Send Orders of Reprints at reprints@benthamscience.org Reviews on Recent Clinical Trials, 2012, 7, 00-00 1 1574-8871/12 $58.00+.00 © 2012 Bentham Science Publishers Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Turnover: An Evidence-Based Review Ioannis Konstantinidis 1* , Spyridon N. Papageorgiou 2* , Athanassios Kyrgidis 3,4 , Thrasivoulos- George Tzellos 4 and Dimitrios Kouvelas 4 1 Mount Sinai School of Medicine, New York, NY, USA 2 Endowed Chair of Oral Technology, School of Dentistry, Bonn University, Bonn, Germany 3 Department of Oral Maxillofacial Surgery, School of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, Greece 4 Department of Pharmacology & Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing com- puterized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorp- tion. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of hu- man patients are limited. Further research is required to confirm or refute the findings of this systematic review Keywords: Bone metabolism, bone remodeling, non-steroidal anti-inflammatory drug, randomized controlled trial. INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are fre- quently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs inhibit cyclooxygenase-1 and 2 (COX-1 and 2) en- zymes, which results in decreased formation of the prosta- glandin precursors that mediate the initial inflammatory re- sponse in the bone healing process. However, evidence about the relationship of NSAIDs to bone metabolism is inconclu- sive [1-3]. NSAIDs are considered effective inhibitors of bone formation in experimental models of fracture healing, spinal fusion, bone ingrowth into implants, mechanically- induced bone remodeling, and heterotopic ossification [4]. A recent meta-analysis of observational studies found that the degree of risk for nonunion was significantly elevated in patients using NSAIDs when moderate quality studies of long bone fractures and higher quality studies of spinal fu- sion were considered together, but this effect was not signifi- cant when only higher quality studies were analyzed [5]. Nevertheless, the dynamic impact of NSAID exposure on bone remodeling has not been evaluated thoroughly. * Address correspondence to this author at the 3 Papazoli St, Thessaloniki, 546 30, Greece; !el: +30-6947-566727; Fax: +30-2310-546701; E-mails: akyrgidi@gmail.com, kyrgidis@auth.gr * The first two authors had equal contribution in the writing of this manu- script and equally share first authorship. Bone homeostasis is regulated by the opposing processes of bone formation and bone resorption, which result in the production of several biochemical markers (BMs) that can be measured in serum and urine. BMs include cell-derived en- zymes and nonenzymatic peptides, and are usually classified according to the metabolic procedures they reflect [6]. Bone formation BMs include bone-specific alkaline phosphatase (BAP), osteocalcin (OC), the carboxy terminal propeptide of type I procollagen (PICP) and the amino-terminal propeptide of type I procollagen (PINP). Typical BMs of bone resorp- tion are deoxypyridinoline (DPD), the carboxy terminal cross-linked telopeptide of type I collagen (CTX-MMP), the amino-terminal cross-linked telopeptide of type I collagen (NTx), the carboxy terminal cross-linked telopeptide of type II collagen (CTX-II) and the glycosylated analog of pyridi- noline, glucosyl-galactosyl pyridinoline (Glc-Gal-PYD). Overall, BAP and PINP are regarded as the most clinically useful markers of bone formation, while urinary NTx and serum CTX-MMP are the most useful markers of bone re- sorption. Because BMs reflect dynamic changes in bone me- tabolism, they show promise as tools for monitoring rapid response to treatment and predicting clinical outcomes, espe- cially in patients with metabolic bone disease [7-12]. Al- though BMs have been used in investigational trials to de- scribe the pharmacodynamics of therapeutic agents, their role in the care of individual patients is not well established.