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Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors

Altieri B1Di Dato C2Modica R3Bottiglieri F3Di Sarno A4Pittaway JFH5Martini C6Faggiano A7Colao A3.

Nutrients. 2020 Apr 8;12(4). pii: E1021. doi: 10.3390/nu12041021.



Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.

Discussion and Conclusions

Bone is a highly dynamic organ that undergoes significant constant remodeling balanced by

osteoblastic bone formation and osteoclastic bone resorption. Disturbance of this equilibrium leads to skeletal diseases, including osteoporosis [2]. Osteopenia and osteoporosis have been described in a large percentage of GEP–NET patients (up to 76% of cases) [18,21,25,26], and an increased risk of lower BMD is particularly pronounced in younger patients (<50 years old) [18]. This association with low BMD observed in GEP–NET patients could be explained by the fact that, besides bone metastasis [13], GEP–NETs are associated with several factors that could interfere with the normal bone homeostasis, including hypersecretion of substances biologically active on bone tissue, miRNA expression, nutritional status, which in turn could be a_ected by medical and surgical treatments, vitamin D deficiency, worsening quality of life and aspects correlated to MEN1 [21]. Among the hormones that could be secreted by functioning GEP–NET, 5-HT, cortisol and PTH-rp could play a major role in a_ecting bone metabolism [28,41,48,53]. Nutritional status in GEP–NET patients is deeply a_ected by the excessive production of gastrointestinal hormones, surgical resection changing the anatomy of the gastrointestinal tract, and treatment with SSA and chemotherapy. All these factors

cause malabsorption with a consequent deficit of vitamin D and other electrolytes involved in bone metabolism [19,22,70]. Vitamin D deficiency is highly prevalent in GEP–NET patients [21,22,29,30].

Since vitamin D plays a central role in bone metabolism [86], its deficiency may negatively impact bone health in GEP–NET patients. However, studies focusing on vitamin D and bone in GEP–NETs are missing. Weak or indirect e_ects on bone are described for depression, low physical activity, as well as specific miRNAs (miRNA-210, -21 and -196a) [56,57,83,130]. Finally, specific aspects of MEN1 syndrome, including primary HPT and gastrinoma, have been shown to worsen BMD. Moreover, the protein menin has a direct e_ect on VDR and other bone-related factors, as well as playing a central role in the di_erentiation of osteoblasts [113,114].

Although patients with GEP–NETs usually have good long-term survival, they have a greater

clinical burden of disease than healthy controls and are at high risk of presenting with osteoporosis at a younger age. Osteoporosis, together with other comorbidities, may negatively impact the quality of life of these patients and could contribute to higher medical expenses. Due to the lack of scientific evidence, there are no specific guidelines designed to regulate the diagnosis and clinical management of disturbances of bone metabolism in GEP–NETs. Bone assessment and the pathological exams in NET needs a multidisciplinary approach. We suggest supplementation with vitamin D in those patients who have insu_cient or deficient vitamin D levels since it has been demonstrated that supplementation does improve the vitamin D levels and may correlate with better clinical outcomes. Moreover, optimal vitamin D levels are also necessary to prevent bone damage. Finally, we recommend screening with a

bone density scan in those patients who present with more than one factor that could be associated with bone loss. Further studies are urgently needed to better delineate the relationships and associations between these interesting areas of medicine and science.