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  • X rays commonly show a typical licked

    2019-06-11

    X-rays commonly show a typical licked candy stick appearance, based on concentric bone resorption. Common blood tests are usually normal, but bone alkaline phosphatase (BAP) may be elevated if a fracture occurred [8]. GSD is a diagnosis of exclusion. Diseases responsible of bone osteolysis such as infections, inflammatory or endocrine disorders, intraosseous malignancies or metastases should be considered [1]. Radiographic and anatomopathological characteristics are used as pathognomonic features for the diagnosis of GSD [1]. Treatments include surgery, radiation and medical therapy. Surgery is reserved for severe cases, e.g. when pathological fractures need to be fixed or when en bloc resection is required. Reconstruction is achieved with bone grafts or alloplastic prostheses if instability occurs. Interventions are often quite invasive. Recurrence rate is close to 20% [1]. Radiotherapy is usually chosen in order to reverse the progression of the lymphangiomatosis and to treat lesions that are not surgically resectable, at least without major consequences. Post-operative radiotherapy is required when the lesion could not be resected in one piece [9]. There are no “Food and Drug Administration” (FDA) approved therapies for the treatment of GSD. Several drugs have nevertheless been tried, including bisphosphonates (etidronate, clodronate, pamidronate and zoledronic acid) [10–14], interferon alpha-2b [14,15], anti-VEGF-A antibody, bevacizumab, propranolol [16], low molecular weight heparin, steroids, vitamin D and calcitonin [17,18]. However the experience with these compounds, including bisphosphonates, is extremely limited. We found only one report of a patient treated with zoledronic FK506 [11]. On the opposite, the use of zoledronic acid, the most powerful bisphosphonate, has become an integral component of cancer treatment in patients with metastatic bone disease. The drugs markedly delay and decrease the occurrence of skeletal-related events [19]. Etiology and mechanism of bone resorption in GSD remain poorly understood [3,7,8,20]. In a recent review the potential role of endothelial cells, macrophages, osteoclasts and osteoblasts is discussed. Active lymphangiomatosis and haemangiomatosis may be triggered by secretion of VEGF through activation of receptors of lymphatic and blood endothelial cells. Patients presenting GSD have high VEGF-A and -C blood levels whereas anti-lymphagiogenic factors levels (VEGFR2, TGF-beta, IFN-gamma, etc.) are reported to be low, maybe contributing to uncontrolled growth of lymphatic vessels in the affected bones [21]. Osteoclastic activity may vary according to the phase of the disease. On the one hand, osteoclast differenciation is stimulated by macrophages, VEGF-A, -C, -D and IL-6. On the other hand, high levels of TNF-alpha (produced by macrophages) inhibit osteoblastogenesis and promote osteoclastogenesis. Inhibition of osteoprotegerin and enhanced production of RANKL contribute to stimulate bone resorption. Bone homeostasis appears to be unaffected in other parts of the skeleton [21–22]. Bone is in a constant state of remodeling. The functions of osteoblasts and osteoclasts are well balanced to maintain bone homeostasis [23]. Bone diseases such as bone metastases that alter this equilibrium in favor of osteoclasts can induce loss of structural integrity of the skeleton. In this situation osteoclasts resorb bone by secreting proteases that dissolve the matrix and acids that release bone mineral into the extracellular space. In GSD the situation is more complex because of replacement of the bone by a fibrous tissue [23]. Nevertheless, considering the existence of a high osteoclastic activity, use of combination of radiotherapy and bisphosponate has been tried in a few patients. Bisphosphonates have been chosen because of their anti-osteoclastic but also anti-angiogenic activities. Side effects of zoledronic acid are usually mild and, although renal function has to be checked before each infusion, the risk of osteonecrosis of the jaw is not negligible at high doses [23–24].