Identification of Early Postmenopausal Women with No Bone Response to HRT: Results of a Five-Year Clinical Trial

Hormone replacement therapy (HRT) prevents postmenopausal bone loss and fractures. However, the occurrence of women with no bone response to HRT has not been widely examined. We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women. The study population was a subsample of the Kuopio Osteoporosis Study (n= 14.220). A total of 464 early postmenopausal women were randomized into four treatment groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate); (2) vitamin D₃; (3) HRT + Vitamin D₃ combined; and (4) placebo. In this study, the data from HRT and placebo groups were analyzed. Lumbar (L2–4) and femoral neck bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline and after 5 years of treatment. A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change (+ 95% CI) of the placebo group or worse. Altogether, 74 women in the HRT group and 104 women in the placebo group complied with the treatment. According to spinal BMD analysis, 11% of the women were classified as densitometric nonresponders; the corresponding proportion for femoral BMD analysis was 26%. Both smoking (p= 0.003) and low body weight (p= 0.028) were significant risk factors for densitometric nonresponse to HRT. After 6 months of treatment the densitometric nonresponders (hip) had a significantly higher mean serum follicle stimulating hormone (FSH) level (p= 0.038) and lower increases in serum estradiol levels (p= 0.006) than the densitometric responders. The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders (spine) than responders (p= 0.043 and 0.017, respectively). In conclusion, this prospective study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT. Repeated serum FSH, estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT. Received: 29 January 1999 / Accepted: 2 August 1999     

Increase in Serum Magnesium Level in Haemodialysis Patients Receiving Sevelamer Hydrochloride

Background: Clinical studies have shown that sevelamer hydrochloride improves lipid profiles and attenuates the progression of the cardiovascular calcifications in haemodialysis patients. It is known that both of these properties are associated with increased magnesium levels. The effect of sevelamer on serum magnesium level is not well documented. The aim of this study was to determine the effects of sevelamer treatment on serum magnesium in haemodialysis patients and to assess the association of magnesium levels with lipid profiles and intact parathyroid hormone (iPTH). Methods: Phosphate binders were discontinued during a two week washout period. Forty-seven patients, whose serum phosphate was greater than 6.0 mg/dl at the end of washout, received sevelamer hydrochloride for eight weeks. The patients were then washed off sevelamer for another two weeks. Results: Mean serum phosphorus concentration declined from 7.5 ± 1.3 to 6.4 ± 1.2 mg/dl (P < 0.001), mean serum magnesium levels increased from 2.75 ± 0.35 to 2.90 ± 0.41 mg/dl (P < 0.001) and median serum iPTH levels decreased from 297 to 213 pg/ml (P=0.001) during the eight weeks of sevelamer treatment. After the two week post-treatment washout phosphorus levels increased to 7.3 ± 1.3 mg/dl (P < 0.001), magnesium levels were reduced to 2.77 ± 0.39 mg/dl (P < 0.001) and iPTH levels increased to 240 pg/ml (P=0.012). No change was observed in serum calcium levels during the sevelamer treatment period and the subsequent washout period. The mean decline in total and low density lipoprotein (LDL) cholesterol during sevelamer treatment was 16.3 and 28.3 (P < 0.001), respectively. The mean increase in high density lipoprotein (HDL) cholesterol and in apolipoprotein A1 was 2.9 ± 5.8 mg/dl (P=0.004) and 6.8 ± 11.1 mg/dl (P=0.001), respectively. Multivariate analysis showed that the rise in serum magnesium concentration significantly correlated with reductions in iPTH levels (r=−0.40, P=0.016), but did not have any significant correlation with the changes in lipid profiles. Conclusions: Our findings indicate that patients on haemodialysis receiving sevelamer have a significant increase in serum magnesium concentrations. This increase in serum magnesium is associated with reduction in iPTH levels. The changes in lipid profiles of these patients however are not related to changes in serum magnesium levels.     

Effects of combined androgen blockade on bone metabolism and density in men with locally advanced prostate cancer

Objective: To investigate whether combined androgen blockade (CAB) produces any adverse effects on bone metabolism and mineral density in patients with locally advanced prostate cancer.Materials and methods: The study group consisted of 17 stage T4 prostate cancer patients treated with CAB and had no evidence of bone metastasis on bone scintigraphy. The mean duration of CAB and final total prostate specific antigen (PSA) level at the time of study were found at 28.5 ± 15.9 (6–58) months and 0.39 ± 0.5 (0.1–2) ngml, respectively. Twenty age and socioeconomically matched benign prostate hyperplasia (BPH) patients were taken as the control group. Both groups were compared with regard to lumbar bone mineral density (LBD), femur bone mineral density (FBD) and serum parameters of bone metabolism namely calcium (Ca), phosphate (P), magnesium (Mg) and alkaline phosphatase (ALP). Bone mineral density was measured with dual energy x-ray absorptiometry.Results: The mean FBD, LBD and serum Ca, P, Mg and ALP measurement of the patients treated with CAB were 0.85 ± 0.1 g/cm², 1.16 ± 0.2 g/cm², 9.1 ± 0.3 mg/dl, 3.6 ± 0.6 mg/dl, 1.95 ± 0.14 mg/dl, 187.5 ± 61 mg/dl, respectively. No significant difference was found between patients subjected to CAB and the age matched controls in any of the studied parameters namely age, FBD, LBD, Ca, Mg and ALP except serum phosphate. Serum phosphate levels were significantly (p =0.001) higher in patients treated with CAB suggesting a minor effect of CAB on bone metabolism.Conclusion: No convincing evidence was found about the detrimental effect of CAB on bone mineral density and metabolism in a highly selected group of patients with advanced prostate cancer without bone metastases.     

Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men

Both estrogens and androgens play important roles in skeletal development and maintenance in men. The relative importance of estrogens and androgens in male bone metabolism, however, remains undefined. Anastrozole is an oral aromatase inhibitor that decreases estrogen production and increases androgen production in men. Currently, anastrozole is being investigated as a potential agent for the treatment of hypogonadism in aging men. Because anastrozole lowers estrogen levels and raises androgen levels, its effect on bone metabolism is difficult to predict. To assess the effects of anastrozole on bone turnover, we randomized 37 elderly (ages 62–74) mildly hypogonadal men (serum testosterone <350 ng/dl) to receive either anastrozole 1 mg daily ( n =12), anastrozole 1 mg twice weekly ( n =11), or daily placebo ( n =14) for 12 weeks. Serum gonadal steroid levels, serum and urine biochemical markers of bone turnover, serum osteoprotegerin, and total body bone mineral density were measured at baseline and week 12. Mean serum levels of total and bioavailable testosterone increased substantially in both treated groups. Specifically, mean ± SD bioavailable testosterone levels increased from 99±31 ng/dl to 207±65 ng/dl in the group receiving 1 mg of anastrozole daily and from 115±37 ng/dl to 178±55 ng/dl in the subjects receiving 1 mg of anastrozole twice weekly ( p <0.001 vs placebo for both groups). Serum estradiol levels decreased modestly in both treated groups (from 26±8 pg/ml to 17±6 pg/ml in the daily treatment group and from 27±8 pg/ml to 17±5 pg/ml in the twice-weekly treatment group, p <0.001 vs placebo for both groups). Despite these hormonal changes, no increases in biochemical markers of bone resorption were observed. Specifically, mean serum N-telopeptide and urinary deoxypyridinoline concentrations remained stable in both treated groups over the 12-week treatment period. Similarly, serum biochemical markers of bone formation (osteocalcin and amino-terminal propeptide of type 1 collagen), serum osteoprotegerin, and total body bone mineral density did not change. These data demonstrate that although short-term administration of anastrozole decreases serum estradiol levels in elderly men with mild hypogonadism, this intervention does not adversely affect bone metabolism over a 12-week period. This lack of an effect may be due to the concomitant increase in testosterone production, the relative modest effect on estradiol production, or a combination of both factors. These results suggest that anastrozole therapy is unlikely to have an adverse effect on bone metabolism when taken over extended periods and may prove to be a valuable method of normalizing testosterone production in older men.     

Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome

Steroid treatment has several side effects, including the deterioration of the bone and mineral metabolism in children with nephrotic syndrome. This randomized prospective study was conducted to determine the effects and prophylactic role of calcium plus vitamin D treatment on bone and mineral metabolism in children receiving prednisolone treatment. 40 children (27 boys and 13 girls) with NS (18 new onset and 22 relapsing) were included in the study. Their mean age was 4.6±1.8 years. All patients received prednisolone treatment (2 mg/kg/day for 4 weeks followed by alternate days at the same dose for 4 weeks). The patients were randomized into treatment (vitamin D 400 IU plus calcium 1 g daily) and non-treatment groups. Bone mineral density, serum Ca, P, alkaline phosphatase and urinary Ca and P excretions were analyzed at the beginning and 2 months after the treatment. The XR36 Norland device was used for bone mineral density analysis. Bone mineral density was significantly decreased in both the treatment (0.54±0.15 to 0.51±0.1 g/cm², P =0.001) and non-treatment (0.52±0.18 to 0.45±0.16 g/cm², P <0.001) group. But the percentage of bone mineral density decrease was found to be significantly lower in the treatment group than in the non-treatment group (4.6±2.1% vs. 13.0±4.0%, respectively; P <0.001). Serum calcium and urinary calcium excretion increased in the treatment group (8.0±1.0 to 10.0±0.5 mg/dl and 1.1±0.5 to 3.2±1.0 mg/kg/day) and non-treatment group (8.1±0.8 to 10.0±0.6 mg/dl and 1.4±0.9 to 3.8±3.3 mg/kg/day) after prednisolone treatment (P <0.001). Steroid treatment decreases bone mineral density in children with nephrotic syndrome. Vitamin D plus calcium therapy at the current doses reduces but does not completely prevent bone loss, with no additional adverse effects.     

Cyclosporine A induced remission of relapsing nephrotic syndrome in children

We treated 20, steroid resistant or steroid dependent and cyclophosphamide or chlorambucil treated, relapsing nephrotic patients with oral cyclosporine A for eight weeks. Cyclosporine A was started at 7 mg/kg/day and titrated to maintain HPLC level of 100 to 200 ng/ml. Of 20 patients, 14 had a complete remission and the remaining 6 had a reduction in their proteinuria. The mean serum albumin of the 14 responders rose from 2.1 g/dl to 4.1 g/dl (P less than 0.00001) after cyclosporine A therapy. The mean serum cholesterol of the 14 responders decreased from 394 mg/dl to 184 mg/dl (P less than 0.0001) after cyclosporine A therapy. The mean creatinine clearance of the 20 patients (104 ml/min/1.73 m2) was unchanged (107 ml/min/1.73 m2) after eight weeks of cyclosporine A. By life table analysis, 40% of the responders show a sustained remission of up to a year. Cyclosporine A responders had a higher T3 cell count prior to therapy compared to nonresponders (69 +/- 5.54% vs. 61 +/- 6.4%, P less than 0.02). Pre-therapy interleukin-2 levels measured in 10 patients were normal or supranormal in 8, 6 of whom were treatment responders. Two patients with low interleukin-2 levels were nonresponders. Cyclosporine A can be used to induce a remission in relapsing nephrotic patients, and short-term cyclosporine A therapy does not produce nephrotoxicity.     

Do Intraoperative Total Serum and Ionized Calcium Levels, Like Intraoperative Intact PTH Levels, Correlate with Cure of Hyperparathyroidism?

Intraoperative parathyroid hormone (ioPTH) monitoring is useful in the operative management of hyperparathyroidism. Measurement of intraoperative total serum calcium (TSC) and ionized calcium (ICa) levels may be less expensive and more readily available methods of intraoperative guidance during neck dissection than ioPTH levels, the gold standard. We compared the accuracy of monitoring intraoperative TSC and ICa to that of ioPTH for predicting surgical cure during parathyroidectomy. Over a 10-month period, 47 parathyroidectomies were performed, during which ioPTH, TSC, and ICa were measured. Samples were obtained at the start of the operation and 5 and 10 minutes after gland removal. Data were compared and trends analyzed with respect to removal of abnormal parathyroid tissue as confirmed by pathology. The Wilcoxon signed rank test was used to determine if decreases in TSC and ICa were significant. The mean baseline ioPTH level (253 ± 247 pg/ml) dropped by 70% at 5 minutes after removal of the abnormal glands (68 ± 85 pg/ml) and by 83% at 10 minutes (32 ± 25 pg/ml). The mean baseline TSC level (10.1 ± 0.9 mg/dl) dropped by 4% at 5 minutes after removal of the abnormal glands (9.7 ± 0.8 mg/dl) and remained at 4% at 10 minutes (9.6 ± 0.7 mg/dl). The mean baseline ICa level (1.4 ± 0.1 mmol/dl) also dropped by 4% at 5 minutes after removal of the abnormal glands (1.3 ± 0.1 mmol/dl) and remained at 4% at 10 minutes (1.3 ± 0.1 mg/dl). ioPTH dropped by ≥ 50% in 39 patients (83%) at 5 minutes and in 46 patients (98%) at 10 minutes after gland resection. TSC decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 37 patients (79%). In the remaining 21% of patients, TSC decreased inconsistently, if at all, with respect to baseline at both the 5- and 10-minute time points. ICa decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 35 patients (77%). In the remaining 23% of patients, ICa, like TSC, changed inconsistently at 5 and 10 minutes after parathyroidectomy with respect to baseline levels. Decreases in TSC and ICa during parathyroidectomy, if present, are thus minimal. Unlike ioPTH levels, TSC and ICa levels do not consistently decrease at 5 and 10 minutes after gland resection. Although inexpensive and readily available, monitoring the intraoperative TSC and ICa is not clinically reliable for confirming removal of hyperfunctioning parathyroid glands.This work was presented at the International Association of Endocrine Surgeons Conference, Uppsala, Sweden, June 2004     

Teriparatide in Bisphosphonate-Resistant Osteoporosis: Microarchitectural Changes and Clinical Results After 6 and 18 months

A number of osteoporotic patients under bisphosphonate treatment present persistent fragility fractures and bone loss despite good compliance. The objective of this 18-month prospective study was to investigate the effect of teriparatide [rhPTH(1–34)] in 25 female osteoporotics who were inadequate responders to oral bisphosphonates and to correlate microarchitectural changes in three consecutive iliac crest biopsies measured by micro-computed tomography (μCT) with bone mineral density (BMD) and bone serum markers. Scanned biopsies at baseline (M0), 6 months (M6), and 18 months (M18) demonstrated early significant (P < 0.01) increases in bone volume per tissue volume (+34%) and trabecular number (+14%) at M6 with only moderate changes in most μCT structural parameters between M6 and M18. μCT-measured bone tissue density was significantly decreased at M18, expressing an overall lower degree of tissue mineralization characteristic for new bone formation despite unchanged trabecular thickness due to increased intratrabecular tunneling at M18. μCT results were consistent with serum bone turnover markers, reaching maximal levels of bone alkaline phosphatase and serum β-crosslaps at M6, with subsequent decline until M18. BMD assessed by DXA demonstrated persistent increases at the lumbar spine until M12, whereas no significant change was observed at the hip. Type (alendronate/risedronate) and duration (3.5 ± 4 years) of prior bisphosphonate treatment did not influence outcome on μCT, BMD, or bone marker results. The overall results indicate a positive ceiling effect of teriparatide on bone microarchitecture and bone markers after 6 and 12 months for lumbar spine BMD, with no additional gain until M18 in bisphosphonate nonresponders.     

Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

We performed adult hepatocyte transplantation (HCTx) and fetal liver transplantation (FLTx) into the spleens of hyperbilirubinemic Gunn rats in congenic combination and we compared the long-term effects of these procedures for as long as 12 months. Proliferative activity of intrasplenic hepatocytes was evaluated using antiproliferating cell nuclear antigen (PCNA) immunohistochemical staining. The serum total bilirubin levels (T. Bil) significantly decreased from 7.16±0.25 mg/dl to 4.38±0.60 mg/dl 2 months after HCTx and gradually decreased thereafter until 12 months after transplantation (3.23±0.37 mg/dl, P<0.05 vs preoperative value). The T. Bil change after FLTx was similar to that of HCTx: 7.22±0.24 mg/dl before FLTx, and 4.92±0.24 and 3.06±0.47 mg/dl, 2 and 12 months after FLTx (P<0.05), respectively. Bilirubin glucuronides, which were not detectable in the bile from untreated Gunn rats, appeared in considerable amounts 4 months after HCTx and FLTx (27.5% and 36.0% of total bile, respectively). PCNA labeling indices of intrasplenic hepatocytes (4.9%±0.9% and 3.7%±0.7%, 6 months after HCTx and FLTx, respectively) were slightly higher than those of normal hepatocytes (1.0%±0.1%) in the host liver. In conclusion, both adult and fetal rat hepatocytes transplanted into the spleen in congenic combination functioned for at least a year in terms of bilirubin glucuronidation. The spleen is considered to be one of the optimal grafting sites for hepatocytes, with nearly lifelong significant function and proliferative activity.     

Bone mineral density in children with myelomeningocele: effect of hydrochlorothiazide

Children with myelomeningocele experience difficulty with ambulation, which leads to immobilization and secondary loss of bone mineral density (BMD). In addition, non-ambulatory myelomeningocele patients have higher urinary calcium losses than their ambulatory counterparts. Hydrochlorothiazide (HCTZ) is known to reduce urinary calcium loss and increase BMD in non-myelomeningocele patients with hypercalciuria. This study examines the effect of HCTZ on urinary calcium and BMD in non-ambulatory children with myelomeningocele. Thirteen of 20 non-ambulatory patients with myelomeningocele completed the year-long randomized double-blinded study (placebo = 7 and HCTZ = 6). Evaluation included electrolytes, PTH, osteocalcin, 1, 25-OH vitamin D, urinary pyridinolines/deoxypyridinolines (U_pyr/dpyr), urinary calcium/creatinine (U_Ca/Cr), and forearm BMD (dual X-ray absorptiometry). Follow-up electrolytes were obtained at 1–2, 6, and 12 months and U_Ca/Cr and BMD was obtained again at 12 months. There were no initial differences between the placebo and HCTZ groups. U_Ca/Cr decreased in the HCTZ group after treatment (0.20±0.09 vs. 0.04±0.02, p<0.05). However, forearm BMD (z-scores) after 1 year remained unchanged in both the HCTZ (–5.95±0.98 to –5.86±0.92) and placebo (–7.19±0.69 to –6.67±0.63) groups. While use of HCTZ for 1 year did not affect BMD, it reduced urinary calcium excretion in non-ambulatory children with myelomeningocele.     

Changes in bone density in women starting hormone replacement therapy compared with those in women already established on hormone replacement therapy

It is well established that hormone replacement therapy (HRT) will prevent postmenopausal loss of bone. However, it is not known to what extent HRT will continue to affect bone mineral density (BMD) in women established on HRT compared with those commencing treatment. We recruited 48 healthy early postmenopausal women into a prospective, comparative study. Twenty-nine women had never taken HRT (group A) whilst 19 women were already taking HRT (group B) (conjugated equine oestrogens, 0.625 mg daily; mean (±SD) years of use 2.2 (1.5) years). All of the women were started on, or switched to, micronized 17-oestradiol (2 mg/day) continuously with dydroges-terone (10 mg/day) for the first 14 days of each cycle. BMD measurements were performed at the lumbar spine and proximal femur using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 and 24 months of treatment. Group A showed a significantly greater increase in lumbar spine BMD after 12 months (mean (±SD)=5.3 (4.6)%) compared with group B (mean(±SD)=2.1 (2.1)%) and 24 months of treatment (group A, mean(±SD)=6.4 (5.2)%; group B, mean (±SD)=2.3 (2.6)%; bothp<0.01). Femoral neck and Ward's triangle BMD increased significantly in both groups but there were no significant differences between the groups. Baseline BMD correlated with change in lumbar spine BMD for women in group A after 12 months (r=–0.67,p<0.01) and 24 months of treatment (r=–0.59,p<0.05). These data demonstrate that HRT has the greatest effect on BMD when it is first administered, especially in those women with low BMD, but improvements may still be observed in women continuing HRT in the longer term.     

Tumoral calcinosis: Evidence for concurrent defects in renal tubular phosphorus transport and in 1α,25-dihydroxycholecalciferol synthesis

Summary A 50-year-old Latin American man with tumoral calcinosis presented with hyperphosphatemia (6.62±1.04 SD mg/dl), elevated renal threshold phosphorus concentration (TmP) (7.3 mg/GFR), and 1,25-dihydroxyvitamin D [1,25-(OH)₂D] (69 pg/ml) hypercalciuria (239 mg/day), and a high fractional intestinal calcium (Ca) absorption (0.74). Sodium cellulose phosphate therapy (20 g/day) lowered urinary Ca, and partially reduced serum phosphorus (P) and TmP to 5.91±0.63 mg/dl and 6.2 mg/GFR, respectively. Serum 1,25-(OH)120D remained elevated at 58–64 pg/ml. Amphojel therapy (4 oz/day) decreased urinary P to 23±21 mg/day and lowered serum P to 5.75±0.36 mg/dl (P<0.05). TmP increased to a value of 8.0 mg/GFR while serum 1,25-(OH)₂D continued to remain elevated at 53 pg/ml. This case illustrates the probable operation of dual abnormalities in tumoral calcinosis represented by augmented renal conservation of P and an elevation in the circulating concentration of 1,25-(OH)₂D.     

Effects of growth hormone on kidney function in pediatric transplant recipients

Recent evidence suggests that treatment with recombinant human growth hormone (rhGH) after a successful kidney transplant improves the growth rate of children with short stature. We prospectively investigated eight children (6 boys, 2 girls), focusing on acute rejection episodes and changes in serum creatinine levels during rhGH treatment. The children (mean age 11.6±3.4 years) received rhGH daily (0.04–0.05 mg/kg subcutaneously). Seven patients completed at least 12 months (20±8 months) of rhGH treatment. Their mean serum creatinine level was 1.3±0.7 mg/dl 12 months before, and increased to 3.4±4.2 mg/dl after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.06). Their mean calculated glomerular filtration rate was 58±20 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.08). Of the seven patients, two developed acute rejection after 5 and 6 rejection-free years; three lost their grafts and returned to dialysis. These preliminary observations describe untoward renal events in children receiving rhGH treatment after a kidney transplant.     

Minimal levels of serum estradiol prevent postmenopausal bone loss

Summary Biochemical parameters reflecting bone resorption [urinary calcium/creatinine (Ca/Cr) and hydroxyproline/ creatinine (OH/Cr)] were related to serum estrogens [estrone (E1) and estradiol (E2)] in 262 healthy women including 158 patients receiving estrogen replacement therapy (ERT) for at least 6 months, 49 eugonadal women, and 55 untreated postmenopausal women. A significant (P<0.001) correlation exists between serum E2 and Ca/Cr: Ca/Cr (mg/dl)=-0.00044 E2 (pg/ml)+0.129 (n=262; r=-0.37), serum E2 and OH/Cr: (OH/Cr (mg/g)=-0.049 E2 (pg/ml)+18.76 (n=262; r=-0.36), serum E1 and Ca/Cr: Ca/Cr (mg/dl)=-0.0003 E1 (pg/ml)+0.127 (n=261; r=-0.28) but not between serum E1 and OH/Cr. Women with circulating levels of E2 between 60 and 90 pg/ml have a significant (P< 0.01) reduction of Ca/Cr and OH/Cr when compared with those with lower levels of E2. Higher values of E2 do not provide additional benefit. We conclude that in postmenopausal women receiving an estrogen replacement therapy (ERT), a significant reduction of bone resorption is achieved when circulating levels of estradiol reach a value (60 pg/ml) corresponding to the one measured, in eugonadal women, during the last days of the early follicular phase of the menstrual cycle. We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.     

Remifentanil, Isoflurane, and Preconditioning Attenuate Renal Ischemia/Reperfusion Injury in Rats

Background

The purpose of this investigation was to examine the effect of isoflurane, remifentanil, and preconditioning in renal ischemia/reperfusion injury (IRI).

Methods

All 52 male Wistar rats were anesthetized with isoflurane, intubated and mechanically ventilated. The animals were randomly divided into: S group (sham; n = 11) that underwent only right nephrectomy; as well as the I group of right nephrectomy and ischemia for 45 minutes by clamping of left renal artery. (n = 11); the IP (n = 9), the R (n = 10), and the RP (n = 11) groups. In addition, the R and RP animals received remifentanil (2 μg · kg⁻¹ · min⁻¹) during the entire experiment. The IP and RP group underwent ischemic preconditioning (IPC = three cycles of 5 minutes). Serum creatinine values were determined before and after IRI, as well as 24 hours later. In addition to an Histological study, cells from the left kidney were evaluated for apoptosis by flow cytometry (FCM).

Results

The Creatinine value of 0.8 ± 0.2 mg/dl in the S group was significantly lower at 24 hours than the I 3.9 ± 1.5 mg/dl; IP 2.6 ± 1.7 mg/dl; R 3.3 ± 2.8 mg/dl; or RP 1.8 ± 0.5 mg/dl groups. The RP group value was significantly lower than those of the I, IP, and R groups (p < 0.05). The S group showed less proximal tubular cell damage than the I, IP, R, and RP groups (p < 0.05). The percentages of apoptotic cells (FITC⁺/PI⁻) were: S group = 11.6 ± 6.5; I = 16.7 ± 7.3; IP = 37.0 ± 28.4; R = 11.7 ± 6.6, and RP = 8.8 ± 1.5. The difference between the IP vs RP group was significant. Similar percentages of necrotic cells (FITC⁺/PI⁺) and intact cells (FITC⁻/PI⁻) were observed among the groups.

Conclusions

Ischemic preconditioning showed no protective effect in the isoflurane group (IP) but when isoflurane was administered associated with remifentanil (RP), there was a beneficial effect on the kidney, as demonstrated by flow cytometry and serum creatinine values.     

Role of oral pamidronate in preventing bone loss in postmenopausal women

We have performed a 2-year prospective double-masked study to determine whether the bisphosphonate pamidronate can prevent bone loss in postmenopausal women and its optimal dosage regimen. One hundred and twenty-one such women (mean ± SD age 57.6±3.4 years; mean ± SD time since menopause 7.5±3.5 years) were randomized to receive either oral pamidronate (300 mg/day) for 4 weeks every 4 months (group A), oral pamidronate (150 mg/day) for 4 weeks every 2 months (group B) or identical placebo capsules (group C). Bone mineral density (BMD) measurements at the lumbar spine and proximal femur were performed at baseline and at 6-month intervals for 2 years using dual-energy X-ray absorptiometry. BMD at the lumbar spine (L2–4) increased significantly in groups A and B after 2 years of treatment (mean ± SD 2.8±2.1% and 3.0±2.9% respectively, bothp<0.001) but decreased in the placebo group (–1.6±3.1%,p<0.01). Identical results were seen for BMD at the femoral neck, which increased significantly in groups A and B after 2 years of treatment (1.2±2.3% and 1.3±2.9% respectively, bothp<0.05) but decreased in the placebo group (–1.9±3.9%,p<0.05). There were significant differences over 2 years between the groups at all anatomical sites (lumbar spine, femoral neck and trochanteric region, allp<0.001; Ward's triangle,p<0.01). However, there were no significant differences between groups A and B, suggesting that the two treatment regimens were equally effective in conserving BMD. There were, however, marked differences in tolerability between the two treatment regimens: 13 women (34%) in group A withdrew from the study because of side-effects, but only 5 women (12%) in group B, which was comparable with placebo. These data demonstrate that intermittent oral pamidronate will prevent bone loss from the lumbar spine and proximal femur of postmenopausal women, and that the more frequent but lower dose regimen is well tolerated.     

Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin-D-replete elderly patients

The efficacy of calcium (Ca) in reducing bone loss is debated. In a randomized placebo-controlled double-masked study, we investigated the effects of oral Ca supplements on femoral shaft (FS), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD), and on the incidence of vertebral fracture in vitamin-D-replete elderly. Ninety-three healthy subjects (72.1±0.6 years) were randomly allocated to three groups receiving 800 mg/day Ca in two different forms or a placebo for 18 months. Sixty-three patients (78.4±1.0 years) with a recent hip fracture were allocated to two groups receiving the two forms of Ca without placebo. FS BMD changes in Ca-supplemented non-fractured women were significantly different from those in the placebo group (+0.6±0.5% v –1.2±0.7%,p<0.05). There was no difference in effect between the two forms of Ca. The changes of +0.7±0.8% v –1.7±1.6% in FN BMD of Ca-supplemented women and the placebo group did not reach statistical significance. In fractured patients, FS, FN and LS BMD changes were –1.3±0.8, +0.3±1.6 and +3.1±1.2% (p<0.05 for the last). The rate of new vertebral fractures was 74.3 and 106.2 fractures per 1000 patient-years in Ca-supplemented non-fractured subjects and in the placebo group, respectively, and 144.0 in Ca-supplemented fractured patients. Thus, oral Ca supplements prevented a femoral BMD decrease and lowered vertebral fracture rate in the elderly.     

Bone Mineral Density in Menopausal Women with Primary Hyperparathyroidism before and after Parathyroidectomy

The relationship between osteoporosis and primary hyperparathyroidism (pHPT) has not been definitely established because both diseases occur predominantly in postmenopausal women, and because PTH has a paradoxical effect on bone. We have investigated the prevalence of reduced bone mineral density (BMD) in women with pHPT, its relationship with metabolic parameters, and its course after parathyroidectomy. A prospective observational study was carried out on perimenopausal and postmenopausal women consecutively diagnosed and operated on for pHPT. Demographic data were recorded, as well as, PTH, Ca, calciuria/24h, P, vitamin D, adenoma weight. The BMD was measured at three sites: femoral neck (FN), proximal femur (PF), and lumbar spine (LS). Fifty-two patients were included with a mean age of 61 ± 12 years. The prevalence of reduced BMD ( 1SD, T-score) was 80%–100% depending on site. Parathyroid hormone was higher in patients with osteoporosis (319 ± 181 pg/ml) than in those with osteopenia (230 ± 83 pg/ml) or normal BMD (148 ± 81 pg/ml; p < 0,04). Twenty-eight patients were investigated 1 year after parathyroidectomy. The BMD improved significantly at all sites, particularly in patients with osteoporosis. Age correlated inversely with BMD increases at the femoral sites (r= –0,47; p = 0,02) but not at the LS. 25-OHD₃ plasma levels correlated inversely with BMD increases at PF (r= –0,76; p < 0,0001). In pHPT, there is a high prevalence of BMD abnormalities. No metabolic variables had a definite influence on BMD values but a tendency was observed for lower BMD in severe pHPT. One year after parathyroidectomy, there were significant BMD increases that were more marked at femoral sites, in younger patients, in patients with preoperative osteoporosis, and in those with lower plasma levels of 25-OHD₃.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14–17, 2004.     

Lumbar bone mineral density in very long-term renal transplant recipients: Impact of circulating sex hormones

The influence of circulating sex hormones and gender on the bone mineral density (BMD) in long-term renal transplant recipients needs further investigation. We performed a retrospective analysis of lumbar BMD between 6 years and 20 years after renal transplantation. In 67 patients (47±12 years, 38 male) with a minimum interval of 72 months after transplantation, lumbar BMD measurements (dual energy X-ray absorptiometry) were performed (=complete cohort). Thirty-one patients (=longitudinal cohort) underwent at least three serial BMD measurements (mean follow-up 39±18 months, start at 86±22 months). All patients received prednisolone. In the complete cohort, BMD was significantly reduced in comparison to young healthy (mean T -score –1.33±1.40) and age-matched controls (mean Z -score –0.91±1.45) at 88±31 months ( p <0.05). Osteopenia or osteoporosis were present in two-thirds of patients. In the longitudinal cohort, a mean annual lumbar BMD loss of –0.6±1.9% was detectable equivalent to a –0.03±0.15 reduction of Z -scores per year (regression analysis). Impact of hormonal status: In the complete cohort, postmenopausal status was associated with significantly lower BMD levels compared to men ( p =0.0441). Women and men within the lowest tertile of sex hormone levels (LH, FSH, DHEAS, testosterone, progesterone, estradiol) did not exhibit significant differences in terms of lumbar BMD compared to those in the highest tertile. The mean annual bone loss was statistically indistinguishable between men and women. There was no significant correlation of sex hormone levels and BMD in men and premenopausal women. In postmenopausal women, however, low estradiol and high LH levels correlated with the extent of annual BMD loss ( p <0.05). Our data confirm significantly reduced lumbar T -scores in the very late period after renal transplantation. The lumbar BMD decreased by –0.6±1.9% per year. In postmenopausal long-term renal transplant recipients, low estradiol levels were associated with accelerated bone loss.The data were presented in part at the 37th annual meeting of the American Society of Nephrology, ASN 2004 (Renal Week 2004)     

Rescue therapy with tacrolimus in simultaneous pancreas/kidney transplantation

Tacrolimus has been effective both in primary and rescue therapy following steroid and OKT3-resistant acute rejection in liver and kidney transplantation. Due to the effects of tacrolimus on glucose metabolism, there has been concern about its use in simultaneous pancreas/kidney transplantation. We report on the results of six patients (three female, three male, age 35.2 ± 7.3 years) converted from cyclosporin A to tacrolimus following simultaneous pancreas/kidney transplantation in steroid-resistant acute rejection. Tacrolimus was induced 2.8 ± 1.7 months (range 1–4.8 months) after transplantation; follow-up was 3–18 months. Following conversion, creatinine levels declined in all patients [3.5 ± 1.2 mg/dl before conversion, 3.0 ± 1.9 mg/dl (n = 6) at three months, 1.4 ± 0.1 mg/dl at 1 year (n = 3)]. Before conversion, fasting blood glucose levels averaged 154 ± 33 mg/dl, with three patients receiving insulin. Three months later no patient required insulin, the mean glucose level being 107 ± 23 mg/dl (n = 6); at 1 year it was 92 ± 9 mg/dl (n = 3). One patient lost his pancreatic graft after 4 months due to a mycotic aneurysm. We conclude that conversion to tacrolimus is a safe and effective treatment in cases of steroid-resistant rejections following pancreas/kidney transplantation.