Bone health assessment in haemophilic arthropathy: A single centre study from Kolkata, West Bengal, India

In this cross-sectional study, PWH with arthropathy involving ≥3 joints attending the haemophilia clinic at Nil Ratan Sircar Medical College and Hospital, Kolkata, over a period of five years from January 2016 to December 2020 were included. People with haemophilia A and haemophilia B of all severities without inhibitors were included in the study. The included PWH were divided into four groups according to age and the number of joints affected by haemophilic arthropathy was recorded. Hemophilia Joint Health Score (HJHS) (clinical scoring system) and Pettersson score (radiological scoring system) for the target joints were calculated for each patient.

HJHS 2.1 is the most recent version and consists of assessments of swelling (0–3), duration of swelling (0–1), muscle atrophy (0–2), crepitus on motion (0–2), flexion loss (0–3), extension loss (0–3), joint pain (0–2) and strength (0–4) for elbows, knees and ankles and a global gait score (0–4). Scores range from 0 to 20 per joint and the global gait score ranges from 0 to 4, resulting in a total HJHS score from 0 to 24 points ^[24,25].

The Pettersson score covered eight parameters scored on radiographs of the affected joint taken in two planes (Table 1). The extent of irreversible joint changes was assessed by scoring each of the parameters on a 0–2-point scale. Essentially reversible findings such as soft tissue swelling or synovial thickening were disregarded. The maximum possible score for a given joint was 13 points ^[26].

Levels on serum calcium, phosphorus, vitamin D3 and b-ALP were assayed in all cases. The percentage of PWH with low serum calcium, low phosphorus levels, low vitamin D3 levels or high b–ALP levels adjusted for age and sex were calculated, according to the standard reference range. Data was analysed using Pearson's correlation coefficient (r) and p-value <0.05 was taken as statistically significant.

A total of 320 PWH were included in the study. The median age was 17 years (range 1–70 years). Overall, 78.13% (250/320) had haemophilia A; 21.87% (70/320) had haemophilia B. The majority (85%; 272/320) had severe haemophilia; 13.44% (43/320) had moderate haemophilia; 1.56% (5/320) had mild haemophilia. At the time of examination and evaluation, 34.37% (110/320) were on prophylaxis; the remainder were on on-demand therapy.

Table 2 shows joint health scoring and biochemical parameters across the different age groups. With increasing age, the number of joints involved increased significantly (r=0.2250, p<0.05). When adjusted for age, b-ALP was higher than normal for the majority of PWH (88.75%). Also, a positive correlation was seen between higher-than-normal b-ALP (adjusted for age and sex) with increased number of joint involvement (r=0.2112, p=0.0001) and severity of disease (r= 0.2652 p<0.0001). Patients with a higher Pettersson score also had higher than normal b-ALP, though the result was not statistically significant (r=0.0994, p=0.0758). There was no association between b-ALP and HJHS score. PWH with higher-than-normal b-ALP had lower calcium (r=-0.0909, p=0.1048) and phosphorus levels (r=-0.0256 p =0.6484), although the difference was not statistically significant. A significant positive correlation was seen between Pettersson score and HJHS score (r score 0.1126, p=0.04). No correlation was seen between Pettersson score or HJHS score with calcium, phosphorus or vitamin D levels (p<0.05). There was no significant correlation between the number of joints involved, severity of disease and serum vitamin D3 level across the whole cohort.

Osteoporosis in general has been considered to be an important cause of morbidity in both men and women, and more so in haemophilia and other bleeding disorders. Specific triggering factors in PWH include abnormal liver function because of viral infection, bleeding and inflammation, lack of physical and athletic activities, low body weight and others ^[27]. Although the pathogenesis of osteoporosis is not clear, it has been considered as a severe comorbidity in PWH in both developing and developed countries. This is more evident in developing countries where there is limited access to factor concentrates, and primary prophylaxis is beyond the reach of vast majority of the patients ^[27]. In the present study, the majority of patients were on on-demand therapy and not on regular prophylaxis.

The present study indicates a positive association between b-ALP (adjusted for age and sex), a marker that indicates high bone turnover with number of affected joints and severity of the disease. Similar to the present study, Anagnostis et al. ^[21] found a positive association of b-ALP with the severity of haemophilia and number of affected joints. They found a negative association with BMD in hip and femoral neck, history of fracture, and level of physical activity, though these points were not evaluated in the present study. Anagostis et al. also reported that b-ALP was high in patients who had low BMD ^[21].

Our study found a radiological and clinical correlation, with patients who had a high Pettersson score on X-ray also having a high HJHS score on clinical examination. Poonnoose et al. ^[28] also showed a good correlation between HJHS and Pettersson score (r=0.66). PWH in the present study with a high Pettersson score also had high b-ALP, although the results were not statistically significant. This indicates that b-ALP may be of help in evaluating bone health in PWH, though more studies are needed to further establish the association. We could not find any similar studies in haemophilia from this geographic region.

Many studies have shown PWH to have low BMD. Barnes et al. ^[11] showed significantly reduced BMD in PWH. Mansouritorghabeh et al. ^[12] showed that BMD is significantly reduced even in cases of severe haemophilia B, and the effect on BMD is not dependent on the severity of haemophilia ^[11,12]. PWH with low BMD have been found to have reduced bone formation activity but no difference with regard to bone resorption markers ^[13]. Abdelrazik et al. ^[14] showed that reduction in BMD is not dependent on age and body size. Naderi et al. ^[15] have reported that bleeding into the joints is more pronounced in osteoporotic patients compared with osteopenic or normal healthy controls. Wallny et al. ^[16] reported osteopenia and osteoporosis in 69% of people with severe haemophilia. However, the majority of these studies used DEXA scans as the technique to evaluate the BMD.

We are aware of two studies in India where DEXA scans have been used to measure BMD in relatively small cohorts. Nair et al. ^[10] found that in 50 people with severe haemophilia aged 20–50 the prevalence of osteoporosis was 50% higher than in age- and sex-matched controls; they concluded that developing osteoporosis is a significant problem for people with severe haemophilia in India. In a cohort of 38 children with haemophilia (>18 years), Ashritha et al. ^[19] found low bone mineral content in 58% and low BMD in 21% compared with age- and sex-matched controls.

We were unable to use DEXA to calculate BMD in our study as, in common with many hospitals in India, there are no DEXA facilities in our hospital. Availability of DEXA in India has been given as between 200 and 300 machines nationally to serve a population of 1.3 billion ^[20]. Even where DEXA is available, scans are costly and not always covered by healthcare schemes. It is therefore important that alternative, cost-effective tools that are more readily available can be used to assess BMD. Various studies have shown an association between high b-ALP and low BMD, indicating high b-ALP as a surrogate marker for low BMD ^[21,29]. However, few studies have evaluated b-ALP in haemophilia and compared this with clinical or radiological scoring for bone arthropathy. It is clear from our findings that b-ALP might serve as a surrogate marker to assess bone health in PWH in clinics where DEXA is not available. Further studies including other bone markers are required to further establish this fact.

PWH with severe disease and haemophilic arthropathy appear to have higher than normal bone-specific ALP (b-ALP), which may in turn reflect increased bone turnover and low bone mineral density (BMD). Hence, b-ALP might serve as a surrogate marker to help assess bone health in PWH, particularly in settings where access to DEXA scans is constrained. Further studies will be needed to confirm this conclusion.