MASAC Document 291 - Physical Therapy Management for Bone Health in People with Bleeding Disorders

Authors: J Nicole Clark (1), Sarah Dunn (2,3), Lora Joyner (4), Anne Gonzales (5)

1. University of Colorado Hemophilia and Thrombosis Center 
2. Penn Comprehensive Hemophilia and Thrombosis Program  
3. Good Shepherd Penn Partners at Penn Presbyterian Medical Center
4. ECU Health Lifespan Hemophilia Treatment Center
5. Nationwide Children’s Hospital Hemostasis and Thrombosis Center 

Executive Summary

The National Bleeding Disorder Foundation’s (NBDF) Medical and Scientific Advisory Council (MASAC) convened an expert panel of physical therapists to develop recommendations for physical therapy assessment and treatment of bone health in people with bleeding disorders (PWBD). The recommendations are based on a systematic review of the published medical literature, professional experiences of the panel experts, and external multistakeholder reviews.

INTRODUCTION

Background 

Ensuring a healthy skeletal system is vital to overall health, quality of life, and prevention of disability. Bone health refers to the condition and strength of the skeletal system. Impaired bone health such as low bone mineral density (i.e., osteopenia and osteoporosis) effects nearly 45 million Americans over the age of 50.¹ Bone remodeling is the lifelong process of bone resorption and bone formation and is measured by bone mineral density (BMD). There are many influences within the body such as hormones, cytokines, growth factors, and peptides that impact bone homeostasis. Additional influences on bone health, sometimes referred to as modifiable, include smoking, alcohol and caffeine consumption, and physical activity.² When bone resorption exceeds bone formation, homeostasis is lost and results in reduced BMD.² 

People with bleeding disorders face a heightened risk of bone health conditions compared to the general population. There is evidence suggesting that Factor VIII (FVIII) and Factor IX (FIX) deficiency may contribute to decreased BMD, independent of the history of joint bleeds or hemarthroses associated with PWBD.² This could be related to the decreased thrombin generation which impairs bone formation due to the reduction of osteoblasts.³  Primary prophylaxis is crucial for managing hemophilic arthropathy by preventing joint damage, preserving bone health, and enhancing overall quality of life for individuals with PWBD. Hemophilic arthropathy is a multifactorial condition involving repeated joint bleeding, chronic synovial inflammation, hemosiderin deposition, and subsequent cartilage destruction.⁴ The combination of inflammatory and degenerative processes results in joint damage, stiffness, and reduced joint function, significantly impacting the quality of life of PWBD. The inherent risks to bone health in PWBDs underscore the critical need for continuous surveillance of bone health from childhood through the lifespan.

Current guidelines for osteoporosis management and fall prevention for PWBD are inadequate due to lack of evidence.³ Variability exists between recommendations from the World Federation of Haemophilia (WFH), British guidelines, and Australian guidelines; this includes timing of screenings for osteoporosis and qualifiers to identify those people at higher risk for osteoporosis.^{3, 5} This document summarizes current literature and best practice recommendations for physical therapists managing bone health in PWBD.     

Methods and Process

The National Bleeding Disorder Foundation’s (NBDF) Medical and Scientific Advisory Council (MASAC) leadership, in collaboration with the NBDF Physical Therapy Working Group (PTWG), created this physical therapy task force to address the issue of bone health in the inherited blood disorders community. The task force led the development of the physical therapy specific recommendations for the assessment and treatment of bone health in PWBD.

The task force conducted a systematic review of available evidence through December 2023 to guide the development of the recommendations presented in this document. PubMed was used to identify current literature regarding bone health assessment and management in PWBD. Only full-text articles were included, with a ten-year restriction on date of publication. No restrictions were applied on the age of participants or original language of article. There were 30 articles reviewed and after thorough screening of abstracts, six articles were identified as addressing PWBD, bone health, and physical therapy interventions. They were then evaluated using components of the GRADE process. Forty-one additional articles were identified through the review process and bibliographies of the six original articles and were included. Further reference material was utilized to bridge the gap in evidence between the bleeding disorder community and the general population research. 

The strength and quality of evidence in the literature and expert opinion of assessment and treatment of bone health were considered in these recommendations. Draft recommendations were reviewed and revised by all members of the MASAC Bone Health Subcommittee of the Geriatric Task Force and made available for external review by the NBDF’s PTWG. Pertinent comments were integrated and addressed in the final version of this document. 

The final recommendations were subdivided into (A) Assessment of bone health, fall risk, fracture risk and (B) Treatment/Interventions.² To delineate the separate components of physical therapy interventions, recommendations were further subdivided into Education, Pediatrics, Therapeutic Exercise, and Therapeutic Modalities. 

Recommendation Statements

1. Assessment
   1. Physical therapists evaluating PWBD should screen for modifiable and non-modifiable risk factors of poor bone health to prevent and minimize the potential negative effects of low BMD.
   2. Physical therapists should screen all PWBD over the age of 30 for fall risk at least annually.
   3. Physical therapists should utilize the Fracture Risk Assessment Tool (FRAX) to identify fracture risk in PWBD prior to engaging in physical therapy plan of care.
2. Interventions
3. Education:
4. Physical therapists should provide education on modifiable and non- modifiable risk factors for low BMD. 
5. Physical therapists should provide education on the safety and efficacy of exercise to improve BMD.
6. Physical therapists should provide education on appropriate rehabilitation after a musculoskeletal acute bleed.
7. Pediatrics
8. Physical therapists working with children with bleeding disorders should provide education and recommendations to maximize peak bone mass.   
9. Physical therapists working with children with bleeding disorders should provide education on health and wellness related to physical activity and exercise.
10. Therapeutic Exercise
11. Assessment and intervention for aerobic capacity and endurance is beneficial to preserve BMD in PWBD.
12. Participation in progressive strength training exercise increases BMD in PWBD.
13. A therapeutic exercise program should incorporate balance training to decrease falls in PWBD.
14. Therapeutic Modalities 
15. Pulsed Electromagnetic Field (PEMF) could be a viable addition or alternative treatment to resistive exercises in PWBD.
16. Whole-body vibration training (WBV) could be a viable addition or alternative treatment to resistive exercises in PWBD.

RECOMMENDATIONS

General Considerations

Primary prophylaxis is considered the gold standard from prevention of the sequelae of complications from hemophilic arthropathy including cartilage damage, synovitis, chondral cysts, and sequalae of acute and subacute hemarthrosis. Thus, breaking the cycle of injury, disuse, bone loss, fractures, atrophy and then further injury.⁶ While prophylactic treatment for people with severe hemophilia may influence BMD outcomes compared to on-demand treatment, the key factor influencing BMD differences seems to be age rather than the specific treatment regimen with older individuals having lower BMD, regardless of treatment regimen.⁷ Beyond joint bleeds and cyclical hemophilic arthropathy damage, individuals with bleeding disorders face unique challenges contributing to poor bone health, including reduced BMD and vitamin D levels at younger ages compared to the general population.^{8, 9} 

An interdisciplinary team, which can include a hematologist, endocrinologist, orthopedic surgeon and physical therapist, is highly recommended to monitor bone health. Each discipline plays a vital role in assessing and treating bone health concerns. The scope of this document is to guide physical therapy assessment and treatment for bone health in PWBDs and should be used in conjunction with medical guidelines that are outside the scope of physical therapy practice. These may include recommendations regarding vitamins and supplements, medications, and screening tools.¹⁰ The physical therapy portion of the plan of care needs to be individualized based on the unique needs of each patient and should integrate a combination of treatment approaches. Close collaboration between the physical therapy and hematology providers will be necessary to ensure appropriate medical management and factor levels. Patient adherence to the plan of care will be necessary for optimal outcomes.

Assessment

1. Risk factors of impaired bone health

Rationale: It is well documented that people living with hemophilia, hemophilia carriers and people with Von Willebrand Disease (VWD) have higher rates of low bone mineral density and fracture compared with the general population.  

The following are risk factors which are more present in people who are hemophilia carriers and people with VWD then in the general population: vitamin D deficiency, body mass index (BMI) greater than 30, hypothyroid, smoking, diabetes mellitus, hypocalcemia, corticosteroid use, malignancy, nonsteroidal anti-inflammatory drugs (NSAID), and renal failure.¹¹ 

Modifiable risk factors for low BMD include smoking, alcohol consumption, physical activity, low body mass index (BMI), hypothyroidism, hypogonadism, decreased dairy intake, excessive tea and coffee, and sedentary lifestyle.  Non-modifiable risk factors for low BMD include Hepatitis C (HCV) and the interferon treatment, human immunodeficiency virus (HIV) and antiretroviral therapy.¹²

A common bone disease in PWBDs, hemophilic arthropathy, is associated with impaired mobility and avoiding weight bearing activity.¹³  Lack of activity limits the production of peak bone mass in adolescence. Hemophilic arthropathy with consecutive immobilization plays paramount role in vitamin D deficiency, due to limited outdoor activity, and diminished BMD,¹⁴ affecting both cortical thickness and trabecular bone volume.^{15, 16}

Statement: Physical therapists evaluating PWBD should screen for modifiable and non-modifiable risk factors of poor bone health to prevent and minimize the potential negative effects of low bone mineral density

Practice implications: In addition to the modifiable and non-modifiable risk factor above, special attention to screening and documenting number of lifetime joint bleeds, amount of time immobilized, level of physical activity, occupation, disability status, HIV, HCV status is crucial for PWBD.

Special considerations: If a risk factor is identified that falls outside the scope of physical therapy, the physical therapist should refer to the appropriate specialist. 

1. Assessment of fall risk

Rationale: Research indicates that falls are commonplace in people with hemophilia.¹⁷ Fall risk increases with age and PWBD are increasingly entering the over 65 age group.¹⁸ Fall risk factors can include environmental conditions (e.g. height difference of walking surfaces, outdoor environment, time of day, rugs), history of previous fall, urinary incontinence, poor orthopedic status (e.g. arthritis, decreased strength in lower extremities, and decreased hip extension range of motion), pain with daily activities, avoidance of pain-related exercise, depression,³ and HIV infection.^{3, 19}

In addition to the age-related and environmental risk factors the general population experiences, PWBD also have a predisposition to falls due to arthropathy.²⁰ Hemophilic arthropathy leads to biomechanical alterations, decreased strength, proprioception, balance, and impairments of gait and mobility.¹⁷ The limited mobility further increases the risk of falling, creating a negative cycle.²⁰ 

Statement: Physical therapists should screen all PWBD over the age of 30 for fall risk at least annually.

Practice implication: People with hemophilia over the age of 31 are twice as likely to have a fracture when compared with those 30 and younger.^{3, 21} Starting fall risk screening with PWBD at age 31 may prevent fall-related fractures. If PWBD presents with other fall risk factors before age 30, screening at that time is indicated. Fall risk screening (e.g. Timed Up and Go, Mini-Balance Evaluation Systems Test, Single Leg Stance, Five Times Sit to Stand, Berg Balance Scale) can be used in conjunction with musculoskeletal examination to assess joint health, presence of hemophilic arthropathy, proprioception, and other functional limitations. If a balance impairment is identified in the screening, please refer to recommendation 6c below. Other factors that must be evaluated as needed include home assessment, ADL and IADL modifications, assistive devices prescription, and appropriate footwear.²²

Special Considerations:The multidisciplinary team must be involved to address all aspects of fall prevention including vitamin D or calcium supplementation, the fear of falling, management of blood pressure, visual impairments, and monitoring medications that can affect balance. 

The aforementioned balance screening tools do not require special equipment, but knowledge of the performance criteria and scoring is vital. These balance screening tools are not validated on PWBD. The physical therapist should have experience with evaluating PWBD to complete an evaluation with competence. Refer to Appendix 1 of this document or the American Physical Therapy Association (APTA) for age-specific balance screening tests as referenced in Appendix 2. 

1. Assessment of fracture risk

Rationale: There is a higher fracture risk in PWBD than people without bleeding disorders,²¹ and the prevalence of osteoporosis and fractures is significantly greater in hemophilia carriers and people with VWD than in the standard population.¹¹ The incidence of fracture in people with hemophilia (PWH) compared to the general population is 24.8 vs 9.6 per 1000 patient years.²³ 

Fractures increase the risk of morbidity and mortality and negatively affect quality of life. History of fracture is positively associated with severity of hemophilia, level of physical activity, and HCV or HIV infections. Often presenting with impaired BMD and fall risk with PWBD could be at increased risk of fractures.^{11, 20} This necessitates the assessment of fracture risk for PWBD.

Statement: Physical therapists should utilize the FRAX to identify fracture risk in PWBD prior to engaging in physical therapy plan of care.

Practice implication: The FRAX is the most widely used tool that provides a framework for estimation and management of fracture risk.²⁴ The FRAX tool estimates 10-year risk for major osteoporotic and hip fracture. The risk was greater in people with hemophilia with low BMD than normal BMD.¹⁰ The average age of fracture in PWH is 28-30 years old.³ Risk of bone fracture for PWBD over the age of 31 is twice as likely compared with PWBD younger than age 31.²¹ 

Special considerations: The FRAX has not been validated for PWBD, however, bone disease, which is validated, is highly prevalent in PWBD. In addition to the FRAX, PWBD should be followed by a physician to assess Vitamin D levels, calcium levels and order DEXA, as indicated. 

Interventions 

1. Education

Rationale: Patient education on musculoskeletal health in PWBD is critical. Education topics should include recognition of risk factors, and recognition and treatment of a musculoskeletal bleed, joint and muscle health, pain management, and the importance of physical therapy and rehabilitation.²⁵

Lack of compliance with personal healthcare management is associated with poor clinical outcomes, increased hospitalizations, lower quality of life, and higher overall healthcare costs. Compliance may be particularly poor in treatment for asymptomatic chronic diseases such as osteoporosis.²⁶ Patient education has been shown to significantly improve treatment compliance by increasing knowledge, competence, and confidence in self-management skills.²⁶

4a Statement: Physical therapists should provide education on modifiable and non- modifiable risk factors for low BMD. 

Practice implications: Education of risk factors that may be controlled or changed with appropriate intervention should be incorporated into standard clinical practice to increase awareness of variables that impact BMD. Some risk factors may not be modifiable by physical therapy interventions; however, it is important to educate PWBD on the effect on bone health for risk factors they are not able to control. 

Special Considerations: Additional medical education outside of a physical therapist's scope may be provided by the appropriate healthcare provider.

4b Statement: Physical therapists should provide education on the safety and efficacy of exercise to improve BMD.

Practice implications: Patient education on the safety and efficacy of exercise to improve BMD should be incorporated into standard clinical practice. Treatment interventions such as aerobic exercise, resistive exercise,²⁷ and balance interventions have been shown to be safe in PWBD,²⁸ and effective in the management of BMD.²⁹

Special Considerations: Although therapeutic exercise is proven to positively impact BMD in the general population, there is a lack of published literature that addresses the effectiveness of therapeutic exercise on BMD in PWBD. For specific interventions, see section 6.

4c Statement: Physical therapists should provide education on appropriate rehabilitation after a musculoskeletal acute bleed.

Practice implications: Patient education on appropriate rehabilitation after an acute bleed should be incorporated into standard clinical practice to return joint function to pre-bleed state.²⁵ Inadequate understanding of the acute and subacute phases of musculoskeletal injury with bleeding can lead to poor compliance with rehabilitation protocol (e.g. return to activity too soon, improper form with exercise, re-injury). Best practice involves assessing the individual’s learning style to provide the information in a format that allows for optimal comprehension.

Special Considerations: Additional education related to other aspects of managing an acute bleed may be provided by the appropriate healthcare provider.   

1. Pediatrics 

Rationale: Children can optimize their peak bone mass in childhood and into adolescence through proper nutrition and healthy lifestyle choices, engaging in physical activity and exercise safely, and education on specific bone loading activities for bone building.² 

Promoting a healthy diet, including adequate calcium and vitamin D, and regular exercise can contribute to establishing good bone health early in life.² Children should engage in regular physical activity and exercise which includes bone-loading activities; as with Wolff’s Law, with increased mechanical loading, the bones will become stronger from the cancellous bone to the outer cortical layer.^{30, 31} This agrees with the Center for Disease Control’s (CDC) recommendation for children and adolescents to participate in aerobic, strengthening and bone building exercises as part of their regular physical activity.³² Furthermore, bone banking, the creation of a reservoir of bone that can be stored, is optimal for children ages 9-18 years with peak bone mass achieved by 18-25 years of age.^{17, 18}Achieving more bone mass in adolescence is protective against osteoporosis later in life. 

Maximizing peak bone mass is pivotal for children with bleeding disorders as they are at greater risk of poor bone health. Children with hemophilia present with decreased bone mineral density when compared to their peers³³. The findings of lower BMD could be due to a myriad of factors including increased osteoclast resorption and decreased osteoblast activity.^{34, 35} This, in combination with prolonged immobilization and decreased weight bearing activities secondary to hemarthroses, contributes to decreased bone mineral density.³⁴ 

5a. Prevention 

Statement: Physical therapists working with children with bleeding disorders should provide education and recommendations to maximize peak bone mass.   

Practice Implications: To prevent poor bone health in adults with bleeding disorders, physical therapists can promote safe participation in physical activity and exercise for children. To maximize peak bone mass in the pediatric population, activities such as jumping, running, and other high-impact activities should be encouraged, as they allow for adequate forces to promote bone building.³⁶ 

Following an injury with MSK bleeding, physical therapists can provide education and therapeutic exercises for children to return to activity. A skilled plan of care to address avoiding re-injury, return to sport timeline, and resolution of bleeding symptoms is crucial to decrease the time of immobility.

Special Considerations: Children with bleeding disorders should work closely with their hematologist to ensure adequate bleeding disorder management specific to their activity. Additionally, children should routinely follow-up with their primary care physician who can medically manage factors related to bone health (vitamin D, calcium), including screening to identify risk factors.

5b. Pediatrics Education 

Statement: Physical therapists working with children with bleeding disorders should provide education on health and wellness related to physical activity and exercise. 

Practice Implications: Physical therapists can use the Playing It Safe resource to help children with bleeding disorders make educated choices when engaging in exercise and physical activity as recommended by the CDC.^{32, 37, 38} Children who engage in higher intensity physical activity should do so with appropriate protective equipment and medical management for bleed prevention.

As a child ages, the physical therapist should provide education on continued physical activity and exercise with transition education and promote self-management of their bleeding disorder.  Despite newer advances in pharmaceuticals and increased physical activity, the risk for decreased bone mineral density in PWBD still remains present.¹¹ For this reason, it is essential to provide education throughout the lifespan and specifically starting in childhood.

The PT Working Toward Success booklet can provide adolescents and young adults, and their families, with knowledge on transition to adulthood and choosing a career that matches their physical abilities with health status.³⁹ 

Special Consideration: The physical therapist can collaborate with a physical activity specialist in the community (i.e. physical education teacher, coaches, trainers) to ensure safe participation in physical activity. 

1. Therapeutic Exercise: 

Rationale: Therapeutic exercise can be used to prevent bleeds by increasing balance, strength and stability.^{6, 40} It can also be used to treat joint and muscle bleeds, hemophilic arthropathy, and orthopedic surgery sequelae.^{6, 40} Early identification and treatment of these impairments of the musculoskeletal system is imperative to decrease the impact on function and participation.⁶ Common impairments include decreased range of motion, strength, and endurance, and increased muscle atrophy and pain which can be addressed with an individualized therapeutic exercise program.^{6, 41, 42} De la Corte-Rodriguez, et al. published age-specific recommendations for physical activity applying the WHO guidelines for persons with hemophilia based on current evidence,⁶ which can be used in combination with the recommendations below. Interventions should be managed and monitored by a licensed physical therapy specialist in conjunction with adequate prophylactic medication. 

6a. Aerobic Exercise 

Statement: Assessment and intervention for aerobic capacity and endurance is beneficial to preserve BMD in PWBD. 

Practice Implications: Prolonged rest after injury, decreased participation in high intensity sports, and disability due to joint disease decreases a person’s aerobic tolerance.⁴³ Assessment of sub-maximal aerobic capacity with the Six Minute Walk Test (6MWT) is recommended to create an aerobic exercise program.⁴³ Aerobic exercise has been shown to maintain BMD in adults,²⁹ and is safe for PWBD.⁴⁴ In another study, moderate intensity aerobic exercise on the treadmill was shown to improve markers for bone metabolism.⁴⁵ 

Special Considerations: It is recommended to use a 12-meter-long hallway for the 6MWT. However, if space of that length is not available, it is recommended that assessment and reassessment occur at the same place. Contraindications of aerobic testing are unstable angina and myocardial infarction in the last month since testing.⁴⁶ 

6b. Strength Training

Statement: Participation in progressive strength training exercise increases BMD in PWBD.

Practice Implications: Research demonstrates that PWBD have lower baseline dynamic strength and anaerobic power than age-matched peers/controls.^{47, 48} Evaluation of muscle strength via manual muscle testing (MMT) and timed sit to stand test (5xSTS) can help determine the type and intensity of muscle strengthening intervention necessary. In addition to increasing BMD,²⁷ progressive resistance training has been found to be safe and effective for PWBD.²⁸  

Special Considerations: With adequate prophylactic management, PWBD should follow CDC guidelines for strength training recommendations. PWBD with advanced bone disease should be cleared by a medical provider prior to engaging in strength training.⁴² 

6c. Balance

Statement: A therapeutic exercise program should incorporate balance training to decrease falls in PWBD. 

Practice Implications: Impaired lower extremity strength and proprioception, fear of falling, and decreased activity level are factors contributing to falls.⁴⁹ Using a balance assessment tool, such as single leg stance (SLS), can identify balance impairments. A combination of interventions addressing the identified impairments may include strengthening, flexibility, endurance, and neuromuscular control.⁵⁰ Mobility training and functional skills must also be incorporated in the prevention plan as falls happen mostly during movement activities.²² Decreasing the risk for falls in PWBD decreases risk of fracture from a fall.² 

Special Considerations: See assessment of balance and fall risk in Section 2 above. The risk of falling is inherent when training balance. Precautions to mitigate these risks include use of a gait belt, securing the environment, and decreasing distractions. PWBD should contact their hematology care team if a fall or other injury occurs to assess for bleeding. 

1. Therapeutic Modalities

Rationale: Resistance training can improve bone formation, joint function, and decrease pain in patients with severe hemophilia with osteoporosis. However, people with significant arthropathy or pain may not be able to participate in resistance exercise.⁵¹ Alternative physical therapy interventions for targeting bone health include therapeutic modalities such as pulsed electromagnetic fields and vibration plates. 

7a. Pulsed Electromagnetic Fields (PEMF)

Statement: Pulsed Electromagnetic Fields (PEMF) could be a viable addition or alternative treatment to resistive exercises in PWBD.

Practice Implications: PEMF may be used as a safe modality to promote bone formation⁵¹. Pulsed electromagnetic fields (PEMF) can slow or prevent bone loss,⁵² and has been shown to stimulate new bone formation.⁵³

Special Considerations: PEMF is a tool that uses specialized equipment and requires additional training. The equipment may not be readily available at most physical therapy clinics. The evidence for PEMF for bone health markers is conflicting in the literature⁵⁴.

7b. Vibration Plate

Statement: Whole-body vibration (WBV) training could be a viable addition or alternative treatment to resistive exercises in PWBD.

Practice Implications: Whole body vibration, at a frequency of 30-40 Hz, 2-4 mm of peak-to-peak vertical plate displacement, and exercise durations ranging from 12 to 15 minutes for two vibration exercises 3x/week for 12 weeks,⁵⁵ increases bone formation in children with bleeding disorders. WBV has been shown to increase quadriceps muscle strength, BMD and functional capacity. While WBV seems to influence muscle strength, findings are controversial on improvement of BMD.⁵⁵ According to this study, WBV has been an effective modality to improve balance and reduce the risk of falling thereby reducing the risk of fracture.²⁹

Special Considerations: Whole body vibration is a tool that uses specialized equipment and requires additional training. The equipment may not be readily available at most physical therapy clinics. The evidence to support WBV is limited.⁵⁵

Conclusion

In conclusion, maintaining optimal bone health is essential for overall well-being and quality of life. Factors such as bone mineral density, influenced by bone remodeling processes and various internal and external factors, play a critical role in skeletal strength. Individuals with bleeding disorders, particularly those with Factor VIII deficiency, face elevated risks of bone health complications despite managing joint bleeds. Continuous surveillance and early intervention are paramount to preserving bone health and mitigating the impact of conditions like hemophilic arthropathy on joint function and overall quality of life.

Appendix 1

Appendix 2 

References

1.            Office of the Surgeon G. Reports of the Surgeon General.  Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville (MD): Office of the Surgeon General (US); 2004.

2.            Rodriguez-Merchan EC. Osteoporosis in hemophilia: what is its importance in clinical practice? Expert Rev Hematol. 2022;15(8):697-710.

3.            Petkovic MJ, Tran HA, Ebeling PR, Zengin A. Osteoporosis management and falls prevention in patients with haemophilia: Review of haemophilia guidelines. Haemophilia. 2022;28(3):388-96.

4.            van Meegeren ME, Roosendaal G, Jansen NW, Lafeber FP, Mastbergen SC. Blood-Induced Joint Damage: The Devastating Effects of Acute Joint Bleeds versus Micro-Bleeds. Cartilage. 2013;4(4):313-20.

5.            Kempton CL, Antoniucci DM, Rodriguez-Merchan EC. Bone health in persons with haemophilia. Haemophilia. 2015;21(5):568-77.

6.            De la Corte-Rodriguez H, Rodriguez-Merchan EC. The role of physical medicine and rehabilitation in haemophiliac patients. Blood Coagul Fibrinolysis. 2013;24(1):1-9.

7.            Klintman J, Akesson KE, Holme PA, Fischer K. Bone mineral density in haemophilia - a multicentre study evaluating the impact of different replacement regimens. Haemophilia. 2022;28(2):239-46.

8.            Sahin S, Sadri S, Baslar Z, Ar MC. Osteoporosis in Patients With Hemophilia: Single-Center Results From a Middle-Income Country. Clin Appl Thromb Hemost. 2019;25:1076029619861689.

9.            Ekinci O, Demircioglu S, Dogan A, Merter M, Yildiz S, Demir C. Decreased bone mineral density and associated factors in severe haemophilia A patients: A case-control study. Haemophilia. 2019;25(5):e315-e21.

10.          Anagnostis P, Karras SN, Goulis DG. Bone disease in patients with haemophilia A and B – where are we now? Haemophilia. 2015;21(1):1-3.

11.          Citla‐Sridhar D, Sidonio RF, Ahuja SP. Bone health in haemophilia carriers and persons with von Willebrand disease: A large database analysis. Haemophilia. 2022;28(4):671-8.

12.          Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections. Ther Adv Musculoskelet Dis. 2017;9(1):22-34.

13.          Anagnostis P, Karras S, Paschou SA, Goulis DG. Haemophilia A and B as a cause for secondary osteoporosis and increased fracture risk. Blood Coagul Fibrinolysis. 2015;26(6):599-603.

14.          Eldash HH, Atwa ZT, Saad MA. Vitamin D deficiency and osteoporosis in hemophilic children: an intermingled comorbidity. Blood Coagul Fibrinolysis. 2017;28(1):14-8.

15.          Józsa L, Réffy A, Järvinen M, Kannus P, Lehto M, Kvist M. Cortical and trabecular osteopenia after immobilization. A quantitative histological study of the rat knee. Int Orthop. 1988;12(2):169-72.

16.          Koseki H, Osaki M, Honda Y, Sunagawa S, Imai C, Shida T, et al. Progression of microstructural deterioration in load-bearing immobilization osteopenia. PLoS One. 2022;17(11):e0275439.

17.          Flaherty LM, Schoeppe J, Kruse-Jarres R, Konkle BA. Balance, falls, and exercise: Beliefs and experiences in people with hemophilia: A qualitative study. Res Pract Thromb Haemost. 2018;2(1):147-54.

18.          Sammels M, Vandesande J, Vlaeyen E, Peerlinck K, Milisen K. Falling and fall risk factors in adults with haemophilia: an exploratory study. Haemophilia. 2014;20(6):836-45.

19.          Bauer LO, Wu Z, Wolfson LI. An obese body mass increases the adverse effects of HIV/AIDS on balance and gait. Phys Ther. 2011;91(7):1063-71.

20.          Forsyth AL, Quon DV, Konkle BA. Role of exercise and physical activity on haemophilic arthropathy, fall prevention and osteoporosis. Haemophilia. 2011;17(5):e870-6.

21.          Gay ND, Lee SC, Liel MS, Sochacki P, Recht M, Taylor JA. Increased fracture rates in people with haemophilia: a 10-year single institution retrospective analysis. Br J Haematol. 2015;170(4):584-6.

22.          Karinkanta S, Piirtola M, Sievänen H, Uusi-Rasi K, Kannus P. Physical therapy approaches to reduce fall and fracture risk among older adults. Nat Rev Endocrinol. 2010;6(7):396-407.

23.          Booth J, Lu M, Gallo D, Ito D, Valentino LA. Increased Risk of Adverse Bone Health Outcomes in People with Bleeding Disorders. Blood. 2016;128(22):250-.

24.          Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19(4):385-97.

25.          Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26 Suppl 6:1-158.

26.          Gold DT, McClung B. Approaches to patient education: emphasizing the long-term value of compliance and persistence. Am J Med. 2006;119(4 Suppl 1):S32-7.

27.          Eid M, Ibrahim M, Aly S. Effect of resistance and aerobic exercise on bone mineral density, muscle strength and functional ability in children with hemophilia. Egyptian Journal of Medical Human Genetics. 2014;15.

28.          Calatayud J, Pérez-Alenda S, Carrasco JJ, Cruz-Montecinos C, Andersen LL, Bonanad S, et al. Safety and Effectiveness of Progressive Moderate-to-Vigorous Intensity Elastic Resistance Training on Physical Function and Pain in People With Hemophilia. Physical Therapy. 2020;100(9):1632-44.

29.          Benedetti MG, Furlini G, Zati A, Letizia Mauro G. The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients. Biomed Res Int. 2018;2018:4840531.

30.          Frost HM. Wolff's Law and bone's structural adaptations to mechanical usage: an overview for clinicians. Angle Orthod. 1994;64(3):175-88.

31.          Rowe P, Koller A, Sharma S. Physiology, Bone Remodeling.  StatPearls. Treasure Island (FL): StatPearls Publishing

Copyright © 2023, StatPearls Publishing LLC.; 2023.

32.          CDC. Youth Physical Activity Guidelines Toolkit 2017 [updated January 24, 2017. Available from: https://www.cdc.gov/healthyschools/physicalactivity/guidelines_backup.htm.

33.          Soucek O, Komrska V, Hlavka Z, Cinek O, Rocek M, Zemkova D, et al. Boys with haemophilia have low trabecular bone mineral density and sarcopenia, but normal bone strength at the radius. Haemophilia. 2012;18(2):222-8.

34.          Tlacuilo-Parra A, Morales-Zambrano R, Tostado-Rabago N, Esparza-Flores MA, Lopez-Guido B, Orozco-Alcala J. Inactivity is a risk factor for low bone mineral density among haemophilic children. Br J Haematol. 2008;140(5):562-7.

35.          Alioglu B, Selver B, Ozsoy H, Koca G, Ozdemir M, Dallar Y. Evaluation of bone mineral density in Turkish children with severe haemophilia A: Ankara hospital experience. Haemophilia. 2012;18(1):69-74.

36.          Gómez-Bruton A, Matute-Llorente Á, González-Agüero A, Casajús JA, Vicente-Rodríguez G. Plyometric exercise and bone health in children and adolescents: a systematic review. World J Pediatr. 2017;13(2):112-21.

37.          Hernandez G, Baumann K, Knight S, Purrington H, Gilgannon M, Newman J, et al. Ranges and drivers of risk associated with sports and recreational activities in people with haemophilia: results of the Activity-Intensity-Risk Consensus Survey of US physical therapists. Haemophilia. 2018;24 Suppl 7:5-26.

38.          Anderson A, Forsyth A. Playing It Safe - Bleeding Disorders, Sports and Exercise. New York, NY: National Hemophilia Foundation; 2017.

39.          Baumann K, Herman-Hilker S, Newman J. Working for Success - Matching Your Physical Abilities and Job Requirements. New York, NY: National Bleeding Disorders Foundation; 2023.

40.          Gomis M, Querol F, Gallach JE, González LM, Aznar JA. Exercise and sport in the treatment of haemophilic patients: a systematic review. Haemophilia. 2009;15(1):43-54.

41.          Cuesta-Barriuso R. Effectiveness of Physiotherapy in the Treatment of Hemophilic Arthropathy a Systematic Review. Annals of Hematology & Oncology. 2017;4.

42.          Wagner B, Krüger S, Hilberg T, Ay C, Hasenoehrl T, Huber DF, et al. The effect of resistance exercise on strength and safety outcome for people with haemophilia: A systematic review. Haemophilia. 2020;26(2):200-15.

43.          Cruz‐Montecinos C, Núñez‐Cortés R, Vasconcello‐Castillo L, Solís‐Navarro L, Carrasco‐Alonso B, Calatayud J, et al. Exercise capacity in people with haemophilia: A systematic review. Haemophilia. 2022;28(6):891-901.

44.          Salim M, Brodin E, Spaals-Abrahamsson Y, Berntorp E, Zetterberg E. The effect of Nordic Walking on joint status, quality of life, physical ability, exercise capacity and pain in adult persons with haemophilia. Blood Coagul Fibrinolysis. 2016;27(4):467-72.

45.          Al-Sharif FA-G, Al-Jiffri OH, Abd El-Kader SM, Mohamed Ashmawy E. Impact of Mild versus Moderate Intensity Aerobic Walking Exercise Training on Markers of Bone Metabolism and Hand Grip Strength in Moderate Hemophilic A Patients. African Health Sciences. 2014;14(1):11.

46.          Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J. 2009;39(8):495-501.

47.          Falk B, Portal S, Tiktinsky R, Weinstein Y, Constantini N, Martinowitz U. Anaerobic power and muscle strength in young hemophilia patients. Med Sci Sports Exerc. 2000;32(1):52-7.

48.          Falk B, Portal S, Tiktinsky R, Zigel L, Weinstein Y, Constantini N, et al. Bone properties and muscle strength of young haemophilia patients. Haemophilia. 2005;11(4):380-6.

49.          Fearn M, Hill K, Williams S, Mudge L, Walsh C, McCarthy P, et al. Balance dysfunction in adults with haemophilia. Haemophilia. 2010;16(4):606-14.

50.          Chimeno-Hernández A, Querol-Giner F, Pérez-Alenda S, Núñez-Cortés R, Cruz-Montecinos C, Carrasco JJ, et al. Effectiveness of physical exercise on postural balance in patients with haemophilia: A systematic review. Haemophilia. 2022;28(3):409-21.

51.          Parhampour B, Torkaman G, Hoorfar H, Hedayati M, Ravanbod R. Effects of short-term resistance training and pulsed electromagnetic fields on bone metabolism and joint function in severe haemophilia A patients with osteoporosis: a randomized controlled trial. Clin Rehabil. 2014;28(5):440-50.

52.          Funk RH, Monsees T, Ozkucur N. Electromagnetic effects - From cell biology to medicine. Prog Histochem Cytochem. 2009;43(4):177-264.

53.          Darendeliler MA, Darendeliler A, Sinclair PM. Effects of static magnetic and pulsed electromagnetic fields on bone healing. Int J Adult Orthodon Orthognath Surg. 1997;12(1):43-53.

54.          Spadaro JA, Short WH, Sheehe PR, Hickman RM, Feiglin DH. Electromagnetic effects on forearm disuse osteopenia: a randomized, double-blind, sham-controlled study. Bioelectromagnetics. 2011;32(4):273-82.

55.          El-Shamy S. Effect of whole body vibration training on quadriceps strength, bone mineral density, and functional capacity in children with hemophilia: a randomized clinical trial. J Musculoskelet Neuronal Interact. 2017;17(2):19-26.

56.          Kear BM, Guck TP, McGaha AL. Timed Up and Go (TUG) Test: Normative Reference Values for Ages 20 to 59 Years and Relationships With Physical and Mental Health Risk Factors. J Prim Care Community Health. 2017;8(1):9-13.

57.          King L, Horak F. On the Mini-BESTest: Scoring and the Reporting of Total Scores. Physical Therapy. 2013;93(4):571-5.

58.          Springer BA, Marin R, Cyhan T, Roberts H, Gill NW. Normative values for the unipedal stance test with eyes open and closed. J Geriatr Phys Ther. 2007;30(1):8-15.

59.          Melo TA, Duarte ACM, Bezerra TS, França F, Soares NS, Brito D. The Five Times Sit-to-Stand Test: safety and reliability with older intensive care unit patients at discharge. Rev Bras Ter Intensiva. 2019;31(1):27-33.

60.          Miranda-Cantellops N, Tiu TK. Berg Balance Testing.  StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2024.