Effects of highly active antiretroviral therapy on paediatric metabolite levels.

OBJECTIVES: Highly active antiretroviral therapy (HAART) has extended survival of HIV-infected children into adulthood, raising concerns about long-term metabolic changes in childhood. METHODS: A longitudinal study of metabolite levels in paediatric HIV-infected patients before and after starting HAART (January 2000 to June 2003). The effects of HAART on nonfasting blood levels of total (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, cholesterol ratio and lactate were analysed using mixed-effects regression. RESULTS: A total of 146 children attended 1208 appointments (median 6.7/child). Of these, 99 (68%) were African. At baseline, 75 (51%) were on HAART and had higher TC (4.19 vs 3.49 mmol/L, P<0.0001), HDL (1.03 vs 0.82 mmol/L, P<0.0001), and LDL (2.54 vs 2.11 mmol/L, P=0.0003) than those not on HAART. Metabolites increased with time on HAART exposure and then stabilized. At 2 years, TC had increased by 0.93 mmol/L (P<0.0001), with 29 children (20%) having repeated TC levels above the 95th centile. LDL and HDL had increased by 0.69 and 0.31 mmol/L at 2 years, respectively (both P<0.0001). Lactates declined with increasing age (-0.06 mmol/L/year, P=0.0001). CONCLUSIONS: This is the first cohort study to demonstrate significant elevations of HDL as well as LDL in children on HAART. This rise in cardio-protective HDL may represent a positive effect of treatment.

Vertebral deformities and low bone mineral density in adults with cystic fibrosis: a cross-sectional study.

Patients with cystic fibrosis (CF) have low bone mineral density (BMD). The clinical relevance of this is not clearly established. The aim of this study was to determine the prevalence of low BMD and vertebral deformities in CF adults with varied disease severity. One hundred and seven patients (58 men) aged 18-60 years underwent dual-energy X-ray absorptiometry scanning of the lumbar spine and hip, radiology of the spine and biochemical studies. Thirty-eight percent had a Z-score of < -1, with 13% having Z-scores < -2. Seventeen percent had evidence of vertebral deformity on radiography, mostly in the thoracic spine. Thirty-five percent reported past fractures, of which 9% were rib fractures. Percent predicted forced expiratory volume in 1 second (FEV1) and the amount of daily physical activity were positively related to BMD. The number of intravenous antibiotic courses in the previous 5 years was negatively related to BMD. Patients with a history of rib fracture and CF-related diabetes had significantly lower femoral neck BMD (p < 0.02). The median serum 25-hydroxyvitamin D was 28 nmol/l, with 36% of patients having levels below 25 nmol/l despite vitamin D supplementation. Forty-four percent had raised levels of urinary pyridinium crosslinks (NTx). In conclusion, fragility fractures and hypovitaminosis D occur commonly in adult patients with CF. Low BMD occurs in patients with more severe disease and significantly relates to FEV1, infective exacerbations and daily energy expended in physical activity.

The relationship between active renin concentration and plasma renin activity in Type 1 diabetes.

AIMS: Circulating activity of the renin-angiotensin-aldosterone system (RAAS) can be assessed by measuring plasma active renin concentration (ARE), as well as by measuring plasma renin activity (PRA). We aimed to assess the relationships between ARE and PRA in Type 1 diabetic compared with non-diabetic control subjects. We also assessed concentrations of the active renin precursor, prorenin. PATIENTS AND METHODS: Thirty-five Type 1 diabetic subjects and 34 non-diabetic control subjects were assessed. Groups had similar ages, sex distributions, body mass indices, systolic and diastolic blood pressures. PRA was measured by radioimmunoassay of angiotensin I generation from endogenous substrate. ARE and total renin concentration (TRE) were measured by immunoradiometric assay (Nichols Institute Diagnostics, USA). Prorenin concentration was calculated as the difference between ARE and TRE. RESULTS: PRA was significantly lower in Type 1 diabetic than in control subjects (0.8 (0.4-1.1) vs. 1.1 (0.9-1.9) pmol/ml per h; P < 0.005), while ARE was similar (17 (9-33) vs. 18 (15-25) mU/l; P = 0.548). PRA (loge transformed) correlated strongly with ARE in diabetic (r = 0.49; P = 0.003) and control subjects (r = 0.59; P = 0.0002), but there was significant vertical separation of the regression lines for the two groups (P < 0.0001). Prorenin concentrations were significantly higher in Type 1 diabetic subjects (249 (170-339) vs. 171 (153-219) mU/l; P = 0.005). Diabetic subjects with high prorenin concentrations (> 400 mU/l (control mean + 3 SD)) were more likely to have microalbuminuria (P = 0.027) and peripheral neuropathy (P = 0.049). CONCLUSIONS: Type 1 diabetes is associated with an altered relationship between ARE and PRA, such that ARE is higher for a given PRA compared with non-diabetic control subjects. Both ARE and PRA are used to assess circulating RAAS activity. The altered relationship between the two in Type 1 diabetic subjects suggests that neither parameter alone is necessarily an adequate and reliable index of such activity. Higher prorenin concentrations, particularly in association with microvascular complications, were confirmed in the Type 1 diabetic subjects. Diabet. Med. 18, 451-458 (2001)

Bone loss associated with the use of LHRH agonists in prostate cancer.

Hypogonadism is a recognised cause of osteoporosis in men. When patients with advanced prostate cancer are treated with luteinising hormone releasing hormone (LHRH) agonist analogues their circulating testosterone levels decline and these patients may develop fractures.We have undertaken a cross-sectional study on a cohort of patients treated with goserelin (n=41) and compared their bone density and bone turnover with patients with prostate cancer not on goserelin and elderly patients living in the community.There was no difference in bone density between the patients on treatment and those living in the community and there was a similar incidence of osteoporosis (50 and 42%, respectively). The bone marker measurements were higher in the treated patients: urine N-telopeptide (NTX) 80.1 (9) (mean (s.e.)) BCE/mmol, compared to 30.1 (2.9), P<0.001 in elderly patients; and bone alkaline phosphatase 41.9 (6.1) u/l in treated patients and 20.7 (1.5) in untreated prostate cancer patients, P<0.002. Patients on treatment with radionuclide scan evidence of metastases did not have higher bone marker values than those with negative scans.As increased bone turnover and low bone density are associated with enhanced risk of osteoporotic fractures, we suggest that patients on LHRH agonist analogues should receive advice and possibly anti-bone resorptive treatment with bisphosphonates to prevent further bone loss and fractures.Prostate Cancer and Prostatic Diseases (2001) 4, 161-166.

Response to alendronate in osteoporosis after previous treatment with etidronate.

Bisphosphonates such as etidronate and alendronate are widely accepted as effective agents for the treatment of osteoporosis. However, some physicians find the choice of which one to use in different patients, and the comparative magnitude of response, unclear. Fifty postmenopausal women with osteoporosis [group 1: 27 women who had received 3 years of previous cyclical etidronate treatment, mean age 70.5 years, bone mineral density (BMD) mean T-score lumbar spine (LS) -3.58 and femoral neck (FN) -2.51; group 2: 23 women who had not previously received cyclical etidronate treatment, mean age 73.7 years, BMD mean T-score LS -3.65 and FN -2.96] were treated with 10 mg alendronate daily, to determine whether pretreatment with etidronate affected the response to alendronate, and whether patients who did not respond to etidronate, responded to alendronate. There was a significant increase in LS BMD after 2 years of treatment with alendronate compared with baseline (group 1: 7.84%, p<0.001; group 2: 6.69%, p<0.001), but there was no statistical difference between the groups. In the group 1 patients there was a significant difference between the initial response (at the LS BMD) to 2 years of cyclical etidronate (1.86%) and later response to 2 years of alendronate (7.84%) (p<0.0001). The 10 patients who did not respond at the LS to etidronate alone, showed a significantly better response (mean BMD change +6.3%) when subsequently treated with alendronate (a net difference of 9.3%, p=0.002). In 15 patients who did not respond at the FN to etidronate alone, the mean response to alendronate was +0.96% (a difference of 7%, p= 0.004). This study shows that pretreatment with 3 years of cyclical etidronate is not detrimental to the subsequent LS BMD response to alendronate. There is evidence that alendronate produced a greater bone density response than etidronate, and patients who did not respond to etidronate with an increase in LS bone density, subsequently did so following alendronate.

Effects of 7 years of growth hormone replacement therapy in hypopituitary adults.

Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids, with neutral or occasionally adverse effects on glucose tolerance. Fasting hyperinsulinemia has been reported. GH effects on cardiac function have been variable. The effects of long-term GH therapy, taking into account the consequences of increasing age, are not fully known. Thirty-three hypopituitary, initially middle-aged adults were studied over a 7-yr period; 12 patients took GH therapy (mean, 0.7 mg daily) continuously (group A); 11 took GH for only 6-18 months, a minimum of 5 yr previously (group B); and 10 patients never received GH therapy (group C). Other pituitary replacement was maintained. Effects on anthropometry, body composition (by bioimpedance analysis, total body potassium, and dual energy x-ray absorptiometry), circulating lipids, glucose and insulin concentrations, cardiac 2-dimensional and Doppler echocardiography, and exercise tolerance were assessed before and after the treatment period. Continuous GH therapy had no significant effect on body weight, but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution (waist to hip ratio, group A, 0.87+/-0.08 at baseline, 0.85+/-0.09 at 7 yr; group B, 0.89+/-0.11 at baseline, 0.94+/-0.11 at 7 yr; P < 0.005 for GH effect; group C, 0.87+/-0.10 at baseline, 0.92+/-0.10 at 7 yr; P < 0.005 for GH effect). A GH-induced decrease in subscapular skinfold thickness was also observed. By bioimpedance analysis, GH therapy caused an increase in total body water and fat-free mass, and a decrease in the percent body fat. Although changes occurred with time in all groups, no significant additional GH therapy effects were observed on glucose tolerance, insulin concentrations, lipid levels, cardiac dimensions, echocardiographic diastolic function, or exercise tolerance. In conclusion, prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition. Other benefits, e.g. on lipid levels and exercise tolerance, were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls. Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy.

Increased excretion of urinary glycosaminoglycans in meningococcal septicemia and their relationship to proteinuria.

OBJECTIVES: Meningococcal septic shock is a devastating illness associated with an increase in vascular permeability leading to hypovolemia and accumulation of plasma proteins and fluid in tissues. The capillary leak syndrome is often associated with widespread thrombosis in the skin, limbs, and digits. We postulated that the increase in vascular permeability and the intravascular thrombosis might be caused by an inflammation-induced loss of endothelial and basement membrane glycosaminoglycans (GAGs), which play a role in the permeability and thromboresistant properties of the microvasculature. DESIGN: Prospective, single-center observational study. SETTING: University-affiliated meningococcal research unit and pediatric intensive care unit. PATIENTS: Eighteen children requiring intensive care for meningococcal sepsis, 18 children with steroid-responsive nephrotic syndrome, and 18 healthy control children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum concentrations and urine excretion of glycosaminoglycans were measured and related to changes in glomerular permeability to plasma proteins. The size-distribution and nature of glycosaminoglycans were defined by Polyacrylamide Gel Electrophoresis and specific enzyme digestion. Urinary excretion of heparan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate were significantly increased in meningococcal disease (MD) relative to healthy controls and children with steroid-responsive nephrotic syndrome. The urinary GAGs in MD were of similar size to those in controls when analyzed after pronase digestion. However, analysis of proteoglycan size before proteolytic digestion showed the urinary GAGs in MD were of lower molecular weight and unattached to proteins. The fractional excretion of albumin and immunoglobulin G in MD increased with severity of disease. Patients with severe or fatal MD had albumin clearances overlapping those seen in steroid-responsive nephrotic syndrome. There was a significant correlation between proteinuria in MD and urinary excretion of heparan sulfate (r2 = 0.611, p < .0001), chondroitin-4-sulfate (r2 = 0.721, p < .0001), and chondroitin-6-sulfate (r2 = 0.395, p < .0001). CONCLUSIONS: The capillary leak in meningococcal disease is associated with increased plasma and urine concentrations of GAGs, which may be proteolytically cleaved from endothelial and basement membrane sites. The correlation between the severity of protein leakage and the urine excretion of GAGs suggests that loss of GAGs may be causally related to the increase in permeability to proteins.

Clinical usefulness of biochemical resorption markers in osteoporosis.

We have evaluated three commercial assays for collagen cross-links, two urine assays and a recently developed serum assay, as markers of bone turnover in 30 postmenopausal women with osteoporosis during their first year of treatment with the anti-resorptive drug alendronate. Before treatment, urine free deoxypyridinoline crosslinks (Dpd), urine N-telopeptide crosslinks (NTx) and serum C-telopeptide (CTx) values were within postmenopausal reference ranges. After 3 months' treatment the decrease in NTx and CTx was greater than that of Dpd (-50%, P < 0.0001 and -48%, P < 0.0001, compared with -11%, NS), as it was after 6 months (-51%, P < 0.0001, and -57%, P < 0.0001, compared with -19%, P < 0.01). The decrease in resorption markers after 6 months was significant in 23% (Dpd), 66% (NTx) and 66% (CTx) of individuals. Neither baseline resorption marker values nor the per cent change after 6 months' therapy correlated with bone mineral density change (BMD) at either lumbar spine or femoral neck after one year's therapy, except baseline Dpd and lumbar spine BMD (P < 0.01). We conclude that NTx and serum CTx were more sensitive markers of bone turnover suppression by alendronate, but only baseline Dpd was useful in the prediction of individual bone density response after one year.

Clinical usefulness of bone alkaline phosphatase in osteoporosis.

We have evaluated two commercial assays for serum bone specific alkaline phosphatase (bALP) as a marker of bone turnover in a group of 35 postmenopausal women with osteoporosis during their first year of treatment with the anti-resorptive drug, alendronate. The immunoradiometric assay (bALP-I) measured protein mass, whereas the immunocapture assay (bALP-E) measured activity. Before treatment, bALP values with both methods were within the postmenopausal reference ranges. Treatment with alendronate produced a decrease in bALP after 3 months, reaching a plateau after 6 months: for bALP-I a mean change of -34%, (P < 0.0001), bALP-E, -19% (P < 0.001), and total ALP, -19% (P < 0.0001). The decrease was significant in 53% (bALP-I) and 31% (bALP-E) of patients. The ratio of serum bALP-E/bALP-I in patients was not constant but rose after therapy with alendronate. Neither baseline bALP, nor the per cent change in bALP after 6 months, correlated with bone mineral density (BMD) change after 1 year at either lumbar spine or femoral neck. We conclude that bALP-I appeared to be a more sensitive marker of the suppression of bone turnover by alendronate than did bALP-E, but that neither was useful in the detection of osteoporosis, nor the prediction of individual BMD response to alendronate therapy.

The use of cyclical etidronate in osteoporosis: changes after completion of 3 years treatment.

An open study over 4 yr has been conducted to determine the efficacy of cyclical etidronate treatment in patients from the community, with osteoporosis and in those at risk who attended an osteoporosis clinic; and to clarify whether bone remodelling returns to baseline values and bone mass is maintained after completion of a 3 yr course of treatment. One hundred and fifteen female patients, with and without osteoporotic fractures (n = 62 and 53, respectively), who were unsuitable for, or declined, hormone replacement therapy, received 3 yr cyclical etidronate treatment (400 mg etidronate disodium for 14 days followed by 500 mg elemental calcium for 76 days repeated in 3-monthly cycles) and 1 yr treatment-free follow-up. There was an overall increase in lumbar spine bone density (patients without fractures 2.6%, P < 0.001; with fractures 4.3%, P < 0.01) with minimal change at the femoral neck. The serum concentration of bone formation markers (osteocalcin and bone alkaline phosphatase) fell in response to treatment to a nadir at 6/12 (75 and 83% of baseline, respectively; P < 0.001). A cohort of patients (n = 29), 14 without fractures and 15 with fractures, was studied in more detail. After completion of treatment in the following treatment-free year, there was a resurgence of bone turnover (osteocalcin and bone alkaline phosphatase 117 and 122% of baseline, respectively; P < 0.05 and P < 0.01) with some evidence of maintenance of bone mass already gained. There is no evidence of persistent suppression of bone turnover after completion of treatment.

The effects of prolonged growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults.

OBJECTIVE: Short-term GH replacement in hypopituitary adults increases bone turnover; data on the consequences of longer-term GH treatment are limited. We report on the effects of 12-18 months of GH replacement treatment with biosynthetic human GH on bone metabolism and bone mass in hypopituitary adults. DESIGN: Patients were studied before and after GH treatment for 12 months (n = 11) and 18 months (n = 27) respectively in an open trial. GH dose was 0.04 +/- 0.01 IU/kg daily. MEASUREMENTS: Plasma calcium, phosphate and intact PTH concentrations, 24-hour urinary calcium excretion, 3 markers of bone formation (total alkaline phosphatase, osteocalcin and procollagen 1 carboxy terminal peptide (P1CP)) and serum concentration of carboxyterminal cross-linked telopeptide of type 1 collagen (ICTP), as a marker of bone resorption, were measured at 6-month intervals. Lumbar spine and total body bone mineral mass was measured by dual-energy X-ray absorptiometry. RESULTS: Small increases were observed in plasma calcium and phosphate concentrations at 12 months of GH therapy but the differences at 18 months were not statistically significant. Serum intact PTH concentration did not change. Plasma total alkaline phosphatase increased significantly on GH from 75 +/- 26 to 92 +/- 30 (P < 0.01) and 85 +/- 31 U/I (NS) at 12 and 18 months respectively. Serum osteocalcin increased from 6.5 +/- 3.7 to 15.7 +/- 6.2 (P < 0.0001) and 16.6 +/- 5.7 micrograms/I (P < 0.001) at 12 and 18 months respectively and P1CP increased significantly from 106.0 +/- 47.3 micrograms/I to 165.5 +/- 95.3 (P < 0.0001) and 177.2 +/- 72.2 micrograms/I (P < 0.01) at 12 and 18 months respectively. Plasma ICTP concentration increased also from 3.4 +/- 1.8 to 7.3 +/- 3.4 (P < 0.0001) and 7.0 +/- 2.7 micrograms/I (P < 0.003) at 12 and 18 months of GH therapy respectively. No significant change was observed in total body or lumbar spine bone mass, over the 18 months of GH treatment CONCLUSIONS: Replacement therapy with GH in hypopituitary adults for 6-18 months produced a sustained increase in bone turnover (both formation and resorption). Bone mass was maintained but did not increase over the study period.

The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism.

OBJECTIVE: The importance of growth hormone (GH) for normal skeletal growth in childhood and adolescence is well established but much less is known about its action on the adult skeleton. We therefore wished to investigate the effects of replacement treatment with biosynthetic human GH in hypopituitary adults on aspects of calcium homeostasis, bone metabolism and bone mineral mass. PATIENTS: Forty hypopituitary adults (21 females and 19 males; aged 19-67 years). DESIGN: A prospective randomized double-blind placebo-controlled trial lasting for 6 months. PROTOCOL: Following baseline assessments, GH was given in a daily dose of 0.02-0.05 IU/kg body weight subcutaneously (or a placebo (P)) at bedtime. Patients were reviewed at 1, 3 and 6 months. MEASUREMENTS: Plasma calcium, phosphate and total plasma alkaline phosphatase were measured at 0, 1, 3 and 6 months. Serum insulin like growth factor I (IGF-I), osteocalcin, procollagen 1 carboxyterminal peptide (P1CP) and intact parathyroid hormone (PTH) level, 24-hour urinary calcium and creatinine excretion were all measured at 0 and 6 months. Bone mineral density of total body and lumbar spine was also measured by dual energy X-ray absorptiometry at 0 and 6 months in 12 patients on GH and 14 on placebo. RESULTS: Thirty-eight patients completed the study (18 on GH, 20 on placebo). Serum IGF-I increased significantly on GH treatment (mean +/- SD) (GH: 276 +/- 197 vs P: 88 +/- 50 micrograms/l, P < 0.0001 at 6 months). Plasma calcium increased slightly but significantly in the GH-treated group (2.23 +/- 0.11-2.29 +/- 0.11 mmol/l, P < 0.05). At the end of the study, plasma calcium was however similar on GH and placebo (GH, 2.29 +/- 0.11; P, 2.26 +/- 0.09 mmol/l). Plasma phosphate increased on GH (GH: 1.02 +/- 0.23-1.32 +/- 0.19; P: 0.99 +/- 0.16-0.96 +/- 0.12 mmol/l over the 6 months of treatment, P < 0.001). There was no significant change in the urinary calcium excretion on GH therapy. Plasma total alkaline phosphatase, osteocalcin and P1CP were significantly higher on GH than P at 6 months (alkaline phosphatase: GH: 104 +/- 32 vs P: 69 +/- 32 U/l, P < 0.01, osteocalcin: GH: 17.2 +/- 8.0 vs P: 5.3 +/- 3.2 micrograms/l, P < 0.001 and P1CP: GH: 207 +/- 152 vs P: 93 +/- 31 micrograms/l, P < 0.01). There was no difference in the intact parathyroid hormone level (GH: 31 +/- 14 vs P: 31 +/- 15 ng/l, NS). No significant change was observed in bone mass after 6 months of GH treatment, either in total body bone mineral content or in the lumbar spine. CONCLUSION: In this large study, GH replacement in hypopituitary adults for 6 months increased bone turnover but did not affect bone mineral content. Longer-term studies are required to assess further any effect on bone mass.