Valentina Camozzi

Endocrine Therapy of Breast Cancer

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus

The aims of this study were to evaluate the prevalence of osteopenia and the relationships between osteocalcin (OC), bone alkaline phosphatase (bALP), and bone mineral density (BMD) in patients with insulin‐dependent diabetes mellitus (IDDM). A group of 18 patients (median age 47, range 36–51) with uncomplicated IDDM (Group A) were matched by sex, age, and body mass index with 21 healthy control volunteers (Group B). All subjects underwent osteodensitometry with measurement of BMD at the lumbar spine and femoral neck. Osteopenia was present in 11 (61.1%) and 2 (9.5%) of Group A and B patients (P= 0.01), respectively. Both OC (28.4 ± 16.4 versus 41.2 ± 14.6 ng/mL; P= 0.005) and bALP (51.3 ± 11.8 versus 61.7 ± 10.6 U/L; P= 0.006) serum levels were significantly lower in patients with IDDM. BMD did not correlate with either OC or bALP. In conclusion, osteopenia is common among patients with IDDM, but the relationship between bone formation markers and BMD is still unclear.

Recovery of Bone Mineral Density after Surgical Cure, but not by Ketoconazole Treatment, in Cushing’s Syndrome

Abstract: The aim of our study was to retrospectively assess the effect of treatment on bone mineral density (BMD) in patients with Cushing’s syndrome. Nineteen patients (17 women, 2 men; mean age ± SD, 41 ± 10 years; preoperative duration of disease 20 ± 15 months) were studied. Six patients had a cortisol-producing adenoma and 13 had pituitary-dependent bilateral adrenal hyperplasia. BMD of the lumbar spine (L2–L4) was measured by dual-energy X-ray absorptiometry just before and 1–10 years after adrenalectomy or pituitary adenomectomy. Patients were divided in two groups. The first group of 9 patients (6 adrenal and 3 pituitary adenomas; group A) included those treated successfully by surgery (>5 years follow-up in the case of pituitary surgery). The second group of 10 patients (group B) included those treated with the steroidogenesis inhibitor ketoconazole, 300–600 mg/day, after unsuccessful pituitary surgery. In group A, restoration of normal cortisol was associated with a significant increase in BMD (from 829 ± 112 mg/cm2 to 952 ± 107 mg/cm2; p = 0.002). In group B, no changes in BMD were observed (from 857 ± 160 to 847 ± 163 mg/cm2), in spite of markedly decreased or normalized cortisol levels during ketoconazole treatment. These findings indicate that definitive correction of hypercortisolism restores BMD to normal levels in patients with Cushing’s syndrome. In patients treated with ketoconazole after unsuccessful pituitary surgery, even when normalization of cortisol levels was achieved, BMD remained low. This would suggest an interfering effect of this drug on bone metabolism.

Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS

INTRODUCTION AND AIM As initial screening for Cushings syndrome (CS), The Endocrine Society guidelines recommend one of the following: the 1-mg dexamethasone suppression test (DST) or late-night salivary cortisol (LNSC) or urinary free cortisol (UFC) measurement. We examined the diagnostic performance of the above-mentioned tests in a series of patients. MATERIALS AND METHODS We retrospectively analyzed 137 patients with clinical conditions suggestive of hypercortisolism: 38 with confirmed CS diagnosis and 99 without (termed non-CS). UFC was measured by liquid chromatography tandem-mass spectrometry, whereas LNSC by the radioimmunometric method and serum cortisol were measured by a chemiluminescence immunoassay. RESULTS Comparing CS vs non-CS, a cutoff of 138 nmol/L after 1-mg DST revealed the best specificity (SP; 97%), whereas the 50-nmol/L cutoff confirmed the best sensitivity (SE; 100%); the SE and SP for LNSC greater than 14.46 nmol/L were, respectively, 84% and 89%, whereas the SE and SP for UFC greater than 170 nmol per 24 hours, they were 97% and 91%. Overall, UFC revealed both a combined higher positive and a lower negative likelihood ratio among first-line tests (respectively 10.7 and 0.03). Computing a receiver-operating curve -contrast analysis to compare the power of each single test with that of the others, alone or combined (DST+LNSC, DST+UFC, and LNSC+UFC) or with that of all the tests together (DST+LNSC+UFC), the UFC assay was at least as good as all the other possible combinations. CONCLUSIONS Measuring UFC by liquid chromatography tandem-mass spectrometry achieves the best accuracy in diagnosing CS among patients presenting with suspected hypercortisolism.

Diagnosis and complications of Cushing's disease: gender‐related differences

Cushings disease (CD) presents a remarkable preponderance in female gender, with a female‐to‐male ratio of 3–8:1. The aim of this study was to evaluate gender‐related differences in the presentation of CD, as regards: biochemical indices of hypercortisolism; sensitivity of diagnostic tests; clinical features and complications of disease.

Changes of bone formation markers osteocalcin and bone-specific alkaline phosphatase in postmenopausal women with osteoporosis.

The relationship between bone formation markers osteocalcin (OC) and bone‐specific alkaline phosphatase (bALP) and age in postmenopausal women was investigated. Forty‐eight osteoporotic women (median age 62, range 49–76 years) were enrolled in the study. There were 17 (35%) patients aged 49–59 years (Group A), and 31 (65%) patients aged over 59 years (Group B). Parathyroid hormone, calcium, and creatinine serum levels did not differ significantly between groups. Compared with Group A, patients in Group B had higher levels of both OC (28.5 ± 17.8 versus 46.2 ± 19.3 ng/mL; P= 0.003) and bALP (57.3 ± 12.4 versus 66.4 ± 8.7 U/L; P= 0.005). A significant relationship between age and both OC (R= 0.49, P= 0.002) and bALP (R= 0.41, P= 0.009) was found only in Group B, but there was no relationship with bone mineral density. In conclusion, in postmenopausal women the increase of bone formation markers later in life may be an expression of increased bone turnover, which is partially the cause of osteoporosis.

Effect of licorice on PTH levels in healthy women

UNLABELLED Licorice has been considered a medicinal plant for thousands of years. Its most common side effect is hypokalemic hypertension, which is secondary to a block of 11beta-hydroxysteroid dehydrogenase type 2 at the level of the kidney, leading to an enhanced mineralocorticoid effect of cortisol. This effect is due to glycyrrhetinic acid, which is the main constituent of the root, but other components are also present, including isoflavans, which have estrogen-like activity, and are thus involved in the modulation of bone metabolism. We investigated nine healthy women 22-26 years old, in the luteal phase of the cycle. They were given 3.5 g of a commercial preparation of licorice (containing 7.6%, w/w of glycyrrhizic acid) daily for 2 months. Plasma renin activity (PRA), aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D (1,25OHD), 25-hydroxycholecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase (ALP), calcium, phosphate and creatinine, urinary calcium and phosphate and mineralometry were measured. PTH, 25OHD and urinary calcium increased significantly from baseline values after 2 months of therapy, while 1,25OHD and ALP did not change during treatment. All these parameters returned to pretreatment levels 1 month after discontinuation of licorice. PRA and aldosterone were depressed during therapy, while blood pressure and plasma cortisol remained unchanged. CONCLUSIONS licorice can increase serum PTH and urinary calcium levels from baseline value in healthy women after only 2 months of treatment. The effect of licorice on calcium metabolism is probably influenced by several components of the root, which show aldosterone-like, estrogen-like and antiandrogen activity.

Bone Mineral Density Improvement After Successful Parathyroidectomy in Pre-and Postmenopausal Women with Primary Hyperparathyroidism : A Prospective Study

Abstract:  The aim of this study was to evaluate the short‐term (1 year) changes of the lumbar spine (L2–L4) bone mineral density (LS‐BMD) after parathyroidectomy (PTx) in pre‐ and postmenopausal women with primary hyperparathyroidism (PHPT). A series of 48 women (median age 56 years, range 23–82 years) with confirmed PHPT were prospectively enrolled in the study. Patients who received both oral contraceptives less than 2 years before the diagnosis and estrogen replacement therapy have previously been excluded. All patients underwent LS‐BMD by dual energy x‐ray absorptiometry before surgery. Patients were divided into two groups: group A (n= 12) premenopausal, and group B (n= 36) postmenopausal patients. The LS‐BMD was repeated 12 months after successful PTx. Basal LS‐BMD (0.852 ± 0.061 vs. 0.748 ± 0.142 g/cm2), serum calcium (2.95 ± 0.23 vs. 2.94 ± 0.26 mmol/L), creatinine (69.2 ± 17.5 vs. 82.0 ± 24.2 μmol/L), alkaline phosphatase (107.4 ± 43.6 vs. 151.3 ± 95.7 U/L), osteocalcin (28.6 ± 9.3 vs. 28.2 ± 8.3 μg/L), and PTH (192.7 ± 133.2 vs. 175.2 ± 132.1 ng/L) levels did not differ significantly (P= NS) between groups. The 1‐year LS‐BMD was 0.921 ± 0.048 and 0.825 ± 0.151 g/cm2 in group A and B, respectively. In group B patients, the 1‐year LS‐BMD value did not improve significantly (P= NS), while in group A patients the difference between basal and postsurgical LS‐BMD was significant (P < 0.01). In conclusion, PTx should be considered for all patients with PHPT and loss of bone density, but in premenopausal patients a greatest improvement of BMD may be found, suggesting the need of endogenous estrogens in complete lumbar bone recovery after surgery.

Use of quantitative ultrasonography in differentiating osteomalacia from osteoporosis : Preliminary study

The aim of this work was to use ultrasonographic technology to differentiate osteoporosis from osteomalacia on the basis of different patterns of the graphic trace. Three patients with osteomalacia and three with osteoporosis, all with the same lumbar spine bone mineral density, were studied. The velocity of the ultrasound beam in bone was measured by a DBM Sonic 1,200/I densitometer at the proximal phalanges of the hands in all the patients. The ultrasound beam velocity was measured when the first peak of the waveform reached a predetermined minimum amplitude value (amplitude‐dependent speed of sound) as well as at the lowest point prior to the first and second peaks, before they reached the predetermined minimum amplitude value (first and second minimum speeds of sound). The graphic traces were further analyzed by Fourier analysis, and both the main frequency (f0) and the width of the peak centered in the f0 (full width at half maximum) were measured. The first and second minimum speeds of sound were significantly lower in the patients with osteomalacia than in the osteoporosis group. The first minimum speed of sound was 2,169 +/‐ 73 m/s in osteoporosis and 1,983 +/‐ 61 m/s in osteomalacia (P < 0.0001); the second minimum peak speed of sound was 1,895 +/‐59 m/s in osteoporosis and 1,748 +/‐ 38 m/s in osteomalacia (P < 0.0001). The f0 was similar in the two groups (osteoporosis, 0.85 +/‐ 0.14 MHz; osteomalacia, 0.9 +/‐ 0.22 MHz; P = 0.72), and the full width at half maximum was significantly higher in the osteomalacia patients (0.52 +/‐ 0.14 MHz) than in the osteoporosis patients (0.37 +/‐ 0.15 MHz) (P = 0.022). This study confirms that ultrasonography is a promising, noninvasive method that could be used to differentiate osteoporosis from osteomalacia, but further studies should be carried out before this method can be introduced into clinical practice.

Use of ultrasonography in the diagnosis of osteomalacia: preliminary results on experimental osteomalacia in the rat.

This study was performed to investigate the ability of ultrasonographic technique to distinguish osteomalacia from normal bone with the same mineral content. Ten rats with experimentally induced osteomalacia (group A) and 12 control rats having similar body size and weight (group B) were studied. Histomorphometric analysis confirmed the presence of osteomalacia in two rats from group A and showed normally mineralized bone in two rats from group B. Whole body bone mineral density, measured by dual‐energy x‐ray absorptiometry, was similar in the two groups (86 +/‐ 6 mg/cm2 in group A and 89 +/‐ 4 mg/cm2 in group B). The velocity of the ultrasound beam in bone was measured by densitometer at the first caudal vertebra of each rat. The velocity was measured when the first peak of the waveform reached a predetermined minimum amplitude value (amplitude‐dependent speed of sound) as well as at the lowest point of this curve before it reaches the predetermined minimum amplitude (first minimum speed of sound). Although the amplitude‐dependent speed of sound was similar in the two groups (1381.9 +/‐ 11.8 m/s in group A and 1390.9 +/‐ 17.8 m/s in group B), the first minimum speed of sound was clearly different (1446.1 +/‐ 8.9 m/s in group A and 1503.3 +/‐ 10.9 m/s in group B; P < 0.001). This study shows that ultrasonography could be used to identify alterations in bone quality, such as osteomalacia, but further studies need to be carried out before this method can be introduced into clinical practice.