Effects of NSAIDs on pre‑osteoblast viability and osteogenic differentiation

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of a variety of musculoskeletal conditions, injuries and after surgery for postoperative pain management. Their use has been associated with impaired bone healing, possibly due to a multifactorial function, which may include inhibition of osteoblast recruitment and differentiation. However, up to date, there is no consensus regarding the impact of NSAIDs on bone-healing. The aim of the current study was to investigate the effects of five NSAIDs on the cellular functions of mouse MC3T3-E1 pre-osteoblasts. Cells were treated with the non-selective COX inhibitors lornoxicam and diclofenac, the COX-2 selective inhibitors parecoxib, meloxicam and paracetamol, as well as steroidal prednisolone at different doses and exposure times. The PrestoBlue™ technique was used to measure cell viability, an enzymatic assay was employed for alkaline phosphatase (ALP) activity and alizarin red S mineral staining was used to determine osteogenic differentiation. All drugs had a negative impact on pre-osteoblast cell growth, with the exception of paracetamol. Lornoxicam, diclofenac and meloxicam reduced ALP activity, while the other NSAIDs had no effect and prednisolone strongly increased ALP activity. In contrast, calcium deposits were either unaffected or increased by NSAID treatments but were significantly decreased by prednisolone. These results provide evidence that NSAIDs may adversely affect the viability of mouse pre-osteoblast cells but their actions on the osteogenic differentiation are drug-specific. The direct comparison of the effects of different NSAIDs and prednisolone on pre-osteoblasts may serve to place some NSAIDs in a preferential position for analgesic and anti-inflammatory therapy during bone repair.

Effect of Diclofenac and Simvastatin on Bone Defect Healing—An In Vivo Animal Study

“…It has also been reported that diclofenac inhibits BMP-7 which induces the differentiation, maturation and proliferation of osteoblasts from mesenchymal cells [ 26 ]. Recently reported data state that NSAIDs could demonstrate a negative effect on the bone healing process by down-regulating chondrogenesis and endochondral ossification [ 27 ], and that diclofenac has a negative impact on pre-osteoblast cell growth [ 17 ]. Bissinger et al [ 28 ] investigated the effect of diclofenac on fractures through a biomechanically, morphologically and by 3-dimensional microstructural analysis and reported an inhibiting effect on bone healing, but also additional changes which occurred in the microstructural bony network.…”

“…The negative effect of diclofenac on bone healing may be attributed to its adverse effects, since it has been reported that diclofenac inhibits the proliferation and induces the apoptosis of human osteoblast cells [ 16 ]. Furthermore, on a cellular level, diclofenac may show a negative impact on pre-osteoblast cell growth [ 17 ]. However, recent studies have assumed the negative impact of diclofenac on bone metabolism to be subsidiary [ 18 ], while Cai et al [ 19 ] reported that diclofenac did not adversely affect the osseointegration of dental implants and bone healing in the calvaria, neither in the short nor the long term.…”

The Effect of Diclofenac Sodium on Callus Formation in White Male Rat (Rattus norvegicus) Cruris Fracture Healing

“…NSAIDs affect the osteoblastic cell cycle and cell death. A study showed that osteoblastic density was significantly decreased in groups exposed to diclofenac sodium compared to the control group (Hadjicharalambous et al 2021). The osteoclastic densities were found to be statistically significantly higher in a group exposed to diclofenac sodium than in the control group (p< 0.05).…”

IL-6-induced response of human osteoblasts from patients with rheumatoid arthritis after inhibition of the signaling pathway

“…Treatment of pre-osteoblasts with prednisolone resulted in increased ALP activity and decreased calcium deposition, decreased cell viability, and proliferation. It is already known that prednisolone can induce apoptosis of confluent osteoblasts [ 61 ]. While cortisol, a glucocorticoid hormone secreted in response to stress, can promote osteoblast differentiation at physiological concentrations [ 59 ], there are conflicting data on whether prednisolone can inhibit or increase the biological activity of osteoblasts and osteoclasts.…”

“…While cortisol, a glucocorticoid hormone secreted in response to stress, can promote osteoblast differentiation at physiological concentrations [ 59 ], there are conflicting data on whether prednisolone can inhibit or increase the biological activity of osteoblasts and osteoclasts. The effect seems to be concentration-dependent and depends on the developmental stage of the osteoblasts [ 61 – 63 ].…”