This is the first systematic review that investigated lifestyle risk factors and showed that female gender, low bone mineral density, smoking, and T2D can predispose to a new fracture after vertebroplasty. This knowledge can be invaluable because we can examine these risk factors, manage them accordingly if possible, and eliminate the fracture risk after surgery.

Female sex was found to be a risk factor for subsequent fractures after vertebroplasty. Postmenopausal women face a higher risk of experiencing a fragility fracture as a clinical consequence of osteoporosis because of bone loss caused by estrogen reduction compared to males of the same age. Women with postmenopausal osteoporosis have a higher risk of three to fourfold to suffer an osteoporotic vertebral fracture compared to men of the same age [18]. This risk pre-exists and remains after surgery. Obviously, it has to do with female physiology, not the operation itself. The physiology of female participants is apparently a personal risk factor, to be taken into consideration in subjects receiving VP, for the provision of additional pharmacological prescription in combination with other possible bone-retaining strategies, like particular types of exercise or physical activity [6, 19]. Female gender is a factor that should be considered since most patients who undergo this procedure are women. Although it is important to know the risk we cannot modify this factor to reduce it.

Our study identified low bone mineral density as an essential risk factor for secondary fractures after vertebroplasty. Meta-analysis of Zhu et al. [20] showed relevant results to our study. Interestingly, a positive relationship has been identified between low t-scores and refractures after vertebroplasty regardless of the location of the new fracture (adjacent, remote, or cemented vertebrae [12, 21, 22]. Consistent results were found by Zhai et al. [14], who found that low bone mass was a high-risk factor for postoperative secondary fractures. However, in the literature, secondary fractures have been attributed to the natural course of the disease rather than the operation. Vertebrae with lower t-scores are more likely to fracture. Decreasing the disease's progression seems essential and can be achieved with anti-osteoporotic medication [23]. Bouxsein et al. [24] concluded that improvements in BMD with osteoporosis therapies can decrease the fracture risk. In two studies included in the current meta-analysis, anti-osteoporosis treatment after the operation was proved to be a protective factor for secondary fractures, although we did not select this factor for meta-analysis because studies that included it were excluded based on set criteria. [25, 26]. Apart from medication, more physical modalities like exercise seem to be able to increase BMD scores. According to a Cochrane review, a multicomponent training exercise program was the most effective for BMD in menopausal women with osteoporosis [27]. It remains to be explored if exercise can increase BMD postoperatively in these patients.

In the current study, two lifestyle factors (smoking and T2D) were included as possible risk factors for future fractures post VP surgery. It was confirmed that both these factors were significant (OR = 1.62, 95% CI 1.22; 2.15, z = 3.32; P = 0.001; OR = 1.40, 95% CI 1.11; 1.76, z = 2.83, P = 0.005 respectively).

Tobacco smoking has more than 7.000 chemicals, which have been proven to have a harmful effect on the skeletal system [28]). According to a systematic review [29], smoking can reduce BMD and increase fracture risk.

There is high-quality evidence that tobacco affects the mechanisms of bone turn, rendering the bones more fragile, and eventually, the possibility of fracture [30]. It has been proved that bony mass deterioration driven by tobacco results from multiple mechanisms that affect bone angiogenesis, osteogenesis, bone metabolism, and body hormones and increase oxidative stress on bony tissues [29]. Secondhand smokers, especially females, seem to have similar harm to their skeletal system [31]. On the other hand, stopping smoking has been proven to reverse this process and improve the bone health of patients. We found that patients who smoked were at higher risk of having future fractures after vertebroplasty compared to nonsmokers. Patients who smoked had fractures of the same, adjacent, or other vertebrae postoperatively. If we combine our knowledge about tobacco effects and smoking as a confirmed risk factor [26, 32] then smokers who are going to undergo vertebroplasty should be informed about the risk of refracture, the positive effects of smoking cessation and be strongly advised to stop smoking at least postoperatively. Nonsmokers have the lowest possibility of fracture compared to people who quit smoking and those who continue to smoke. Even people who stopped smoking managed to lower the fracture risk compared to current smokers with smoking exposure > 20 pack years [32] nevertheless how many years the formers were exposed to smoking. Since smoking alone can impair bone metabolism and increase the risk of fractures, its effect on the bone health of individuals with osteoporosis is even more harmful. Patients with osteoporosis should be suggested to avoid this habit or cut it off in order to lower the danger of fracture. PVP may be a minimal, safe, and reliable surgery, but it still includes some anesthesia, immobilization, and recovery time that puts an extra burden on people who smoke. If we add the fact that osteoporotic patients already have bone structure deterioration, then smoking cessation is a precautionary strategy before PVP [32, 33].

Diabetes as a risk factor was included in 3 chosen studies for meta-analysis. However, none of these studies specifies the type of diabetes examined and we accept this as limitation. On the other hand, multiple reasons make us believe that they are referred to type 2 diabetes(2 TD). We specify that they all referred to type 2 diabetes for the following reasons: First, 2 TD is the most common in people over 45 years old and all study groups were above 66 years old. Second, they talk about rising incidence the last decades as an outcome of way of life and this is characteristic of 2 TD which is more related to obesity, unhealthy diet, sedentary life and financial problems [34]. The global prevalence of type 2 diabetes is expected to reach 7,079 cases per 100,000 individuals by 2030, indicating a sustained increase across all regions worldwide [34]. T2D is caused by impaired insulin secretion by pancreatic β-cells and reduced responsiveness of insulin-sensitive tissues to insulin [35]."Factors such as hyperglycemia, insulin resistance, advanced glycation end products (AGEs), and proinflammatory cytokines all contribute to disruptions in normal bone turnover by interfering with the functions of osteoblasts and osteoclasts"[35, 36]. Microstructure deterioration makes bones fragile susceptible to fractures [37,38,39,40,41]. Apart from complex pathophysiology, T2D can be managed if we access its modifiable risk factors. These are diet, exercise levels, sleep, stress and medication. All these can lead to glycaemic control and reduce fracture risk. [42,43,44,45]. T2D causes secondary osteoporosis and patients may have a fracture because of diabetes. The addition of a surgical process like PVP does not decrease the existing fracture risk. People with 2 TD and osteoporosis seem to face a higher fracture risk than subjects who have only diabetes or osteoporosis. Since we found that diabetes is a risk factor for a future fracture patients should be guided and properly supported to modify their lifestyle accordingly in order to achieve the optimum glucose level before and after surgey. Proper exercise, a healthy diet rich in fibers, novel drug therapies and probiotics can contribute to good bone health through different pathways [42,43,44,45,46].

Osteoporotic vertebral compression fractures can be detrimental to patients'quality of life and survival. Secondary fractures, whose incidence we found 16,6%, may require repeated PVP or revision surgery with all the possible complications [44]. Although it seems a vital issue that needs scientific attention, there is a scarcity of high-quality studies examining possible risk factors for secondary fractures to prevent them. Most relevant systematic reviews have examined only cemented vertebrae fractures and focused mainly on surgical risk factors [11, 13, 20]. Almost all reviews included risk factors related to patient characteristics. The current study did not show that cement leakage is a risk factor for refracture compared to other reviews [12, 14]. Also, a risk factor we did not examine because the included studies did not meet study criteria was intervertebral cleft, which appears to be a significant risk factor in other reviews [11, 13, 20]. The main difference in this study was that we tried to include risk factors that had to do with patient lifestyle, which has not been done in previous studies.

A raised concern when reflecting on the current study findings is whether the identified risk factors (gender, BMD, smoking, and T2D) for new fractures after PVP put patients at risk irrespective of surgery. Reviewing the literature for these factors separately, we see that all of them, through different mechanisms, make patients susceptible to osteoporotic fractures irrespective of PVP. The question is whether combining these factors and PVP increases this risk. Unfortunately, we are not in a position to answer this question till we review studies that have one group that does not undergo vertebroplasty. Then, we could compare the fracture incidence of this group to that of the one that underwent PVP. This could be a future suggestion that could “clear” the operation role in all this. Until then, the information we have based on our findings is that these factors increase the possibility of patients having a fracture post-operatively, so they need to be addressed.

However, our study has several limitations. Although we did not set it as a restriction, the population was mainly from Asia. Thus, results may not apply to the global population. The final number of studies was small (9), and the strength of this reduced outcome, but this resulted from our effort to include only studies with PVP and not PKP and studies with homogenous fractures. Also, the level of evidence for included studies was not relatively high since all of them were retrospective studies except for one RCT. Another limitation was that the median follow-up was 21 months, which was relatively short for reaching solid conclusions about the fracture incidence and factors that contribute to it. In smoking, diabetes, and kyphosis analysis, we included studies that included cemented or adjacent vertebrae fractures. Ideally, there must be a distinct concomitant analysis for different kinds of fractures for all the risk factors in future studies.