Low dose aspirin therapy decreases blood glucose levels but does not prevent type i diabetes-induced bone loss.
Diabetes is strongly associated with increased fracture risk. During T1-diabetes onset, levels of blood glucose and pro-inflammatory cytokines (including TNFα) are increased. At the same time, levels of osteoblast markers are rapidly decreased and stay decreased 40 days later at which point bone loss is clearly evident. Inflammation is known to suppress bone formation and induce bone loss. Previous co-culture studies indicate that diabetic bone is inflamed and diabetic bone marrow is capable of enhancing osteoblast death in vitro. Here we investigate a commonly used non-steroidal anti-inflammatory drug, aspirin, to prevent T1-diabetic bone loss in vivo.
We induced diabetes in 16-week-old male C57BL/6 mice and administered aspirin in the drinking water.
Our results demonstrate that aspirin therapy reduced diabetic mouse non-fasting blood glucose levels to less than 400 mg/dl, but did not prevent trabecular and cortical bone loss. In control mice, aspirin treatment increased bone formation markers but did not affect markers of bone resorption or bone density/volume. In diabetic mice, bone formation markers and bone density/volume are decreased and unaltered by aspirin treatment. Bone resorption markers, however, are increased and 2-way ANOVA analysis demonstrates an interaction between aspirin treatment and diabetes (p<0.007). Aspirin treatment did not prevent the previously reported diabetes-induced marrow adiposity.
Taken together, our results suggest that low dose aspirin therapy does not negatively impact bone density in control and diabetic mice, but could potentially increase bone resorption in T1-diabetic mice.
Coe LM, Denison JD, McCabe LR
Cell. Physiol. Biochem. 2011
PMID: 22178944 | Free Full Text
Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.
Pountos I, Georgouli T, Calori GM, Giannoudis PV
PMID: 22272177 | Free Full Text
The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review.
The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting prostaglandin suppression on fracture-healing have been suggested.
A systematic literature review involving searches of electronic databases and online sources was performed to identify articles exploring the influence of NSAIDs on fracture-healing.
A structured search approach identified 316 papers as potentially relevant to the topic, and these were manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with limited control of potentially confounding variables, or presented little key information that was not also present in other studies.
Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing.
Kurmis AP, Kurmis TP, O’Brien JX, Dalén T
J Bone Joint Surg Am May 2012
Anti-inflammatory treatment increases angiogenesis during early fracture healing.
Both inflammation and angiogenesis are crucial for normal fracture healing. The goal of this work was to determine how anti-inflammatory treatment affects angiogenesis during early stages of fracture repair.
Tibia fractures were created in adult mice and animals were treated with indomethacin (2 mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6 days after fracture. Animals were killed at 7, 14, and 28 days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7 days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7 days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization.
Indomethacin significantly decreased bone and cartilage formation at 7 days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3 days after fracture but did not affect the recruitment of macrophages or neutrophils to injured limbs. Indomethacin-treated fractures had similar length density and surface density of vasculature as the controls at 3 days after injury. At 7 days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28 days after injury, indomethacin-treated fractures still exhibited defects in fracture repair.
Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.
Lu C, Xing Z, Wang X, Mao J…
Arch Orthop Trauma Surg Aug 2012
[Effect of cyclooxygenase-2 on bone loss in ovariectomized rats].
To investigate mechanism of cyclooxygenase-2 (COX-2) in bone loss in a postmenopausal osteoporosis (PMOP) rat mode with ovarietomy (OVX).
Forty female Sprague Dawley adult rats at age of 3 months were randomly divided into 4 groups, 10 in each group, including sham-operated (sham) group, OVX group, OVX treated with nilesteriol (OVX + E) group and OVX treated with aspirin (OVX + P) group. All rats in OVX, OVX + E and OVX + P groups underwent ovarietomy under abdominal anesthesia with 10% chloral hydrate. Rats in sham group were only taken with fat tissue with same weight under bilateral ovary. After surgery, penicillin was administered to prevent infection. At day 7 after surgery, agents were given by intragastric administration for 12 weeks. Nilestriol at 1.0 mg/kg was used in OVX + E group once a week, aspirin at 45 mg×kg⁻¹(×d⁻¹ was used in OVX + P group once a day. Saline with same volume was used in rats in sham and OVX groups. All agents were administered one time per day. Dose of agents were adjusted by weight per week. At end of study, bone mineral density (BMD) of right femurs and lumbar vertebrae 3-5 (L(3-5)) were measured. Morphology of bone was detected by hematoxylineosin, and expression of COX-2 was determined by immunohistochemistry staining.
(1) BMD:BMD of right femur and L(3-5) was (0.209 ± 0.010) g/cm² and (0.230 ± 0.012) g/cm² in sham group and (0.181 ± 0.008) g/cm² and (0.201 ± 0.016) g/cm² in OVX group, which reached statistical difference (P < 0.01). BMD of right femur and L(3-5) was (0.203 ± 0.009) g/cm² and (0.224 ± 0.028) g/cm² in OVX + E group and (0.200 ± 0.011) g/cm² and (0.204 ± 0.003) g/cm² in OVX + P group, which were all higher than those in OVX group (P < 0.01, P < 0.05). However, there was no statistical difference in BMD between OVX + E and OVX + P group (P > 0.05). (2) Morphology of bone:bone trabeculae became fewer and degenerated in OVX group. However, bone trabeculae were regular and dense in OVX + P group and OVX + E group, which were similar to those in sham group. (3) Expression of COX-2:cells with COX-2 positive and expression of COX-2 around bone trabeculae in OVX group were more than those in sham, OVX + E and OVX + P group.
COX-2 plays an important role in PMOP. Aspirin could prevent bone loss by decreasing COX-2 expression in OVX rats.
Guo Y, Zhang CY, Tian Y, DI JM…
Zhonghua Fu Chan Ke Za Zhi Jun 2012
Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review.
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 computerized 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 resorption. 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 human patients are limited. Further research is required to confirm or refute the findings of this systematic review.
Konstantinidis I, Papageorgiou SN, Kyrgidis A, Tzellos TG…
Rev Recent Clin Trials Mar 2013
[No evidence of malicious effect of NSAID treatment on bone healing].
The use of NSAIDs for postoperative pain management following orthopaedic surgery or during conservative treatment of fractures is controversial. Experimental animal models suggest NSAIDs inhibit bone healing. In a review of the literature, there was no clinical evidence to support categorical discard of NSAID for postoperative pain relief in uncomplicated cases. However, NSAID should be considered a potentiel risk factor of impaired bone healing and avoided in patients with a high risk of pseudoarthrosis. Recommended daily doses should be respected and duration of treatment should be limited.
Janum S, Kristensen BB
Ugeskr. Laeg. Nov 2012
Effect of aspirin on bone healing in a rabbit ulnar osteotomy model.
Aspirin is frequently prescribed following orthopaedic surgery. Although there is substantial evidence that some nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with delayed bone healing, there have been few studies of the effects of aspirin on bone healing and, to our knowledge, none on the effects of physiologic dosages.
Following ulnar osteotomy, fifty-six rabbits were administered a placebo (nine rabbits), indomethacin (nine rabbits given 12.5 mg/kg daily), or aspirin at various doses and schedules (2.7 mg/kg daily for ten rabbits, 10 mg/kg daily for nine rabbits, 50 mg/kg twice daily for ten rabbits, and 100 mg/kg three times daily for nine rabbits). The aspirin doses were chosen to span the clinical dosing range. The indomethacin group served as a positive control and as a relative comparison with the effect of aspirin. Radiographs were obtained every two weeks and the animals were killed at eight weeks. Mechanical testing was performed on all rabbits except for six selected for histological evaluation.
Aspirin delayed bone healing, as demonstrated radiographically and with mechanical testing, in a dose-dependent fashion at salicylate levels equivalent to those resulting from typical human dosing (low-dose aspirin). Receiver operating characteristic analysis demonstrated a plasma salicylate threshold above 20.7 μg/mL predicting delayed bone healing. This approximates a single human dose of 325 mg. Salicylate levels above this threshold were associated with delayed bone healing similar to that caused by indomethacin. Aspirin dosing frequency did not affect bone healing. Mechanical testing was highly predictive of radiographic healing. The interobserver reliability of radiographic assessment of healing at six and eight weeks (kappa = 0.83 and 0.79, respectively) compared favorably with interobserver reliability in previous studies assessing cortical bridging.
In a rabbit ulnar osteotomy model, aspirin delayed bone healing with a threshold equivalent to a human dose of 325 mg.
Lack WD, Fredericks D, Petersen E, Donovan M…
J Bone Joint Surg Am Mar 2013