Impact of the Timing of Indomethacin Treatment in a Model of Synchronized Bone Remodelling in Rats

Abstract

Prostaglandins (PGs) promote both bone resorption and formation in vitro and in vivo. In a synchronised model of bone remodelling, indomethacin, an inhibitor of PG synthesis, given from the start of the sequence, transiently impaired bone resorption. In this study we further explored the involvement of PGs in this model by treating rats with indomethacin (7.5 mg kg _1 day _1 ) for 6 days from the peak of resorption (day 4 after activation in this model) or during reversal (day 6 after activation). In rats treated from day 4, the resorption surface (Oc.S/BS) and the number of osteoclasts (N.Oc/BPm) were higher on day 10 (+69 %, P < 0.01, and +60 %, P < 0.02 compared with controls, respectively); no effect on cell resorptive activity was observed. The bone formation surface (OS/BS) was reduced (_50 %, P < 0.01). The inactive surface (In/BS) was not modified. In rats treated from day 6, the Oc.S/BS was also higher than in controls (P < 0.02), as was the N.Oc/BPm (P < 0.05). Osteoclast activity appeared to be increased, as the osteoclast-bone interface was larger (P < 0.02), but the mean lacuna area was reduced (_23 %, P < 0.05). Bone formation was also strongly affected: the OS/BS was decreased (_66 %, P < 0.01), as was the osteoid seam thickness (_24 %, P < 0.05). The In/BS was increased 1.5-fold (P < 0.05). These data indicate that PGs intervene at various stages of this remodelling sequence, as both resorption and formation were affected by indomethacin. Although resorption resumed in the two treatment groups despite treatment continuation, the timing of treatment was clearly important. Only inhibition of PG synthesis at the peak of resorption delayed all phases of the remodelling sequence. In contrast, inhibition during the reversal phase prevented activation of a significant part of the bone surface usually involved at this stage of remodelling; this treatment schedule reduced the resorptive capacity of the system, and depressed osteoblast activity. Experimental Physiology (2001) 86.3, 373-379. 2135

The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes

“…Recent evidence in a rat model of bone remodelling shows different effects of indomethacin at different time points. 38 These in vitro findings need further study to clarify the relationship between length of exposure to NSAID and the ability of cells to recover from the insult.…”

“…It would appear that in fracture healing an alternative analgesic is preferable where an increase in osteoblast numbers is important. 38 Probably at one to two weeks post- fracture their use is acceptable and could even be desirable at stages where optimisation of ALP activity is important, e.g. during matrix synthesis and mineralisation of callus.…”

Conservative Otosclerosis Treatment With Sodium Fluoride and Other Modern Formulations: A Systematic Review

“…Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs work by blocking the enzyme cyclooxygenase, which is essential for the production of prostaglandins (Pgs) from the arachidonic acid [68,69].…”

Influence of indomethacin on the regenerative process of the tail fin of teleost: morphometric and ultrastructural analysis

“…It is utilised in the treatment of diseases such as osteoarthritis, rheumatic arthritis (Sadowski and Steinmeyer, 2001), gout, cancer and in the prevention of cardiovascular diseases and gynaecologic diseases (Pai et al, 2001) and also used to alleviate the pain after damage or surgery in the tendons and ligaments (Riley et al, 2001). According to some studies (Collier and Ghosh, 1991;Leroux and Saffar, 1993;Guez et al, 2001;Pai et al, 2001;Riley et al, 2001;Forslund et al, 2003;Cohen et al, 2006;Azoubel et al, 2007) indomethacin can interfere in the restoration of the tissue of many organisms, since it inhibits the action of the ciclooxygenase enzyme and consequently the conversion of arachidonic acid into prostaglandin, elements that perform important functions in cell protection, growth, angiogenesis and extracellular matrix production (Savla et al, 2001).…”

“…Guez et al (2001) analysed the action of indomethacin in a model of bone remodelling in rats and showed that the drug affected various stages of this remodelling sequence like bone resorption and formation. Several studies have shown the influence of indomethacin in the synthesis of the extracellular matrix of connective tissue (Arumugham and Bose, 1981;Riley et al, 2001).…”