHvidovre University HospitalCopenhagenDenmark
  4. 4.Department of Cardiology and Endocrinology, Hillerød HospitalHillerødDenmark
  5. 5.The Osteoporosis ClinicAarhus University Hospital THGAarhus CDenmark

Personalised recommendations