Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review.

BACKGROUND: Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria. RESULTS: Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies. CONCLUSIONS: Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis.

Team approach: Management of osteonecrosis in children with acute lymphoblastic leukemia.

With current treatments for acute lymphoblastic leukemia (ALL), the overall prognosis for survival is favorable. Increasing emphasis is placed on recognizing and managing the long-term consequences of ALL and its treatment, particularly involving osteonecrosis. Early osteonecrosis diagnosis and management may improve outcomes and is best accomplished through coordinated teams that may include hematologic oncologists, radiologists, orthopedic surgeons, physical therapists, and the patient and their family. Magnetic resonance imaging is the "gold standard" for diagnosis of early-stage and/or multifocal osteonecrosis. Treatments for osteonecrosis in ALL patients are risk stratified and may include observation, corticosteroid or chemotherapy adjustment, and pharmaceutical or surgical approaches.

Operation Change: A New Paradigm Addressing Behavior Change and Musculoskeletal Health Disparities.

BACKGROUND: In this study, we examined the implementation and efficacy of Operation Change, a community-based, culturally sensitive program to stimulate behavioral changes in activity level and improve musculoskeletal health in African-American (AA) and Hispanic/Latina (H/L) women with obesity and early-stage osteoarthritis. METHODS: Sixty-two women (32 AA and 30 H/L), 40-75 years old, with nontraumatic knee pain and body mass index values > 30, participated in a 12-week program of presentations, motivational interviewing, goal setting, and physical activities. Assessments (at 0, 6, and 12 weeks) included a demographic questionnaire, physical assessment, timed 50-ft walking test, Western Ontario and McMaster Universities Arthritis Index (WOMAC), Short Form-36 Health Survey (SF-36), 8-Item Physical Health Questionnaire (PHQ-8), and motivational interview assessment. RESULTS: Walking time improved significantly for H/L women (P < 0.0001) but not AA women (P = 0.0759). Both groups had significant mean weight loss (P < 0.05) with high variability among individuals. WOMAC scores for both groups indicated decreased pain (P < 0.0001) and stiffness (P < 0.0001) and improved physical functioning (P < 0.0001) by 12 weeks. SF-36 results were comparable to those of the WOMAC. PHQ-8 results improved significantly for H/L women (P < 0.0001) but not AA women (P = 0.077). Participants scored the motivational interviewing component of the program favorably. CONCLUSIONS: Participation in Operation Change increased physical activity, resulting in improvements in pain and function scores. This supports a new paradigm for behavioral modification that helps AA and H/L women take an active role in living with osteoarthritis.

Dexamethasone-induced lipolysis increases the adverse effect of adipocytes on osteoblasts using cells derived from human mesenchymal stem cells.

The increased bone marrow lipid deposition in steroid-associated bone loss diseases indicates that abnormalities in fat metabolism are associated with disease development. Recent studies have suggested that bone marrow adipocytes are secretory cells and that they may release substances that have an inhibitory effect on the differentiation and function of osteoblasts. We hypothesized that exposure of bone-marrow-derived adipocytes to corticosteroids exacerbates their deleterious effects on osteoblast metabolism and function. Adipocytes and osteoblasts derived from a human mesenchymal stem cell line (240L) were co-cultured in the absence of direct cell contact with or without dexamethasone treatment. After 6days of co-culture, osteoblasts demonstrated significantly lower levels of function based on lower mineralization, alkaline phosphatase activity and expression of osteogenic (Runx2, osteocalcin) mRNA marker. Dexamethasone treatment resulted in significantly lower levels of osteoblastic function compared with co-cultured cells without dexamethasone. Furthermore, conditioned media from dexamethasone-treated adipocytes induced a similar toxic effect and increased apoptosis involving activation of caspases 3/7 compared with conditioned media without dexamethasone treatment. Within the conditioned media, a substantial increase in the levels of leptin and two saturated fatty acids (FAs; stearate and palmitate) was observed after dexamethasone treatment. Although leptin supplementation failed to induce the inhibitory effect on osteoblasts, similar toxic results were produced with stearate and palmitate treatment, and an increase in intracellular reactive oxygen species was observed. Stearate- and palmitate-induced apoptosis was blocked by a reactive oxygen species scavenger pyrrolidine dithiocarbamate. These data show that saturated FAs secreted from adipocytes induce lipotoxic effects via mechanisms that may involve reactive oxygen species accumulation in osteoblasts. Our results suggest that inhibition of saturated FA secretion would protect osteoblasts against adipocytes in corticosteroid-associated bone loss diseases.

New treatment approaches for osteonecrosis of the femoral head: an overview.

Osteonecrosis of the femoral head is a debilitating disease that ultimately leads to hip joint destruction. Various efforts have been made in an attempt to enhance the healing of osseous defects in the femoral head before collapse occurs. Examples of noninvasive treatment modalities include pharmacologic measures, electrical stimulation, shock wave therapy, and electromagnetic field therapy. In addition, biologic alternatives will induce new bone formation. Many of these agents or techniques are still undergoing preclinical and clinical trials, and some are not approved by the Food and Drug Administration for the treatment of osteonecrosis of the femoral head. It is important to review new treatment opportunities that are currently available or on the horizon.