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/lp/springer-journals/pathogenesis-and-treatment-of-osteoporosis-in-patients-with-hemophilia-HHKLTi07ZX
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- Springer Journals
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- Copyright © The Author(s) 2022
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- 1862-3522
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- 1862-3514
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- 10.1007/s11657-022-01203-9
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Abstract
Introduction Hemophilia is a rare X-linked recessive inherited bleeding disorder caused by mutations of the genes encod- ing coagulation factor VIII (FVIII) or IX (FIX). Patients with hemophilia (PWH) often have a high risk of osteoporosis and fractures that is usually ignored. Herein, we review the underlying mechanisms of osteoporosis and the increased risk of fractures and their treatment in patients with FVIII or FIX deficiency. Methods The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on the mechanisms or treatment of osteoporosis in PWH. Results The pathogenic mechanisms of osteoporosis in PWH are multifactorial and remain unclear. The available evidence shows that FVIII and FIX deficiency may directly affect bone metabolism by interfering with the RANK/RANKL/OPG pathway. Other potential mechanisms of osteoporosis in PWH include thrombin deficiency and the unloading and immo- bilization of bone, which will affect osteoblast and osteoclast activity by changing the cytokine profiles. The treatment of osteoporosis in PWH includes antiresorptive, anabolic, and dual-action drugs; weight-bearing exercise; fall prevention; and prophylactic coagulation factor replacement therapy. However, clinical studies of the efficacy of anti-osteoporotic agents in osteoporosis of PWH are urgently needed. Conclusion This review summarizes recent progress in research on the pathogenesis of osteoporosis in PWH and provides insights into potential treatment for osteoporosis in PWH. Keywords Hemophilia · Osteoporosis · Factor VIII · Thrombin Introduction PWH [3], with a prevalence of approximately 1:30,000 in male neonates [4]. Patients with hemophilia A and B have Hemophilia is a rare X-linked recessive inherited bleed- similar clinical phenotypes, including spontaneous hemor- ing disorder caused by mutations of the genes encoding rhages into joints (ankles, knees, and elbows), muscles, or coagulation factor VIII (FVIII) (hemophilia A) or IX (FIX) soft tissues [5]. Hemophilia A and B can be divided into (hemophilia B) [1]. Hemophilia A is the most prevalent form three phenotypes on the basis of plasma coagulation fac- of hemophilia, accounting for 85% of patients with hemo- tor levels: mild (> 5–40 IU/dL), moderate (1–5 IU/dL), and philia (PWH), with a prevalence of approximately 1:5000 severe (< 1 IU/dL) [6]. in male neonates [2]. Hemophilia B accounts for 15% of Currently, the developed treatments for hemophilia include prophylactic infusion of coagulation factors and molecular therapies such as antibody, gene, and RNA thera- * Mei Li pies [7], which significantly prolong the life expectancy and limeilzh@sina.com improve the quality of life of PWH. The life span of PWH is close to that of the general population [8]; however, con- Department of Endocrinology, National Health Commission comitant comorbidities are becoming increasingly preva- Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & lent. As a clinically common comorbidity of PWH, osteo- Peking Union Medical College, Beijing, China porosis is characterized by decreased bone mineral density Department of Orthopedic Surgery, Peking Union Medical (BMD) and deteriorated bone microarchitecture, resulting College Hospital, Chinese Academy of Medical Sciences & in impaired bone strength and increased risks of fragility Peking Union Medical College, Beijing, China Vol.:(0123456789) 1 3 17 Page 2 of 8 Archives of Osteoporosis (2023) 18:17 fractures [9–11]. A previous study showed that 27% of PWH biomechanical strength than their wild-type littermates [15], had osteoporosis, and 43% of PWH had osteopenia [12]. The which indicated that FVIII directly affected bone mass, inde- risk of osteoporotic fractures in PWH was 4.37 times that of pendent of recurrent hemarthrosis, and differences in physi- the general population of the same sex and age [13]. In PWH, cal activity levels. Another study demonstrated that FVIII acute massive blood loss during fracture due to coagulation KO mice had significantly reduced bone mass, cancellous deficiency might obviously increase the risk of osteoporosis bone fractional area, and trabecular number and increased and refracture. However, the exact mechanisms underlying trabecular separation in the absence of hemorrhage [16]. hemophilia combined with osteoporosis have not been fully These findings suggested that the reduction in the BMD of elucidated. Therefore, we review recent progress in research hemophilia A was intrinsic to FVIII deficiency. Moreover, on the pathogenesis and treatments of osteoporosis in PWH. although hemophilia B is less common and milder than hemophilia A, patients with severe hemophilia B had lower lumbar spine and proximal femur BMD than healthy con- Methods trols [17]. FIX KO mice were also found to have reduced BMD, diminished cortical and cancellous bone mass, The PubMed, Web of Science, Embase, and Cochrane impaired bone strength, and increased fracture risk [18]. A Library databases were searched up until June 2022 to iden- study revealed that BMD was substantially increased after tify research articles, meta-analyses, and scientific reviews FIX replacement treatment, which confirmed that FIX plays on hemophilia and bone health. The keywords used for a critical role in bone homeostasis [19]. literature searches included “osteoporosis,” “osteopenia,” The molecular mechanisms of FVIII or FIX deficiency “BMD,” “bone mass,” and “fracture” in combination with leading to osteoporosis have been explored. Studies have “hemophilia” or “factor VIII deficiency” or “factor IX defi- shown that the RANK/RANKL/OPG signaling pathway ciency.” These keywords were combined using the Boolean plays a role in the development of osteoporosis in PWH operators. The search was limited to publications in the Eng- [6, 20, 21]. Receptor activator of nuclear factor kappa-B lish language and those with access to the full text. Articles ligand (RANKL) binds to its receptor, RANK, and promotes were carefully studied independently by all authors, and the osteoclastogenesis, resulting in increased bone resorption included articles were agreed upon. [22]. Osteoprotegerin (OPG) attenuates osteoclastogenesis We screened the titles and abstracts to identify relevant by competitive binding with RANKL [23]. This pathway is articles. The inclusion criteria for the articles were explora- essential for maintaining bone turnover homeostasis. The tions of the pathogenesis of osteoporosis or osteopenia in FVIII-VWF complex has been found to be directly involved patients with hemophilia A/B and the treatment of osteoporo- in bone remodeling by binding to RANKL and OPG, inhib- sis or osteopenia in patients with hemophilia A/B. Literature iting RANKL-induced osteoclastogenesis, and enhancing such as conference abstracts and case reports and articles the inhibitory effects of OPG on osteoclasts, thereby pro- for which the full text could not be obtained were excluded. moting osteogenesis (Fig. 1) [24]. In FVIII mutant mice, after replacement therapy with FVIII, RANKL expression was reduced by 25% during the differentiation of bone mar - Results and discussion row-derived mesenchymal stem cells into osteoblasts [25]. These data suggested that FVIII independently affected bone Pathogenesis of osteoporosis in PWH homeostasis through the RANK/RANKL/OPG pathway. Some clinical studies have found that children and adults Deficiency of FVIII or FIX with hemophilia had significantly higher RANKL and lower OPG levels than healthy controls [21, 26]. However, other Recent research indicates that FVIII and FIX play criti- studies have found no significant difference in serum levels cal roles in bone homeostasis. In the intrinsic coagulation of RANKL or OPG or the RANKL/OPG ratio between PWH pathway, activated FVIII detaches from von Willebrand and healthy controls [27, 28]. These inconsistent results may factor (VWF) to form a complex with activated FIX and be related to the complexity of hemophilia and differences in then combines with phospholipids on platelet membranes, the severity, course, and treatment of hemophilia. 2+ which in turn activates FX in the presence of Ca . Acti- In contrast, few studies have focused on the role of the vated FX converts prothrombin to thrombin, increases the Wnt/β-catenin pathway in hemophilia. In the Wnt signaling amount of thrombin, and initiates the process of coagulation pathway, Wnt binds to a receptor complex on the cell surface [14]. When either FVIII or FIX is deficient, the coagula - that includes Frizzled protein (FZD) and lipoprotein recep- tion cascade cannot be activated appropriately. Interestingly, tor-related protein 5 (LRP5) or LRP6, leading to the recruit- recent studies found that FVIII knockout (KO) mice had ment of DVL and the axin–GSK3β–APC–CK1 complex to significantly lower hip BMD, cortical bone thickness, and the receptor. This step suppresses the phosphorylation of 1 3 Archives of Osteoporosis (2023) 18:17 Page 3 of 8 17 Fig. 1 The regulation of FVIII, FIX, thrombin, and cytokines in bone metabolism. TNF-α, IFN-γ, IL-1β, etc., directly increase the expres- metabolism. FVIII regulates bone homeostasis through the RANK/ sion RANKL, resulting in increased bone resorption. On the other RANKL/OPG axis. The FVIII/VWF complex binds to RANKL and hand, FVIII or FIX regulates bone metabolism through the Wnt/β- OPG, inhibits RANKL-induced osteoclastogenesis, and enhances the catenin pathway. FVIII or FIX might decrease the levels of sclerostin, inhibitory effects of OPG on osteoclasts, thereby promoting osteogen- further attenuating the inhibitory effect of sclerostin on the Wnt sign- esis. Another possible factor that regulates bone metabolism is throm- aling pathway and thus promoting bone formation. AKT, PI3K-pro- bin. Activated FVIII detaches from VWF and forms a complex with tein kinase B; COX-2, cyclooxygenase 2; EP4, PGE2 receptor 4; IFN- activated FIX, which further activates FX. FXa catalyzes the conver- γ, interferon-γ; IL-1β, interleukin-1β; IL-6, interleukin-6; MAPK, sion of prothrombin into thrombin. Thrombin regulates bone metab- mitogen-activated protein kinase; OC, osteocalcin; OPG, osteopro- olism by binding to PAR-1 on osteoblast membranes, which further tegerin; PAR-1, protease-activated receptor 1; PGE2, prostaglandin upregulates the expression of IL-6. Upregulated IL-6 stimulates the E2; PI3K, phosphoinositide 3-kinase; RANK, receptor activator of expression of RUNX2 and osteocalcin and reduces the expression of nuclear factor-kappa B; RANKL, receptor activator of nuclear factor- RANKL, further reducing osteoclastogenesis. Cytokines produced kappa B ligand; RUNX2, runt-related transcription factor 2; TNF-α: from recurrent intra-articular bleeding are also involved in bone tumor necrosis factor α β-catenin, leading to increased β-catenin levels in the cyto- deficiency. Recent studies have indicated that the thrombin plasm. The induced β-catenin translocates to the nucleus and downstream of FVIII and FVIX may also play a pivotal role in activates the transcription of target genes, such as Runx-2 bone homeostasis [6]. This n fi ding suggested that the under - and osteoprotegerin (Fig. 1) [29]. Sclerostin and Dickkopf-1 lying mechanisms of osteoporosis in PWH were complicated (DKK-1), antagonists of Wnt, bind to LRP5/6 and inhibit their and multifactorial. The process of prothrombin conversion to availability to Wnt ligands [30]. Recent studies found a sig- thrombin is a pivotal step necessary for clot formation. Muta- nificantly higher sclerostin level in children with hemophilia tions in the genes encoding FVIII or FIX can result in FX acti- than age-matched controls, while no significant difference in vation disorder and thrombin generation failure. Thrombin has serum DKK-1 levels was found between patients and controls been found to inhibit osteoclast differentiation and stimulate [27, 31]. The above results led to the hypothesis that FVIII or osteoblast proliferation [20], thus promoting bone formation. FIX deficiency would increase the levels of sclerostin, which A study showed that osteoblasts can express thrombin recep- would inhibit bone formation through the Wnt signaling path- tors [34], and thrombin plays its role mainly through protease- way and lead to bone loss (Fig. 1). Further studies are needed activated receptors (PARs) and seven-transmembrane domain to explore the role of sclerostin in PWH with osteoporosis. G protein-coupled receptors [35]. There are two types of throm- bin receptors, PAR-1 and PAR-4, expressed on the osteoblast Deficiency of thrombin membrane [36, 37]. Thrombin can promote the proliferation of bone marrow mesenchymal stem cells and inhibit the apopto- Recent studies have shown that FVIII KO and FIX KO mice sis of osteoblasts by binding to PAR-1 [37]. PAR-1 KO mice presented similar bone phenotypes [19, 32, 33], suggesting that have been shown to exhibit decreased BMD and compromised bone loss may be attributable to more than just FVIII or FIX bone architecture, which was similar to the pattern of FVIII 1 3 17 Page 4 of 8 Archives of Osteoporosis (2023) 18:17 KO mice [35]. The above research indicates that the FVIII/ increased [50]. The associations between bone turnover thrombin/PAR1 axis is closely linked to bone remodeling [38]. markers and hemophilic arthropathy were also explored, and Moreover, thrombin influences bone metabolism mainly a positive correlation was found between serum sclerostin by altering the expression of cytokines [20]. Thrombin is levels and the severity of joint arthropathy [31]. The lev- involved in the metabolism of arachidonic acid by binding els of the bone resorption markers CTX-1 and NTX-1 were to PAR-1 on the osteoblast membrane [6]. PAR-1 stimulates also positively correlated with the degree of arthropathy and the expression of cyclooxygenase-2 (COX-2) through the number of affected joints [51]. However, another study found mitogen-activated protein kinase (MAPK) pathway [39], and no significant correlation between serum levels of RANKL, upregulated COX-2 catalyzes the conversion of arachidonic OPG, and OC and the severity of hemophilic arthropathy acid to prostaglandin E2 (PGE2). PGE2 exerts osteogenic [26]. The discrepancies may be attributed to confounders for ee ff cts by activating PGE2 receptor 4 (EP4) in sensory nerves bone turnover, such as vitamin D nutritional status, physical and inhibiting sympathetic nerve activity in the central nerv- activity levels, and comorbidities. ous system [40]. In addition, activated PAR-1 upregulates the The mechanisms of arthropathy associated with low BMD expression of interleukin-6 (IL-6) through the PI3K/AKT and include mechanical unloading and inflammatory stimulation. MAPK pathways [6], which stimulates the expression of the Hemophilia was found to lead to spontaneous early-onset pro-osteogenic factors RUNX2 and osteocalcin (OC), pro- joint bleeding, which induced joint pain; decreased weight- motes the differentiation of mesenchymal stem cells into oste- bearing ability and activity levels; caused impaired muscle oblasts, and inhibits the apoptosis of osteoblasts (Fig. 1). IL-6 and skeletal function and vitamin D deficiency; and increased reduces the expression of RANKL (Fig. 1), osteoclastogenic the risk of osteoporosis, falls, and fractures [52]. In addi- cytokines IL-1, and tumor necrosis factor-α (TNF-α) and tion, the recurrent intra-articular bleeding and chronic syno- stimulates the production of anti-osteoclastogenic cytokines vitis in PWH also stimulate the production of inflammatory IL-4 and IL-10 [41, 42], which can reduce bone resorption cytokines, such as TNF-α, interferon-γ (IFN-γ), and IL-1 [46, and enhance bone formation. These findings supported the 53, 54], which increases osteoclast activity. In mouse models, proposition that FVIII or FIX is involved in bone remodeling the iRhom2/ADAM17/TNF-α pathway was hypothesized to through thrombin generation and multiple cytokines. contribute to the activation of osteoclasts and the pathogen- However, the findings of a study indicated that more esis of osteoporosis in hemophilic arthropathy. This path- than 85% of prothrombin knockdown mice did not show a way could be prevented by genetic inactivation of TNF-α or significantly different bone phenotype from wild-type mice iRhom2 or treatment with anti-TNFα biologics [53], which [43], which indicated that thrombin deficiency may not be suggested that this signaling axis could be a potential target a key mechanism of osteoporosis in PWH. Additionally, a for the prevention of osteoporosis in arthropathy PWH. In study showed that the immunological profile of untreated contrast, other study findings indicated that serum levels of PWH presented higher levels of IL-6, IL-4, IL-10, and IL-2 IL-1α and IFN-β or TNF-α were significantly lower in PWH than that of the age-matched healthy controls, which was than in controls [55, 56]. However, the levels of the inflam- inconsistent with the above findings [44]. The above studies matory cytokines IL-1β, IFN-γ, and TNF-α in the synovial suggest that the interrelationship between thrombin and bone fluid of hemophilic mice were significantly increased in is quite complicated. injured joints compared with control joints [57]. These study findings suggested that bone turnover in PWH is regulated by Unloading status and immobilization of bone mechanical unloading and inflammatory stimulation. The unloading status and systemic immobilization of bone Progress on the management of osteoporosis can induce disuse osteoporosis [45]. In PWH, long-term in PWH spontaneous bleeding in the ankles, knees, or elbows leads to hemarthrosis, cartilage damage, and hemophilic arthropathy Physical activity and fall prevention [46]. Numerous studies have indicated that BMD is inversely correlated with the severity of arthropathy in PWH [12, 28, The World Federation of Hemophilia (WFH) guidelines 47–49]. The arthropathy severity of PWH was evaluated encourage weight-bearing activity for PWH to build bone according to the clinical score of the Orthopedic Advisory mass and reduce the risk of osteoporosis, especially for Council of the World Federation of Hemophilia [28], and young PWH, as late childhood and adolescence are an the results showed that the risk of osteoporosis increased important period for the acquisition of peak bone mass. Aer- by 2.42 times for each 10-point increase in the total clinical obic exercise, strength/resistance training. and balance and score. Moreover, the radiographic joint score could inde- flexibility exercises are suitable for PWH [58]. PWH should pendently explain 23% of the variability in the femoral neck be referred to physical therapists for evaluation, education, BMD of PWH, and BMD decreased as the arthropathy score and instruction before commencing any exercise regimen 1 3 Archives of Osteoporosis (2023) 18:17 Page 5 of 8 17 [59]. Supervised physical therapy is recommended for PWH PWH are scarce. To date, only one study has evaluated the with arthropathy [59]. A randomized controlled trial (RCT) efficacy of ibandronate for osteoporosis in PWH [62]. In this demonstrated that training in combination with exercise study, 10 PWH with osteoporosis received ibandronate treat- machines (programmed sports therapy) for 6 months had a ment for 12 months, and the lumbar spine BMD increased positive effect on physical performance, especially strength, by 4.7%, but no significant change was found in the BMD balance, and endurance, in adult PWH regardless of disease of the total hip or femoral neck [71]. As the sample size of course [60]. Notably, no increased risk of bleeding events this study was relatively small, larger sample clinical trials was observed in these PWH participating in weight-bearing are needed. activity of such an intensity [60]. Denosumab is a fully human monoclonal antibody target- PWH have a predisposition to falls because of abnormal ing the bone resorption mediator RANKL that is effective in joint function, impaired mobility, and poor balance [61]. In the treatment of postmenopausal osteoporosis, male osteo- PWH, the annual incidence of falls is 32–50%, and 53–81% porosis, and glucocorticoid-induced osteoporosis [72–74]. of fractures are due to falls [62]. The WFH guidelines rec- Nevertheless, no studies have explored the efficacy of den- ommend that musculoskeletal assessment should be per- osumab in PWH with osteoporosis. We have previously formed in adult PWH annually and in pediatric PWH every treated a man with hemophilia complicated with osteoporo- 6 months [59]. A performance-based measure to evaluate tic fracture and delayed healing after surgery. After 4 months functional mobility and fall risk is recommended [63]. When of teriparatide treatment and 1 year of denosumab treatment, PWH have an increased risk of falling, balance exercises, the fracture healed, and BMD increased significantly. How - lower limb strengthening exercises and walking are recom- ever, the efficacy and safety of denosumab in PWH with mended [64]. osteoporosis need further investigation. Teriparatide, a recombinant human parathyroid hormone, Supplementation with calcium and vitamin D is an anabolic agent that can significantly increase BMD and reduce the incidence of vertebral fractures [75–77]. In PWH, 47% were found to have vitamin D deficiency, and The effects of teriparatide on the bones of PWH are unclear. 25-hydroxyvitamin D levels could independently predict low Therefore, studies are needed to assess whether teriparatide BMD [48]. The WFH guidelines recommended that PWH is beneficial to PWH with osteoporosis. It is worth noting receive adequate calcium and vitamin D supplementation that PWH are likely to suffer bruising and bleeding from [59]. Sufficient calcium intake is necessary for the acquisi- subcutaneous injection of teriparatide, which should be bal- tion of peak bone mass and the maintenance of bone health. anced with the effects of teriparatide on bone. Adequate vitamin D intake is helpful to facilitate calcium Romosozumab, a humanized monoclonal antibody that absorption, improve muscle strength, and reduce the risk binds and inhibits sclerostin, has a unique dual effect of pro- of falling [65]. Nevertheless, the efficacy of calcium and moting bone formation and inhibiting bone resorption. It is vitamin D supplementation for the prevention of osteoporo- approved by the Food and Drug Administration (FDA) for tic fractures is controversial [66]. The large VITAL study the treatment of women with postmenopausal osteoporosis showed that daily supplementation with high-dose vitamin and high fracture risk [78]. In studies of children with severe D did not improve BMD or bone structure or prevent falls hemophilia A, serum sclerostin levels were significantly in a generally healthy population [67, 68]. However, the increased [27, 31], which suggested that romosozumab results of the VITAL study cannot be applied to persons with might be effective in treating the osteoporosis of PWH. extremely low vitamin D levels or osteoporosis or younger Further prospective clinical studies need to be conducted to adults since this study did not include any participants with determine the efficacy and safety of romosozumab in PWH low bone mass or vitamin D insufficiency or young age. with osteoporosis. Anti‑osteoporotic agents Prophylactic coagulation factor replacement therapy The effective drugs for osteoporosis include antiresorptive, Prophylactic FVIII:C replacement is a standard treatment anabolic, and dual-action agents. However, the efficacy of for patients with hemophilia A, as it can reduce bleeding these agents remains undetermined in PWH with osteoporo- episodes, prevent joint damage, and improve quality of life sis. Several studies indicated that the bone resorption marker [79]. Prophylactic coagulant factor replacement treatment CTX-1 was significantly increased in PWH [28, 55, 69, 70]. might be helpful in reducing bone loss in PWH. Direct Given the reported higher bone turnover in PWH, antiresorp- evidence from animal models showed that FVIII replace- tive therapies such as bisphosphonates or denosumab might ment therapy led to a 25% reduction in RANKL levels [25], be effective in PWH with osteoporosis. However, large- which suggested that FVIII replacement therapy might be sample prospective drug therapy studies for osteoporosis in useful in reducing bone loss in PWH. Another mouse study 1 3 17 Page 6 of 8 Archives of Osteoporosis (2023) 18:17 demonstrated that long-term FIX replacement normalized Declarations −/− the BMD of FIX KO (FIX ) mice to that of wild-type mice Conflict of interest None. [19]. Additionally, long-term FVIII replacement was benefi- cial to preserve the BMD of patients with severe hemophilia Open Access This article is licensed under a Creative Commons Attri- [80]. Furthermore, prophylactic coagulation factor replace- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long ment therapy also reduces the occurrence of bleeding, as you give appropriate credit to the original author(s) and the source, facilitates joint mobility, and thus reduces the risk of disuse provide a link to the Creative Commons licence, and indicate if changes osteoporosis. Nonetheless, the generation of autoantibod- were made. The images or other third party material in this article are ies to FVIII or FIX, such as anti-FVIII or FIX alloantibod- included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in ies, is a major complication of at least one-third of patients the article's Creative Commons licence and your intended use is not with severe hemophilia A and approximately 3 to 5% of permitted by statutory regulation or exceeds the permitted use, you will those with severe hemophilia B [6, 81] that leads to PWH need to obtain permission directly from the copyright holder. To view a unresponsiveness to replacement therapy. To overcome this copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . limitation, the FDA approved new nonreplacement therapeu- tic strategies, such as enhancing coagulation and inhibiting anticoagulant pathways [81, 82]. However, less is known References about the effects of these new agents on bone homeostasis. In summary, appropriate weight-bearing exercise and 1. Bolton-Maggs PH, Pasi KJ (2003) Haemophilias A and B. 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Journal
Archives of Osteoporosis – Springer Journals
Published: Jan 4, 2023
Keywords: Hemophilia; Osteoporosis; Factor VIII; Thrombin