NSAIDs’ Effect on Bone
and Implant Integration

A commonly prescribed medication after implant surgery are one of the non-steroidal anti-inflammatory drugs (NSAIDs). In addition to pain control, many of our patients are taking low dose aspirin for prevention of cardiovascular disease and cancer. When the mechanism of action of these drugs are evaluated, it is obvious they have an impact on the metabolic pathways responsible for bone formation and resorption. This discussion will outline the pharmacology of the NSAIDs and what we know about how they affect implant integration and bone regeneration. This discussion is an excerpt from the live online course “Bone Biology” presented periodically by SteinerBio.

Non-Steroidal Anti-Inflammatory Drugs

There are many NSAIDs on the market and while they have differences in pain control and reduction of inflammation, they all work via inhibition of cyclooxygenase (COX) enzymes. The cox enzymes are responsible for the production of the prostaglandins. There are four principal bioactive prostaglandins generated in vivo:

  • prostaglandin (PG) E2 (PGE2)
  • prostacyclin (PGI2)
  • prostaglandin D2 (PGD2)
  • prostaglandin F2α (PGF2α)
They are ubiquitously produced—usually each cell type generates one or two dominant prostaglandin—and act as autocrine and paracrine lipid mediators to maintain local homeostasis in the body. During an inflammatory response, both the level and the profile of prostaglandin production changes dramatically. Prostaglandin production is generally very low in uninflamed tissues but increases immediately in acute inflammation prior to the recruitment of leukocytes and the infiltration of immune cells. Ever wonder why they are called prostaglandins? They were first discovered in 1934 in semen and they were thought to be produced in the prostate gland.

The COX-1 enzyme is normally produced in cells and is expressed constitutively throughout most cell lines in almost all mammalian tissues. It is described as a housekeeping enzyme, being responsible for cell-to-cell signaling, tissue homeostasis, and cytoprotection. Only COX-1 produces baseline prostaglandins that activate platelets and protect the stomach and intestinal lining. COX-2 enzymes are responsible for releasing prostaglandins after infection or injury and are the primary target for pain control.

Conventional NSAIDs, like aspirin, diclofenac, ibuprofen, and naproxen, are non-selective COX inhibitors which block the production of both physiologic (COX-1) and inflammatory (COX-2) prostaglandins.

By blocking both COX-1 and COX-2, the non-selective COX inhibitors have the downside of blocking the protective effects of COX-1 for the stomach and intestinal lining. The selective COX-2 inhibitors were developed to avoid the stomach problems caused by blocking COX-1. However, the selective COX-2 inhibitors cause retention of sodium and water which can lead to edema and high potassium levels. It was found that taking COX-2 inhibitors increased risk of cardiovascular thrombotic events such as a heart attack or stroke. For this reason, many of the selective COX-2 inhibitors were removed from the market and today the only COX-2 inhibitor still on the market is Celebrex.

The role of prostaglandins is multifactorial as prostaglandins can either promote osteoclastic activity, thereby increasing bone resorption, or they will activate osteoblastic activity, which will increase bone production. The COX-modulated prostaglandins E2 (PGE2) and F2α promote active bone formation and their effect in bone metabolism has had extensive study. During the first two weeks of fracture callus formation, PGE2 is released locally with rates falling drastically by day 21 and then returning to near normal levels by week six of healing. Animal studies suggest that inhibition of PGE2 may reduce bone density and stiffness, and increase fibrous tissue formation in healing. These effects are at their most significant during the first two weeks of bone callus formation and research has shown these effects impair the transition of soft callus to hard callus.

Low Dose Aspirin (81mg)

Low dose aspirin slightly upregulates telomerase activity in bone marrow mesenchymal stem cells (BMMSCs) and elongates their telomere lengths to avoid replicative senescence, improve stem cell functions, and has the capability to increase bone formation. 50μg/mL and 100μg/mL aspirin significantly increased transforming growth factor β-1 (TGF-β1) production of human BMMSCs, then induces migration of MSCs to the bone remodeling sites. Lower concentrations of aspirin (1μΜ and 10μM) promoted cell growth and increased ALP levels and RUNX2 expression, while higher concentrations (100μΜ and 1000μΜ) inhibited cell growth (P < 0.05), and lost their effect on ALP activity after 3 days, while even showing an inhibitory effect on the expression of RUNX2. Aspirin at a concentration of 100μM promoted cell mitosis from the S phase to the G2/M phase, and 1000μM arrested the cell cycle in the resting phase G0/G1 (P < 0.05). Parallel apoptosis/necrosis studies showed the percentage of cells in apoptosis decreased dramatically at any dose of aspirin. Mesenchymal stem cell-based intervention with low dose aspirin (< 100μg/mL) may benefit osteoporosis treatment by inhibition of osteoclast differentiation and activities. Aspirin at a dose of 50μg/mL can partially block the formation of osteoclasts induced by RANKL. The end result of these findings is that low dose aspirin promoted bone growth and high dose inhibits bone growth.

In the following schematic, low dose aspirin stimulates osteoblasts and inhibits osteoclasts. While there are not enough human clinical trials on low dose aspirin to establish low dose aspirin as a significant benefit for bone regeneration, there is no question from the pharmacology and animal studies that low does aspirin has positive effects on bone regeneration.
The red arrows indicate the promotion of cellular processes, and the green lines indicate inhibition of cellular processes.

The following schematic outlines the metabolic pathways altered by high dose aspirin showing an increase in bone resorption and a decrease in bone formation.
High Dose Aspirin (325mg) and Other NSAIDs

High dose aspirin and the other NSAIDs have similar metabolic pathways. While low dose aspirin (81mg) has an undeniable positive effect on bone formation and fracture healing, high dose aspirin and other NSAIDs have the opposite effect. In evaluating the pharmacology of high dose aspirin and other NSAIDs, there is a finding that the pharmacology of these medications indicates that they impart a negative effect on bone growth. In general, terms the overall effects of these medications inhibit osteoblasts and stimulate osteoclasts. However, there is considerable debate as to the clinical relevance of the negative pharmacology of these drugs when it come to fracture healing and bone regeneration.

The two following charts summarize the animal and human clinical research on the effects of high dose aspirin and other NSAIDs used for pain control.

Table 1
Animal studies regarding the functions of NSAIDs in bone remodeling and fracture healing
NSAIDs nonsteroidal anti-inflammatory drugs, BMD bone mineral density
Table 2
Clinical effects of aspirin and NSAIDs on BMD and skeletal regeneration
NSAIDs nonsteroidal anti-inflammatory drugs, BMD bone mineral density
To summarize these two tables, it can be seen that the studies found either no negative effect or an inhibitory effect on bone formation. But what about dental implants? One retrospective study evaluated long term implant failure in relation to NSAID consumption. One hundred and four patients with initially 468 implants had experienced 238 implant failures, of which 197 were due to failing osseointegration (42%). Sixty of the participants, initially with 273 implants, had used NSAIDs perioperatively and experienced 44% implant failures, versus 38% in the non-NSAID cohort. The NSAID cohort experienced 3.2 times more cases of radiographic bone loss greater than 30% of the vertical height of their remaining implants and 1.9 times more cases of cluster failures, defined as failure of 50% or more of the implant(s) placed. This retrospective study indicates that NSAID medications did result in a higher failure rate over time, but the nature of the study does not allow us to conclude that NSAIDs result in a higher implant failure rate.

Two studies done by the same group looked at bone to implant contact around titanium implants placed in rats. Click on each link to see the studies:
Effect of aluminum oxide-blasted implant surface on the bone healing around implants in rats submitted to continuous administration of selective cyclooxygenase-2 inhibitors.
Int J Oral Maxillofac Implants. 2009 Mar-Apr;24(2):226-33.

The animals received the NSAID meloxicam or saline for 60 days.

RESULTS: The Al2O3-blasted surface resulted in significantly increased BIC in both groups, and meloxicam significantly reduced bone healing around implants (P < .05). For the machined surface, significant differences were observed for BIC (39.48 +/- 10.18; 25.23 +/- 9.29), BA (60.62 +/- 4.09; 42.94 +/- 8.12), and BD (56.31 +/- 3.64; 49.30 +/- 3.15) in the saline and meloxicam groups, respectively. For the Al2O3-blasted surface, data analysis also demonstrated significant differences for BIC (45.92 +/- 11.34; 33.30 +/- 7.56), BA (61.04 +/- 4.39; 44.89 +/- 7.11), and BD (58.77 +/- 2.93; 50.04 +/- 3.94) for the saline and meloxicam groups, respectively.

CONCLUSIONS: The Al2O3-blasted surface may increase BIC; however, it does not reverse the negative effects promoted by a selective COX-2 inhibitor on bone healing around implants.
Selective cyclooxygenase-2 inhibitor may impair bone healing around titanium implants in rats.
J Periodontol. 2006 Oct;77(10):1731-5

The animals received the NSAID meloxicam or saline for 60 days.

RESULTS: Intergroup comparisons demonstrated that meloxicam significantly reduced bone healing around implants. For zone A, significant differences were observed regarding Bone in contact (47.01 +/- 10.48 A; 35.93 +/- 12.25 B), Bone area between threads (86.42 +/- 3.66 A; 61.58 +/- 12.09 B), and Bone denisty (96.86 +/- 0.96 A; 91.06 +/- 3.05 B) (P <0.05). For zone B, data analysis also showed significant differences among groups for BIC (30.76 +/- 13.80 A; 16.86 +/- 11.48 B), BA (34.83 +/- 8.18 A; 25.66 +/- 9.16 B), and BD (15.76 +/- 7.05 A; 7.73 +/- 4.61 B) (P <0.05).
From this discussion, it is obvious why there is such debate and confusion with regard to the use of NSAIDs for pain control associated with dental implants. In an effort to distil the science, we can conclude low dose aspirin has a positive effect on bone and patients undergoing dental implant therapy should be encouraged to continue the use of this medication. High dose aspirin and the other NSAIDS produce a negative effect on bone formation, but the effect may not be clinically significant. Our position at SteinerBio is if a medication has the potential for a negative effect on bone growth, it should be avoided if another suitable pain control medication is available. Knowing the biology of osseointegration and the pharmacology of the NSAIDs, it is appropriate that an NSAID such as ibuprofen can be prescribed for three days post surgery with no negative effects followed by low dose aspirin starting three days after surgery and continuing for two months. This discussion is part of our ongoing “Bone Biology” lecture series.
Charts and tables are reprinted from:
Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration.


American Society for Bone and Mineral Research (ASBMR)

Tissue Engineering and Regenerative Medicine International Society (TERMIS)