Effects of a growth hormone receptor antagonist on bone markers in acromegaly.

OBJECTIVE: Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF-I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF-I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy-terminal propeptide (PICP), osteocalcin and N-telopeptide (NTx). DESIGN AND SUBJECTS: Twenty-seven patients with acromegaly were enrolled as part of a multicentre 12-week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20). MEASUREMENTS: Serum markers of bone turnover were determined at baseline and 12 weeks. RESULTS: Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12-week placebo-controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (-2.2 +/- 0.44 vs. placebo +0.01 +/- 0.39 nmol/l, P = 0.009) and PICP (-23.6 +/- 9.6 vs. placebo +18.1 +/- 12.8 micro g/l, P = 0.022) and a serum marker of bone resorption, NTx (-4.4 +/- 1.4, placebo +1.0 +/- 0.3 nm, P = 0.024). CONCLUSIONS: Using a specific GH receptor antagonist, we found that normalization of IGF-I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF-I in modulating bone turnover. The independent contributions of GH and IGF-I to these effects and the long-term effects on BMD in this population remain to be determined.

Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome.

Multiple endocrine and metabolic consequences of human immunodeficiency virus (HIV) infection exist that may contribute to bone loss in men with the acquired immune deficiency syndrome (AIDS) wasting syndrome. Recent studies suggest that anabolic strategies can increase lean body mass in men with AIDS wasting. Prior studies have not examined the effects of anabolic agents on bone mineral density (BMD) or bone turnover in these men. To determine the effects of testosterone and progressive resistance training on BMD and bone turnover in eugonadal men with AIDS wasting, we randomly assigned 54 eugonadal men with AIDS wasting (weight < 90% IBW or weight loss >10% from preillness baseline) to receive either testosterone enanthate (200 mg/week, im) or placebo and to progressive resistance training (3 times/week) or no training in a 2 x 2 factorial study design for 3 months. The BMD of the lumbar spine, proximal femur, and total body; lean body mass; and fat mass were measured by dual energy x-ray absorptiometry. Total body scans were repeated after 12 weeks of therapy. Baseline bone turnover and BMD were compared with those in 35 age-matched healthy non-HIV-infected control subjects. Compared with controls, lumbar spine BMD (1.021 +/- 0.018 vs. 1.084 +/- 0.025 g/cm(2); P = 0.04) and total hip BMD (0.951 +/- 0.017 vs. 1.070 +/- 0.019 g/cm(2); P < 0.0001) were reduced in men with AIDS wasting. T-scores were lower in men with AIDS wasting at the lumbar spine (-0.62 +/- 0.17 vs. -0.07 +/- 0.23, P = 0.05) and total hip (-0.65 +/- 0.11 vs. +0.20 +/- 0.014, P < 0.0001). Total hip T scores were less than -1.0 in 33% of men with AIDS wasting. Neither the use of protease inhibitors nor the duration of protease inhibitors use correlated with BMD. Serum osteocalcin levels were lower (3.63 +/- 0.29 vs. 4.54 +/- 0.31 nmol/L; P < 0.04) and urinary N-telopeptide excretion was higher (45.4 +/- 4.5 vs. 26.8 +/- 3.0 nmol BCE/mmol creatinine; P = 0.004) in men with AIDS wasting than in controls. Lumbar spine BMD, as assessed on regional total body dual energy x-ray absorptiometry scan, increased over the 12-week treatment period in response to testosterone (+2.4 +/- 1.3 vs. -1.3 +/- 1.0%, testosterone vs. placebo, respectively; P = 0.02), but not in response to training (+0.8 +/- 1.0 vs. +0.4 +/- 1.3%, training vs. no training; P = 0.70). Lumbar spine and total hip BMD are reduced in eugonadal men with AIDS wasting. Biochemical markers of bone turnover suggest that bone formation and bone resorption are uncoupled in these men. Testosterone administration, but not resistance training, over 3 months increases lumbar spine BMD in eugonadal men with AIDS wasting.

Effects of testosterone and exercise on muscle leanness in eugonadal men with AIDS wasting.

Loss of lean body and muscle mass characterizes the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). Testosterone and exercise increase muscle mass in men with AWS, with unclear effects on muscle composition. We examined muscle composition in 54 eugonadal men with AWS who were randomized to 1) testosterone (200 mg im weekly) or placebo and simultaneously to 2) resistance training or no training in a 2 x 2 factorial design. At baseline and after 12 wk, we performed assessments of whole body composition by dual-energy X-ray absorptiometry and single-slice computed tomography for midthigh cross-sectional area and muscle composition. Leaner muscle has greater attenuation. Baseline muscle attenuation correlated inversely with whole body fat mass (r = -0.52, P = 0.0001). This relationship persisted in a model including age, body mass index, testosterone level, viral load, lean body mass, and thigh muscle cross-sectional area (P = 0.02). Testosterone (P = 0.03) and training (P = 0.03) increased muscle attenuation. These data demonstrate that thigh muscle attenuation by computed tomography varies inversely with whole body fat and increases with testosterone and training. Anabolic therapy in these patients increases muscle leanness.

Neurotransmitter interactions in the stomatogastric system of the spiny lobster: one peptide alters the response of a central pattern generator to a second peptide.

Two of the peptides found in the stomatogastric nervous system of the spiny lobster, Panulirus interruptus, interacted to modulate the activity of the cardiac sac motor pattern. In the isolated stomatogastric ganglion, red-pigment-concentrating hormone (RPCH), but not proctolin, activated the bursting activity in the inferior ventricular (IV) neurons that drives the cardiac sac pattern. The cardiac sac pattern normally ceased within 15 min after the end of RPCH superfusion. However, when proctolin was applied within a few minutes of that time, it was likewise able to induce cardiac sac activity. Similarly, proctolin applied together with subthreshold RPCH induced cardiac sac bursting. The amplitude of the excitatory postsynaptic potentials from the IV neurons to the cardiac sac dilator neuron CD2 (1 of the 2 major motor neurons in the cardiac sac system) was potentiated in the presence of both proctolin and RPCH. The potentiation in RPCH was much greater than in proctolin alone. However, the potentiation in proctolin after RPCH was equivalent to that recorded in RPCH alone. Although we do not yet understand the mechanisms for these interactions of the two modulators, this study provides an example of one factor that can determine the "state" of the system that is critical in determining the effect of a modulator that is "state dependent," and it provides evidence for yet another level of flexibility in the motor output of this system.