Sex- and gender-specific medicine deals with the detection and study of the disparity between males and females or men and women in biology and medicine. For years this issue was completely neglected by investigators, but, in the last years, epidemiological evidence first and clinical data later clearly demonstrated that the incidence, the prevalence, the course and sometimes the symptoms themselves of many diseases clearly displayed that sex (biological) or gender (sociocultural such as lifestyles including nutritional habits) should be considered in all aspects of diseases (Table 1). Cardiovascular diseases, immune and autoimmune diseases, and oncological or infectious diseases showed impressive sex/gender disparity if the dataset was analyzed after stratification of the results considering this issue. Hence, recent studies demonstrated that from diagnosis to therapeutic intervention, the relevance of gender-specific medicine could provide useful insights into the development of tailored prevention strategies and the appropriateness of the cures. On the basis of these works and the recommendations to pay more attention to sex and gender issues from institutional agencies (the US National Institutes of Health proposed considering sex as a biological variable in 2016), medical specialties other than those reported above began to investigate if gender medicine could be of interest. Among these also, orthopedics has recently been involved in this matter with the aim of clarifying if bone fracture and healing could be a further field of investigation [1,2,3,4,5,6].

In fact, orthopedics and bone research and clinics have provided some interesting clues in recognizing the determinants of sex disparity in various diseases. For example, it has been observed that sex and gender-related differences may influence the outcome of patients undergoing total hip arthroplasty. Female patients seem to require specific care rules either in the preoperative or intraoperative and postoperative phases [7]. Proximal humerus fractures are more common in the elderly female population, together with other fragility fractures such as proximal femur and hip fractures. However, there is evidence that the mortality rate in patients with proximal humerus fractures is higher in the male population [8,9,10].

A further relevant issue came from the studies on cartilage repair. It was observed that males and females differ in cartilage degeneration and repair. Stem cell therapy could contribute to these differences. In particular, the sex of the stem cell donor as well as that of the recipient, seems to play a role [11]. However, the fields of interest appear to be extremely diverse. For instance, the outcomes following anterior cruciate ligament reconstruction clearly display significant sex disparity [12] and, even in pediatric age, differences between females and males in anatomy, hormone and neuromuscular patterns lead to a higher vulnerability of females to knee injury; in particular, for patellofemoral pain syndrome and anterior cruciate ligament rupture [13]. These are just a few examples of completely different applications of gender medicine in clinical practice that underscore how the complex interplay among biological, physiologic, and social issues should be more deeply investigated in the different fields of orthopedics.

Notwithstanding, the ideal management for complex bone fractures also represents a significant unresolved matter in orthopedics and related specialties from a mechanistic point of view. Fracture healing is a multistage process that includes several complex steps starting after tissue injury. In particular, bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Even though understanding of the biological processes and molecular signals that coordinate fracture repair has advanced, the causes of variability observed in fracture repair are poorly understood. From a general point of view, body weight might play a crucial role in bone regeneration processes, influencing the healing process since local tissue tensions are important for callus tissue development. Elevated strains at the fracture area induce mesenchymal cells to form fibrous tissue, whereas low-stress conditions lead to the generation of osseous tissue. At intermediate stresses, mesenchymal cells differentiate into chondrocytes and induce the development of cartilaginous callus [14,15,16].

Epidemiological studies report a very high number of patients with hip fractures worldwide (more than 1.6 million) with significant differences between men and women, e.g., concerning spinal fractures (29.3/1000 for women and 13.6/1000 for men) [17,18]. In fact, the main sites of fracture are the hip and the spine, with the former being very common due to fragility that can be present in elderly people with osteoporosis, which can be one of the main causes of disability. In particular, it was noted that 22% of women and 33% of men die in the first year after hip fracture [19], so this represents a critical issue either for patients or, in view of hospitalization needs, also for the public health services. Furthermore, the quality of life of these patients can be strongly impaired since they could suffer from spinal deformities [20], reduction of pulmonary function [21] changes and impairment of their daily activity, and, more generally, pain [22,23]. Fracture healing is a complex and long-term process, and osteogenesis and healing time can be influenced by several different factors (such as blood supply and/or inflammatory state). Failures in fracture healing are also detected in 5–10% of patients [22,24].

Skeletal tissue displays sex differences in morphology and physiological function, which can have an impact on bone healing [25]. For example, men tend to have stronger and larger bones compared to women, which can make them more resilient to injury and less prone to fractures. Moreover, in females, the risk of developing osteoporosis sharply increases after menopause, while the occurrence of osteoporosis in men progressively rises with age [26], and this represents a fundamental issue. Hence, from a clinical point of view, these sex differences lead to an epidemiological gap not only in the occurrence and fracture risk but also in the patient management and clinical outcome [27].

Regarding bone fracture healing, some clinical studies reported that males show more rapid fracture healing. In contrast, women may have an increased risk for atrophic non-unions rather than hypertrophic non-unions, as observed in males [28,29]. By contrast, in other clinical studies, no influence of sex on fracture healing in specific fracture types has been observed [14,30,31].

In the elderly, men show higher post-operative complications and mortality after hip fractures, whereas women have a higher risk for developing non-unions after femoral neck fractures. To note, up to a third of patients with hip fractures can be totally disabled because of non-union [32]. In a prospective study of more than one thousand patients with intracapsular fractures of the femoral neck, a significantly higher incidence of non-union has been found in females in comparison to males [33].