RE: Aliuskevicius M, Ostgaard SE, Hauge EM, et al. 2019. Influence of ibuprofen on bone healing after Colles’ fracture: A randomized controlled clinical trial (2020)

We read with interest the study by Aliuskevicius et al,1 which examined the effect of short-term ibuprofen use on fracture healing in terms of bone mineral density (BMD) in the distal radius, histomorphometric estimations of the callus, and the response of bone biomarkers after Colles’ fracture. Findings were based on 95 patients who were treated with external fixation and receiving ibuprofen as a postoperative analgesic. The patient population study included 80 (84.21%) females, thus lacking an adequate male study group, even though bone measurements are known to differ between men and women. Nabipour et al,2 for example, studied serum osteocalcin and serum CrossLaps in an apparently healthy Iranian population and found that men had significantly higher markers of bone turnover compared with age-matched females. With respect to the composition of study groups in investigations of bone turnover, it is, therefore, important to separately assess male and female results before suggesting that ibuprofen is “bone-safe” for both men and women. As already implied by the authors, the wide age range of female subjects (40-85 years) is an additional potentially confounding factor. While this may be representative of the population sustaining fractures of the distal radius, studying the parameters of bone turnover in a population so heterogeneous, merging premenopausal, perimenopausal, and postmenopausal women, is likely again to risk missing important differences in drug effect in these subsets of patients3. Within the above-mentioned paper of Nabipour et al2 a striking difference in markers of bone turnover was identified in women based on age: there were progressive increases in serum CrossLaps after 30 years of age, peaking at >60 years, while for osteocalcin there was a statistically significant decrease from 20-29 to 30-49 years, followed by a progressive increase at 50 to 59 years, with the peak at >60 years. This seems to be reflected in the manuscript by Aliuskevicius et al,1 with marked heterogeneity in the data, as displayed by the high standard deviations for serum CrossLaps and osteocalcin, as shown in Figure 5. In addition, the presence or absence of osteoporosis also significantly affects basal CrossLaps, as previously described by Martinez et al.4 Ultimately it is very likely that age, sex, and initial bone density all affect not only bone homeostasis but also the magnitude of the bone's response to fracture. Furthermore, the authors provide no data on the ethnic background of their study population. Ethnic disparities are reported to impact the recovery following distal radius fracture with respect to physical function and pain,5 as well as on BMD, for example, resulting in increased bone strength among individuals with African heritage with respect to cortical area, trabecular thickness, and total BMD.6 These differences attributed to ethnic differences might alter turnover biomarkers or histomorphometric characteristics as well as the biomarker response during the course of fracture healing. Even though the presented Danish study population might display a homogenous ethnic background it is of utmost importance to reflect on this when describing the study population, and when offering treatment recommendations for other populations. Finally, current literature suggests that the patients’ body mass index (BMI) impacts ibuprofens metabolism, subsequent elimination, and bioavailability by disturbing renal excretion. As this might ultimately cause changes in bioavailability, pharmacodynamics and clearance of ibuprofen BMI should be assessed and an equal distribution between study groups should be assured. Accordingly, excess weight might ultimately alter serum levels of osteocalcin and CrossLaps, ultimately affecting BMD as proposed by Brill et al.7 In summary, in this study Aliuskevicius et al1 studied the impact of ibuprofen on a rather heterogeneous group of female patients of unknown ethnic background, and important differences in the effect of ibuprofen on bone metabolism may have been missed by not controlling for age, sex, ethnicity, and BMI. To further strengthen the implications of the study the impact of these factors should be taken into account while planning a study like this as well when analyzing the data. Ultimately, further studies in larger cohorts, which have the power to assess the impacts of these additional factors are needed. In their absence, studies with small sample sizes and incomplete characterization of data by these clinically relevant subgroups may impair the ability even of systematic reviews and meta-analyses to further elucidate the impact of sex, age, ethnic background, and other differences on clinical outcomes. JS wrote the letter. JB-B and PCA edited and approved the final version.