Failure of successful renal transplant to produce appropriate levels of 1,25-dihydroxyvitamin D.

INTRODUCTION: Bone metabolism disturbances following renal transplantation (RT) are complex and multifactorial in origin. Abnormalities in 1,25-dihydroxyvitamin D levels in RT patients under treatment at our Bone Center prompted this retrospective study. METHODS: Parameters of vitamin D metabolism were compared in RT patients and a cohort of patients with primary hyperparathyroidism (PHTP) who mimicked the hyperparathyroid state of the RT patients. Thirty-one RT recipients (from 300 reviewed) matched our inclusion criteria with a stable graft function for more than 1 year and a glomerular filtration rate (GFR) >50 mL/min per 1.73 m(2) (Group A); these were compared with 42 consecutive patients with PHTP who had been referred to the same Bone Center for treatment for over 1 month (Group B). Statistical analysis included the chi-square or Fisher's exact tests for categorical data and the Wilcoxon rank sum test for quantitative measures. RESULTS: The mean (+/-SD) 1,25-dihydroxyvitamin D level was significantly lower (p < 0.001) in Group A patients (29.8 +/- 16.2) than in Group B patients (70.2 +/- 25.9) despite non-significant differences in the levels of parathyroid hormone (PTH) (mean: 184.0 vs.101.1;p < 0.29), phosphorus (mean: 3.2 vs. 3.1; p < 0.3) and 1,25-vitamin D (mean: 19.5 vs. 25.2; p < 0.06). Group A patients had lower levels (p < 0.05) of mean serum calcium and calculated GFR (9.3 mg/dL, 65.7 mL/min) than Group B patients (10.6 mg/dL, 97.6 mL/min). 1,25-Dihydroxyvitamin D significantly correlated with calcium (p < 0.001), 25-vitamin D (p < 0.005) and GFR (p < 0.001) in both groups, but there was a notable lack of association between 1,25-dihydroxyvitamin D and PTH (p < 0.64) or phosphorus (p < 0.26) in Group A patients. In this group, 1,25-dihydroxyvitamin D was not influenced by the type of immunosuppresion regimen (p < 0.06), use of biphosphonates (p < 0.73), presence of diabetes (p < 0.59), menopause in women (p < 0.08), season (p < 0.43) or race (p < 0.31). Our data indicate that 1,25-dihydroxyvitamin D metabolism remains disturbed for a considerable time after successful RT, with the result that the level of 1,25-dihydroxyvitamin D in RT patients is lower despite physiological signals that should stimulate its production. Our analysis of many clinical variables was unable to elucidate the underlying mechanism(s) for this disturbance. CONCLUSION: Successful RT may not produce appropriate levels of 1,25-dihydroxyvitamin D commensurate to the elevated levels of PTH. This abnormality along with sustained hyperparathyroidism may contribute to bone loss following transplantation.

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover.

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

Role of alendronate and risedronate in preventing and treating osteoporosis.

Alendronate and risedronate, the two oral bisphosphonates approved in the United States for preventing and treating osteoporosis, have never been compared in direct head-to-head trials, but they appear to have similar pharmacokinetics, drug interactions, adverse effect profiles, and efficacy. Alendronate, however, can be given as a once-weekly dose, whereas risedronate is not yet available in this dosage form. On the other hand, alendronate is not approved for preventing glucocorticoid-induced osteoporosis, whereas risedronate carries this indication.

Ultrasound of the skeleton: review of its clinical applications and pitfalls.

Quantitative ultrasound (QUS) is receiving considerable attention in the assessment of osteoporosis because of its ease of use, lack of radiation exposure, region of interest, and relatively low costs. These features have made the technique appealing for screening adult and pediatric patients. This article discusses some of the clinical applications, limitations, and strengths of QUS.

Tolerability of risedronate in postmenopausal women intolerant of alendronate.

Bisphosphonates are effective treatments for osteoporosis, but some have been associated with upper gastrointestinal intolerance. This randomized, double-blind study assessed the upper gastrointestinal tolerability of risedronate in postmenopausal women who had discontinued alendronate treatment because of upper gastrointestinal adverse events. Sixty-six women who had previously discontinued treatment with alendronate 10 mg/day because of upper gastrointestinal symptoms received placebo (N=31) or risedronate 5 mg (N=35) daily for 3 months. The primary outcome was the rate of discontinuation due to upper gastrointestinal adverse events: 5/31 (16.1%) in the placebo group, and 4/35 (11.4%) in the risedronate group. Discontinuation rates were also similar in the two treatment groups among subgroups of patients with a history of gastrointestinal disorder, prior use of acid suppression drugs, and concomitant use of NSAIDs. The overall incidence of upper gastrointestinal events was comparable between the placebo (19.4%) and risedronate (20.0%) groups. Overall, risedronate 5 mg/day for 3 months was as well tolerated as placebo in patients who could not tolerate alendronate 10 mg. These results are consistent with, and complement those from previous studies showing that risedronate 5 mg has a gastrointestinal tolerability similar to that of placebo.

Raloxifene: a new choice for treating and preventing osteoporosis.

Selective estrogen receptor modulators (SERMs) are a new class of drugs that provide a new option for addressing the health challenges of postmenopausal women. This review discusses the proposed mechanism of action of SERMs and describes clinical findings on raloxifene, a SERM now available for treating and preventing osteoporosis.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms.

BACKGROUND: There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been > or =30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. OBJECTIVE: To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. METHODS: This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. RESULTS: A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences. CONCLUSION: The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Risedronate, a novel pyridinyl bisphosphonate for the treatment of osteoporosis and Paget's disease of bone.

Osteoporosis and Paget's disease of bone are the most common metabolic bone diseases. They cause considerable disability and pain, and reduce quality of life. The elderly are at greatest risk of osteoporotic fractures, and in an ageing world population, the burden of the disease is likely to increase. Bisphosphonates are known to be effective antiresorptive agents for the treatment of Paget's disease of bone, postmenopausal osteoporosis (PMO) and corticosteroid-induced osteoporosis (CIO). However, some bisphosphonates have been associated with troublesome gastrointestinal side-effects. Risedronate is a novel pyridinyl bisphosphonate recently approved in the USA for the treatment of Paget's disease, and is under development for the treatment of PMO and CIO. Risedronate is effective and well-tolerated in the treatment of Paget's disease. It has the shortest treatment regimen of any oral bisphosphonate; a two month course of therapy results in sustained remission, as determined by biochemical indices. The results of recent clinical trials suggest that risedronate is also an effective, well-tolerated therapy for PMO and CIO. Risedronate represents an advance in the therapeutic options available for the treatment of Paget's disease, and is expected to be of further value for treatment of PMO and CIO when it receives approval for use in these conditions.

Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Effects of amiodarone on thyroid function.

PURPOSE: To review the literature on the effects of amiodarone on thyroid physiology and management of amiodarone-induced thyroid disease. DATA SOURCES: English-language articles identified through a MEDLINE search (for 1975 to 1995, using the terms amiodarone and thyroid) and selected cross-referenced articles. STUDY SELECTION: Articles on the effects of amiodarone on thyroid physiology and function tests and occurrence, recognition, and management of amiodarone-induced thyroid disease. DATA EXTRACTION: Data were manually extracted from selected studies and reports; emphasis was placed on information relevant to the practicing clinician. DATA SYNTHESIS: Amiodarone can have many effects on thyroid function test results, even in the absence of hyperthyroidism or hypothyroidism. It may cause an increase in serum levels of thyroxine, reverse triiodothyronine, and thyroid-stimulating hormone and a decrease in serum triiodothyronine levels. Thyrotoxicosis occurs in some patients and is related to several pathogenetic mechanisms. It often present dramatically with obvious clinical manifestations and further changes in thyroid function test results. Medical options include therapy with thionamides, perchlorate, and prednisone. Radioactive iodine is of little use. Thyroidectomy is effective and is the only measure that consistently allows continued use of amiodarone. Unlike thyrotoxicosis, hypothyroidism is related to a persistent Wolff-Chaikoff effect and often has a vague presentation. The goal of treatment of amiodarone-induced hypothyroidism is to bring serum thyroxine levels to the upper end of the normal range, as often seen in euthyroid patients who are receiving amiodarone. CONCLUSIONS: Thyroid dysfunction commonly occurs with amiodarone therapy. It may be difficult to recognize the dysfunction because of the many changes in thyroid function test results that occur in euthyroid patients who are receiving amiodarone. Effective strategies exist for the management of hyperthyroidism and hypothyroidism; these should be tailored to the needs of the individual patient.

Regional body FDG-PET in postoperative recurrent hyperparathyroidism.

PURPOSE: The use of preoperative imaging studies in patients with persistent or recurrent hyperparathyroidism after initial operation is generally accepted to improve the success rate and minimize the morbidity from reoperative surgery. The purpose of this study was to define the performance of FDG-PET for the localization of hyperfunctioning parathyroid tissue prior to reoperation. METHOD: Twenty patients with biochemical evidence of recurrent or persistent hyperparathyroidism following previous neck surgery were investigated. Regional body PET imaging of the neck and upper chest (axial field of view 27.5 cm) was acquired 45 min after 5-10 mCi FDG was given intravenously. RESULTS: Subsequent surgery revealed solitary parathyroid adenomas in 14 patients, seven hyperplastic glands in 2 patients, and parathyroid carcinoma in 1 patients. FDG-PET correctly identified 79% (11/14) of the parathyroid adenomas, 29% (2/7) of the hyperplastic glands, and the parathyroid carcinoma. FDG-PET was negative in 79% (30/38) of the surgically identified normal parathyroid glands. Eight false-positive findings led to a positive predictive value of 64%. CONCLUSION: These preliminary data suggest that regional body FDG-PET is a promising procedure in the evaluation of patients with persistent or recurrent postoperative hyperparathyroidism.

Bisphosphonate therapy.

The bisphosphonates are long-lived synthetic analogs of pyrophosphate, a natural, short-lived inhibitor of bone. Oral doses share similar qualities (ie, they inhibit bone resorption, poor absorption, and potential gastrointestinal irritants), but each one has a unique spectrum of potency and a probable mechanism of action. The parent compound, etidronate, was first used in multicentered trials for the treatment of primary osteoporosis and showed some success in increasing bone density and perhaps controlling fracture rates. The recently approved drug alendronate is a more potent agent than etidronate, produces a greater increase in bone density, and decreases fractures. Oral and intravenous pamidronate have similar positive effects on bone density. Studies with tiludronate, risedronate, and clodronate show similar promise as therapeutic agents.

Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment.

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy. PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs. RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures. CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

Amiodarone induced hyperthyroidism: a case series and brief review of literature.

To delineate the incidence, clinical features, diagnosis, and treatment options for amiodarone induced hyperthyroidism (AIH), we reviewed the medical records of ten patients with AIH. Eight of these 10 patients were detected on initial review of the records of 200 patients in treatment with amiodarone, and the other 2 following notification by their endocrinologists. AIH occurred in 4.2% of patients being treated with amiodarone. At the time of diagnosis of AIH, the mean (SD) values for age, duration of treatment with amiodarone, and dose of amiodarone were 62.9 (8.96) years, 38.3 (20) months, and 366.7 (122) mg/day, respectively. The most common clinical features were weight loss and goiter (each seen in 90% of patients). Serum thyroxine (T4), triiodothyronine, and free thyroxine index (FTI) showed an increase of 84%, 47%, and 110%, while thyroid stimulating hormone (TSH) and resin T4 uptake decreased 96% and 14%, respectively, from previous values. The most consistent laboratory findings, seen in all patients, were subnormal TSH and abnormally high FTI. One patient required no treatment; another underwent prompt total thyroidectomy. The other eight were treated medically; two of them underwent total thyroidectomy later, for medical failure or adverse effects. Amiodarone was continued in four patients. The most commonly used antithyroid medication was propylthiouracil. AIH presents in the early or late phases of treatment with amiodarone with typical clinical features of a hyperthyroid state, fall in TSH, and increase in FTI. Antithyroid medications are reasonably effective in the management of AIH.

Comparison of FDG-PET and sestamibi-SPECT in primary hyperparathyroidism.

UNLABELLED: Preoperative localization of hyperfunctioning parathyroid tissue in patients with primary hyperparathyroidism has been a longstanding diagnostic challenge. This study directly compared FDG-PET and sestamibi-SPECT for preoperative detection of abnormal parathyroid tissue. METHODS: Twenty-one consecutive patients with primary hyperparathyroidism were studied prospectively before surgical neck exploration. SPECT of the neck and chest was performed at 15 min and 2 hr after intravenous 99mTc-sestamibi. Regional body PET was performed 45 min after intravenous FDG. RESULTS: Surgery revealed 19 solitary parathyroid adenomas, 2 parathyroid adenomas in one patient; and 3 hyperplastic parathyroid glands in one patient, and 51 normal parathyroid glands. The diagnostic sensitivities for detection of parathyroid adenomas of 43% (9 of 21) for dual-phase sestamibi-SPECT and 86% (18 of 21) for FDG-PET were significantly different (p < 0.001). The difference in diagnostic specificities of 78% (40 of 51) for FDG-PET and 90% (46 of 51) for dual-phase sestamibi-SPECT approached statistical significance (p = 0.063). CONCLUSION: This study demonstrates that FDG-PET is more sensitive than sestamibi-SPECT in the preoperative localization of parathyroid adenomas in patients with primary hyperparathyroidism.

Prevention and osteoporosis management.

BACKGROUND: Primary osteoporosis affects one in four women over the age of 65 and reflects lifelong processes and trends. SUMMARY: Skeletal bone constantly repairs the microscopic damage it sustains as a result of the normal activities of living. Women achieve their maximum bone density by the close of adolescence. Hereditary, nutritional, hormonal, and life-style factors affect the process of osteoporosis. Bone densitometry can detect very small deficits long before losses become clinically apparent. Intervention can halt osteoporosis at any point and perhaps increase bone density, but no known therapy can restore the normal bone architecture once it is lost. KEY POINTS: Women should maintain an adequate intake of calcium throughout their lifetime, especially during adolescence. Bone densitometry at the time of menopause detects preclinical osteoporosis and enables physicians to start therapy to preserve the bone structure.

Primary hyperparathyroidism: preoperative parathyroid imaging with regional body FDG PET.

PURPOSE: To explore the feasibility of use of positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) to localize abnormal parathyroid tissue. MATERIALS AND METHODS: Regional body FDG PET with attenuation correction was performed in 17 adult patients with primary hyperparathyroidism (HPT) prior to surgical neck exploration. The regional body FDG PET results were correlated with surgical and histopathologic findings. RESULTS: Surgical neck exploration revealed 18 parathyroid adenomas in 16 patients and four hyperplastic parathyroid glands in one patient. Regional body FDG PET allowed correct localization of 17 of the 18 parathyroid adenomas (94% sensitivity) and two of the four hyperplastic parathyroid glands (50% sensitivity). Three false-positive FDG PET findings were encountered, including two follicular thyroid adenomas. CONCLUSION: Regional body FDG PET is a promising procedure for preoperative localization of pathologic parathyroid tissue in patients with primary HPT.