Table 1.
Principal clinical studies evaluating bone metabolism and vitamin D in GEP–NET.
| Author, Year and Reference | Type of Study | Number of Patients | Principal Aim | Principal Findings Associated with Bone Metabolism or Vitamin D |
|---|---|---|---|---|
| Hess et al. 2012 [18] |
Retrospective case-control. | 1762 NET and 3524 controls (1:2 ratio). | Comorbidities in NET. | Adjusted risk of osteoporosis/osteopenia was higher in NET patients among those 50 years or younger. |
| Van Dijk et al. 2012 [24] | Retrospective. | 84 carcinoid patients: 61 with increased 5-HT levels and 23 with low 5-HT levels (controls). | Differences in markers of bone metabolism between the two groups. | No significant differences in markers of bone metabolism between hyper-secretors and controls. |
| Sen Gupta et al. 2014 [25] | Observational. | 46 consecutive NET. | Relationships between urinary 5-HIAA and BMD measured by DXA | 41.3% had osteoporosis and 32.6% osteopenia. Urinary 5-HIAA was not an independent predictor for BMD. |
| Walsh et al. 2013 [26] |
Cross-sectional. | 25 patients with carcinoid syndrome and 25 healthy controls. | Association of carcinoid syndrome with bone formation markers, BMD and bone structure. | No measures of bone density or bone structure differed significantly between cases and controls. |
| Byun et al. 2017 [27] |
Case report. | Case of pNET producing ACTH. | Descriptive. | 40-year-old female patient with ophthalmologic discomfort, osteoporosis, and hypokalemia with diagnosis of pNET. |
| Dobnig et al. 1996 [28] |
Case report. | Case of appendix carcinoid producing ACTH- | Descriptive. | 34-year-old female patient with multiple spontaneous rip fractures and T-score at lumbar spine -4.3 SD. Increasing of BMD after tumor resection. |
| Lind et al. 2016 [21] |
Intervention. | 50 consecutive SI-NET (25 controls and 25 supplemented with vitamin D, B12 and calcium). | DXA and gastrointestinal disorders. | Control group: 46% vitamin D deficiency and 76% low BMD. Supplemented group: 28% vitamin D deficiency and 60% low BMD. Vitamin D supplementation avoid severe deficiency. |
| Massironi et al. 2017 [22] |
Observational. | 138 GEP–NET. | Impact of vitamin D and OS and PFS. | 68% cases had vitamin D deficiency. Patients treated with SSA had lower vitamin D levels. At multivariate analysis, vitamin D levels significantly correlate with OS. |
| Motylewska et al. 2016 [29] | Observational. | 36 NET and 16 healthy controls. | Evaluation of vitamin D levels between the two groups. | No significant difference in vitamin D levels between NET and controls. SSA therapy did not aggravate vitamin D deficiency. |
| Robbins et al. 2018 [30] |
Longitudinal, intervention. | 183 GEP-NET. | Effect of vitamin D treatment after 2 year of follow-up. | Vitamin D insufficiency decreased from 66.6% at baseline to 44.9% and 46.2% after 12 and 24 months, respectively. Previous abdominal surgery predicted vitamin D levels. |
| Lourenco et al. 2010 [31] |
Cross-sectional. | 36 MEN1 patients with HPT. | Outcome of bone and renal complications. | Patients with long-standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. |
| Coutinho et al. 2010 [32] | Case series. | 16 HPT/MEN1. | Impact of total PTx on BMD in patients with HPT/MEN1. | BMD improvement in the lumbar spine, femoral neck, and total femur after 15 months from PTx. |
| Silva et al. 2017 [33] |
Retrospective. | 14 HPT/MEN1 and 104 sporadic HPT. | Impact of total PTx on BMD in patients with HPT/MEN1 vs sporadic HPT. | At baseline, HPT/MEN1 had significantly lower Z-score at lumbar spine, total hip, and femoral neck than sporadic HPT. 1 year after PTx, HPT/MEN1 showed a better Z-score only at lumbar spine compare to baseline. |
| Giusti et al. 2016 [34] |
Longitudinal, intervention. | 33 MEN1. | Effect of cinacalcet on HPT. | No significant changes in BMD, and bone turnover markers after 1 year of treatment |
Abbreviation: BMD, bone mineral density; HPT, primary hyperparathyroidism, DXA, dual X-ray absorptiometry; MEN1, multiple endocrine neoplasia type 1; NET, neuroendocrine tumor; GEP–NET, gastro-entero-pancreatic NET; OS, overall survival; PFS, progression-free survival; pNET, pancreatic NET; PTx, parathyroidectomy; SI-NET, small intestinal NET; SSA, somatostatin analog; 1/3DR, proximal one-third of the distal radius; 5-HIAA, urinary 5-hydroxy-indoleacetic acid; 5-HT, serotonin.