Haemophilia and Fragility Fractures: From Pathogenesis to Multidisciplinary Approach

Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.


Introduction
Haemophilia A (HA) and haemophilia B (HB) are rare, inherited, recessive, X-linked bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively [1]. A third rare form is haemophilia C, which is associated with a deficiency of clotting factor XI [2].
HA is the most common form (85%) with a prevalence of about 1:5000 in male live births [3]. Conversely, HB occurs in approximately 15% of people with haemophilia (PWH), with an estimated prevalence at birth of 1:30,000 in males [3]. Advances in the development of effective and safe treatments over the last 50 years and their regular and widespread availability have led to a significant increase in the patients' life expectancy [4]. The management of this new cohort of middle-aged and older patients is challenging due to the thy [27]. Repeated episodes of haemorrhage during growth lead to restriction of movement, limitation of weight-bearing exercise and fear of pain and re-bleeding, resulting in a reduction in achievable peak bone mass (PBM) [28]. As a result, reduced bone mineral density (BMD) and impaired bone microarchitecture lead to an increased risk of fragility fractures in PWH [29]. However, the pathogenesis of osteoporosis in PWH is not yet fully elucidated and includes thrombin deficiency [30], altered osteoblast and osteoclast activity [31] and reduced mobility or prolonged immobilization [12]. Three distinct HA and HB phenotypes can be distinguished based on the reduction in serum FVIII or FIX levels: severe (<1 IU/dL), moderate (1-5 IU/dL) and mild (5-40 IU/dL) [19]. Nowadays, the replacement therapy has led to PWH having life expectancy like that of age-matched patients with comorbidities [20].
PWH, particularly those with the untreated severe forms, frequently exhibit recurrent bleeding in various organs [5] and, in particular, the musculoskeletal system [21].
Bleeding occurs in the major synovial joints, such as the ankles, knees and elbows, and its repetitive nature is widely recognized as key to the development of haemophilic arthropathy [22]. Several authors recognize inflammatory synovial changes as the main cause of bleeding because of the high vascularization and friability of the blood vessels, which reduces the ability to drain blood away from the joint [23,24]. This leads to hyperplasia of the synovial membrane with deposition of haemosiderin that perpetuates the cycle, resulting in the production of inflammatory mediators that cause cartilage and focal bone damage and joint remodelling [25,26]. In addition, several studies have shown that subclinical and untreated joint bleeding may be a factor in the worsening of arthropathy [27]. Repeated episodes of haemorrhage during growth lead to restriction of movement, limitation of weight-bearing exercise and fear of pain and re-bleeding, resulting in a reduction in achievable peak bone mass (PBM) [28]. As a result, reduced bone mineral density (BMD) and impaired bone microarchitecture lead to an increased risk of fragility fractures in PWH [29]. However, the pathogenesis of osteoporosis in PWH is not yet fully elucidated and includes thrombin deficiency [30], altered osteoblast and osteoclast activity [31] and reduced mobility or prolonged immobilization [12].
Treatment of osteoporosis in PWH includes calcium and vitamin D supplementation. Treatment of osteoporosis in PWH includes calcium and vitamin D supplementation. Several options have been proposed: both antiresorptive and osteoanabolic drugs may be considered, such as bisphosphonates and denosumab, selective estrogen receptor modulators (SERMs) and teriparatide, although the use of these agents should be avoided in young PWH [32].
Overall, osteoporosis is recognized as a serious problem for PWH, since a four-fold increased fracture risk has been reported in comparison with the healthy population [33,34].
Advances in the management of PWH have led to significant improvements in clinical outcomes and quality of life, but these patients continue to suffer from bone fragility and high fracture-related mortality [35]. Because of the peculiar pathophysiology of bone fragility in PWH, which could be associated with both reduced bone formation and increased bone resorption, patients may benefit from both anabolic agents (teriparatide or neutralising antibodies against Dkk-1 or sclerostin such as romosozumab) [36,37] and antiresorptive agents, such as bisphosphonates or denosumab (human monoclonal antibody to RANKL) [38]. Curiously, serum sclerostin levels were significantly elevated in studies of children with severe HA [18]; therefore, romosozumab, a specific anti-sclerostin antibody that inhibits sclerostin-LRP5/6 interaction and that indirectly activates canonical Wnt signalling pathways and bone formation, may be effective in the pharmacological treatment of osteoporosis in PWH. However, further clinical trials are needed to evaluate the efficacy and safety in this specific cohort [39]. Recent studies have even shown a statistically significant difference in 25(OH)D 3 and DEXA Z-scores between patients receiving twice-weekly FVIII prophylaxis (15 U/kg/dose) and those receiving on-demand therapy, suggesting a possible bone benefit of prophylaxis in PWH [40]. Therefore, by preventing bone and muscle damage and possibly reducing fracture rates, vitamin D supplementation may counteract the vicious circle that leads to reduced mobility in PWH [41]. With regard to the research studies investigating anti-osteoporotic agents in PWH, only one work is currently available on the efficacy of ibandronate, but data on fracture risk reduction are lacking. Administration of this amino-bisphosphonate for 12 months to 10 PWH resulted in an increase in lumbar spine BMD of 4.7%, but no significant change in hip or femoral neck BMD [42]. The limited data on the use of denosumab in PWH by Lin et al. documented an improved fracture healing in a man whose BMD increased significantly after 4 months of teriparatide followed by 1 year of denosumab treatment [12]. Therefore, regarding teriparatide, an anabolic agent, the effects on bone health of PWH are poorly understood to date [39].
Alongside causes closely related to clotting alterations, several mechanisms have been proposed to contribute to the development of fragility fractures in PWH, including nutritional deficiencies [43], impaired joint ROM [44], reduced muscle strength [42], balance deficits [45], HIV or HCV infection [31], and impaired biomechanics [46].
These risk factors predisposing to reduced bone mineral density are not exclusive to haemophilia but are a specific determinant of reduced bone mineralisation in many comorbidities associated with osteopenia/osteoporosis [47]. Therefore, appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications [48][49][50]. Rehabilitation is a key component in restoring function and maintaining mobility, while avoiding bleeding episodes or muscle trauma during rehabilitation exercises that delay patient recovery [51].
The aim of this narrative review is to summarize the pathogenesis of osteoporosis, analyse the causes and incidence of fragility fractures, and explore the need for a multidisciplinary approach in PWH.

Search Strategy
A comprehensive literature search was conducted to identify published studies on the management of fragility fractures in PWH. Three researchers independently conducted the review using the same keywords. Finally, papers were selected by consensus. The databases PubMed, Scopus and Cochrane Library were searched. The following string was used (haemophilia OR haemophilia) AND (fracture OR fragility fracture). Identified articles were screened using the following inclusion criteria: (i) study design: randomised controlled trials (RCTs), reviews, mini reviews, original articles, (ii) written in English, (iii) published in the last 20 years (2003-2023) in indexed journals, and (iv) dealing with fracture management in PWH. Exclusion criteria were drug use, animal studies, radiological studies, and other article types such as letters to the editor, case reports, editorials, and conference abstracts. Ethical approval was not required due to the study setting. Articles were screened first by title and abstract and then by full text analysis. The following data were collected: (1) study design; (2) patient characteristics; (3) fracture incidence; and (4) association between haemophilia and fractures.
A flowchart of the process is shown in Figure 2. The initial search yielded 383 articles (PubMed, 128; Scopus, 255, Cochrane Library: 0). Duplicate articles were excluded. After evaluation of the inclusion and exclusion criteria, nine studies were included in this review.
setting. Articles were screened first by title and abstract and then by full te following data were collected: (1) study design; (2) patient characteristics; cidence; and (4) association between haemophilia and fractures.
A flowchart of the process is shown in Figure 2. The initial search yiel (PubMed, 128; Scopus, 255, Cochrane Library: 0). Duplicate articles were evaluation of the inclusion and exclusion criteria, nine studies were inclu view.

Evidence of Fractures in Haemophilia
The authors analysed articles analysing the genesis and risk of fractur sidering age and gender. The articles included in this review are listed in the analysed studies showed that PWH are associated with a reduction i increased risk of fracture. No data about biochemical profile, gonadal sta tropic status at baseline were provided in the papers considered. Data ab cidence was only driven historically and not by the performance of imagi rospective analysis, Gay et al. analysed 382 male patients with HA and HB them with a large cohort of the general healthy population matched for a

Evidence of Fractures in Haemophilia
The authors analysed articles analysing the genesis and risk of fracture in PWH, considering age and gender. The articles included in this review are listed in Table 1. All of the analysed studies showed that PWH are associated with a reduction in BMD and an increased risk of fracture. No data about biochemical profile, gonadal status and calciotropic status at baseline were provided in the papers considered. Data about fracture incidence was only driven historically and not by the performance of imaging. In their retrospective analysis, Gay et al. analysed 382 male patients with HA and HB and compared them with a large cohort of the general healthy population matched for age and gender. They found that the risk of fracture increased with disease severity and age (with the risk doubling after the age of 31), with an increase of about 1.3% per year of age [52].
Anagnostis and colleagues highlighted in their review that bone loss in PWH begins in childhood, suggesting the need for a multidisciplinary approach to prevent further bone loss with regular assessment of fracture risk [28].
In their cohort study of 75 patients, Tuan et al. noted the late diagnosis of osteoporosis in PWH, more often reached at the time of the first fragility fracture. They also found that the incidence of osteoporotic fractures in haemophilia patients was significantly higher than in the general population. The authors also suggested a long follow-up period, given the chronic nature of the disease [32].
In their paper, Lee et al. studied 11 HA patients with intracapsular femoral fractures and showed that these fractures occurred almost 20 years earlier in PWH in comparison with healthy individuals. They also suggested a standard post-operative management (i.e., early mobilization and verticalization if possible) with the need for adequate haemostasis [53].
Pai et al. performed a 14-year cohort study showing a higher risk of fragility fracture with a no effect in all sites of fracture and repeated fractures [35].
Angelini and colleagues emphasized the importance of managing chronic pain and preventing falls and fractures in older PWH considering the typical comorbidities of ageing [54,55].
Finally, in 2015, a study by Caviglia et al. reported that osteoporotic fractures due to low-energy or overuse trauma in PWH are more common in younger people of the same age. In addition, with the advent of replacement therapy, there has been a reversal in the trend of lower and upper limb fractures, with a reduction in the average age [56].   Case report (comprehensive report on the management of a cohort of patients with fracture of neck of femur in haemophilia)

11
Age: mean age was 30 years (range: 16-55) Sex: NA In PWH, most of the femoral neck fractures (9 out of 11) are seen almost two decades earlier than in general population (where they occur in patients over 50 years of age) In PWH, femoral neck fractures can be treated as in the general population, with modest dose of factor replacement. Postoperatively, prolonged use of plaster immobilization should be avoided and early mobilization of the ipsilateral knee joint should be initiated.
Although physical activity is often reduced in PWH, poor musculature, osteoporosis and haemophilic bone changes may predispose to an increased risk of fractures.
NA= Not Available.

Discussion
Modern replacement therapies have increased the average life expectancy of PWH, as well as the incidence of chronic diseases (e.g., diabetes, stroke, cardiovascular disease, renal failure, osteoarthritis) and the risk of falls and fractures [35,54]. Osteoporosis in PWH is also highly prevalent and multifactorial, but it is not always recognised as secondary osteoporosis [46]. Data in the literature agree that factor replacement therapy in PWH may directly impact bone health and fracture risk, supporting the already known role of FVIII and FIX in bone metabolism [52,58].
Several studies have shown that physical activity limitation during growth to prevent trauma, nutritional deficiencies and recurrent bleedings can lead to a reduction in BMD [12,58,59]. Most of the existing evidence has shown an association between low BMD and fractures only in children with haemophilia [60], not in adults [28].
As described by Anagnostis et al., PWH show low BMD from an early age and appear to be at increased risk of minor trauma fractures and falls [28]. Reduced trabecular bone mineralization from early childhood, even in the absence of cortical damage, contributes to increased fragility [28]. To support the data on low BMD in PWH, Lee and colleagues performed a high-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of 18 adult patients and found microarchitectural changes in cortical and trabecular bone compared with the general population [62]. Interestingly, Zang and colleagues reported a case of intra-articular femoral microfracture in which they observed increased osteoclast activity with reduced ability to repair damage due to the inflammatory environment [26]. These findings support a multifactorial genesis of bone fragility [5].
There is a direct correlation between the severity of haemophilia and changes in bone turnover homeostasis [59], with patients with severe haemophilia having a greater risk of fractures [52]. In addition, the development of target joints (at least three haemorrhages in 6 months) and the concomitant presence of muscle haemorrhages lead to reduced mobility and an increased risk of falls [58,63].
Furthermore, this arthropathy is not just about one joint-it has a widespread effect on bone metabolism and has a relationship with BMD [64]. So, it is often not just a question of avoiding high-risk activities, but also conditions such as fatigue, muscle weakness and contractures that restrict movement that contribute to the early development of osteoporosis [53].
Many authors have focused on the need for early assessment of BMD to allow primary prevention, as osteoporosis is often diagnosed after fracture occurrence [32,35,65]. The literature suggests that PWH have a higher risk of fracture than their peers, particularly those under 65 years or age, and that this may be explained by a combination of factors such as reduced previous physical activity, comorbidities, early bone loss and nutritional deficiencies [32,52,58].
Despite the interest in fragility fractures in PWH, there is no clear evidence of an increased fracture risk [58], with a surprising lack of increase in refracture risk likely explained by a reduction in physical activity [35].
Therefore, PWH should be monitored throughout the life course, as the incidence of fragility fractures in PWH appears to be higher 5 years after diagnosis, with a higher annual increase today [32]. It is interesting to note that the improvement in prophylactic treatment has changed the attitude of both patients and carers, allowing PWH to participate in outdoor activities and contact sports at a young age, with physical and psychological benefits [56]. This trend reversal led to an increase in the number of fractures in young PWH, particularly in the upper limbs [56]. These findings provide further evidence of the impact that replacement therapy has had over the last 50 years and the change in the quality of life of PWH [66].
Fracture management in PWH is the same as in the general population, with the aim of healing and restoring function, with surgery being the preferred option if conservative management is not possible [52,53,67,68]. Today, PWH with severe arthropathy or fractures requiring surgery (e.g., hip replacement) can be rehabilitated with less anxiety and improved outcomes, even with pre-operative physiotherapy programs [69]. The concept of rehabilitation for PWH has evolved over the last 30 years from a role in the bleeding phase only, to one of limiting disability, to one of prevention [70]. Management of bone disease in PWH should begin in childhood to achieve the best possible PBM, encouraging low-impact resistance training throughout life, regular assessment of BMD and fracture risk, and avoidance of smoking, alcohol consumption and obesity [28]. It is, therefore, important to remember that PWH are at increased risk of falling due to the combined effects of arthropathy, reduced muscle strength and balance problems [33], so, an exercise program focusing on strength, balance and motor coordination should be encouraged at all ages [71].
There are several limitations to this review, such as the unspecified fracture site and its effect on quality of life, few studies specifying the type of rehabilitation patients underwent, and the lack of randomised clinical trials. Assessment of fractures not by imaging techniques but by extrapolating them from medical record data and the absence of baseline evaluation of gonadal and calciotropic status further weaken this work. However, our research originally provides a deep explanation of mechanisms underlying fracture risk in PWH and gives an extensive view of the multidisciplinary fracture management in this setting of patients, leading to an improvement in quality of life and prevention of long-term complications.

Conclusions
In summary, this paper confirms the significant association between fracture risk and PWH, although it is difficult to correlate this with age. The results of this study suggest an association between age at fracture and haemophilia, and that haemophilia tends to occur at a younger age, with an average age of 25-30 years. In addition, the increased fracture risk in PWH appears to be due to a combination of factors that contribute to an increase in falls, such as comorbidities, balance, and motor impairments. On the other hand, younger PWH seem to be more prone to fractures because of the greater promotion of normal lifestyles that encourage exercise and physical activity. However, a fundamental role is certainly played by the ability of the bone to resist despite the weakening of its trabecular component and its poor acquisition of BMD.

Future Directions
Young PWH have an increased susceptibility to fracture, probably due to a combination of factors such as repeated joint bleeding, reduced physical activity, and FVIII and FIX deficiency. However, the available literature does not give us confidence that these are the only reasons contributing to the pathogenesis of osteoporosis in PWH. Future studies could focus more on the quality of life and disability associated with different types of fractures.