Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management

Abstract

Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient’s quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice.

Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors

“…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 affected 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 affecting bone metabolism [28,41,48,53].…”

“…MiRNAs are small noncoding single-stranded RNAs of 21-23 nucleotides long that regulate the expression of 1%-4% of human genes at a posttranscriptional level. Therefore, miRNAs are involved in many physiological and pathological conditions, including GEP-NET progression and metastatic spread [13,54].…”

“…Bone metastasis are reported in 4-12% of NET patients, but the real incidence is probably higher [13][14][15][16]. However, except for those patients who have a metastatic disease associated with shorter survival [13], patients with NET usually have good long-term survival [10,17]. It has been demonstrated that NET patients have a greater clinical burden of disease than matched control subjects, with increased risk of cardiovascular, hepatic, and gastrointestinal diseases, as well as osteopenia and osteoporosis [18].…”

“…The frequency of NET is reported to be increasing in a number of countries over the last few decades [11,12]. Bone metastasis are reported in 4-12% of NET patients, but the real incidence is probably higher [13][14][15][16]. However, except for those patients who have a metastatic disease associated with shorter survival [13], patients with NET usually have good long-term survival [10,17].…”

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

“…Main acute toxicities of external beam radiotherapy include erythema, loss of appetite, fatigue, nausea and vomiting, irrespective of the adoption of a single-dose or fractionated treatment schema [63]. Although their use is recommended by the ENETS guidelines [64], the administration of bisphosphonates in patients with NETs varies widely across different institutions given an apparent lack of survival benefit associated with this form of bone-directed treatment [7, 8, 65]. Consistent with reports in other malignancies [66], the monthly administration of bisphosphonates did not show any advantage over less intensive treatment schemes in a small group of patients with NET [13].…”