Bone Disease among Children with Sickle Cell Disease: A Scoping Review of Incidence and Interventions

Figures & data

Table 1 Critical Appraisal Tool

Study	Study Design	JBI Critical Appraisal Tool
Williams et al (2018)^Citation12	Prospective cohort	7/11 (63.63%)
Grimbly et al (2022)^Citation13	Retrospective cohort	6/11 (54.54%)
Novais et al (2015)^Citation15	Retrospective cohort	7/11 (63.63%)
Alabi et al (2021)^Citation21	Prospective cohort	7/11 (63.63%)
Gatin et al (2016)^Citation22	Prospective cohort	7/11 (63.63%)
Itzep et al (2019)^Citation23	Retrospective cohort	6/11 (54.54%)

Figure 1 PRISMA Flow diagram. Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated :guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.

Table 2 Characteristics of Studies Reporting Bone Disease Management of Children with SCD (n = 6)

Ref	Country	Study Design	Population	Sample (N)	Gender		Age (range)	Type of SCD	Event	Bone Disease
					Male (N)	Female (N)
Williams et al (2018)^Citation12	USA	Prospective cohort	Children with SCD	4	1	3	11–16	HbSS	4	Chronic arthritis, non-displaced fracture, Central end plate depression of thoracic, and Joint bony infarct
Alabi et al (2021)^Citation21	Nigeria	Prospective cohort	Children with SCD	27	8	19	12–19	HbSS	27	AVN
Grimbly et al (2022)^Citation13	Canada	Retrospective cohort	Children with SCD	46	26	20	<18 years	HbSS HbS-B^0 HbSC HbSS Arab-Indian haplotype	40 3 2 1	AVN
Novais et al (2015)^Citation15	USA	Retrospective cohort	Children with SCD	11	9	2	9–18	HbSS HbS-B^0 HbSC	5 3 3	ONFH
Gatin et al (2016)^Citation22	France	Prospective cohort	Children with SCD	10	5	5	4–15	HbSS	10	ONFH
Itzep et al (2019)^Citation23	USA	Retrospective cohort	Children with SCD	16	8	8	7–19	HbSS HbSC HbS-B^0	13 1 2	AVN

Abbreviations: SCD, Sickle cell disease; ONFH, Osteonecrosis of the Femoral Head; HbSS, sickle cell anemia hemoglobin SS disease; HbS-B⁰ Thal, sickle beta thalassemia with no HbA; HbSC, sickle cell disease; AVN, Avascular Necrosis.

Table 3 Percentage Analysis by Demographic Variable in Selected Studies

Subgroup	Number of Studies (N)	Sample Size (N)	Percentage (%)
Overall studies	6	114	100
Age
0–19	6	114	100
Gender
Male	6	57	50.0
Female	6	57	50.0
Country Region
Eropa	1	10	8.77
Amerika	4	77	67.54
Afrika	1	27	23.69
Study Design
Retrospective cohort	3	73	64.03
Prospective cohort	3	41	35.97
Type of SCD
HbSS	6	99	86.84
HbS-B^0	3	8	7.01
HbSC	3	6	5.27
HbSS Arab-Indian haplotype	1	1	0.88
Bone Disease
AVN	3	89	78.08
ONFH	2	21	18.420
Other	1	4	3.50
Type of Interventions
Physical therapy	1	5	3.88
Oral pharmacological	1	4	3.10
Invasive	2	67	51.93
Surgical	4	53	41.09

Abbreviations: ONFH, Osteonecrosis of the Femoral Head; HbSS, sickle cell anemia hemoglobin SS disease; HbS-B⁰ Thal, sickle beta thalassemia with no HbA; HbSC, sickle cell disease; AVN, Avascular Necrosis.

Table 4 Interventions in the Management of Bone Disease in Children with SCD (n = 6)

Ref	Sample (N)	Intervention	Type of Intervention	Procedure	Instrument	Follow-up	Intervention effect	Outcome
Williams et al (2018)^Citation12	4	Vitamin D3 (cholecalciferol)	Oral pharmacological	Children received oral vitamin D3 100,000 IU weekly for two months, followed by once-monthly doses of 100,000 IU for 22 months. In addition, monitoring for hypercalcemia and hypercalciuria is carried out. Finally, after the study, the patient was prescribed oral vitamin D 600 IU daily	DXA	12 month	All children showed positive results from vitamin D3 therapy without hypervitaminosis D or hypercalcemia.	After the intervention, serum 25(OH)D levels increased, BMD increased, and PTH normalized.
Alabi et al (2021)^Citation21	27	THA	Surgical	Harris Hip Scoring (HHS) and Oxford Hip Scoring (OHS) assessments; Assessment of genotype, bilaterality, and previous treatments; determine the child’s stable Hb before surgery; Regional anesthesia (spinal or epidural); Surgical time ranges from 80–185 minutes. The implants used are made of metal on an acetabular polyethylene layer, namely Depuy, Surgival, and Zimmers; The size of the acetabular shell used ranges from 44 mm to 54 mm; Uncemented THA was performed using a direct lateral approach. Subperiosteal detachment of the iliopsoas muscle and adductor tenotomy are performed when indicated. Finally, weight-bearing ambulation was initiated on the second postoperative day.	HHS dan OHS	24 month	Two children experienced superficial surgical wound infections that were resolved using antibiotics and wound care. Additionally, there are no life-threatening side effects. Arthroplasty in SCD children with AVN is considered safe and beneficial, although challenging. The intervention provided excellent functional outcomes with minimal complications.	The mean preoperative HHS and OHS each increased significantly with a p-value <0.0001 at two years, namely HHS from 27.7 ± 6.6 to 93.0 ± 2.2 and OHS from 10.0 ± 4.9 52.8 ± 2.7.
Gatin et al (2016)^Citation22	10	Osteotomy	Surgical	Postel Merle d’Aubigne´ and Harris scoring before and surgery; anesthesia; exchange transfusion, heterologous transfusion and perioperative analgesia support; traction on the legs; Surgery begins with a triple acetabular osteotomy, if the acetabular coverage of the femoral head is insufficient, a varus femoral osteotomy is performed.	MRI and HPMA	12 month	No complications. All children had functional benefits after surgery. There was one child who experienced lung disease (pneumonia) 2 days after surgery without acute respiratory distress syndrome because the child had ACS. Pneumonia can be treated with antibiotics without complications.	All children had significant objective functional improvement by Wilcoxon Signed-Rank test (0.00338) in pain and range of motion with a mean increase in Harris score of 29 points.
Novais et al (2015)^Citation15	11	Multiple epiphyseal drilling with AMBI	Surgical	The patient is positioned supine and receives general anesthesia; Sterilization and closure of the entire lower extremity including the hemipelvis; 1–2 cm incision in the anterior superior iliac spine towards the iliac crest; A fenestrated 11-G needle for bone marrow aspiration is inserted into the iliac spine and bone marrow is aspirated with a total volume of approximately 60–120 mL. The aspiration was concentrated into approximately 15 mL of bone marrow cells using a bone marrow aspiration cell system (Harvest Technologies Corporation, Plymouth, MA); An approximately 3 cm incision is made on the lateral thigh and dissection down to the fascia layer. The fascia lata divides longitudinally, and the vastus lateralis divides in the midline just distal to the broad tubercle of the femur; Under C-arm guided fluoroscopic imaging, three 2.8 mm Steinman pins were inserted into the necrotic zone of the femoral head to perform drilling of the femoral epiphysis; Select the Steinman pin most central to the necrotic area to use as a guide for the perforation trocar (8-G trocar). The selected Steinman pin was removed and exchanged for the trocar; A 2 mL 50% solution (ioversol and sterile saline) was injected to ensure the marrow could migrate to the femoral head. The concentrated marrow is injected slowly into the femoral head to reduce leakage, and fluoroscopy is used to confirm the dissipation of the previously injected contrast, indicating that the marrow has displaced the contrast into the necrotic bone. The trocar and Steinman pins were then removed; Postoperative hospital stay of approximately 24 hours for hydration, pain management, and observation; There is no use of a brace or cast, and the patient is instructed to bear weight on the affected extremity and use crutches for two months.	CHOHES and Steinberg	12 month	There were no reports of complications. However, when evaluated, two children required further surgical procedures, and one child underwent hip dislocation surgery	There was no significant difference in the degree of femoral head involvement assessed using necrotic arc angle (P = 0.2251), femoral head collapse on AP (P = 0.4258) and lateral (P = 0.4609) radiographs. The majority of hips in the Steinberg stage of disease had either improvement (4/14 hips) or no further development of the necrotic process (7/14 hips)
Itzep et al (2019)^Citation23	5	Surgical	Surgical	NA	MRI	NA	NA	The results of surgical management showed no radiographic improvement
Grimbly et al (2022)^Citation13	46	IV bisphosphonates	Invasive	Administer vitamin D supplementation of at least 50 nmol/L before IV bisphosphonate therapy to optimize serum 25(OH)D levels. IV bisphosphonate therapy is administered according to the bone pain/osteoporosis protocol via one of three regimens: IV pamidronate: annual dose (4.5–9 mg/kg body weight/year) given every 4 months, namely 1 mg/kg/day for 3 days each (9 mg/kg/year) or 1.5 mg/kg in 1 day (4.5 mg/kg/year) IV zoledronic acid: annual dose of 0.05–0.1 mg/kg body weight, divided into two doses every 6 months or Give an initial dose of pamidronate followed by zoledronic acid to reduce side effects	DXA	Five month	There were no reports of osteonecrosis, pain events, hemolytic crisis, stroke, or other complications. There was only one episode of symptomatic hypocalcemia that was treatable with five days of oral calcium and calcitriol.	Children who received IV bisphosphonate therapy had a mean 25(OH)D level of 58 nmol/L (n=23, SD 34.9), above the normal limit. The rate of bone formation increased by 265% of the healthy pre-IV bisphosphonate average. However, DXA did not show a significant increase in height-adjusted LS or TBLH aBMD Z scores, namely LS HAZ aBMD Z-score (0.4) TBLH HAZ BMD Z-score (0.4)
Itzep et al (2019)^Citation23	16	HU	Invasive	Children are given HU with an MTD of 48%-45%.	MRI	NA	There were no reports of complications and none of the children who received HU underwent observation arthroplasty	Study results show that radiographic improvement in AVN occurs at a younger age
Itzep et al (2019)^Citation23	5	CD with bone marrow aspirate concentrate injection	Invasive	NA	MRI	NA	NA	None showed results in radiographic improvement
Itzep et al (2019)^Citation23	5	Physical therapy	Physical therapy	NA	MRI	NA	NA	Only one in five children showed radiographic improvement

Abbreviations: AMBI, Autologous Bone Marrow Implantation; CHOHES, the Children’s Hospital Oakland Hip Evaluation Scale; HU, The University of Pennsylvania (Steinberg); HU, hydroxyurea; DXA, dual-energy x-ray absorptiometry; HHS, Harris Hip Scoring; OHS, Oxford Hip Scoring; MRI, Radiographs, magnetic resonance imaging; HPMA, Harris and Postel Merle d’Aubigne´ scores; PTH, parathyroid hormone; BMD, bone mineral density; 25(OH)D, serum 25- hydroxyvitamin D; THA, total hip arthroplasty; LS, Lumbar spine; TBLH, total body less head; aBMD, areal BMD; HAZ, height-for-age Z-score; MTD, maximum tolerated dose; CD, core decompression; IV, Intravenous.

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