Elsevier

Bone

Volume 48, Issue 6, 1 June 2011, Pages 1277-1281
Bone

Paracetamol (acetaminophen) use, fracture and bone mineral density

https://doi.org/10.1016/j.bone.2011.03.435Get rights and content

Abstract

Paracetamol is the most widely prescribed simple analgesic and antipyretic. It exerts its effects via cyclooxygenase and endocannabinoid pathways, which may affect signalling in bone cells and hence influence bone metabolism. Given the high rates of paracetamol use in the community and the evidence linking its mechanism of action to bone metabolism, we aimed to investigate the association between paracetamol use, fracture, and bone mineral density (BMD) in women participating in the Geelong Osteoporosis Study (GOS). Cases (n = 569) were women aged ≥ 50 years identified from radiological reports as having sustained a fracture between 1994 and 1996. Controls (n = 775) were women without fracture recruited from the same region during this period. BMD was measured at the spine, hip, total body and forearm using dual energy absorptiometry. Medication use, medical history and lifestyle factors were self-reported. There were 69 (12.1%) paracetamol users among the cases and 63 (8.1%) among the controls. Paracetamol use increased the odds for fracture (OR = 1.56, 95%CI 1.09–2.24, p = 0.02). Adjustment for BMD at the spine, total hip and forearm did not confound the association. However, incorporating total body BMD into the model attenuated the association (adjusted OR = 1.46, 95%CI 1.00–2.14, p = 0.051). Further adjustment for age, weight, physical activity, smoking, alcohol, calcium intake, medication use, medical conditions, falls and previous fracture did not explain the association. These data suggest that paracetamol use is a risk factor for fracture, although the mechanism of action remains unclear.

Research highlights

► Paracetamol use is associated with a 56% increase in fracture risk. ► The mechanism of action remains to be established. ► Given the widespread use of paracetamol, this is of public health relevance.

Introduction

Paracetamol (acetaminophen), available over the counter in most countries, is among the most widely used medications. Its clinically significant effects are analgaesia and antipyresis but it has negligible antiinflammatory effects [1]. Although paracetamol has been used clinically since 1887, its mechanism of action was unclear until quite recently. It has been reported to exert its effects via cyclooxygenase and endocannabinoid pathways [2], [3], which may affect signalling in bone cells and hence influence bone metabolism. Given the high rates of paracetamol use in the community and the evidence linking its mechanism of action to bone metabolism, we investigated, in a population-based sample of women, the association between paracetamol use, fracture, and bone mineral density (BMD).

Section snippets

Participants

This case–control study set in the Barwon Statistical Division, South East Australia, utilised data from women aged ≥ 50 years enrolled in the Geelong Osteoporosis Study (GOS). Cases (n = 569) were women with incident fracture (excluding pathological fractures and those resulting from motor vehicle accidents), identified prospectively from the two radiological practices servicing the region using a keyword search for the 2-year period, February 1994–1996. The search identified 119 vertebral, 107

Subject characteristics

Characteristics of cases and controls and paracetamol users and non-users are shown in Table 1. There were no differences detected between the cases and controls in age, weight, height, smoking status (current or past), dietary calcium, alcohol intake, number of medical conditions and nitrate and thiazide use, although the cases differed in regards to physical activity, number of falls, previous fracture history and glucocorticoid, HT, ß-blockers, statin, calcium/vitamin D supplement, NSAID,

Discussion

Our case–control data demonstrate that paracetamol use is associated with a 56% increase in fracture risk independent of a number of potential confounders including age, weight, height, smoking, physical activity, alcohol consumption, calcium intake, medications, falls, number of medical conditions and previous fracture. Total body BMD attenuated this association; however, paracetamol use was not associated with BMD among the controls.

These findings are in support of the only other papers to

Conclusions

These data suggest that paracetamol may have an independent impact on fracture risk, although the exact mechanism of action is unknown. Given the widespread use of paracetamol, this is of clear public health relevance, and the result merits replication and validation in other clinical and pre-clinical studies.

Contributions

Lana Williams took part in the conception and design of the study, prepared the data, undertook the statistical analysis, interpreted the findings, wrote the first draft, and contributed to subsequent drafts. Julie Pasco took part in the conception and design of the study, contributed to the analysis, interpreted the findings and critically revised the manuscript. Margaret Henry contributed to the statistical analysis and interpretation of the data and critically revised the manuscript. Kerrie

Funding

The study was funded by the National Health and Medical Research Council of Australia (#251638).

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, and the decision to submit for publication. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Conflicts of interest

Lana Williams and Julie Pasco have received research support from an unrestricted educational grant from Eli Lilly.

Margaret Henry, Kerrie Sanders, Geoffrey Nicholson and Mark Kotowicz have no conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript.

Michael Berk has received Grant/Research Support from the Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical

Acknowledgments

We would like to thank Melissa Borracci for assisting in the preparation of the data.

References (27)

  • J.A. Pasco et al.

    Calcium intakes among Australian women: Geelong Osteoporosis Study

    Aust N Z J Med

    (2000)
  • P. Vestergaard et al.

    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

    (2006)
  • J.B. Richards et al.

    The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study

    Osteoporos Int

    (2006)
  • Cited by (21)

    • Effect of acetaminophen on osteoblastic differentiation and migration of MC3T3-E1 cells

      2018, Pharmacological Reports
      Citation Excerpt :

      The osteoblast differentiating effect of APAP was assumed based on numerous reports of the effect of long-term NSAID use on bone fracture healing [8,9], which were related to the pivotal role of COX activity in maintaining bone metabolism [13,14]. However, because APAP does not inhibit COX as strongly as other NSAIDs do [1], its effect on bone are still unclear [8,9,11,15]. In this study, we showed that AM404, a metabolite of APAP, suppressed COX activity and inhibited osteoblastic differentiation.

    • Simultaneous voltammetric determination of tyrosine and paracetamol using a carbon nanotube-graphene nanosheet nanocomposite modified electrode in human blood serum and pharmaceuticals

      2013, Colloids and Surfaces B: Biointerfaces
      Citation Excerpt :

      The detection of Tyr is usually accomplished by spectrophotometric [11], fluorimetric [12], liquid chromatography [13] and high-performance liquid chromatography [14]. Paracetamol (N-acetyl-p-aminophenol, PC) is among the most widely used medications as analgesic and antipyretic drugs [15]. It is remarkably safe in standard doses, but, because of its wide availability, deliberate or accidental overdoses are not uncommon.

    View all citing articles on Scopus
    View full text