Musculoskeletal problems of people with hemophilia aged > 65 years

Abstract

Both the health-related quality of life and total life expectancy of people with hemophilia (PWH) have improved in recent decades. This can be attributed mostly to advancements in replacement therapy, antiviral medications, and improvements in global inclusive care rendered by the increasing number of multi-disciplinary specialized centers. The purpose of this article was to analyze what the literature reveals about the musculoskeletal problems of PWH aged > 65 years. For this narrative review of the literature, a search was conducted on PubMed and The Cochrane Library. It has been found that progressive hemophilic arthropathy and declining fitness in PWH aged > 65 risks loss of independence, falls and fractures. Additionally, hemophilic arthropathy is an important cause of pain and disability. It is a frequent indication for surgical intervention in PWH aged > 65 years. However, hemophilia per se is not a contraindication for emergency orthopedic surgery in PWH aged > 65 years. PWH aged > 65 years are at elevated risk of postoperative hemorrhage, which might be increased in individuals with coagulation abnormalities or thrombocytopenia due to liver cirrhosis from previous hepatitis C infection. In immunocompromised individuals with human immunodeficiency virus, there is an elevated risk of infection and prosthetic loosening. In conclusion, hemophilic arthropathy and fractures of PWH aged > 65 years should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Prevention of falls is paramount. Major orthopedic surgery should be managed by multidisciplinary teams at Hemophilia Treatment Centers.

Key Words: Hemophilia; Elderly; Musculoskeletal problems; Hemophilic arthropathy; Orthopedic surgery

Core Tip: Hemophilic arthropathy and fractures of people with hemophilia aged > 65 years should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Prevention of falls is paramount. Major orthopedic surgery should be managed by multidisciplinary teams at Hemophilia Treatment Centers.

INTRODUCTION

More people with hemophilia (PWH) are reaching advanced ages. Hemophilia center physicians increasingly face the challenges of managing age-related clinical problems not witnessed in previous eras[1-3].

In 2006, Street et al[4] stated that we need to be aware of the ageing issues in hemophilia and develop “wellness” programs which are directed to the early identification of disease as well as preventative strategies to reduce the physical and psychological impacts of ageing.

In 2009, Siboni et al[5] compared individuals with severe hemophilia, aged > 65 years, with men without bleeding disorders matched for age, sex, geography and social status. They reported that PWH aged > 65 years had more comorbidities and issues with activities of daily living but exhibited a similar cognitive status as their non-hemophilic peers. While PWH aged > 65 years had more chronic viral infections and hypertension they developed less cardiovascular diseases.

In 2019, Shapiro and Makris[6] reported that international collaboration is critical, including comprehensive registry data and future prospective trials, to achieve future optimal and evidence-based orthopedic surgical outcomes for elderly PWH.

In a 2021 study in the Netherlands, researchers looked at the life expectancy of over 1000 men with hemophilia from 2001 to 2018. About 87% of men had hemophilia A, and the rest had hemophilia B. The researchers estimated that half of the men in their study would live to be 77, which is about 6 years lower than the general population of Dutch males[7].

In a 2026 study in France, Tabélé et al[8] analyzed 9928 PWH included in the FranceCoag database between 1994 and 2022. Compared with the general population Tabélé et al[8] found broadly comparable life expectancy in PWH, although differences remain according to disease severity.

Many PWH aged > 65 years have at least one co-morbid condition, other than hemophilia. Most of them have between 3-6 co-morbidities. The most frequently encountered comorbidities are chronic hepatitis C, hypertension, human immunodeficiency virus (HIV), chronic arthropathy, and overweight/obesity[6]. However, such a list is not exhaustive. Older PWH may suffer from other conditions additional to those mentioned above[9-12].

The purpose of this review article has been to analyze what the hemophilia literature reveals about musculoskeletal (MSK) problems in PWH aged > 65 years.

Compared with previous reviews on “hemophilia and ageing,” this review adds important updates on sarcopenia, fracture risk, spinal stenosis, and modern perioperative management.

METHODOLOGY

On July 31, 2026, a bibliographic search was conducted on PubMed and the Cochrane Library using the following sets of keywords: “Hemophilia aging”, “hemophilia orthopedic surgery elderly”, “hemophilia elderly bone mineral density”; “hemophilia elderly perioperative thromboprophylaxis”; “hemophilia elderly perioperative hemostatic management”; “hemophilia elderly pain treatment”; “hemophilia elderly fracture management”; “hemophilia aged > 65 years”, and “hemophilia sarcopenia”.

Of the total number of articles found (n = 1379), 57 were selected because they were considered the most relevant to the title of this article. In other words, they were selected subjectively based on the information they provided in relation to the purpose of this article. Search strategy is shown in Figure 1.

Figure 1  Search strategy.

We chose “> 65 years” as the main age cutoff because most developed countries consider people elderly at age 65 years [https://eldersavvy.com/what-age-is-considered-elderly/(last accessed August 30, 2026)].

SUMMARY OF FINDINGS

In 2010, Philipp[13] stated that joint disease increases progressively with age. In 2013, Stephensen and Rodriguez-Merchan[14] reported that increased pain, muscle weakness and atrophy, along with an increased risk of falling, were key features of advanced hemophilic arthropathy and ageing. Exercise programs undertaken 2-3 times per week for at least 12 weeks seemed to be very effective in diminishing the impact of age-related changes on the MSK system.

The data below include data directly obtained from PWH aged > 65 years and data extrapolated from broader adult hemophilia cohorts. In fact, several studies include younger or middle-aged adults, and therefore the evidence is indirect. This is especially important in the sections on sarcopenia, handgrip strength, physical activity, bone density, and exercise benefits.

Sarcopenia rates in (older) PWH

There are emerging data, though not yet a large, elderly-specific epidemiology.

Sarcopenia in severe hemophilia A (adult cohort): In 2024, Uzuner et al[15] assessed sarcopenia in 30 adults with severe hemophilia A using bioelectrical impedance analysis-derived appendicular skeletal muscle mass index (ASMI) and an ultrasound-based Modified Sonographic Tight Adjustment Ratio (STAR) method. Depending on the metric, sarcopenia prevalence ranged from 6.6% (ASMI) to 50% (STAR), with strong correlations to joint damage and functional tests.

Handgrip strength as a sarcopenia proxy: In 2026, Demirci et al[16] compared handgrip strength in 20 adults with hemophilia A (mean age 37 years, range up to 67 years) vs controls, showing significantly reduced grip strength and arguing for routine sarcopenia screening in hemophilia.

Physical activity, lean mass and bone quality: In 2025, Ransmann et al[17] studied 223 PWH (mean age, 44 years) and showed that handgrip strength and step activity correlate positively with lean mass, bone mineral density (BMD) and trabecular bone score—essentially linking muscle function to skeletal health in ageing hemophilia populations.

Frailty (including sarcopenia-like constructs) in older PWH: In 2025, McKeown et al[18] reviewed frailty and frailty syndromes in PWH, highlighting increased frailty in older, severely affected patients with arthropathy and calling for systematic screening and tailored interventions.

Direct, large-scale data on sarcopenia rates specifically in elderly (> 65 years) PWH are still sparse, but these papers collectively support a high burden of muscle weakness/low muscle mass and frailty in ageing PWH.

Prophylactic physiotherapy/exercise benefits in older PWH

There is not a single “elderly-only prophylactic physiotherapy” randomized clinical trial (RCT), but there is a growing body of work on structured exercise and physical activity in PWH—much of it including middle-aged and older adults—and it consistently supports benefit when combined with adequate hemostatic prophylaxis.

Exercise programs in PWH—scoping review: In 2026, Veríssimo et al[19] mapped 36 studies of exercise programs in hemophilia. Strength, flexibility and aerobic training (typically 2-4 sessions/week for 4-30 weeks) were generally safe under appropriate factor prophylaxis and improved MSK health, pain, function and quality of life.

Safety and efficacy of exercise (including older adults): The same scoping review and earlier Cochrane-type analyses show that supervised, multimodal programs at light-moderate intensity can be delivered without increased bleeding when timed to prophylaxis and can reduce pain and functional impairment from arthropathy[19].

Physical activity as a “pillar” of care in the modern prophylaxis era: In 2026, Cruz-Montecinos et al[20] have reported that physical activity (resistance and aerobic exercise) in PWH under individualized prophylaxis (extended halflife factors, emicizumab, gene therapy) should be actively promoted. Physical activity is beneficial for muscle strength, coordination, bone density, cardiovascular health, chronic pain modulation and quality of life. Therefore, physical activity is a core therapeutic strategy in ageing hemophilia populations.

Evidence directly in > 65-year-olds is limited but: Frailty and MSK decline are clearly increased in older PWH. Adult cohorts already show high sarcopenia/low muscle strength and strong links to joint damage and function. Exercise/physiotherapy programs, when aligned with prophylactic factor or nonfactor therapy, are consistently beneficial and safe, and are now recommended as part of standard care.

There is growing, reasonably robust evidence that prophylactic, structured physiotherapy/exercise (strength, flexibility, aerobic, balance) under adequate hemostatic cover is beneficial, and should be considered a proactive, positive intervention in ageing PWH, even though elderlyspecific RCTs are still lacking.

Loss of independence and falls

Street et al[4] and Angelini et al[12] reported that progressive hemophilic arthropathy and declining fitness in elderly PWH might cause loss of independence and falls with increasing fracture risk.

The impact of hemophilia severity on BMD

In 2024, Ransmann et al[21] observed that BMD was diminished in 63.1% of the study cohort (n = 255, mean age 43 years). They advised routine osteoporosis screening in aging PWH. Using the World Health Organization definition of osteoporosis, the disease affects approximately 6.3% of men over the age of 50 years and 21.2% of women over the same age range globally. Based on the world population of men and women, this suggests that approximately 500 million men and women worldwide may be affected[22].

In individuals with severe hemophilia A, in 2024, Biernat et al[23] analyzed BMD and bone mineral content (BMC) using dual X-ray absorptiometry (DXA). The study confirmed that BMD and BMC were low in PWH. Factors that contributed to low BMD included vitamin D deficiency, low body mass index (BMI), high neutrophil/lymphocyte ratio, and low testosterone/estradiol ratio.

In 2022, according to Petkovic et al[24] prevention of osteoporosis should include vitamin D repletion, lifestyle changes, e.g., smoking cessation, alcohol moderation, and weight-bearing exercises. BMD should be assessed with DXA screening at age 50 years, or earlier, for individuals with additional risk factors such as HIV, hepatitis C, hypogonadism, or chronic corticosteroids utilization.

According to several authors there are three ways to define osteoporosis[16-18]: Existence of a fragility fracture (spontaneous or minimal trauma fracture); T-score ≤ 2.5 at the lumbar spine, femoral neck, or total hip; or T-score between -1 and -2.5, as well as a 10-year likelihood of hip fracture ≥ 3% or a 10-year likelihood of a major osteoporosis-related fracture ≥ 20%.

A T-score of -1 or above indicates normal bone density; a T-score between -1 and -2.5 indicates osteopenia (low bone mass); a T-score of -2.5 or lower indicates osteoporosis; T-scores are calculated by comparing a patient’s bone density test results to the average bone density of a young, healthy reference population. The formula involves subtracting the mean bone density of the reference population from the patient’s bone density and then dividing by the standard deviation of the reference population’s bone density. DXA is considered the gold standard for measuring bone density.

The Fracture Risk Assessment Tool should be utilized to predict 10-year fracture risk. Osteoporosis management, e.g., anabolic treatment, antiresorptive treatment, should be taken when needed[25-27].

Increased fracture risk compared to the general population

Hemophilia Treatment Centers (HTCs) should use comprehensive screening protocols to detect BMD from early adulthood[28-30]. In a meta-analysis, Divaris et al[31] demonstrated a low BMD with a > 4-fold increased fracture risk in PWH compared to the general population.

In 2026, Germini et al[32] reported that PWH have a higher risk of bone fractures than the general population. The severity of hemophilia and the presence, or history, of an inhibitor are particular risk factors for a bone fracture. The study included 1080 PWH and 21597 controls. About 9% of PWH and 6% of controls experienced a fracture (the difference was statistically significant).

Orthopedic surgery

In 2009, Mauser-Bunschoten et al[11] described how hemophilic arthropathy was an important cause of pain and disability, and frequent indication for surgery in elderly PWH.

The HTCs should have access to a multidisciplinary team of nurses, social workers, orthopedic surgeons, physical medicine and rehabilitation (PMR) physicians, physical therapists, and hematologists familiar with the needs of elderly PWH[33]. Orthopedic procedures should be undertaken early in the week (ideally on Tuesdays), and early in the day by experienced orthopedic surgeons[34].

In 2014, Siboni et al[35] described the combination of optimal hemostasis control and an adequate surgical technique as being required for successful outcomes in orthopedic surgery in PWH. This needs the involvement of HTCs.

Hemophilia is not a contraindication for emergency orthopedic surgery. Major orthopedic surgery should be managed by, or in close collaboration with, a multidisciplinary team at a HTC. Surgeries are best carried out at a center able to monitor perioperative factor activity levels in a timely way[33,34]. In 2005, Silva and Luck[36] revealed that total joint arthroplasty in PWH had a 30% complication rate.

With regard to total knee arthroplasty (TKA), in 2024, Rodriguez-Merchan et al[37] reported that the complication rates of TKA ranged between 8.5% and 28.7%, with postoperative hemarthrosis being the most frequent (7.6%). Compared to individuals without hemophilia, PWH had a substantially higher incidence of periprosthetic joint infection (PJI) and 1-year revision/re-operation. Therefore, although TKA substantially improves the quality of life of PWH, it is a surgical procedure that has a significant proportion of adverse events[37].

Total hip arthroplasty (THA) has been reported to have a higher 1-year infection rate (8.1% vs 3.4%) in PWH than in the general population: Additionally, a higher length of stay (6 days vs 3 days) and a higher 30-day readmission rate (22.6% vs 4.1%)[38]. Elderly PWH are at elevated risk of postoperative hemorrhage, which is increased in individuals with thrombocytopenia due to liver cirrhosis from prior hepatitis C infection[39]. There is also an elevated risk of PJI and prosthetic loosening, especially in immunocompromised subjects with HIV[40].

Besides osteoporosis-related fractures, PWH, who have not received effective prophylaxis from an early age, are at high risk of suffering from chronic hemophilic arthropathy needing joint arthroplasty. Knee joints and hip joints are the most replaced joints[33,39].

Conditions other than MSK problems that may affect orthopedic-surgery outcomes in PWH aged > 65 years include the following[1-12]: HIV and/or hepatitis C virus infection; genitourinary problems; psychological symptoms; cardiovascular problems (hypertension, acute coronary syndromes, non-valvular atrial fibrillation, intracranial hemorrhage; overweight/obesity; diabetes mellitus; liver disease; and cancer).

In 2020, Gould et al[41] stated that in the general population the following comorbidities were strongly associated with unplanned 30-day readmission following TKA: Bleeding disorder, diabetes, chronic kidney disease and dialysis, chronic immunosuppressant use and history of cancer. Other significant comorbidities included: Dementia; depression; hematological (coagulopathy and anemia), cardiovascular (atrial fibrillation, cardiovascular disease, coronary artery disease and congestive heart failure), respiratory (chronic obstructive pulmonary disease) and liver diseases; and cerebrovascular accident/transient ischemic attack (but only in revision TKA patients).

Fourteen HIV-positive hemophilia patients (7 THAs and 14 TKAs) were included in the study of Wang et al[42] in 2023. The cohort was followed up for about 4 years. There were 4 complications noted among 21 arthroplasties performed, giving a 19% complication rate. Wang et al[42] concluded that THA or TKA of the PWH with HIV was a worthwhile procedure and can be performed by an experienced and collaborative multidisciplinary team in a tertiary center with a good hemophilia care system.

In a 2023 systematic review and meta-analysis, Fu et al[43] found that in PWH, HIV was related to worse prosthetic survivorship.

In 2026, Tsai et al[44] evaluated the incidence and clinical predictors of postoperative urinary retention (POUR) following total joint arthroplasty in the general population; they also assessed whether preoperative bladder voiding efficiency (BVE) could independently predict POUR. The overall incidence of POUR was 16.5% (33/200). Compared to the non-POUR group, the POUR group exhibited significantly higher International Prostate Symptom Score (IPSS) and lower BVE. Higher BMI, hypertension, and diabetes mellitus were significantly associated with POUR development. Higher preoperative IPSS and lower BVE seemed to be independently associated with POUR following total joint arthroplasty. Routine preoperative assessment of BVE and IPSS may aid in the early identification of high-risk patients, enabling the implementation of targeted strategies to prevent POUR and its associated complications.

In the study of Lee et al[45] in 2026 subclinical cognitive and somatic psychological symptoms in the general population were linked to postoperative delirium after TKA, emphasizing the need for preoperative identification of high-risk patients.

An emerging complication of elderly PWH: Symptomatic spinal stenosis

In 2025, Kelly et al[46] reported an emerging complication of elderly PWH: Symptomatic spinal stenosis. They reported that spinal stenosis percentages were higher in PWH than in the general population of the same age.

PMR, physiotherapy and pain management

PMR physicians and physiotherapists with hemophilia-specific expertise should develop individualized plans to optimize joint strength and range of motion (ROM), balance evaluation, and provide safe home/rehabilitation discharge planning post-surgically. These plans should be undertaken for all PWH to prevent weakness and joint contractures. If an orthopedic surgical procedure is elective, preoperative PMR and physiotherapy should be carried out to improve strength and ROM[47,48].

According to Makris et al[49] in 2024, despite improvements in overall hemophilic management and decreases in bleeding episodes, MSK pain is usually a significant problem with advancing age. The treatment of pain amongst elderly PWH, who usually suffer from multiple co-morbidities, should entail a person-centered, holistic, multi-disciplinary approach including the input of a dedicated pain specialist.

In 2025, McLaughlin et al[50] demonstrated a gap in confidence in the delivery of effective pain treatment in PWH. There is a need for HTCs to establish responsibility for pain management.

Perioperative hemostatic management in PWH aged > 65 years

Reported guidelines and recommendations for the perioperative hemostatic management of elderly PWH are shown in Tables 1 and 2[51,52]. Factor replacement schedules for older adult individuals with hemophilia A or B without inhibitors are shown in Table 1. Suggested dosing regimens for bypassing drugs in hemophilia patients with inhibitors are shown in Table 2.

Table 1 Factor replacement schedule for people with hemophilia A or B aged > 65 years without inhibitors based on World Federation of Hemophilia guidelines.

Type of surgery	Hemophilia A		Hemophilia B
	Aim peak levels (%)	Time span	Aim peak levels (%)	Time span
Minor orthopedic surgery	50-80	Day of surgery	50-80	Day of surgery
	30-80	Days 1-5	30-80	Days 1-5
Major orthopedic surgery	80-100	Day of surgery	60-80	Day of surgery
	60-80	Days 1-3	40-60	Days 1-3
	40-60	Days 4-6	30-50	Days 4-6
	30-50	Days 7-14	20-40	Days 7-14

Dosing must be individualized according to factor level monitoring, thrombotic risk and center protocols.

Table 2 Dosing regimens of bypassing agents in people with hemophilia with inhibitors aged > 65 years.

Drug	Dosing for minor orthopedic surgery	Dosing for major orthopedic surgery	Comments
Recombinant factor VII activated	90 µg/kg/dose immediately before surgery and every 2 hours for 2 days and then every 2-6 hours until healed	90 µg/kg/dose immediately before surgery and every 2 hours for 2 days. Then every 2-3 hours for 5 days, then every 4 hours until days 7-10, then every 6 hours until days 14-21	Preferred drug for individuals with hemophilia B and high-titer inhibitors per WFH guidelines since aPCCs contains factor IX and may cause or worsen an allergic reaction
			For individuals with factor IX deficiency, low dose (15-30 µg/kg) in combination with tranexamic acid has been shown to be effective for major surgery in limited studies and can be considered for those at risk of thrombosis
aPCCs	50-100 U/kg immediately prior to surgery and then every 6-12 hours	50-100 U/kg immediately prior to surgery, then every 6-12 hours	Maximum: 100 units/kg/dose; 200 units/kg/day)
			Less preferred for hemophilia B individuals with high-titer inhibitors per WFH guidelines

Dosing must be individualized according to thrombotic risk and center protocols. aPCCs: Activated prothrombin complex concentrate; WFH: World Federation of Hemophilia.

Perioperative thromboprophylaxis

Buckner et al[53] reported the prevalence of ultrasound-detectable symptomatic and asymptomatic deep vein thrombosis (DVT) in PWH following TKA or THA in 2016. An incidence of 2.2% symptomatic venous thromboembolism was similar to the estimated incidence in the general population without thromboprophylaxis. No subjects had asymptomatic DVT[53]. Ahmed et al[54] in 2018 and Rodriguez-Merchan et al[55] in 2026 did not recommend routine postoperative use of pharmacological thromboprophylaxis in PWH.

The World Federation of Hemophilia recommends against the routine employment of pharmacologic thromboprophylaxis in individuals with hemophilia A or hemophilia B experiencing major non-cardiac surgery[39]. For orthopedic procedures, the American Academy of Orthopedic Surgeons and the American College of Chest Physicians also recommend avoiding the routine employment of antithrombotic drugs in PWH with the exception of patients with high plasma levels of coagulation factors[56].

However, in 2021, Abou-Ismail and Connell[51] reported older PWH undergoing orthopedic surgery require an individualized risk/benefit evaluation when additional thrombotic risk factors are present. In 2025, Badulescu et al[57] recommended enoxaparin for thromboembolic prophylaxis in PWH undergoing TKA and THA.

In short, regarding whether or not to use pharmacological thromboembolic prophylaxis in major orthopedic surgery for PWH who are over 65 years of age, the evidence is conflicting; therefore, it seems logical to conduct an individualized risk-benefit assessment rather than adopting a single, universal approach.

DISCUSSION

In the last decade there have been dramatic improvements in orthopedic surgery and hematological treatment. It is possible that, in the future, outcomes of orthopedic surgery in elderly PWH will be similar to those in the non-hemophilic population, provided that adequate perioperative hemostasis is achieved and associated co-morbidities are properly managed.

However, current literature for guidance is sparse with very low levels of evidence regarding MSK problems and orthopedic surgery in elderly PWH. Well-designed, multi-centered studies will be necessary to scientifically assess the current state of MSK problems and orthopedic surgery in elderly PWH.

Unique challenges in elderly PWH are: (1) Increased risk of thrombosis with hemostatic therapy or bypassing agents; and (2) Increased risk of volume overload with large volumes of transfusion products. For PWH over 65 years experiencing TKA and THA, current guidelines for the perioperative hemostatic management period are limited due to underrepresentation in clinical studies. The optimal perioperative treatment of elderly PWH is often complex. Best results can be accomplished with a meticulous, individualized, approach that involves orthopedic surgeons, hematologists, PMR physicians and physiotherapists working together in a multi-disciplinary environment.

This article has several limitations: It analyzed articles from only two databases (PubMed and The Cochrane Library); a substantial portion of the cited evidence is not derived from cohorts exclusively aged > 65 years; selection bias in a narrative review; lack of formal quality assessment; differences between older and modern treatment periods; inconsistent age definitions; and the fact that many studies included patients younger than 65 years.

CONCLUSION

The following conclusions can be drawn from the published literature on MSK problems in PWH aged > 65 years: (1) Progressive hemophilic arthropathy and declining fitness in elderly PWH may contribute to loss of independence and falls and fractures. Prevention of falls is paramount; (2) Advanced hemophilic arthropathy is an important cause of pain and disability, and sometimes leads to surgery in elderly PWH; and (3) In general, advanced hemophilic arthropathy and fractures of elderly PWH should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Study heterogeneity, evidence quality, and the lack of evidence specifically from older patients mean that the findings of this study must be confirmed by future studies with a high level of evidence.