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. Author manuscript; available in PMC: 2023 May 23.
Published in final edited form as: Hematol Oncol Clin North Am. 2022 Dec;36(6):1201–1215. doi: 10.1016/j.hoc.2022.08.010

Clinical Vignettes, Part II: Eyes, Teeth, and Bone

Part IIA: Eyes

Adrienne W Scott 1,*, Grace R Reilly 1, Brian Laurence 1, Oyebimpe O Adesina 1
PMCID: PMC10204321  NIHMSID: NIHMS1895243  PMID: 36400539

INTRODUCTION

Microvascular occlusions caused by sickle cell disease (SCD) can affect all ocular and orbital structures (Fig. 1). Sickle cell retinopathy (SCR) is the most common ophthalmic manifestation of SCD. Fortunately, most individuals with SCR are visually asymptomatic. Vision loss in SCD most commonly occurs as a consequence of proliferative sickle cell retinopathy (PSR), in which pathologic retinal neovascularization occurs. To prevent significant vision loss and blindness, which can occur from complications of PSR, regular retinopathy surveillance screening examinations and consistent follow-up with a retina specialist are recommended. Scatter laser photocoagulation is the current gold-standard treatment to prevent vision threatening progression of PSR.

Fig. 1.

Fig. 1.

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Diagram of the eye. AV, arteriovenous. (Reprinted with permission from A.W. Scott and M.F. Goldberg. Ocular Complications in Sickle Cell Disease. In: Gladwin and colleagues, eds. Sickle Cell Disease. New York, NY: McGraw Hill; 2021.)

CASE PART 1

A 31-year-old man with hemoglobin SS (HbSS) presented to the ophthalmology office with 20/12 (normal) vision and a small sea fan neovascular complex on retinal examination (Fig. 2). Observation and follow-up within 6 months were recommended.

Fig. 2.

Fig. 2.

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A 31-year-old patient with HbSS presented with 20/12 vision and a small sea fan neovascular complex (arrow) on ultrawide fundus photograph fluorescein angiogram.

Epidemiology

SCR predominantly affects working-age individuals. The incidence of PSR in all genotypes increases with age with peak incidence occurring between 20 and 39 years old.1 Identifying patients early is critical because rates of vision loss attributed to PSR have been reported to be as high as 10% to 12% in untreated eyes.2

Pathophysiology

Microvascular occlusions cause impaired oxygen delivery to tissues of the eye and an upregulation of growth factors. Although individuals with HbSS have higher systemic morbidity and mortality, they are less likely to experience PSR compared with individuals with hemoglobin SC (HbSC). The pathophysiology behind this difference is not fully understood. An individual’s blood with HbSC has fewer irreversibly sickled cells trapped in the retinal microcirculation, which supports that a complex interaction among cytokines, growth factors, and adhesion molecules may be implicated in PSR.3

Specific associations between systemic factors and vision loss in SCD have not been established. A retrospective study reported older age and male sex are most associated with loss of vision in patients with HbSS, and chronic transfusion therapy may be protective against the need for ophthalmic procedures.4 Hydroxyurea (HU) use may have a protective effect against PSR.5

Sickle Cell Retinopathy

Our 31-year-old patient with HbSS presented with normal visual acuity and a small sea fan neovascular complex on retinal fundus examination (see Fig. 2). Sea fans, named for their fanlike appearance, are a hallmark finding of PSR. Although individuals with HbSS more commonly present with asymptomatic nonproliferative sickle cell retinopathy, PSR can still occur and should be monitored for.

In 1971, Goldberg6 described the currently widely used staging system for SCR based on clinical observation of sequential vascular changes (see Fig. 1). Stage I retinopathy consists of peripheral arteriolar occlusions. Stage II presents as the presence of arteriovenous anastomoses. Stage III is neovascularization and proliferations of hallmark sea fan neovascularization of PSR. Sea fan neovascularization can lead to vitreous hemorrhage (VH; stage IV retinopathy) and retinal detachments (stage V retinopathy).

CASE PART 2

The patient was lost to follow-up. Two years later, the patient presented urgently with decreased vision down to counting fingers. The decreased vision was due to a VH, Goldberg stage IV PSR. The VH cleared with observation, and scattered laser photocoagulation was performed through the retinal periphery (Fig. 3).

Fig. 3.

Fig. 3.

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Ultrawide field fundus photograph of a 31-year-old patient with HbSS following scatter laser photocoagulation.

Diagnosis

Although Goldberg staging was based on clinical examination, contemporary imaging techniques have advanced the ability of clinicians to observe peripheral retinal pathologic condition. Because PSR pathologic condition is located peripherally, modern ultrawide field fundus photography (see Fig. 3) has been shown to detect higher stages of PSR than clinical examination alone.7

Had our patient returned for a 6-month follow-up appointment, growth of the sea fan neovascular complex may have been identified and treated, decreasing his risk for vision loss from VH. Lack of follow-up is not uncommon. Although adherence rates for SCR screening are unknown, adults with SCD and caregivers of children with SCD were surveyed in the United States, and 87% of adults and 65% of caregivers reported missing clinic appointments.8 Increased adherence to appointments has been shown in multidisciplinary care visits that offer screening for stroke prevention and assessment of pulmonary hypertension.9 Recently, nonmydriatic ultrawide field fundus photography in a hematology clinic setting was shown to have utility in screening to identify PSR.10

Management

Scatter laser photocoagulation is the gold-standard treatment for stage III retinopathy to prevent progression to sight-threatening VH or retinal detachment.11 Observation alone can be considered if the sea fan neovascular complexes are small. Observation requires serial examinations, typically every 6 months, with retinal imaging to monitor for neovascular progression. If it is not feasible for a patient to adhere to the recommended follow-up, laser treatment is recommended. Scatter laser photocoagulation is the first treatment for large and rapidly growing neovascularization. Surgical intervention is recommended in specific cases, such as a nonclearing VH and retinal detachment. Antivascular endothelial growth factor (anti-VEGF) therapy is a useful adjunct for facilitating clearance of VH if the hemorrhage impedes placement of scatter laser or in patients with recurrent VH despite adequate scatter laser therapy. Bevacizumab (Avastin; Genentech) is an anti-VEGF intravitreal treatment that has been used with success in PSR treatment. Bevacizumab is well-tolerated and causes decreased vascularity and rapid regression of sea fan neovascular lesions.12 Anti-VEGF intravitreal injections can be given every 1 to 2 months in the retina clinic and then as needed based on how vascularized the sea fan neovascularization remains.

Recommended Screening

Current screening guidelines recommend referral of patients with SCD to an ophthalmologist for a dilated retinal fundus examination annually or biannually starting at age 10. These guidelines for PSR screening are based on expert consensus, but low-quality evidence.13 Hematologists and primary care physicians managing patients with SCD should emphasize to patients the importance of these screenings and that it is possible to have no visual symptoms but potentially vision-threatening PSR. The presence of blurred vision or visual floaters (small opacities in the vitreous that a patient may note as dots in their visual field) are associated with higher rates of PSR, and patients with these symptoms should be referred for retinopathy surveillance.4 It is also important to educate patients that a nondilated eye examination for eyeglasses is not sufficient screening for PSR. Hematologists and primary medical physicians play an important role in educating patients and facilitating ophthalmology screening for PSR.

KEY POINTS.

  • Sickle cell retinopathy is the most common ophthalmic manifestation of sickle cell disease.

  • Although individuals with HbSC have lower systemic morbidity and mortality, they are more likely to experience PSR compared to individuals with HbSS genotype.

  • Patients with sickle cell disease, regardless of genotype, should be receiving dilated proliferative sickle cell retinopathy screening examinations by an ophthalmologist annually to biannually starting at age 10.

CLINICS CARE POINTS.

  • Although more common in hemoglobin SC, patients with hemoglobin SS can experience vision threatening proliferative sickle cell retinopathy.

  • Patients with sickle cell disease should be receiving dilated proliferative sickle cell retinopathy screening examinations by an ophthalmologist annually to biannually starting at age 10.

  • Blurred vision or the presence of visual floaters should prompt referral for retinal examination.

  • Small sea fan neovascular lesions can be observed and monitored for progression with regular follow-up and imaging, ideally in patients with good vision in the unaffected eye. If there is any concern with the patient’s ability to follow up, laser photocoagulation should be considered.

  • Laser photocoagulation is the gold-standard treatment to prevent vitreous hemorrhage.

REFERENCES

  • 1.Fox PD, Dunn DT, Morris JS, et al. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol 1990;74(3):172–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Moriarty BJ, Acheson RW, Condon PI, et al. Patterns of visual loss in untreated sickle cell retinopathy. Eye 1988;2(3):330–5. [DOI] [PubMed] [Google Scholar]
  • 3.Lutty GA, Phelan A, Mcleod DS, et al. A rat model for sickle cell-mediated vaso-occlusion in retina. Microvasc Res 1996;52(3):270–80. [DOI] [PubMed] [Google Scholar]
  • 4.Duan XJ, Lanzkron S, Linz MO, et al. Clinical and ophthalmic factors associated with the severity of sickle cell retinopathy. Am J Ophthalmol 2019;197:105–13. [DOI] [PubMed] [Google Scholar]
  • 5.Mian UK, Tang J, Allende APM, et al. Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease. Br J Haematol 2018;183(5):807–11. [DOI] [PubMed] [Google Scholar]
  • 6.Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol 1971;85(4):428–37. [DOI] [PubMed] [Google Scholar]
  • 7.Han IC, Zhang AY, Liu TYA, et al. Utility of ultra-widefield retinal imaging for the staging and management of sickle cell retinopathy. Retina 2019;39(5):836–43. [DOI] [PubMed] [Google Scholar]
  • 8.Cronin RM, Hankins JS, Byrd J, et al. Modifying factors of the health belief model associated with missed clinic appointments among individuals with sickle cell disease. Hematology 2018;23(9):683–91. [DOI] [PubMed] [Google Scholar]
  • 9.Colombatti R, Montanaro M, Guasti F, et al. Comprehensive care for sickle cell disease immigrant patients: a reproducible model achieving high adherence to minimum standards of care. Pediatr Blood Cancer 2012;59(7):1275–9. [DOI] [PubMed] [Google Scholar]
  • 10.Ahmed I, Pradeep T, Goldberg MF, et al. Nonmydriatic ultra-widefield fundus photography in a hematology clinic shows utility for screening of sickle cell retinopathy. Am J Ophthalmol 2022;236:241–8. [DOI] [PubMed] [Google Scholar]
  • 11.Jacobson MS, Gagliano DA, Cohen SB, et al. A randomized clinical trial of feeder vessel photocoagulation of sickle cell retinopathy. Ophthalmology 1991;98(5):581–5. [DOI] [PubMed] [Google Scholar]
  • 12.Cai CX, Linz MO, Scott AW. Intravitreal bevacizumab for proliferative sickle retinopathy: a case series. J VitreoRetinal Dis 2018;2(1):32–8. [Google Scholar]
  • 13.Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease summary of the 2014 evidence-based report by expert panel members. Surv Anesthesiology 2015;59(4):203–4. [DOI] [PubMed] [Google Scholar]
Hematol Oncol Clin North Am. 2022 Dec;36(6):1201–1215.

Part IIB: Teeth

Brian Laurence 1,*

Among patients with SCD as compared with the general population, dental outcomes observed with increased frequency include orofacial or dental pain that is usually of undetermined origin, dental caries, pulpal necrosis, periapical infections, osteomyelitis of the mandible, neuropathy, medullary hyperplasia with abnormal trabeculae spacing in the mandible, and maxilla and hypomineralization of the teeth.1–4 Delays are observed in the eruption times of the teeth, as well as alterations in the pallor of the oral mucosa and compensatory expansion of the facial bones that can result in changes in the craniofacial bone structure, increasing the likelihood of malocclusion in patients with SCD.5,6

Although there are quite a few potentially adverse oral health outcomes than can accompany SCD, to date, the author could identify little in the way of randomized controlled studies that have examined interventions for the treatment of dental complications in people with SCD. A recent scoping review of orofacial manifestations and dental management of patients with SCD could find no clinical trials on the dental management of SCD but suggested that early detection, intervention, and prevention are important for improving oral health care outcomes in people with SCD and that a multi-disciplinary approach by caregivers can play a crucial role in the management of this complication.7 Another recent scoping review of evidence-based dental management approaches in people with SCD concluded that there was a lack of uniformity in treatment recommendations for oral care and that expert consensus may be the best approach for guiding dentists in clinical practice.8 The investigators also noted that the evidence for dental treatment specific for patients with SCD was limited to case-control studies, case series, and expert opinion, and there was a lack of high-quality evidence.

Despite the lack of consensus, there is evidence that multidisciplinary approaches that include dental providers to improve health outcomes in patients with SCD have merit and deserve further study. One study examined the effect of providing free basic dental care to individuals with SCD to determine if this decreased overall health care utilization.9 After multivariable analyses, the investigators observed a statistically significant decrease in hospital admissions and a significant decrease in total days hospitalized, and they concluded that access to preventive and basic dental care may be an effective approach for decreasing health care utilization and hospitalization among patients with SCD.

A comprehensive guide to the proper dental management of patients with SCD and the accompanying specifics on the management of subjects, such as dental anxiety, restorative treatment, management of dental infections, orthodontic tooth movement, and other details of dental care, are better suited for a dental journal. The goal of this article is to encourage physicians to become aware of the oral clinical conditions that are more prevalent among patients with SCD and emphasize the importance of a comprehensive approach to clinical care that includes close collaboration between the dentist, the primary care physician, and the hematologist, particularly with regards the management of dental conditions that have the potential for more clinically severe consequences. Some conditions, such as the management of dental infections, require careful attention and may be encountered by both dentists and physicians. Dental infections can cause a sickle cell crisis, and having a dental infection complicated by a sickle cell crisis can increase the likelihood of hospital admission among adult patients with SCD.10 Dental infections should be treated using evidence-based approaches with antibiotics and rinses, whereas more severe and complicated infections may require treatment with hospitalization and comprehensive care.7 The literature lacks clarity on which dental procedures require antibiotic prophylaxis for patients with SCD. The American Academy of Pediatric Dentistry recommends the use of antibiotic prophylaxis in certain children and adolescents with compromised immunity for procedures that involve the manipulation of gum tissue, the roots of the tooth, or the perforation of the oral mucosa.11 As mentioned earlier, adult patients with SCD may be at an increased risk of osteomyelitis of the mandible even though this is a rare occurrence. Given the potential for infection and delayed healing in patients with SCD, consultation with the patient’s physician or hematologist is recommended to determine if prophylactic antibiotics are needed before invasive dental treatment. In addition, no elective dental procedures should be started if the patient is having a sickle cell crisis. The observation of excessive, rampant, or uncontrolled dental caries in patients with SCD means that more proactive approaches by the primary care physician and hematologist to ensure regular dental visits are needed. A more involved approach with the patient when it comes to proper oral hygiene, the use of preventive methods such as fluoride varnish and pit and fissure sealants, and education about the high sugar content of certain foods and drinks (such as soda and other sugar-sweetened beverages) can all facilitate a reduction in caries incidence in patients with SCD. Referral to a dietician can also be beneficial in helping patients reduce their sugar consumption.4 Key points that clinicians should especially pay attention to when treating patients with SCD are summarized in Box 1.

Box 1. Recommendations.

  1. Encourage all patients to have regular dental checkups, regardless of their oral health condition. Patients should be educated on the importance of good dental hygiene and the need to have examinations and dental cleanings at least once every 6 months.

  2. If dental caries is present, emphasize to the patient the importance of an early dental intervention and treatment to prevent further spread.

  3. Inform patients that if any dental surgical procedures or dental procedures that involve sedation are planned when the patient is in a noncrisis phase, it is critical to consult with the hematologist before the procedure is started.

  4. Remember that dental infections can not only precipitate a sickle cell crisis but also make an existing crisis more clinically severe.

  5. Prophylactic antibiotics may have to be prescribed before surgical procedures or dental procedures that are considered invasive, including extractions or gum surgery, given the potential for delayed healing and infection, but this is best determined in consultation with the patient’s physician.

  6. If patients are receiving orthodontic treatment (procedures to move the teeth or remodel the dental bone), they should be monitored very closely for any signs of dental infection or tooth loss.

REFERENCES

  • 1.da Fonseca MA, Oueis HS, Casamassimo PS. Sickle cell anemia: a review for the pediatric dentist. Pediatr Dent 2007;29:156–69. [PubMed] [Google Scholar]
  • 2.Demirbas Kaya A, Aktener BO, Unsal C. Pulpal necrosis with sickle cell anemia. Int Endod J 2004;37(9):602–6. [DOI] [PubMed] [Google Scholar]
  • 3.Laurence B, George D, Woods D, et al. The association between sickle cell disease and dental caries in African Americans. Spec Care Dentist 2006;26:95–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Mulimani P, Ballas SK, Abas ABL, et al. Treatment of dental complications in sickle cell disease. Cochrane Database Syst Rev 2016;22(4):CD011633. [DOI] [PubMed] [Google Scholar]
  • 5.Alves PV, Alves DK, de Souza MM, et al. Orthodontic treatment of patients with sickle cell anaemia. Angle Orthod 2006;76:159–69. [DOI] [PubMed] [Google Scholar]
  • 6.Costa CP, Caravalho HL, Souza Sde F, et al. Is sickle cell anemia a risk factor for severe dental malocclusion? Braz Oral Res 2015;29. S1806-83242015000100219. [DOI] [PubMed] [Google Scholar]
  • 7.Kakkar M, Holderle K, Sheth M, et al. Orofacial manifestation and dental management of sickle cell disease: a scoping review. Anemia 2021;2021:5556708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hsu LL, Fan-Hsu J. Evidence-based dental management in the new era of sickle cell disease: A scoping review. J Am Dent Assoc 2020;151(9):668–77. [DOI] [PubMed] [Google Scholar]
  • 9.Whiteman LN, Haywood C Jr, Lanzkron S, et al. Effect of free dental services on individuals with sickle cell disease. South Med J 2016;109(9):576–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Laurence B, Haywood C Jr, Lanzkron S. Dental infections increase the likelihood of hospital admissions among adult patients with sickle cell disease. Community Dent Health 2013;30:168–72. [PMC free article] [PubMed] [Google Scholar]
  • 11.American Academy of Pediatric Dentistry. Antibiotic prophylaxis for dental patients at risk for infection. The reference manual of pediatric dentistry. Chicago, ILL: American Academy of Pediatric Dentistry; 2021. p. 465–70. [Google Scholar]
Hematol Oncol Clin North Am. 2022 Dec;36(6):1201–1215.

Part IIC: Bones

Oyebimpe O Adesina 1,*

Andre Vincent Nichols is a 17-year-old with SCD (HbSC genotype) without prior hospitalizations, who presented with left hip pain on ambulation that had been worsening over the past year. Plain radiographs of his left hip were negative, so he was prescribed ibuprofen and referred for physical therapy. Over the subsequent year, Andre’s pain worsened to the point that he started to miss school. He was prescribed short-acting opioids, and then long-acting opioids were added to his analgesic regimen, without significant pain relief. A repeat radiograph of his left hip showed subchondral lucency, and Andre was referred to orthopedic surgery for further evaluation. He underwent a left hip decortication, but the surgery was complicated by a left lower-extremity deep vein thrombosis. Andre was treated with rivaroxaban for 6 months. Andre’s left hip pain continued to worsen, and he was sent back to orthopedic surgery for consideration of left total hip arthroplasty.

Therapeutic advances and public health interventions like universal newborn screening, penicillin prophylaxis, vaccinations, and early initiation of hydroxyurea (HU) have transformed sickle cell disease (SCD) from an inherited hemoglobin disorder with high childhood mortality to a chronic illness characterized by progressive pain and end-organ damage.1–3 The skeletal system is repeatedly injured when recurrent ischemia-reperfusion stress induces the release of cytokines that heighten bone resorption,4 while nutritional deficits, low muscle mass, delayed puberty, and physical inactivity impair bone formation.5–8 Skeletal complications of SCD, or sickle bone disease,9 range from acute vaso-occlusive bone pain, bone infarcts, and osteomyelitis to more chronic manifestations such as osteonecrosis (ON), osteoporosis, and vertebral deformities.10–12 ON, also known as ischemic or avascular necrosis, presumably arises from cumulative vascular injury to susceptible articular surfaces13; ON associates with severe chronic SCD pain,14,15 frequent acute care utilization,16 and poor health-related quality of life.17 ON causes significant permanent disability with symptoms of joint pain and impaired mobility persisting even after curative hematopoietic stem cell transplantation for SCD.18

OSTEONECROSIS INCIDENT RATES BY SICKLE CELL DISEASE GENOTYPE

Although sickle cell–related ON often presents with multifocal articular involvement, the hip joint is most commonly affected because the femoral head lacks collateral blood flow and is particularly susceptible to vascular injury.19 Using patient discharge data from California’s Office of Statewide Health Planning and Development (OSHPD), the authors found that osteonecrosis of the femoral head (ONFH) affects 22% of people with SCD by a median age of 27 years and undergo total hip arthroplasty by a median age of 35 years.20 They also found ONFH cumulative incidence increases with age, frequent acute care visits (defined as ≥3 emergency department visits or hospitalizations per year in OSHPD, for any indication), and antecedent acute chest syndrome.20 In a cross-sectional study from a single pediatric SCD center, investigators found that age, male gender, and HU exposure were independently associated with ONFH in a subset of participants with HbSS/Sβ0 thalassemia.21 The association between ONFH and HU use is likely due to confounding by indication, that is, ONFH causes severe pain that leads to frequent acute care visits for pain management,14,16 and HU is indicated in SCD complicated by recurrent pain episodes.15

In the landmark Cooperative Study of Sickle Cell Disease (CSSCD), a subset of 1700 study participants underwent serial plain hip radiographs for 3 years to monitor for ON onset, and the investigators found ONFH incident rates (per 100 patient-years) of 4.47 in HbSS genotype with coinherited a-thalassemia trait, 2.35 in HbSS without α-thalassemia trait, and 1.91 in HbSC.22 Similarly, the same investigators screened a subset of 1655 people enrolled in CSSCD with plain shoulder films for 3 years and found age-adjusted incident rates for humeral head ON (per 100 patient-years) per genotype of 4.85 in HbSS with α-thalassemia trait, 4.84 for Hb Sβ0 thalassemia, 2.61 for Hb Sβ+ thalassemia, 2.54 for HbSS without α-thalassemia trait, and 1.66 for Hb SC.23 ON falls under the viscosity vaso-occlusion subphenotype of SCD and associates with high baseline hemoglobin, acute chest syndrome, and frequent vasoocclusive crises (VOCs).24 Others showed high hemoglobin/hematocrit ratio and elevated systolic blood pressure predicted for ON development,25 whereas the correlation between ON and other clinical/laboratory factors was more varied.26

The author recommends plain films of the hip and or shoulder if anyone with SCD presents with joint pain or stiffness, regardless of their genotype.17 In addition to hip joint pain, people with ONFH may also present with referred pain in their lower back, buttocks, thigh, or knees, including abnormal gait or leg length discrepancies on physical examination.27 Humeral head ON may be incidentally diagnosed on chest radiographs that are commonly obtained in people with SCD presenting with acute pain and/or respiratory symptoms, although definite shoulder joint imaging is required to confirm the diagnosis.28,29 As demonstrated in this case, symptoms do not always correspond with imaging results. If plain radiographs of the symptomatic joint are negative and clinical suspicion for ON remains high, magnetic resonance imaging can rule out early-stage ON.30–32

How I Treat Sickle Cell-Related Osteonecrosis

No standard of care exists for the management of sickle cell–related ON. Based on consensus data, the 2014 National Heart, Lung, and Blood Institute’s (NHLBI) Expert Panel on SCD management recommends analgesics, physical therapy, and early referral to orthopedic surgery for consideration of joint replacement surgery in sickle cell-related ON.15 Long-term symptomatic ONFH management with opioid analgesics is suboptimal because of detrimental effects of chronic opioid therapy.14 The 2020 American Society of Hematology’s expert panel on acute and chronic SD pain guidelines suggest against starting chronic opioid therapy unless chronic SCD pain is refractory to other therapeutic modalities like long-acting nonsteroidal anti-inflammatory drugs (NSAIDs) or serotonin-norepinephrine reuptake inhibitors.33 A retrospective cohort study showed spontaneous ONFH regression in 5 of 16 children with SCD34; despite the small sample size, this study suggests surgical risks and benefits should be carefully weighed in prepubescent children with sickle-related ONFH.

The rate of ONFH progression to femoral head collapse is higher in SCD compared with other at-risk groups, and symptomatic ONFH remains the most common indication for orthopedic surgery in young adults with SCD.35 Neumayr and colleagues36 prospectively randomized adults with SCD and symptomatic ONFH to either undergo hip core decompression and physical therapy or physical therapy alone. Both study arms demonstrated similar treatment effect based on changes in the Children’s Hospital Oakland Hip Evaluation Scale, which is a validated tool that measures hip pain, function, and range of motion in people with SCD-related ONFH.37 However, the small sample size, advanced ONFH stage at study entry, and short duration of follow-up may have limited the investigators’ ability to detect a larger and clinically relevant difference between the treatment arms.

In a subset of CSSCD subjects who underwent hip arthroplasty for symptomatic ONFH, 64% reported ongoing pain, whereas 76% reported persistent limited mobility.22 Although ON primarily affects the femoral head, multifocal joint involvement is common in SCD,16,19 and multiple joint surgeries confer unacceptably high perioperative morbidity in people with SCD.38,39 Aggressive supportive care with close monitoring of perioperative hydration, oxygenation, pain control, prophylactic antibiotics, and red blood cell transfusions can reduce adverse surgical outcomes.40,41 As shown in this case, standard perioperative anticoagulation is essential, given the high baseline risk of venous thromboembolism (VTE) in people with SCD,42,43 which is further exacerbated with orthopedic surgery. The benefits of VTE prophylaxis must be carefully weighed against bleeding risk, especially in patients on chronic NSAIDs.44

Optimizing Musculoskeletal Health in Sickle Cell Disease

Using data from the Sickle Cell Clinical Research and Intervention Program, a lifespan prospective cohort study of SCD maintained at St. Jude Children’s Research Hospital,45 the authors showed that low bone density independently associates with ONFH and chronic pain in pediatric SCD.46 Vitamin D deficiency (VDD), defined as serum 25-hydroxyvitamin D less than 20 ng/mL,47,48 is also highly prevalent in SCD.49–51 VDD associates with many adverse skeletal outcomes in children and adults with SCD,52–54 including chronic pain.55 High-dose vitamin D supplementation reduced pain intensity56,57 and decreased inflammatory markers in children and adolescents with SCD and severe VDD.58 Vertebral compression fractures and other spinal deformities may also cause significant morbidity in SCD.12,59 Consider screening for VDD, low bone mineral density with a dual X-ray absorptiometry scan, and vertebral compression fractures with thoracolumbar morphometry in people with radiographically confirmed ON, especially those with bone pain refractory to conservative management with analgesics and physical therapy. Initiate calcium and vitamin D supplementation in those with VDD. Although there are emerging data on the potential therapeutic benefits of bisphosphonates in SCD,12,60–62 there are no randomized placebo-controlled studies of bisphosphonates in SCD to support a full recommendation currently.

KEY POINTS.

  • Osteonecrosis can affect children, adolescents, and adults with sickle cell disease of any genotype.

  • Recurrent vasoocclusive episodes and acute chest syndrome, both markers of sickle cell disease severity, are associated with femoral head osteonecrosis.

  • Supportive care with preoperative red blood cell transfusions, hydration, and prophylactic antibiotics may improve joint arthroplasty outcomes for people with sickle cell disease and symptomatic osteonecrosis.

DISCLOSURE

Dr O.O. Adesina is currently funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Doris Duke Charitable Foundation. She declares no relevant commercial or financial conflicts of interest for this work.

REFERENCES

  • 1.Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med 2010;38(4 Suppl):S512–21. [DOI] [PubMed] [Google Scholar]
  • 2.Chaturvedi S, DeBaun MR. Evolution of sickle cell disease from a life-threatening disease of children to a chronic disease of adults: the last 40 years. Am J Hematol 2016;91(1):5–14. [DOI] [PubMed] [Google Scholar]
  • 3.Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell disease in a high-income setting. Blood 2016;128(10):1436–8. [DOI] [PubMed] [Google Scholar]
  • 4.Dalle Carbonare L, Matte A, Valenti MT, et al. Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease. Blood 2015;126(20):2320–8. [DOI] [PubMed] [Google Scholar]
  • 5.Leonard MB, Zemel BS, Kawchak DA, et al. Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr 1998;132(3 I):467–71. [DOI] [PubMed] [Google Scholar]
  • 6.Buison AM, Kawchak DA, Schall JI, et al. Bone area and bone mineral content deficits in children with sickle cell disease. Pediatrics 2005;116(4):943–9. [DOI] [PubMed] [Google Scholar]
  • 7.Zemel BS, Kawchak DA, Ohene-Frempong K, et al. Effects of delayed pubertal development, nutritional status, and disease severity on longitudinal patterns of growth failure in children with sickle cell disease. Pediatr Res 2007;61(5 PART 1):607–13. [DOI] [PubMed] [Google Scholar]
  • 8.Kawchak DA, Schall JI, Zemel BS, et al. Adequacy of dietary intake declines with age in children with sickle cell disease. J Am Diet Assoc 2007;107(5):843–8. [DOI] [PubMed] [Google Scholar]
  • 9.Osunkwo I An update on the recent literature on sickle cell bone disease. Curr Opin Endocrinol Diabetes Obes 2013;20(6):539–46. [DOI] [PubMed] [Google Scholar]
  • 10.Ganguly A, Boswell W, Aniq H. Musculoskeletal manifestations of sickle cell anaemia: a pictorial review. Anemia 2011;2011(Article ID 794283):1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Almeida A, Roberts I. Bone involvement in sickle cell disease. Br J Haematol 2005;129(4):482–90. [DOI] [PubMed] [Google Scholar]
  • 12.De Franceschi L, Gabbiani D, Giusti A, et al. Development of algorithm for clinical management of sickle cell bone disease: evidence for a role of vertebral fractures in patient follow-up. J Clin Med 2020;9(5):1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.da Silva Junior GB, Daher Ede F, da Rocha FA. Osteoarticular involvement in sickle cell disease. Rev Bras Hematol Hemoter 2012;34(2):156–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Dampier C, Palermo TM, Darbari DS, et al. AAPT diagnostic criteria for chronic sickle cell disease pain. J Pain 2017;18(5):490–8. [DOI] [PubMed] [Google Scholar]
  • 15.Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312(10):1033–48. [DOI] [PubMed] [Google Scholar]
  • 16.Yu T, Campbell T, Ciuffetelli I, et al. Symptomatic avascular necrosis: an understudied risk factor for acute care utilization by patients with SCD. South Med J 2016;109(9):519–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Adesina OO, Neumayr LD. Osteonecrosis in sickle cell disease: an update on risk factors, diagnosis, and management. Hematol Am Soc Hematol Educ Program 2019;2019(1):351–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gallo AM, Patil C, Adeniyi T, et al. Health-related quality of life and personal life goals of adults with sickle cell disease after hematopoietic stem cell transplantation. West J Nurs Res 2019;41(4):555–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Flouzat-Lachaniete CH, Roussignol X, Poignard A, et al. Multifocal joint osteonecrosis in sickle cell disease. Open Orthop J 2009;3:32–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Adesina O, Brunson A, Keegan THM, et al. Osteonecrosis of the femoral head in sickle cell disease: prevalence, comorbidities, and surgical outcomes in California. Blood Adv 2017;1(16):1287–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Mahadeo KM, Oyeku S, Taragin B, et al. Increased prevalence of osteonecrosis of the femoral head in children and adolescents with sickle-cell disease. Am J Hematol 2011;86(9):806–8. [DOI] [PubMed] [Google Scholar]
  • 22.Milner PF, Kraus AP, Sebes JI, et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med 1991;325(21):1476–81. [DOI] [PubMed] [Google Scholar]
  • 23.Milner PF, Kraus AP, Sebes JI, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop Relat Res 1993;289:136–43. [PubMed] [Google Scholar]
  • 24.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007;21(1):37–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Worrall D, Smith-Whitley K, Wells L. Hemoglobin to hematocrit ratio: the strongest predictor of femoral head osteonecrosis in children with sickle cell disease. J Pediatr Orthop 2016;36(2):139–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Leandro MP, De Sa CKC, Filho DPS, et al. Association and risk factors of osteonecrosis of femoral head in sickle cell disease: a systematic review. Indian J Orthop 2022;56(2):216–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Hernigou P, Bachir D, Galacteros F. The natural history of symptomatic osteonecrosis in adults with sickle-cell disease. J Bone Joint Surg Am 2003;85-A(3):500–4. [DOI] [PubMed] [Google Scholar]
  • 28.Lee GC, Khoury V, Steinberg D, et al. How do radiologists evaluate osteonecrosis? Skeletal Radiol 2014;43(5):607–14. [DOI] [PubMed] [Google Scholar]
  • 29.Hernigou P, Allain J, Bachir D, et al. Abnormalities of the adult shoulder due to sickle cell osteonecrosis during childhood. Rev Rhum Engl Ed 1998;65(1):27–32. [PubMed] [Google Scholar]
  • 30.Steinberg ME, Oh SC, Khoury V, et al. Lesion size measurement in femoral head necrosis. Int Orthop 2018;42(7):1585–91. [DOI] [PubMed] [Google Scholar]
  • 31.Gupta R, Adekile AD. MRI follow-up and natural history of avascular necrosis of the femoral head in Kuwaiti children with sickle cell disease. J Pediatr Hematol Oncol 2004;26(6):351–3. [DOI] [PubMed] [Google Scholar]
  • 32.Adekile AD, Gupta R, Al-Khayat A, et al. Risk of avascular necrosis of the femoral head in children with sickle cell disease on hydroxyurea: MRI evaluation. Pediatr Blood Cancer 2019;66(2):e27503. [DOI] [PubMed] [Google Scholar]
  • 33.Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv 2020;4(12):2656–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Itzep NP, Jadhav SP, Kanne CK, et al. Spontaneous healing of avascular necrosis of the femoral head in sickle cell disease. Am J Hematol 2019;94(6):E160–2. [DOI] [PubMed] [Google Scholar]
  • 35.Kamath AF, Sheth NP, Hosalkar HH, et al. Modern total hip arthroplasty in patients younger than 21 years. J Arthroplasty 2012;27(3):402–8. [DOI] [PubMed] [Google Scholar]
  • 36.Neumayr LD, Aguilar C, Earles AN, et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J Bone Joint Surg Am 2006;88(12):2573–82. [DOI] [PubMed] [Google Scholar]
  • 37.Aguilar CM, Neumayr LD, Eggleston BE, et al. Clinical evaluation of avascular necrosis in patients with sickle cell disease: children’s Hospital Oakland Hip Evaluation Scale–a modification of the Harris Hip Score. Arch Phys Med Rehabil 2005;86(7):1369–75. [DOI] [PubMed] [Google Scholar]
  • 38.Vichinsky EP, Neumayr LD, Haberkern C, et al. The perioperative complication rate of orthopedic surgery in sickle cell disease: report of the National Sickle Cell Surgery Study Group. Am J Hematol 1999;62(3):129–38. [DOI] [PubMed] [Google Scholar]
  • 39.Fassihi SC, Lee R, Quan T, et al. Total hip arthroplasty in patients with sickle cell disease: a comprehensive systematic review. J Arthroplasty 2020;35(8):2286–95. [DOI] [PubMed] [Google Scholar]
  • 40.Howard J, Malfroy M, Llewelyn C, et al. The transfusion alternatives preoperatively in sickle cell disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 2013;381(9870):930–8. [DOI] [PubMed] [Google Scholar]
  • 41.Ilyas I, Alrumaih HA, Rabbani S. Noncemented total hip arthroplasty in sickle-cell disease: long-term results. J Arthroplasty 2018;33(2):477–81. [DOI] [PubMed] [Google Scholar]
  • 42.Wun T, Brunson A. Sickle cell disease: an inherited thrombophilia. Hematol Am Soc Hematol Educ Program 2016;2016(1):640–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Brunson A, Keegan T, Mahajan A, et al. High incidence of venous thromboembolism recurrence in patients with sickle cell disease. Am J Hematol 2019;94(8):862–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Hariharan N, Brunson A, Mahajan A, et al. Bleeding in patients with sickle cell disease: a population-based study. Blood Adv 2020;4(5):793–802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Hankins JS, Estepp JH, Hodges JR, et al. Sickle Cell Clinical Research and Intervention Program (SCCRIP): a lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood. Pediatr Blood Cancer 2018;1–12. [DOI] [PubMed] [Google Scholar]
  • 46.Adesina OO, Gurney JG, Kang G, et al. Height-corrected low bone density associates with severe outcomes in sickle cell disease: SCCRIP cohort study results. Blood Adv 2019;3(9):1476–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab 2012;97(4):1153–8. [DOI] [PubMed] [Google Scholar]
  • 48.Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96(7):1911–30. [DOI] [PubMed] [Google Scholar]
  • 49.Goodman IBM, Artz N, Radford B, et al. Prevalence of vitamin D deficiency in adults with sickle cell disease. J Natl Med Assoc 2010;102(4):332–5. [DOI] [PubMed] [Google Scholar]
  • 50.Nolan VG, Nottage KA, Cole EW, et al. Prevalence of vitamin D deficiency in sickle cell disease: a systematic review. PLoS One 2015;10(3):12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Rovner AJ, Stallings VA, Kawchak DA, et al. High risk of vitamin D deficiency in children with sickle cell disease. J Am Diet Assoc 2008;108(9):1512–6. [DOI] [PubMed] [Google Scholar]
  • 52.Arlet JB, Courbebaisse M, Chatellier G, et al. Relationship between vitamin D deficiency and bone fragility in sickle cell disease: a cohort study of 56 adults. Bone 2013;52(1):206–11. [DOI] [PubMed] [Google Scholar]
  • 53.Adams-Graves P, Daniels AB, Womack CR, et al. Bone mineral density patterns in vitamin D deficient African American men with sickle cell disease. Am J Med Sci 2014;347(4):262–6. [DOI] [PubMed] [Google Scholar]
  • 54.Lal A, Fung EB, Pakbaz Z, et al. Bone mineral density in children with sickle cell anemia. Pediatr Blood Cancer 2006;47(7):901–6. [DOI] [PubMed] [Google Scholar]
  • 55.Osunkwo I, Hodgman EI, Cherry K, et al. Vitamin D deficiency and chronic pain in sickle cell disease. Br J Haematol 2011;153(4):538–40. [DOI] [PubMed] [Google Scholar]
  • 56.Osunkwo I Complete resolution of sickle cell chronic pain with high dose vitamin D therapy: a case report and review of the literature. J Pediatr Hematol Oncol 2011;33(7):549–51. [DOI] [PubMed] [Google Scholar]
  • 57.Osunkwo I, Ziegler TR, Alvarez J, et al. High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study. Br J Haematol 2012;159(2):211–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Dougherty KA, Bertolaso C, Schall JI, et al. Safety and efficacy of high-dose daily vitamin D3 supplementation in children and young adults with sickle cell disease. J Pediatr Hematol Oncol 2015;37(5):e308–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Serarslan Y, Kalaci A, Ozkan C, et al. Morphometry of the thoracolumbar vertebrae in sickle cell disease. J Clin Neurosci 2010;17(2):182–6. [DOI] [PubMed] [Google Scholar]
  • 60.Grimbly CBA, Jaremko JL, Girgis R, et al. Bisphosphonates for Sickle Cell Bone Morbidity: A Multicenter Canadian Pediatric Experience. The American Society for Bone and Mineral Research 2020 Annual Meeting. Virtual. J Bone Miner Res 2020;35(Suppl 1). [Google Scholar]
  • 61.Grimbly C BA, Girgis R, Jaremko JL. Successful Bisphosphonate Therapy for Vertebral Avascular Necrosis in an Adolescent with Sickle Cell Disease. The American Society for Bone and Mineral Research 2019 Annual Meeting. Orlando, FL: J Bone Miner Res 32 (Suppl 1); 2019. [Google Scholar]
  • 62.Cico TB, Kullolli S, Harizi I, et al. SAT0381 The use of bisphosphonates in the treatment of low bone mineral density in adults with sickle cell anemia. Annals of the Rheumatic Diseases 2013;71(Suppl 3):600–1. [Google Scholar]

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