Marek Bolanowski

Bone mineral density and turnover in patients with acromegaly in relation to sex, disease activity, and gonadal function

Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion. GH and insulin-like growth factor-I (IGF-I) exert anabolic activity in bones. Nevertheless, bone mineral density (BMD) loss is not uncommon in patients with acromegaly. It is assumed to be due to hypogonadism associated with the acromegaly. The aim of the study was to examine BMD at various skeletal sites and bone turnover and to assess the influence of impaired gonadal function and disease activity on BMD and turnover changes in acromegaly. A total of 62 patients were studied (40 women, 22 men). Among the women, 22 had active disease and 18 were cured; 16 women had normal gonadal function, and 24 were hypogonadal. Altogether, 12 men presented with active acromegaly, and 10 were cured; normal gonadal function was found in 10 men, and hypogonadism was diagnosed in 12 men. Controls were 30 healthy subjects. Densitometry using dual-energy X-ray absorptiometry of the lumbar spine, proximal femur, forearm, and total body was carried out. Bone turnover was studied based on serum osteocalcin, C-terminal collagen type 1 crosslinks, and bone alkaline phosphatase concentration. A disadvantageous effect of acromegaly on bone density was associated with hypogonadism in the distal radius (in women), the proximal femur (in men), and the total body (both sexes). An anabolic effect of GH during active acromegaly was present in the proximal femur only in men. We confirmed increased bone turnover in the presence of acromegaly, and these changes were similar regarding the activity of the disease and the gonadal status.

Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.

BACKGROUND A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. METHODS We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. RESULTS Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. CONCLUSIONS OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

Axial bone mineral density in patients with acromegaly

RATIONALE AND OBJECTIVES The purpose of this study was to assess the influence of long-term elevated levels of growth hormone and insulin-like growth factor I on bone mineral density (BMD) of the spine in patients with acromegaly. MATERIALS AND METHODS The spinal BMD in 40 patients with acromegaly was measured with quantitative computed tomography. The result was expressed as the mean of six measurements of consecutive vertebral bodies and as a z score. Twenty age- and sex-matched healthy persons also underwent spinal BMD measurement and served as controls. RESULTS In 36 of the 40 patients, the BMD z score ranged within 2 standard deviations (SDs) above or below the mean. Only two patients (one man and one woman) had enhanced BMD loss (below 2 SD). Two other female patients had BMD values of more than 2 SD above the mean. Differences between patient subgroups were not statistically significant, but a statistically significant (P < .05) positive correlation was found between basal serum concentration of growth hormone and spinal BMD for the entire patient group. No correlation between BMD and basal serum concentration of insulin-like growth factor I was found. CONCLUSION Hypersecretion of growth hormone in patients with acromegaly, regardless of other factors, has no evident effect on BMD of the lumbar spine.

Diabetes and Cancer: a Review of Current Knowledge

Diabetes mellitus (DM), one of the most common life-threatening illnesses worldwide, is a group of metabolic diseases, characterized by sustained hyperglycemia. The global prevalence of diabetes mellitus among adults reached 387 millions in 2014 and is still rising. It is suggested there is a strong association between diabetes mellitus (especially type 2 diabetes mellitus) and carcinogenesis. The possible biological links between diabetes mellitus and cancer comprise hyperinsulinemia, hyperglycemia and fat-induced chronic inflammation. Although, the strongest association refers to pancreas and liver, there are many other organs involved in carcinogenesis in diabetic patients including breast, endometrium, bladder and kidney.Recent studies suggest that there is also association between cancer incidence and anti-diabetic medications. It was observed that some medications decrease the risk of carcinogenesis and some increase that risk. The majority of studies concern metformin, a drug of choice in type 2 diabetes mellitus, and its anti-neoplastic and tumor-suppressing activity. The positive effect of metformin was found in numerous researches investigating breast, pancreas, liver, colon, ovaries and prostate tumors.Because a variety of studies have suggested that diabetes mellitus and cancer are frequently coexisting diseases, recently published studies try to explain the influence of diabetes mellitus and anti-diabetic medications on carcinogenesis in different organs.We present the review of the latest studies investigating the association between both diabetes mellitus and anti-diabetic medications and cancer incidence and prognosis.Particularly we highlight the problem of concomitant head and neck cancers in diabetics, rarely analysed and often omitted in studies.

The influence of thyroid dysfunction on bone metabolism

Loss of bone mineral density due to osteoporosis is the main cause of fragility fractures and leads to dropped quality of life and increased mortality. Disturbance of balance between bone formation and bone resorption is dangerous, can cause loss of bone mass and disruption of it’s architecture. Correct development, achievement of peak bone mass and normal functioning of human skeleton depend on different factors. The pivotal role in bone metabolism play thyroid hormones. Both excess as well as deficiency of fT4 and fT3 can be potentially deleterious for bone tissue.The aim of this study is to review the current literature concerning the role of thyroid hormones on bone metabolism.

Neuroendocrine neoplasms of the small intestine and the appendix — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

We present revised Polish guidelines regarding the management of patients harbouring neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common origin of these neoplasms. Most of them are well differentiated with slow growth. Rarely, they are less differentiated, growing fast with a poor prognosis. Since symptoms can be atypical, the diagnosis is often accidental. Typical symptoms of carcinoid syndrome occur in less than 10% of patients. The most useful laboratory marker is chromogranin A; 5-hydroxyindoleacetic acid is helpful in the monitoring of carcinoid syndrome. Ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, balloon enteroscopy and somatostatin receptors scintigraphy are used in the visualisation. A histological report is crucial for the proper diagnostics and therapy of NENs, and it has been extensively described. The treatment of choice is surgery, either radical or palliative. Somatostatin analogues are crucial in the pharmacological treatment of the hormonally active and non-active small intestine NENs and NENs of the appendix. Radioisotope therapy is possible in patients with a good expression of somatostatin receptors. Chemotherapy is not effective in general. Everolimus therapy can be applied in patients with generalised NENs of the small intestine in progression and where there has been a failure or an inability to use other treatment options. Finally, we make recommendations regarding the monitoring of patients with NENs of the small intestine and appendix.

Quantitative ultrasound of the heel and some parameters of bone turnover in patients with acromegaly.

Abstract: Acromegaly caused by growth hormone (GH) hypersecretion is characterized by enhanced skeletal growth and soft tissue enlargement. Insulin-like growth factor-1 (IGF-1) is the main peripheral mediator of GH action and it has a crucial role in the maintenance of a normal bone mass. However, in some patients with acromegaly, secondary osteoporosis is observed, despite the strong anabolic effect of GH and IGF-1 in bones. It is thought to be due to hypogonadism. The bone changes are accompanied by increased turnover. The aim of this study was to assess bone properties by ultrasound and turnover in patients with acromegaly. The study was carried out in 26 patients (13 men, 13 women): 14 with active acromegaly and 12 cured by surgery who had non-active disease. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and their combination Stiffness Index (SI) by quantitative ultrasound (QUS) of the heel, hormonal status, serum osteocalcin (OC) concentration and the urinary excretion of pyridinoline collagen crosslinks (PYR) were all studied. Controls were 20 age- and sex-matched healthy persons. We observed statistically significantly lower QUS values in patients with active disease than in those whose disease was cured. The differences were more pronounced in men. QUS values were lower in the entire group of patients compared with the controls; however, the differences were not statistically significant. Serum OC concentrations and urinary PYR excretion were higher in active disease. Statistically significant inverse correlations between serum GH levels and SOS (r=–0.58, p = 0.002); BUA (r=–0.66; p= 0.0001); T-score (r = −0,65, p= 0.0001) and Z-score (r=–0.66, p = 0.0001) were found only in male patients. No correlations between IGF-1, duration of the disease, OC, PYR and other data studied were observed. In conclusion, we have shown decreased QUS parameters suggesting impaired bone properties and quality in terms of density and elasticity in men, but not in women, with active acromegaly. This finding suggests osteoporosis with increased bone turnover. The above-mentioned changes might be caused by the action of GH on trabecular bone and its metabolism, since no hypogonadism in male patients was shown. Moreover, the influence of acromegaly on heel geometry and soft tissue swelling should also be considered.

Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours)

An increased interest in gastro-entero-pancreatic neuroendocrine neoplasms (GEP NENs) has recently been observed. These are rare neoplasms and their detection in recent years has improved. Over 50% of GEP NENs are carcinoids, and they are usually found incidentally during surgery in the small intestine and appendix and at diagnosis in distant metastases, mainly to the liver. There is a need for co-operation between specialists in various disciplines of medicine in order to work out the diagnostic and therapeutic guidelines. In this publication, we present general recommendations of the Polish Network of Neuroendocrine Tumours for the management of patients with GEP NENs, developed at the Consensus Conference which took place in Kamień Śląski in April 2013. Members of the guidelines working groups were assigned sections of the 2008 guidance to update. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - neuroendocrine neoplasms of the stomach and duodenum (including gastrinoma); - pancreatic neuroendocrine neoplasms; - neuroendocrine neoplasms of the small intestine and the appendix; - colorectal neuroendocrine neoplasms. The proposed recommendations by Polish and foreign experts representing different fields of medicine (endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathology) will be helpful in the diagnosis and treatment of GEP NENs patients.

Effective therapy of insulinoma by using long-acting somatostatin analogue. A case report and literature review.

We are reporting a case of 68-year-old woman with insulinoma, after a non-successful tumor surgery and a long-term diazoxide treatment. She had a lot of hypoglycemia cases, and a weight gain of 50 kg. An abdominal CT scan demonstrated a tumor 28 mm in the diameter, in the head of the pancreas. The patient did not agree for the repeated insulinoma surgery. Furthermore, we found a lesion in the left adrenal gland (14 mm in the diameter) and in the right lung (8 mm in the diameter). Pheochromocytoma was diagnosed on the basis of hypertension, elevated levels of normetanephrine in the 24-h urine collection, and an elevated level of norepinephrine in a plasma sample. After the left adrenal gland removal we observed lower blood pressure. Since we had revealed the presence of somatostatin receptors by the somatostatin receptors scintigraphy, we decided to control hypoglycemia by a monthly subcutaneous administration of the long-acting lanreotide. Because of higher glucose levels (300-400 mg/dl) we started an intense insulin therapy. Nowadays, the patient feels better, she has lost 20 kg of her body weight, and we have observed normal blood glucose levels during the long-term lanreotide treatment. We have noticed neither side effects nor hypoglycemic episodes and we have reduced the dose of insulin. The presented case can be an evidence of the effective treatment of the pancreatic neuroendocrine tumor of insulinoma type, with somatostatin analogue.

Acromegaly--a novel view of the patient. Polish proposals for diagnostic and therapeutic procedures in the light of recent reports.

is usually delayed and is often associated with the development of various complications causing premature mortality. In patients with hypertension, heart failure, diabetes, and arthropathy that is non-specific for age, attention should be paid to the occurrence of somatic signs of acromegaly. As a screening test, insulin-like growth factor-1 (IGF-1) concentration should be assessed. Further diagnostic and treatment procedures are possible in specialised centres. The first-line therapy is selective transsphenoidal adenomectomy. Patients with a good prognosis related to a surgical removal of the pituitary tumour should be referred only to centres experienced in performing this type of procedure, after pharmacological preparation. Other patients, and those who have not recovered after surgical treatment, should be subjected to long-term pharmacotherapy with long-acting somatostatin analogues. In each case, the complications of acromegaly should be followed-up long-term and actively treated. This proposed new recommendation should be helpful for the management of patients with acromegaly.