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International Orthopaedics

, Volume 42, Issue 7, pp 1527–1534 | Cite as

Osteonecrosis in sickle cell disease patients from Bahia, Brazil: a cross-sectional study

  • Gildasio Daltro
  • Bruno Adelmo Franco
  • Thiago Batista Faleiro
  • Davi Araujo Veiga Rosário
  • Paula Braga Daltro
  • Vitor Fortuna
Original Paper

Abstract

Purpose

The aim of this study was to describe the clinical features of osteonecrosis (ON) in sickle cell disease (SCD) patients in Bahia, a Northeast state with the highest prevalence of the disease in Brazil.

Methods

Between 2006 and 2017, 283 cases of osteonecrosis in SCD patients were enrolled to analyse the age at diagnosis, genotype, gender, pain, distribution of the lesions and disease staging. MRI and radiograph were obtained at the participation.

Results

Of the 283 SCD cases, 120 (42.4%) were haemoglobin SS genotype while 163 (57.6%) were SC genotype. Two hundred and forty-six cases were bilateral and 37 were unilateral, with an average age at diagnosis of 33.7 (range 10–67) years. The most frequent identified ON site not only was the hip (74.6%), but also affected shoulder, knee and ankle. Most cases presented at early stage I (172, 60.8%) disease. No significant differences on the features of osteonecrosis were identified between haemoglobin SS and haemoglobin SC cases.

Conclusions

Given the relatively high prevalence of bilateral osteonecrosis at early stages, painful symptoms and rather late age at diagnosis, SCD patients should have radiological examination of their joints more often in order to prevent severe functional disability and increase patient’s life quality.

Keywords

Bone necrosis Sickle cell disease Femoral head Joint MRI diagnosis 

Abbreviations

HbS

haemoglobin S

MRI

magnetic resonance imaging

ON

osteonecrosis

SCD

sickle cell disease

Background

Sickle-cell disease (SCD) is a group of genetic haemoglobin disorders characterized by the presence of haemoglobin S (HbS). Under deoxygenated conditions, haemoglobin S polymerizes in red blood cells (RBCs), forming a highly ordered fibber aggregates that distort the cells’ shape (sickled), which are removed from the circulation and destroyed at increased rates, leading to anaemia. Of greater clinical importance, the sickled RBCs cause vascular occlusion, which leads to tissue ischemia and infarction. The patients who are homozygous for the sickle-cell gene (haemoglobin SS, HBSS), or the association with another abnormal haemoglobin gene, particularly with HbC (HBSC), have a devastating and choric disease, with a high risk of bone osteonecrosis [1].

Sickle cell disease affects millions worldwide. In Brazil, the largest country in South America, the sickle cell gene is found at highest frequency in Bahia (Fig. 1), ranging from 6.9 to 15.4% in individuals of African descent [2, 3], and making SCD a major public health problem in northeast Brazil.
Fig. 1

Schematic presentation of frequency of sickle cell disease in Brazil. Frequency of sickle cell disease calculated from data of new-borns (alive) from 20 Brazilian states in 2012, according to National Neonatal Screening Program of the Brazilian Ministry of Health [2, 3]

Osteonecrosis is a common disorder and severe complication of SCD. A report on the natural history of untreated symptomatic ON femoral head in adult SCD demonstrated progression to subchondral collapse and end-stage arthritis in 87% of patients within five years of diagnosis [4]. Other joints including the knees, shoulders and ankles are also particularly vulnerable to osteonecrosis in sickle cell disease [5, 6]. When osteonecrosis is diagnosed in more than one site, the effects on the patient are magnified [6]. Advanced ON eventually requires replacement, which is associated with increased risk of adverse outcome and higher revision rates in SCD patients [7]. For these reason, the early diagnosis and treatment are very important.

Prevalence of osteonecrosis in SCD patients has varied from 2 to 17% in several studies, with a frequency as high as 41% in France and 11.1% in Brazil [5, 8, 9]. Osteonecrosis secondary to sickle cell disease affects middle-aged individuals who commonly have a higher activity level, and it is influenced by geographical location and disease severity. A particular propensity to develop ON has been shown in patients homozygous for the sickle cell gene (HBSS) [5], while some reports no difference in comparison with HBSC patients [9, 10, 11].

Despite the high prevalence of osteoarticular involvement in sickle cell disease patients, there have been no studies of these alterations in sickle cell osteonecrosis in Bahia, a Brazilian state with the highest African ethnic characteristics. Information regarding the epidemiological and clinical features of osteonecrosis could be useful for developing preventive measures and establishing appropriate treatment strategies for SCD patients. We therefore consider important to characterize the osteonecrosis found among sickle cell patients from northeast Brazil. In this cross-sectional study, we aimed to describe the clinical features of osteonecrosis in sickle cell disease patients in Bahia.

Material and methods

Study participants and design

The Committee of Ethics in Research of the Climério de Oliveira Maternity Hospital (Federal University of Bahia, UFBA) approved this study, and informed consent was obtained in accordance with ethical principles and the Helsinki Declaration of 1975 and by the Brazilian resolution 196/96, of the Ministry of Health, Law 6638/79 and Normative Resolution 04/97.

The cross-sectional study involved a group of 283 sickle cell disease patients (120 HBSS and 163 HBSC) from the State of Bahia in northeast Brazil and was carried out between 2006 and 2017. The patients were selected among those attending the orthopaedic outpatient facility at the Prof. Edgar Santos Hospital Complex (UFBA). Diagnosis of osteonecrosis was made with use of plain radiographs or magnetic resonance imaging (MRI). The diagnosis of osteonecrosis (in any epiphysis) on MRI was based on characteristic serpentine double signal line at T2, and band-like hypointense zones on T1-weighted images. Because patients with sickle cell disease have a high risk of multifocal osteonecrosis, this population of patients with osteonecrosis was simultaneously screened for osteonecrosis at other sites. The stage of osteonecrosis was graded with the method modified Ficat and Arlet staging system adapted for the hip [12], knee [13], ankle [6] or shoulder [14] with characteristic MRI findings [15]. The reliability of this system of classification is well known for bone osteonecrosis, and it is stratified into four stages. Stage I was defined as no apparent evidence of the disease on radiographs but abnormal necrotic changes on MRI. In stage II, there are cystic and/or osteosclerotic lesions on radiographs and MRI, with a normal contour of the epiphyseal head but absence of subchondral fractures. A crescent sign (a radiolucent line on the anteroposterior or lateral planes), subchondral fracture or flattening of the articular surface is a characteristic of stage III disease. In end-stage disease (stage IV), there were narrowing of the joint space and secondary changes in the distal aspect, such as cysts and marginal osteophytes. Using these methods for all patients, radiographic and MRI characteristics of the disease such as stage, location of the osteonecrosis and involvement of other joints were recorded. The haematology assays of patients were carried out in an automatic Coulter T 890 device and the haemoglobin pattern was confirmed at UFBA by the electrophoresis method on cellulose acetate ribbons, pH 8.4 and electrophoresis on agar-citrate, pH 5.3, and lately using High Performance Liquid Chromatography (HPLC—VARIANT I/Bio-Rad, Hercules, CA, USA). Inclusion criteria consisted of the following: (1) diagnosis of early stages (pre-collapse) knee osteonecrosis; (2) presence of symptomatic, insidious and progressive pain; and (3) availability of one and five year follow-up assessments. Exclusion criteria were (1) an age younger than ten years or older than 70 years; (2) radiologic diagnosis of advanced osteonecrosis (stage III or IV); (3) comorbidities with general medical conditions (e.g., diabetes or rheumatoid arthritis); (4) previous surgery or presence of total arthroplasty replacement on affected or contralateral limb; and (5) presence of at least one of the following conditions: intra-articular corticosteroid injection in the affected joint, diffuse or degenerative osteoarthritis, infection, neoplastic disease, inflammatory arthritis, immunosuppressive therapy, alcoholism or nicotine abuse.

SCD patient clinical features and physical examination were systematically collected by two-experienced clinician to avoid bias. The examination included inspection, local palpation, passive motion and manoeuvres for all the osteoarticular segments most affected in the pathology secondary to sickle cell disease (foot, knee, hip and shoulder). The joint motion was evaluated for flexion, abduction, medial and lateral rotations. The patients were questioned concerning their pain, the main areas of pain together with the spread areas, the type of onset (sudden or progressive), the presence of limp, the history of a triggering event and the duration of symptoms as well as their medical history check-ups, follow-up care, and delay in establishing the correct diagnosis. A semi-quantitative VAS scale accessed subjective pain measurements, with 10 indicating the highest pain score (severe) and “1” equivalent to no pain at rest.

Statistical analysis

Continuous data were described as mean ± SD and categorical variables as mode and range. Age at diagnosis frequencies was calculated as the number of cases of osteonecrosis observed at presentation divided by the total number of patients in the specific subgroup. The chi-squared Pearson’s test or the Fisher’s exact test was used when necessary to compare both groups of haemoglobinopathy carriers. The independent variables explored were gender, stage of the osteonecrosis, genotype of the sickle cell disease, and presence of bilateral osteonecrosis. A P value of less than 0.05 was considered statistically significant.

Results

Description of the study population

The cohort included 283 SCD patients with osteonecrosis: 120 cases (42.4%) had sickle cell anaemia (HBSS) and 163 cases (57.6%) had HBSC disease followed over a median duration of five years (0–11 years) (Table 1). The population included 154 males (54.4%) and 129 females (45.6%). Average age at diagnosis was 34.9 (range 10–65) years for HBSS cases and 32.9 (range 11–67) years for HBSC cases (P = 0.9802). The peak age distribution was 30–39 years. Only 10.2% of patients on average were diagnosed with osteonecrosis within the first two decades of life. Most patients (63.2%) were diagnosed between the third and fourth decades of life, and 26. 5% were diagnosed after the fifth decade. Baseline characteristics of SCD patients with osteonecrosis were most notably in pain intensity (Table 1). At presentation, mild pain intensity was common between SCD patients (51.2%). Severe pain was observed more frequently in HBSS than HBSC group at presentation (35 vs 11.2%, P < 0.001).
Table 1

Baseline characteristics of SCD patients with osteonecrosis at diagnosis, Bahia, 2006–2017

 

All

HBSS

HBSC

 

N

%

N

%

N

%

P

All

283

100

120

42.4

163

57.6

Gender

 Male

154

54.4

67

55.8

87

53.4

.7816

 Female

129

45.6

53

44.2

76

46.6

.7620

Age at diagnosis (years), mean ± SD

33.7 ± 11.2

34.9 ± 11.3

32.9 ± 11.2

.9802

Age category (years)

 10–< 20

29

10.2

8

6.6

21

13.0

.1065

 20–< 30

96

33.9

37

30.8

59

36.2

.4439

 30–< 40

83

29.3

38

31.7

45

27.6

.5331

 40–< 50

45

15.9

26

21.7

19

11.7

.0368

 50–< 60

26

9.2

9

7.5

17

10.4

.4216

 60 = >

4

1.4

3

2.5

1

0.6

.1871

Pain intensity

 Mild

145

51.2

57

47.5

88

53.9

.4511

 Moderate

78

27.5

21

17.5

57

34.9

.0056

 Severe

60

21.2

42

35.0

18

11.2

< .0001

N number, SD standard deviation

Of the 283 SCD patients, 211 (74.6%) patients had hip osteonecrosis at diagnosis. Other sites included shoulder (14.5%), knee (9.2%) and ankle (1.8%) (Table 2). In total, 573 lesions of osteonecrosis were identified at diagnosis (range 1–3/lesions/patient). Sites of osteonecrosis were found in the proximal femoral epiphysis, in the proximal humeral epiphysis, in the distal femoral epiphysis, in the proximal tibial epiphysis, in the distal tibial epiphysis and in the talus (Figs. 2, 3 and 4). Osteonecrotic lesions at more than one joint were found in 44 (15.5%) cases at diagnosis. All these patients had hip involvement. Concurrent sites included the knee in 15 patients, the shoulder in 21 patients and the ankle in eight patients.
Table 2

Features of osteonecrosis in SCD patients at diagnosis

 

All

HBSS

HBSC

 

N

%

N

%

N

%

P

Location

283

100

120

100

163

100

 

 Hip

211

74.6

85

70.8

126

77.3

.5334

 Shoulder

41

14.5

18

15.0

23

14.1

.8459

 Knee

26

9.2

15

12.5

11

6.7

.1146

 Ankle

5

1.8

2

1.7

3

1.8

.9134

Laterality

 Lateral

37

13.1

16

13.3

21

12.9

.9176

 Bilateral

246

86.9

104

86.7

142

87.1

.9679

Stage of disease

 I

172

60.8

68

56.6

104

63.6

.4466

 II

71

25.1

33

27.5

38

23.3

.4870

 III

40

14.1

19

15.8

21

12.9

.5141

N number

Fig. 2

Osteonecrosis of the femoral head in SCD patients. a, b AP radiographs of the right hip demonstrating osteonecrosis (solid arrowhead). c, d Coronal T2-weighted MR image demonstrating a subchondral area abnormality with classic double line sign (solid arrowheads) representing osteonecrosis of the right hip with super imposed marrow oedema

Fig. 3

Osteonecrosis of the knees in a symptomatic 39-year-old woman with SCD. a, b Sagital and c, d coronal T1-weighted sequence show a T1-hypointense serpiginous lesion with a well-demarcated border, surrounded by a subcortical high-intensity signal in the anterior portion of medial femoral condyle. c, d High-signal intensity inner line represents hypervascular granulation tissue

Fig. 4

Osteonecrosis of the humeral head in SCD patients. a, b AP radiographs of the left (a) and right (b) shoulders reveal patchy sclerosis and crescent sign of humeral heads consistent with osteonecrosis (solid arrowheads). c, d Coronal MR image demonstrating a subchondral area abnormality (solid arrowheads) representing osteonecrosis of the shoulders with super imposed marrow oedema

Overall, 86.9% had bilateral disease, including 74.8% of the hips, 15% of the shoulders, 8.5% of the knee and 1.6% of the ankles. The ratio of unilateral to bilateral cases was 1:6.6. One hundred and twenty-two hips (43.1%) were classified as stage I and 54 hips (19.1%) as stage II, accounting for 62.2% of all hips (Table 3). There was insignificant difference in disease stage at diagnosis or laterality between the HBSS and HBSC groups (P > 0.05).
Table 3

Staging of osteonecrosis in SCD patients at diagnosis

 

I

II

III

N

%

N

%

N

%

Location

172

60.8

71

25.1

40

14.1

 Hip

122

43.1

54

19.1

35

12.4

 Shoulder

26

9.2

10

3.5

5

1.8

 Knee

20

7.1

6

2.1

0

0

 Ankle

4

1.4

1

0.4

0

0

N number

Symptoms and diagnosis

Hip symptoms (with or without multiple joint pain) were the most common at presentation. Patients referred pain of mild to severe intensity, developing gradually in the groin region (39.4%), diffused in the lower limb (38.5%) and buttocks (15%), but significantly less frequent in the low back (7%). Almost half of the patients (48%) had motion limitation in the affected joint at the time of presentation. There was little variation between genotypes HBSS and HBSC (P = 0.7391). Examination of MRI consistently revealed subchondral areas of early-stage osteonecrosis and diffuse bone marrow oedema (Fig. 2). A single-density band-like lesion with low signal intensity rim surrounding the necrosis on T1-weighted images and a double-line sign consisting of a low signal intensity outer rim and a high signal intensity inner rim on a T2-weighted image were considered diagnostic of the disease.

All SCD patients with knee osteonecrosis were symptomatic and suffered with limitation of knee motion. At the time of enrolment, all 26 patients had moderate to severe pain usually localized, occurring both at motion, weight bearing and at rest, causing significant functional impairment in all cases. The distribution of hip pain was not significantly different when patients had osteonecrosis of the knee. The radiological findings were more frequently found in the distal femur, especially in the medial femoral condyle (load transmitting area) (Fig. 3).

The pathology in the shoulder was frequently painful. Overall, 37 (90.2%) of 41 patients with shoulder osteonecrosis had severe pain and limitation of daily activities, with impairment of rotational movements. MRI was considered the imaging method of choice with the highest sensitivity and specificity compared to plain radiographs (Fig. 4).

Discussion

Osteonecrosis has been described as a frequent outcome in patients with sickle cell disease, affecting mainly middle age subjects. In our cohort of SCD patients, the average age at ON diagnosis was 34.9 years for HBSS patients and 32.9 for HBSC patients. Several reports have shown that mean age at diagnosis of osteonecrosis on SCD patients depends on comorbidities but typically ranges from 21 to 40 years [1]. Adesina et al. observed a median age at ON diagnosis of 27 years [16]. In line with this, Milner et al. found differential ages of ON diagnosis based on haemoglobin genotype [9]. Within their HBSS cohort, subjects were diagnosed with ON at a median age of 36 years and subjects with haemoglobin SC disease were diagnosed with ON at a median age of 40 years [9]. In terms of age at diagnosis, our data shows how diagnosis may be delayed. This is very important because early diagnosis is the key for success in preserving the joint and prevents total hip replacement surgery [4, 7]. Late diagnosis was probably caused by the insidious and progressive behaviour of osteonecrosis in these patients or the late onset of symptoms.

Due to lack of specific symptoms, clinical diagnosis of the osteonecrosis in SCD is often difficult. In this study, all patients presented with pain, and the extent of disease was widely variable per case. MRI and plan radiograph findings showed more consistent signs of disease staging than the musculoskeletal-related events. With MRI, several osteonecrotic lesions at early stage were detected in both SCD groups. By location, hip (211 cases, 74.6%) and shoulder (41 cases, 14.5%) accounted for 89.1% of all cases of osteonecrosis. Bilateral osteonecrosis was more frequent than unilateral disease. These results are consistent with those reported by Flouzat-Lachaniette et al. (2009) who also found a high frequency of hip osteonecrosis (87%) and bilateral lesions (70%) in a population of 200 SCD patients [5]. Additional evidence for the association of ON with sickle cell disease can be taken from studies of prospective screening for ON in both paediatric and adult SCD patients in Kuwait using more sensitive MRI imaging. These studies detected prevalence of OFH in 48.6% of adults at a mean age of 26.7 years and 26.7% in children at a mean age of 9.8 years [10, 17]. In contrast, Balogun et al., whose study included SCD patients from West African with symptomatic hip, reported 28 cases (21.4%) diagnosed with hip osteonecrosis [18]. Differences can be explained by definitions between cohorts and systematic routine MRI evaluation of symptomatic joints at diagnosis.

Reports of osteonecrotic lesions in more than one anatomic site are unusual. In our population, we observed 44 cases (15.5%) of symptomatic hip osteonecrosis concurrent with another symptomatic joint (shoulder or knee or ankle osteonecrosis). Previous study has observed that multifocal osteonecrosis is the most common situation in sickle cell disease, with an incidence rate of 44% (87 of 200) [5]. However, the report and distribution of multiple osteonecrotic lesions are laborious because the lesions found in joints in the early stages may not have any signs or symptoms [19]. This was further illustrated by LaPorte et al. who observed that about 75% of patients with other sites of involvement (knee, shoulder or ankle) presented concurrent hip osteonecrosis [20]. In daily clinical practice, we often focus on the osteonecrosis diagnosis of the femoral head without performing an MRI on the other joints. These studies imply that there are possible missed diagnoses of asymptomatic ON, and SCD patients should have their other joints radiologically examined when necessary.

Osteonecrosis is a chronic disease frequently described in both HBSS and HBSC patients. Recent studies have emphasized the differences on laboratory parameters, clinical manifestation and genetic profile between HBSS and HBSC patients [21, 22]. Based on the frequency of hip osteonecrosis, disease staging, laterality and affected joint distribution, our results suggest that clinical features of osteonecrosis at diagnosis were not different between HBSS and HBSC patients. Our findings, while consistent with previous studies [9, 11, 23], should be interpreted with caution. Several studies have reported that different mutations unrelated to the haemoglobin disorder [24] or the coexistence of other variants of abnormal haemoglobin (like alpha-thalassemia with haemoglobin SS genotype) [5] influence the severity of the osteonecrosis. Conversely, there are also many evidences that do not support the genetic and environmental modulation of osteonecrosis in SCD [25, 26]. Differences in cohort age, geographical distribution, sample size, phenotype definitions and analytical approaches could explain these contradictions. Further studies are needed to verify prevalence, predisposing and associated factors of osteonecrosis among different SCD subphenotypes.

The current study has some limitations that need acknowledgment: (1) our study was conducted in an orthopaedic outpatient unit of university hospital, and this may lead to potential selection bias towards the inclusion of the sickest and symptomatic patients, and may not represent the sampling of others parts of the country; (2) it is a cross-sectional study from which a conclusion regarding causality between osteonecrosis and genotype cannot be made; and (3) radiographs and MRIs were not obtained before enrolling the study, and so there is a possibility that ON was present previously. Given the cross-sectional nature of this study, a prospective study will be able to indicate the incidence of ON in SCD patients. In addition, a longitudinal study comparing radiographic and clinical progression of ON in SCD patients is also of interest.

Our study shows that SCD patients with osteonecrosis received a late diagnosis and presented with painful symptoms. Given the relatively high prevalence of bilateral osteonecrosis at early stages in our cohort, we believe that patients should have radiological examination of their joints more often in order to avoid subsequent complications, prevent severe joint functional disability and increase patient’s life quality.

Notes

Authors’ contributions

GD, TBF and DAR were the surgeons who performed surgeries in this study. TBF, BAM and DAR assessed most of the clinical outcomes. GD and VF were responsible for conception, design, critical revision and analysis of the results. PBD assisted data collection. BAF drafted part of the manuscript. VF coordinated and made a major contribution to writing the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the Brazilian National Research Council (CNPq) and the Research Support Foundation of the State of Bahia (FAPESB).

Compliance with ethical standards

The Committee of Ethics in Research of the Climério de Oliveira Maternity Hospital (Federal University of Bahia, UFBA) approved this study, and informed consent was obtained in accordance with ethical principles and the Helsinki Declaration of 1975, and by the Brazilian resolution 196/96, of the Ministry of Health, Law 6638/79 and Normative Resolution 04/97.

Competing interests

The authors declare that they have no competing interests.

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Copyright information

© SICOT aisbl 2018

Authors and Affiliations

  • Gildasio Daltro
    • 1
  • Bruno Adelmo Franco
    • 1
  • Thiago Batista Faleiro
    • 1
  • Davi Araujo Veiga Rosário
    • 1
  • Paula Braga Daltro
    • 2
  • Vitor Fortuna
    • 2
  1. 1.Prof. Edgar Santos Hospital ComplexFederal University of BahiaSalvadorBrazil
  2. 2.Health Science InstituteFederal University of BahiaSalvadorBrazil

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