Spontaneous healing of avascular necrosis of the femoral head in sickle cell disease

Itzep, Nelda; Jadhav, Siddharth P.; Kanne, Celeste K.; Sheehan, Vivien A.

doi:10.1002/ajh.25453

Cited by 8 publications

(4 citation statements)

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“…IV bisphosphonate therapy promotes vertebral body reshaping in pediatric osteoporosis populations such as osteogenesis imperfecta and Duchenne muscular dystrophy (the latter only occurs if glucocorticoid therapy is withdrawn and normal growth resumes) [ 37 – 39 ]. Partial femoral head reshaping following AVN has been seen in a previous report of five children with SCD AVN, without medical or surgical intervention [ 40 ]. To our knowledge, our experience is the first report of vertebral body reshaping in SCD.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell bone disease and response to intravenous bisphosphonates in children

et al. 2022

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Summary Children with sickle cell disease (SCD) have the potential for extensive and early-onset bone morbidity. This study reports on the diversity of bone morbidity seen in children with SCD followed at three tertiary centers. IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. Introduction To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with SCD. Methods We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). Results Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises, or stroke attributed to IV bisphosphonate therapy. Conclusion Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-022-06455-2.

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Section: Discussionmentioning

confidence: 99%

Sickle cell bone disease and response to intravenous bisphosphonates in children

et al. 2022

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“…In the case series by Itzep et al, 23 all 16 children were on comparable HU doses (at MTD) for similar treatment durations over the observation period. The 5 children with ONFH regression (group 1) were younger and had lower mean MCV values compared with the 11 children with stable to progressive ONFH (group 2); however, mean Hb, fetal Hb, whole-blood viscosity, red cell deformability, and percentage dense RBCs were similar in both groups.…”

Section: Effects Of Hu On Onfhmentioning

confidence: 98%

“…Itzep et al 23 recently showed spontaneous ONFH regression in a retrospective cohort of 16 children with SCD (50% female; mean age 13.2 years old; 81% Hb SS, 13% Hb S/b 0 -thalassemia, and 6% Hb SC) who were followed at Texas Children's Hospital Hematology Center from January 2006 to January 2018. Although all 16 children had similar Steinberg stages of ONFH at study entry, 5 children (33%) demonstrated ONFH regression from Steinberg stage IVB to IIB (group 1), whereas the remaining 11 showed stable to progressive ONFH from Steinberg stage IIIB to IVB (group 2).…”

Section: Onfh Prognosismentioning

confidence: 99%

Osteonecrosis in sickle cell disease: an update on risk factors, diagnosis, and management

Adesina

Neumayr

2019

Hematology

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Osteonecrosis, a form of ischemic bone injury that leads to degenerative joint disease, affects ∼30% of people with sickle cell disease. Although osteonecrosis most commonly affects the femoral head (often bilaterally, with asymmetric clinical and radiographic progression), many people with sickle cell disease also present with multifocal joint involvement. We present the case of a young woman with bilateral osteonecrosis of the femoral head at varying stages of progression; we also highlight other important comorbid complications (eg, chronic pain requiring long-term opioids, debility, and social isolation) and postoperative outcomes. In this review, partly based on recommendations on osteonecrosis management from the 2014 evidence-based report on sickle cell disease from the National Heart, Lung and Blood Institutes, we also discuss early signs or symptoms of osteonecrosis of the femoral head, radiographic diagnosis and staging criteria, hydroxyurea effect on progression to femoral head collapse, and surgical outcomes of total hip arthroplasty in the modern era. In summary, we failed to find an association between hydroxyurea use and femoral head osteonecrosis; we also showed that evidence-based perioperative sickle cell disease management resulted in superior postoperative outcomes after cementless total hip arthroplasty in sickle cell–related osteonecrosis of the femoral head.

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“…In treating SCD, Hb quality produced is extremely important, not just amount. Therapies that increase the amount of Hb or number of RBCs without improving the quality may increase viscosity and increase risk of clinical events associated with viscosity, such as pain crises, avascular necrosis, and proliferative retinopathy (Richardson et al, 1976;Hernigou et al, 2006;Lemaire et al, 2013;Abdalla Elsayed et al, 2019;Itzep et al, 2019). It is therefore essential to evaluate multiple aspects of red cell rheology.…”

Section: Introductionmentioning

confidence: 99%

Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model

Nebor

Kanne

Pochron

et al. 2020

Blood

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Background: In sickle cell disease (SCD), elevated blood viscosity is a risk factor for vaso-occlusive crisis (VOC). Blood viscosity is influenced by hemoglobin (Hb) levels, red blood cell (RBC) deformability, density, and aggregation. Voxelotor is an HbS polymerization inhibitor that increases the Hb affinity for oxygen and reduces sickling. In human subjects, voxelotor significantly increases Hb levels. A rise in Hb due to voxelotor does not increase blood viscosity the way a similar increase in unmodified HbS would. However, voxelotor transiently modifies HbS, raising concern that if voxelotor was stopped suddenly, the drug induced extra HbS would revert to its unmodified state, causing a significant rise in blood viscosity and increasing the risk of VOC. This effect could continue until the drug induced Hb is eliminated by hemolysis. To investigate this, we treated a sickle mouse model with GBT1118, a voxelotor analog. We then stopped the treatment and determined the effect on whole blood viscosity, the hematocrit-to-viscosity ratio (HVR), a measure of oxygen carrying capacity, and RBC deformability. As GBT1118 has a half-life of 14 hours in SCD mouse, we measured the post-drug effect 48 hours after drug withdrawal. Methods: Ten Townes HbSS mice were fed control chow, 10 were fed chow containing GBT1118 for 7 days, 10 were fed GBT1118 chow for 7 days, and then returned to control chow for 48 hours. RBC deformability was measured by oxygen gradient ektacytometry (Lorrca with Oxygenscan, RR Mechatronics). Blood viscosity was measured with a cone and plate viscometer (Brookfield DVII+). Hb was measured via ADVIA (Siemens). Results: Treatment with GBT1118 significantly increased Hb without increasing blood viscosity. HVR was increased at both 45 s-1 and 225 s-1 shear rates (Figure 1). GBT1118 treatment also improved RBC deformability under both normoxic (EImax) and hypoxic conditions (EImin). Point of sickling (PoS) was reduced, indicating that treated RBC tolerated lower oxygen concentrations before sickling (Figure 2). When the drug was withdrawn for 48 hours, compared to control animals, 1) Hb declined rapidly (7.1 g/dL in control feed, 13.1 g/dL in treated mice compared to 9.0 g/dL after 48 hours off treatment, P<0.001); 2) viscosity did not increase compared to control feed (at shear rate 45 s-1, 12.8 cP after treatment compared to 11.4 cP in control cohort; at shear rate 225 s-1,10.8 cP after treatment compared to 10.3 cP in controls); 3) HVR returned to baseline (at shear rate 45 s-1, 4.5 after treatment compared to 3.6 in controls; at shear rate 225 s-1, 6.6 after treatment compared to 4 cP in controls), 4) EImin remained elevated (0.16 in controls compared to 0.32 after 48 hours off treatment, P<0.001); 5) Elmax and PoS were not significantly different. Conclusions: The GBT1118-treated sickle mouse had a significant rise in Hb and improvement in PoS and deformability. Forty-eight hours after removing the analog compound, Hb dropped markedly, and the PoS was not different from control animals, suggesting a return to native oxygen affinity and clearance of the drug. Interestingly, deformability (EImin) did not return to baseline, suggesting some residual rheological improvement occurred in the red cell population that did not dissipate when the drug was cleared. These data suggest that potential concerns regarding viscosity rising above pre-treatment levels upon sudden cessation of voxelotor are not warranted. This may be due to retained improvement in red cell rheology after voxelotor is stopped combined with rapid return to baseline Hb levels. Further study in patients treated with voxelotor may be needed to determine if voxelotor produces additional benefits, such as reduction in oxidative stress, that outlive its presence in the red cell. Disclosures Pochron: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Oksenberg:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sheehan:Global Blood Therapeutics: Research Funding; Emmaus: Research Funding; Novartis: Research Funding.

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Spontaneous healing of avascular necrosis of the femoral head in sickle cell disease

Cited by 8 publications

References 8 publications

Sickle cell bone disease and response to intravenous bisphosphonates in children

Sickle cell bone disease and response to intravenous bisphosphonates in children

Osteonecrosis in sickle cell disease: an update on risk factors, diagnosis, and management

Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model

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