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Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

Reportedly, the responsiveness of somatotrope cells to GHRH is reduced in elderly humans but it is totally restored by arginine (ARG) which likely acts by inhibiting hypothalamic release of somatostatin. As this effect was observed after infusion of high doses of the amino acid, in this study, we compared the effect of iv administration of 30,10 and 5 g ARG(group A,B and C, respectively) as well as oral administration of 8 g ARG(group D) on the GH response to 1 μg/kg iv GHRH in 27 healthy elderly subjects (11 M and 16 F, age 70–86 yr, BMI 21–25 kg/m2). In group A (n=7) 30 g iv ARG strikingly enhanced the GHRH-induced GH rise (peak, mean±SE: 41.5±4.4 vs 11.7±5.3 μg/L, p<0.05). Similarly, in group B (n=6) and D (n=7) 10 g iv and 8 g oral ARG enhanced the GH response to GHRH (20.9±4.7 vs 8.3±2.8 μg/L, p<0.03 and 31.0±5.3 vs 11.4±3.4 μg/L, p<0.03, respectively). In contrast, in group C (n=7) 5 g iv ARG failed to modify the GHRH-induced GH rise (6.0±1.6 vs 3.5±0.9 μg/L). The GH responses to GHRH alone did not significantly differ amongst groups; the GH responses to GHRH and ARG were not significantly different among groups A, B and D and were greater than the GH response in group C. These results show that the GH response to GHRH in elderly subjects is enhanced even by low iv doses of arginine and by the orally administered amino acid, the lowest effective dose being 8 g. Moreover, they imply that the combined administration of GHRH and arginine may be a useful approach to restore the impaired function of the GH-IGF axis in aging.

Chemical changes were observed by Fourier transform microspectroscopy (FT-IR-M) in DNA and RNA samples treated with increasing amounts of ozone. The nucleobase reactivity and conformational changes in nucleic acids were followed through the trend of certain spectroscopic parameters calculated from the spectra. The P1and P2parameters (calculated from the ratios of the optical densities of the bands at 1692 and 1654 and at 1728 and 1654 cm−1, respectively), involving base absorptions, are sensitive to the chemical action of ozone on covalent bonds of purinic and pirimidinic bases. The P3parameter (calculated from the ratios of the optical densities of the bands at 1230 and 1090 cm−1) is sensitive to conformational changes in the phosphate-ribose backbone of nucleic acids. We found that, as the amount of ozone increases, the P1, P2, and P3parameters increase for both the DNA and RNA sample spectra, but the curve trend and the concentration range that gave significant parameter changes were different for DNA and RNA. DNA spectra showed a sigmoidal increase in P1and P2parameters (C1/2= 1.6 mg/mL, the concentration of ozone at which the parameters observed changed by 50%), a plateau between 2 and 4.5 mg/mL of ozone, and a slow linear increase for ozone concentrations >5 mg/mL. Instead, a C1/2= 2.5 mg/mL was evaluated from the P3vs. ozone concentration plot. The plots of P1, P2, and P3parameters calculated from the RNA sample spectra vs. ozone concentration showed a saturation-shape curve that reached its maximum value between 0 and 1.9 mg/mL. On the basis of these results, several hypotheses are suggested to explain the reaction mechanism of DNA and RNA nucleobases and the conformational changes in nucleic acids.

Ghigo E, Ceda GP, Valcavi R, Goffi S, Zini M, Mucci M, Valenti G, Muller EE, Camanni F. Effect of 15-day treatment with growth hormone-releasing hormone alone or combined with different doses of arginine on the reduced somatotrope responsiveness to the neurohormone in normal aging. Eur J Endocrinol 1995;132:32–6. ISSN 0804–4643It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65–89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 μg/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 ± 78.5 μg·1−1·h−1) was unchanged after 7 (3720 ± 38 μg·1−1·h−1) and 15 days (377.9 ± 63.8 μg·1−1·h−1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 ± 146.2 μg · 1−1· h−1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7±366.5 μg·1−1·h−1) and 15 days (1631.7 ± 379.1 μg · 1−1· h−1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 ± 219.4 μg·1−1· h−1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B). It was unchanged after 7 (816.2 ± 208.5 μg·1−1· h−1) and 15 days (760.4 ± 165.0 μg · 1−1· h−1) of treatment; these responses were still higher (p < 0.05) than that to GHRH alone. Insulin-like growth factor I levels were not modified by any of the treatments. In conclusion, our results demonstrate that in normal aging the low somatotrope responsiveness to GHRH is not improved by prolonged treatment with the neurohormone but it is enhanced by the combined treatment with ARG and this effect does not vanish after a 15-day treatment period. The effect of ARG is present even after a low oral dose, although less markedly than after a high intravenous dose.F Camanni, Divisione di Endocrinologia, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy

Mast cell growth factor (MGF) (also called stem cell factor) synergizes with several lymphokines, including interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), to promote proliferation and differentiation of certain hemopoietic progenitor cells. Although similar patterns of tyrosine-phosphorylated proteins characterize cells stimulated by MGF, IL-3, and GM-CSF, only the MGF receptor is a tyrosine kinase, and the heterodimeric receptors for IL-3 and GM-CSF share a common beta subunit that is devoid of enzymatic activity. Here we show that signaling pathways utilized by all three cytokines include the cytoplasmic tyrosine kinase JAK2. Analysis of several factor-dependent myeloid cell lines indicated that JAK2 is physically associated with the common beta subunit and with MGF receptor (c-Kit) even prior to ligand binding. However, each of the ligands induced elevated tyrosine phosphorylation of JAK2 and a consequent increase in its catalytic activity. These results demonstrate for the first time the convergence within the same myeloid cells of signaling pathways originating in two distinct lymphokine receptors and a tyrosine kinase receptor on activation of a cytoplasmic tyrosine kinase.

VIP is an established prolactin-releasing factor. VIP gene expression at the anterior pituitary level and the central nervous system is regulated by thyroid hormones. On the other hand, primary hypothyroidism leads in many cases to amenorrhea, galactorrhea and hyperprolactinemia. In this study we assessed prolactin responses to VIP (75 μg iv infusion over 12 min) in a group of six hypothyroid women (mean age±SE, 38.8±3.3 yr; serum TSH levels, mU/L, 116.3±23.9), before treatment and after normalization of thyroid hormone levels during thyroxine (T4) replacement therapy (100–150 μg/day over 12–16 weeks). Furthermore, we assessed if VIP infusion had any effects on serum GH levels in these patients. In hypothyroid women, VIP infusion increased serum prolactin concentrations with peak levels being attained at 15 min (28.8±3.4 μg/L). The Area Under the Curve (AUC) was 1921±103 μg/L/2h. PRL responses to VIP were unchanged after T4 therapy, both in terms of peak levels (28.7±2.2 μg/L, NS) and of AUC (2079±261 μg/L72h, NS). Serum GH levels were unaffected by VIP administration. In conclusion our study shows that, in hypothyroid patients, restoration of normal thyroid hormone levels by thyroxine replacement therapy does not affect lactotroph responsiveness to VIP. Therefore, our data do not support the hypothesis that VIP might contribute to the hypothyroid-induced hyperprolactinemia seen in man.

We report the results of a family-based study of LRRK2G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.