Low Bone Density In Sickle Cell Disease Is a Risk Factor in The Development Of Avascular Necrosis

Introduction Sickle cell disease (SCD) is a highly prevalent disorder in the world, specifically in the region of Kuwait. A wide population suffers from sickle cell anaemia. It has been known that bone involvement is one of the most common clinical manifestations of sickle cell disease, both in the acute setting such as painful vaso-occlusive crises, and as a chronic, progressive process such as osteoporosis ,osteopenia and avascular necrosis (AVN), which can develop due to the low bone mass and the deterioration of the micro architecture of bone tissue. In this ongoing project, we used the radionuclide imaging technique for bone and bone marrow scintigraphy and dual-energy x-ray absorptiometry (DEXA). We attempted a correlation between low bone density and the bone infarct for SCD, and identified if low bone density is a risk factor for the severity and development of osteonecrosis in an at-risk population of sickle cell patients. Patients and Methods A total of 13 sickle cell patients participated in this correlation study; 5 males and 8 females, ages ranged from 16 to 55 years with a mean age of 35.5 years. To meet the participant selection criteria, patients were selected if they were never prescribed bisphosphonates or any type of medicine used to help strengthen bones weakened by osteoporosis, nor exposed to any other AVN risk factors other than SCD. Subjects were subjected to a scintigraphy (3-phase bone SPECT-CT, bone marrow) and bone mineral density scan (BMD). All subjects consented to the study approved by the ethics committee. Bone scintigraphy was performed by Tc-99m MDP, HDP 20mCi / 70kg intravenous injection. Bone Marrow Scintigraphy was performed by Tc-99m sulfur or tin colloid, 10-15 mCi / 70 kg I.V, Bone with Bone marrow scintigraphy imaging is required to assess bone marrow infarction and infection. BMD dual-energy x-ray absorptiometry (DEXA) was also performed to indicate the reliably changes in bone mineral content of the lumbar spine and proximal femur. Statistical analysis involved descriptive statistics and chi-square test. Results According to the WHO criteria used; low bone density was found in 9/13 (69%) while normal bone density was found in 4/13 patients (31 %). Based upon the application of a chi-square test, all those subjects 9/9 having a low bone density were showing AVN in several severity and multiple sites of the skeleton; it was found that there is an association between low bone density and incidents of AVN. However, it is of importance to note that 2/4 (50%) of the normal bone density patients were found to have AVN. Conclusion The preliminary conclusion discern from this ongoing project suggest that low bone mineral density in SCD could be considered a risk factor contributing to the development of AVN. We hypothesise that the severity of AVN develops due to the low bone mass and the deterioration of the micro architecture of bone tissue. The results have shown that low bone density is highly associated with osteonecrosis. Further case studies are needed to confirm or disprove these findings. The findings of this project could inspire new protocols required for effective management of this disease. Our findings could also potentially point out and diagnose new clinical cases, which would normally not be clinically suspected. We also speculate that increasing bone density of this patient population may decrease the severity and incidents of AVN. References 1-Sch2-nog JB, Duits AJ, Muskiet FA, ten Cate H, Rojer RA, Brandjes DP. Sickle cell disease; a general overview. Neth J Med. 2004 Nov;62(10):364-74. Review. PubMed citation 2-Digiovanni, Cw; Patel, A; Calfee, R; Nickisch, F (Apr 2007). “Osteonecrosis in the foot”. The Journal of the American Academy of Orthopaedic Surgeons 15 (4): 208–17. ISSN 1067-151X. PMID 17426292. 3-eMedicine Specialties > Avascular NecrosisAuthor: Jeanne K Tofferi, MD, MPH, FACP; Coauthor: William Gilliland, MD, MPHE, FACP, FACR. Updated: Dec 17, 2009 4-Baksi, Dp (May 1983). “Treatment of post-traumatic avascular necrosis of the femoral head by multiple drilling and muscle-pedicle bone grafting. Preliminary report”. The Journal of bone and joint surgery. British volume 65 (3): 268–73. ISSN 0301-620X. PMID 6341373. Disclosures: No relevant conflicts of interest to declare.

HLA-Haploidentical Hematopoietic Stem Cell Transplantation In An Infant with Malignant Infantile Osteopetorosis.

Abstract 4585 Malignant infantile osteopetrosis is an autosomal recessive disease characterized by a lack of osteoclastic function with incidence of 1: 200,000 to 1: 300,000. In consequence of disturbed bone building and remodeling, affected patients have osteosclerosis, dense fragile bone, and a marked reduction in the bone marrow cavity. Clinical features, such as anemia, thrombocytopenia, hepatosplenomegaly, bone fractures, bone deformity, and cranial nerve entrapment, appear soon after birth or within the first years of life. In the natural course of the disease, only 30% of children can survive to more than six years old. Because osteoclasts are of hematopoietic origin, allogeneic stem cell transplantation is the only curable therapy. Recently, successful HLA-haploidentical hematopoietic stem cell transplantation (HSCT) has been reported for patients without HLA- matched donors. We also present an infant with malignant infantile osteopetrosis who underwent HLA-haploidentical HSCT. A four-month-old boy was referred to our hospital for splenomegaly and pancytopenia. A physical examination revealed failure to thrive, distention of anterior fontanel, and hepatosplenomegaly. Laboratory findings indicated thrombocytopenia and anemia, and elevated alkaline phosphatase. Osteoclasts were hyperplastic in bone marrow. Radiography showed homogeneous and sclerotic bones with absence of corticomedullary junction, and bone marrow scintigraphy showed no accumulation of bone marrow. Subsequently, TCIRG1 mutations are identified. All these findings are compatible with malignant infantile osteopetrosis and the diagnosis was made. We conducted HSCT to revive his osteoclastic function. However, he didn't have HLA-matched donors not only in relatives but also in the bone marrow bank and the cord blood bank of Japan. We attempted HLA-haploidentical bone marrow transplantation (BMT) from his father with written informed consent. The patient was prepared for BMT at 11 months of age by conditioning with busulfan (6 mg/kg × 4/day × 4 days), cyclophosphamide (360mg/m2 × 2 days) and antithymocyte globulin (2 mg/kg/day × 3 days). Prophylaxis for graft-versus-host disease (GVHD) included tacrolimus and short-term methotrexate. Bone marrow nuclear cells (1×109/kg) were collected from his father and transplanted without any manipulations. The engraftment of neutrophils was confirmed on day 9 after BMT. Acute GVHD was limited to the skin (grade I). At 2 months after BMT, neutrophil counts, platelet counts, and hemoglobin level were all within normal limits. Bone marrow scintigraphy revealed a significant uptake in bone marrow. There have been no chronic GVHD up to six months after BMT.HSCT for patients with osteopetrosis is challenging as it is reported that HLA-haploidentical HSCT has the high rate of acute and chronic GVHD. Fortunately, HLA-haploidentical BMT was successful in our patient. This might be due to our regimen for prophylaxis of rejection and GVHD. We used ATG in conjunction with tacrolimus: this regimen may be prophylactic not only for rejection but also for GVHD as previously reported (Schulz et al. Blood 2002; 99: 3458–3460). In conclusion, HLA-haploidentical family donors should be considered as the alternative hematopoietic stem cell source for patients with malignant infantile osteopetrosis in condition without HLA-matched donors. Disclosures: No relevant conflicts of interest to declare.