Our results show that the evolution of pain and quality of life after a symptomatic VF differs according to sex, with a worse evolution in women compared to males.

Thus, the evolution of pain, evaluated by the VAS, and the Qualeffo-41 score clearly varied between genders, particularly two months after initiating treatment for the symptomatic VFs, showing a more marked relief in pain and improvement in the quality of life in males compared to females for up to 6 months of follow-up.

Several studies have shown gender differences in the development of chronic pain, with women being more frequently affected, particularly in relation to musculoskeletal disorders [19,20,21]. This finding has been related not only to the presence of more prevalent chronic pain conditions in women but also to higher acute pain sensitivity in this gender [19,20,21]. In fact, when comparing disease-associated pain scores in men and women with the same diagnosis, women had higher average pain scores than men for several disorders, including osteomuscular diseases and back pain [22].

Vertebral fractures are one of the most common manifestations of osteoporosis. This type of fracture may be associated with the development of chronic back pain and impaired quality of life [1,2,3]. Although the factors related to these complications are not fully clarified, some studies report that the severity of bone disease, particularly the number and the severity of the vertebral deformities, are factors that can be related to the development of chronic pain in these subjects [1, 2, 7,8,9,10]. In a previous RCT performed by our group in the same cohort of patients aimed at comparing the effects of VP versus the conservative approach on the quality of life and pain relief, no significant differences were observed after two months of treatment [11]. In addition, independently of the treatment received, nearly one quarter of patients developed chronic back pain [4]. When we analysed the factors related to the development/maintenance of back pain, subjects with a longer time since symptom onset, particularly greater than four months, having higher VAS values at baseline, having multiple acute VF and female gender were related to the development of chronic back pain [4], with similar findings also reported by Firanescu et al. in a recent randomized study that also addressed the treatment of recent symptomatic VFs [6]. To our knowledge, there are no data comparing the evolution of pain and quality of life in symptomatic VFs according to gender. Therefore, whether or not the clinical evolution of symptomatic VF differs according to gender due to differences in the severity of the disease and/or the therapeutic approach remains to be fully investigated.

In the present study, the differences observed between genders did not seem to be related to differences in disease severity, since besides having a similar age, the men and women studied presented a similar number of VFs at baseline with the same mean number of recent VFs, when evaluated by MR imaging, and similar lumbar and femoral T-scores. In addition, the therapeutic approach in the randomization procedure (i.e., conservative treatment vs. VP) was also similar in both genders, as was the time since symptom onset and the proportion of subjects with less than 4 months from symptom onset. Moreover, the baseline scores for pain (VAS) and Qualeffo-41 were similar in both genders, with all of the above indicating a similar grade of disease severity and disability when comparing the two genders.

It should be noted that the evolution of pain and the Qualeffo-41 score differed after two months of initiating treatment for the symptomatic VFs. Thus, whereas pain relief and quality of life improved by a similar magnitude in both genders at two weeks, after two months males showed a greater improvement in pain and, consequently, in quality of life. These findings could have been related to a differential therapeutic approach or a higher incidence of new VFs in the two genders. However, no differences were observed in the incidence of new VFs, observing a similar proportion in both genders at 6 months. Again, there were no differences in the use of analgesics, including major opiate derivatives; however, despite women having a worse evolution of pain, they tend to have a lower consumption of analgesics, possibly related to the more frequent adverse effects to opiates derivatives described in women [23]. Conversely, a lower percentage of males was receiving antiosteoporotic treatment at 6 months. Nevertheless, whether this finding was due to a lower compliance or persistence of the antiosteoporotic treatment in males was not analysed in the present study. This is a recurrent finding that has been reported in several epidemiological studies, describing not only a less frequent prescription of antiosteoporotic treatment in males after a fragility fracture but also a lower compliance and persistence with antiosteoporotic treatment [24,25,26,27].

All of this suggests the influence of gender in the susceptibility to develop chronic pain in the individuals included in our study. Indeed, recent studies have revealed significant sex differences in the physiological mechanisms underlying pain, including distinct interactions between hormones and the immune system that influence the transmission of signals of pain and sex-specific involvement of genes and proteins [19, 21]. In this sense, genetic variations in the opioid receptor mu 1 have been associated with differences in the evolution of low back pain according to gender, particularly in terms of pain sensitivity and recovery [28]. On the other hand, it has been proposed that gender differences in pain are influenced by the way that male and female brains process emotional and arousal/attentional aspects of pain [28]. There are also gender differences in the structure and function of the brain throughout life, with additional psychosocial factors contributing to these differences. However, it is not known whether gender differences in pain-related brain regions could contribute to differences in the prevalence and severity of chronic pain [19,20,21]. Whatever the mechanisms, it seems clear that gender influences the efficacy of the therapeutic approach in symptomatic VFs, with a worse evolution in women, thereby indicating the need to take gender into account when evaluating the clinical response of these subjects.

Some of the limitations of this study were the low number of patients included in the analysis, particularly of males, and the fact that the study was not addressed to evaluate the effect of gender on the evolution of pain and the quality of life, and particularly on a more individualized evaluation of the cause of vertebral pain (apart from that attributed to the VF/s). Nonetheless, one of the strengths of this study is the precise evaluation of these patients, all included in a RCT with extensive analysis of clinical and radiological factors related to the evolution of pain, quality of life and incidence of new VFs, as well as being the only RCT to date analysing and comparing the clinical evolution of pain and quality of life according to gender.

In conclusion, the evolution of pain and quality of life after a symptomatic VF differs according to patient gender, with a worse evolution in women independently of the type of treatment received. Thus, gender should be taken into account when evaluating the most adequate therapeutic approach in patients with symptomatic VF, as well as effect of gender on the compliance and persistence of treatment. Further research is needed to confirm these results and future studies should be addressed to determine the best therapeutic approach according to gender in these subjects.