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Bone disease is an important non‐malignant late effect after AHSCT [3]. Common bone complications are osteopenia, osteoporosis, and avascular necrosis. Osteopenia and osteoporosis are measured clinically by the T‐score on dual‐energy X‐ray absorptiometry (DEXA) scan [7]. Osteopenia is diagnosed by a T‐score of ‐1.0 to ‐2.5 and osteoporosis is diagnosed by a T‐score of less than ‐2.5 or presence of fragility fractures [37]. Common risk‐factors for bone density loss from broader osteoporosis literature are glucocorticoid use, exposure to radiation, vitamin D deficiency, and hypogonadism. Notably, a prednisone equivalent dose of more than 7.5 mg/day and a cumulative dose of more than 5 grams is associated with an increased risk of osteoporosis [38], which is clinically relevant in myeloma and lymphoma AHSCT recipients who may have exposure to corticosteroids as a part of pre‐ and/or posttransplant therapy, and will be discussed further below.

In a single‐institution study of 493 auto‐transplant survivors, the cumulative incidence of avascular necrosis was 4.3% at a median follow‐up of 3 years from transplant [3]. This further translated into an increased need for joint replacement surgery, with an incidence of 4.2% posttransplant compared to a pretransplant prevalence of 1.8%. Notably, the median time‐to‐diagnosis of avascular necrosis was around 1 year, and the median time‐to‐joint replacement surgery was 3 years from AHSCT. The cumulative incidence of osteoporosis was also higher at 9.7% after transplant compared to a pretransplant prevalence of 2.4% [3]. Risk‐factors for development of osteoporosis in the entire cohort of auto‐ and allogeneic‐transplant survivors were diabetes mellitus, lung disease, chronic graft‐versus‐host‐disease (cGVHD), and avascular necrosis/joint replacement. Another large study of approximately 600 AHSCT survivors showed a 2.9% cumulative incidence of avascular necrosis at 10 years [39]. A prospective study from Roswell Park measured bone mineral density (BMD) at pretransplant baseline and day 100 in both auto‐ and allogeneic transplant recipients to characterize the trajectory and risk‐factors of bone loss [40]. Interestingly, the magnitude of accelerated bone loss in the immediate posttransplant period was similar in auto‐ and allogeneic‐transplant recipients and was comparable to bone loss from 7–17 years’ worth of aging. Furthermore, a primary lymphoma diagnosis was the only risk factor for accelerated bone loss in AHSCT recipients.

Based on the trajectory and risk‐factors of bone complications after AHSCT, DEXA scan should be performed to assess bone density at one year and subsequently as clinically indicated. Diagnostic MRI should be performed when avascular necrosis is suspected, and orthopedic oncology should be consulted. The Fracture Risk Assessment Tool (FRAX) is widely used to risk‐stratify patients with osteoporosis. In patients with calcium or vitamin D deficiency, supplementation with 800–1200 mg of calcium and at least 50 nmol/l of 25‐hydroxyvitamin‐D can be beneficial in preventing fragility fractures [41]. Lifestyle interventions, including regular physical activity, good nutrition, and avoiding smoking or excessive alcohol intake should be implemented in AHSCT survivors for preserving bone health. Patients at a high risk of fragility fracture should initiate pharmacologic therapy with bisphosphonates or monoclonal antibodies directed against receptor activator of nuclear factor‐κB ligand (RANKL) [41]. Though most clinical trials in osteoporosis have limited the duration to around 3 years, optimal duration of bone strengthening agents remains controversial. Novel bone modifying agents, including RANKL inhibitor (Denosumab) is currently being evaluated in transplant survivors.