Khashayar Sakhaee

Treatment of Postmenopausal Osteoporosis with Slow-Release Sodium Fluoride: Final Report of a Randomized Controlled Trial

It seems logical to use fluoride in osteoporosis, because fluoride can stimulate osteoblastic proliferation and new bone formation [1, 2]. However, clinical trials with fluoride have yielded mixed results because excessive exposure to fluoride may cause abnormal bone formation, microfractures, and gastric bleeding [3, 4]. Thus, treatment with a high dosage of plain sodium fluoride did not decrease the spinal fracture rate despite markedly increasing vertebral bone density, and it increased the rate of appendicular fractures and microfractures [4]. To overcome the complications associated with sodium fluoride, we have advocated the cyclical, intermittent use of a lower dose of less bioavailable, slow-release sodium fluoride and continuous supplementation with calcium citrate [5, 6]. This treatment has been shown to maintain serum fluoride concentrations within the narrow therapeutic window [7, 8], thus avoiding toxic peaks in serum [9], and to stimulate the formation of normally mineralized bone [5, 10] with an improved intrinsic quality of cancellous bone [11-13]. We previously reported the results of an interim analysis [6] of a placebo-controlled randomized trial (median duration of treatment for fracture analysis, 2 years). Here, we present the final report of that trial (median duration of treatment for fracture analysis, 3 years). Methods Clinical Data Demographic and baseline presentations were described in the interim report [6]. We recruited 110 women with postmenopausal osteoporosis into the trial. All had radiologic evidence of osteopenia and osteoporosis; one or more vertebral fractures believed to be nontraumatic; and no secondary cause of bone loss. They were randomly assigned to one of two groups and stratified according to estrogen treatment. All study personnel were unaware of group assignment while data were being gathered. Ninety-nine patients completed at least 1 study cycle (1 year of actual treatment). The demographic or baseline presentations of these 99 patients did not differ according to treatment group [6] (Table 1). The two groups were similar in age, time since menopause, dietary calcium intake, height, weight, and number of spinal fractures. Both groups had moderate to severe osteoporosis: The average L2-L4 bone density was approximately 30% less than of a normal 30-year-old woman, and each group had a median of two spinal fractures at baseline. Table 1. Baseline Characteristics* Treatment Patients in the fluoride group received slow-release sodium fluoride (Slow Fluoride, Mission Pharmacal Co., San Antonio, Texas), 25 mg twice daily, orally before breakfast and at bedtime in repeated 14-month cycles (12 months receiving treatment followed by 2 months not receiving treatment). They also received calcium citrate (Citracal, Mission Pharmacal), 400 mg calcium twice daily, before breakfast and at bedtime continuously throughout the study. Those in the placebo group received placebo (identical in appearance to Slow Fluoride but containing excipient only [provided by Mission Pharmacal]) on the same time schedule. The Mission Pharmacal Company had no role in the design of the study or in data retrieval, analysis, or interpretation. Thirteen of 48 patients in the fluoride group and 16 of 51 patients in the placebo group received concurrent treatment with estrogen. Nine of the 29 patients treated with estrogen were recruited at the primary site at Dallas; the other 20 were enrolled and evaluated at the Scott and White Clinic, Temple, Texas. Fracture Quantitation Before treatment and at 12 months of each cycle, a lateral spine roentgenogram was obtained for the assessment of spinal fractures. In the interim analysis [6], prevalent fractures (fractures present at baseline) were identified with the aid of radiology reports. For this final report, prevalent fractures were also analyzed using a computer program that calculated the vertebral dimensions of clearly unaffected vertebrae from landmarks (anterior and posterior corners and midpoints). By comparing these dimensions with published normal values [14], we obtained a correction factor. Using this correction factor, we estimated idealized vertebral dimensions before a fracture had occurred for the remaining vertebrae in the given baseline radiograph. A reduction in any height of more than 20% (from idealized to actual) accompanied by a decrease of at least 10% in vertebral area represented a prevalent fracture. Incident spinal fractures (fractures occurring during the trial) were identified as described previously [6], using a computer-derived method. A reduction in any vertebral height of more than 20% accompanied by a decrease in vertebral area of more than 10% from one year to the next constituted a fracture [15]. A new incident fracture was a fracture that occurred during treatment in a previously unaffected vertebrae. A recurrent fracture was one that developed on a previously fractured vertebra. Bone Mass Measurements The use of different densitometers prompted us to calculate and use percentage changes per year rather than absolute values. The method for calculating changes in L2-L4 bone mineral content and bone density of the femoral neck and the radial shaft was described previously [6]. Safety Variables Serum fluoride concentrations were measured before the morning dose of the test drug at 0, 3, 6, 9, and 12 months of each cycle, and they were analyzed using an ion-specific electrode. At the same visits, a history was taken for gastrointestinal and musculoskeletal side effects. A microfracture was defined clinically as moderate to severe lower-extremity pain that persisted for more than 6 weeks despite a reduction in treatment dose and objectively as changes on bone scan or radiograph. The relation of each side effect to treatment was assessed. A symptom was considered to be related to treatment if it was moderate to severe in intensity, had no other cause, had newly appeared and persisted during the treatment phase, or had disappeared during the withdrawal period or with dose reduction. It was considered to be unrelated if it was present at baseline or during the late withdrawal phase, or if it had newly appeared but was not persistent. The severity and frequency of side effects were also quantitated as adverse symptom scores. We identified 10 gastrointestinal items (symptoms such as nausea, vomiting, and diarrhea), 4 rheumatic items (pain in the foot, knee, hip, and other joints), and 3 skeletal items (pain in the lower, mid-, or upper back). Each item was given a numerical value of 1 to 3 for frequency (infrequent, frequent, or very frequent) and a numerical value of 1 to 3 for severity (mild, moderate, or severe). Side-effect score was the product of the value for frequency and the value for severity for each item. Thus, a constant, severe back pain yielded a score of 9 (3 3). A gastrointestinal score was derived for each patient by adding the scores of the 10 gastrointestinal items for all relevant visits and dividing the sum by the number of visits. A similar computation was done to derive rheumatic and skeletal scores for each patient. Statistical Analysis The data for incident spinal fractures were compared between the two groups-using three methods. Individual Vertebral Fracture Rate For each patient, the individual vertebral fracture rate was obtained by dividing the total number of new fractures by the duration of treatment. Because the data were skewed, this rate was compared between the two groups using the Wilcoxon rank-sum test. Fracture-Free Rate This rate was the percentage of patients without new fractures, unadjusted for covariates. The two groups were compared using the log-rank test to account for differential follow-up. Survival The Cox proportional-hazards regression model [16] was constructed to estimate the relative risk for a new spinal fracture while adjusting for covariates (treatment group, age, prevalent spinal fractures, years since menopause, height, weight, estrogen treatment, and stratum of baseline L2-L4 bone density). Time (in years) to the first fracture was considered to be the survival time. Analyses of fracture rates and logistic regression were also done [6]; the data are not presented because findings were similar to those obtained using the above methods. The arithmetic difference in height from baseline to the end of treatment for each patient was compared between groups using a two-sample t-test and a two-way analysis of variance with the following factors: 1) treatment [fluoride vs placebo] and 2) fracture status (fracture-free vs one or more new or recurrent fractures). For each patient, we calculated the percentage change per year for L2-L4 bone mineral content and bone density of femoral neck and radial shaft. The individual mean change for each patient was calculated as the average of yearly changes. The group mean was obtained by averaging the individual means. One-sample t-tests were then used to compare the percentage change to zero for each year or for the mean. Comparisons between groups were made using two-sample t-tests. Missing data precluded implementing a repeated-measures analysis of variance. For related adverse events, the frequency of each event was compared between the two groups by using the Fisher exact test. Adverse symptom scores were compared between the groups by using the Wilcoxon rank-sum test and within the groups by using the Wilcoxon signed-rank test. For nonvertebral fractures, the exact tests based on the binomial distribution using person-year data were used to compare the two groups. Most analyses were done using BMDP Statistical Software (BMDP, Los Angeles, California). Programs for analyzing person-time data were developed by the authors. Data are presented as mean SD unless otherwise indicated. All reported P values are two-sided. Results Duration of Treatment The total duration of follow-up, including withdrawal periods, was 193 patient-years in th

Low Urine pH: A Novel Feature of the Metabolic Syndrome

BACKGROUND AND OBJECTIVES The metabolic syndrome is associated with alterations in renal function. An overly acidic urine has been described as a renal manifestation of the metabolic syndrome in patients with kidney stone disease. This study examined the association between the metabolic syndrome and urine pH in individuals without a history of nephrolithiasis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 148 adults who were free of kidney stones were evaluated in this outpatient cross-sectional study. Height, weight, BP, fasting blood, and 24-h urine chemistries were obtained. Urine pH was measured by pH electrode. The following features of the metabolic syndrome were evaluated: BP; body mass index; and serum triglyceride, glucose, and HDL cholesterol concentrations. The degree of insulin resistance was assessed by the homeostasis model assessment of insulin resistance. RESULTS Participants with the metabolic syndrome had a significantly lower 24-h urine pH compared with participants without the metabolic syndrome. Mean 24-h urine pH, adjusted for age, gender, creatinine clearance, and 24-h urine sulfate, decreased from 6.15, 6.10, 5.99, 5.85, to 5.69 with increasing number of metabolic syndrome abnormalities. An association was observed between 24-h urine pH and each metabolic feature. After adjustment for age, gender, creatinine clearance, urine sulfate, and body mass index, a significant inverse relationship was noted between 24-h urine pH and the degree of insulin resistance. CONCLUSIONS An unduly acidic urine is a feature of the metabolic syndrome and is associated with the degree of insulin resistance.

The potential role of salt abuse on the risk for kidney stone formation

The kidney stone-forming risk of a high sodium diet was evaluated by assessing the effect of such a diet on the crystallization of stone-forming salts in urine. Fourteen normal subjects participated in 2 phases of study of 10 days duration each, comprising a low sodium phase (basal metabolic diet containing 50 mmol. sodium per day) and a high sodium phase (basal diet plus 250 mmol. sodium chloride per day). The high sodium intake significantly increased urinary sodium (34 +/- 12 to 267 +/- 56 mmol. per day), calcium (2.73 +/- 1.03 to 3.93 +/- 1.51 mmol. per day) and pH (5.79 +/- 0.44 to 6.15 +/- 0.25), and significantly decreased urinary citrate (3.14 +/- 1.19 to 2.52 +/- 0.83 mmol. per day). Arterialized venous blood bicarbonate and total serum carbon dioxide concentrations decreased significantly during the high sodium diet, whereas serum chloride concentration increased. However, no change in arterialized venous pH was detected. Thus, a high sodium intake not only increased calcium excretion, but also increased urinary pH and decreased citrate excretion. The latter effects are probably due to sodium-induced bicarbonaturia and a significant decrease in serum bicarbonate concentration, respectively. Commensurate with these changes, the urinary saturation of calcium phosphate (brushite) and monosodium urate increased, and the inhibitor activity against calcium oxalate crystallization (formation product) decreased. The net effect of a high sodium diet was an increased propensity for the crystallization of calcium salts in urine.

Biochemical profile of stone-forming patients with diabetes mellitus

OBJECTIVES To test the hypothesis that stone-forming patients with type II diabetes (DM-II) have a high prevalence of uric acid (UA) stones and present with some of the biochemical features of gouty diathesis (GD). METHODS The demographic and initial biochemical data from 59 stone-forming patients with DM-II (serum glucose greater than 126 mg/dL, no insulin therapy, older than 35 years of age) from Dallas, Texas and Durham, North Carolina were retrieved and compared with data from 58 patients with GD and 116 with hyperuricosuric calcium oxalate urolithiasis (HUCU) without DM. RESULTS UA stones were detected in 33.9% of patients with DM-II compared with 6.2% of stone-forming patients without DM (P <0.001). Despite similar ingestion of alkali, the urinary pH in patients with DM-II and UA stones (n = 20) was low (pH = 5.5), as it is in patients with GD, and was significantly lower than in patients with HUCU. The urinary pH in patients with DM-II and calcium stones (n = 39) was intermediate between that in those with DM-II and UA stones and those with HUCU. However, both DM groups had fractional excretion of urate that was not depressed, as it is in those with GD, and was comparable to the value obtained in those with HUCU. The urinary content of undissociated UA was significantly higher, and the saturation of calcium phosphate (brushite) and sodium urate was significantly lower in those with DM-II and UA stones than in those with HUCU. CONCLUSIONS Stone-forming patients with DM-II have a high prevalence of UA stones. Diabetic patients with UA stones share a key feature of those with GD, namely the passage of unusually acid urine, but not the low fractional excretion of urate.

Prevention of Recurrent Calcium Stone Formation with Potassium Citrate Therapy in Patients with Distal Renal Tubular Acidosis

Distal renal tubular acidosis is a common cause of intractable calcium nephrolithiasis. We examined the effect of oral potassium citrate therapy in 9 patients with incomplete distal renal tubular acidosis diagnosed on the basis of an abnormal response to an oral ammonium chloride load. Patients were studied during a control phase and after 3 months of potassium citrate treatment (60 to 80 mEq. daily). Potassium citrate caused a significant increase in urinary pH and urinary citrate, and a decrease in urinary calcium. The urinary relative saturation ratio of calcium oxalate significantly decreased during treatment, while that of brushite did not change. Potassium citrate also was shown to inhibit new stone formation. During a mean treatment period of 34 months none of the 9 patients had new stones, although 39.3 plus or minus 79.7 (standard deviation) stones per patient formed during the 3 years preceding treatment. The results support the potential clinical advantage of potassium citrate therapy in patients with distal renal tubular acidosis and recurrent calcium nephrolithiasis.

Urine Composition in Type 2 Diabetes: Predisposition to Uric Acid Nephrolithiasis

Type 2 diabetes is a risk factor for nephrolithiasis in general and has been associated with uric acid stones in particular. The purpose of this study was to identify the metabolic features that place patients with type 2 diabetes at increased risk for uric acid nephrolithiasis. Three groups of individuals were recruited for this outpatient study: patients who have type 2 diabetes and are not stone formers (n = 24), patients who do not have diabetes and are uric acid stone formers (UASF; n = 8), and normal volunteers (NV; n = 59). Participants provided a fasting blood sample and a single 24-h urine collection for stone risk analysis. Twenty-four-hour urine volume and total uric acid did not differ among the three groups. Patients with type 2 diabetes and UASF had lower 24-h urine pH than NV. Urine pH inversely correlated with both body weight and 24-h urine sulfate in all groups. Urine pH remained significantly lower in patients with type 2 diabetes and UASF than NV after adjustment for weight and urine sulfate (P < 0.01). For a given urine sulfate, urine net acid excretion tended to be higher in patients with type 2 diabetes versus NV. With increasing urine sulfate, NV and patients with type 2 diabetes had a similar rise in urine ammonium, whereas in UASF, ammonium excretion remained unchanged. The main risk factor for uric acid nephrolithiasis in patients with type 2 diabetes is a low urine pH. Higher body mass and increased acid intake can contribute to but cannot entirely account for the lower urine pH in patients with type 2 diabetes.

Management of Cystine Nephrolithiasis with Alpha-Mercaptopropionylglycine

The effect of long-term treatment with alpha-mercaptopropionylglycine was examined in 66 patients with cystinuria. Of the patients 49 took D-penicillamine before therapy, whereas 17 did not. Over-all side effects to alpha-mercaptopropionylglycine were common, and occurred in 75.5 per cent of the patients with and 64.7 per cent without a history of D-penicillamine treatment, compared to 83.7 per cent who suffered toxicity to D-penicillamine. Serious adverse reactions requiring cessation of therapy were less common with alpha-mercaptopropionylglycine. Among the patients who took both drugs 30.6 per cent had to stop taking alpha-mercaptopropionylglycine, whereas 69.4 per cent could not tolerate D-penicillamine. Of the latter group with toxicity to D-penicillamine before therapy, whereas 17 did therapy only 5.9 per cent had side effects to alpha-mercaptopropionylglycine of sufficient severity to require withdrawal. Alpha-mercaptopropionylglycine was equally as effective as D-penicillamine in reducing cystine excretion. During long-term treatment with alpha-mercaptopropionylglycine (average dose 1,193 mg. per day) urinary cystine levels were maintained at 350 to 560 mg. per day and urinary cystine was kept at undersaturated levels. Commensurate with these changes, alpha-mercaptopropionylglycine produced remission of stone formation in 63 to 71 per cent of the patients and reduced individual stone formation rate in 81 to 94 per cent. Thus, alpha-mercaptopropionylglycine has a definite therapeutic role in cystinuric patients with toxicity to D-penicillamine.

Novel insights into the pathogenesis of uric acid nephrolithiasis.

Purpose of reviewThe factors involved in the pathogenesis of uric acid nephrolithiasis are well known. A low urinary pH is the most significant element in the generation of stones, with hyperuricosuria being a less common finding. The underlying mechanism(s) responsible for these disturbances remain poorly characterized. This review summarizes previous knowledge and highlights some recent developments in the pathophysiology of low urine pH and hyperuricosuria. Recent findingsEpidemiological and metabolic studies have indicated an association between uric acid nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule, or substrate competition by free fatty acids. The evaluation of a large Sicilian kindred recently revealed a putative genetic locus linked to uric acid stone disease. The identification of novel complementary DNA has provided an interesting insight into the renal handling of uric acid, including one genetic cause of renal uric acid wasting. SummaryThe recognition of metabolic, molecular, and genetic factors that influence urinary pH, and uric acid metabolism and excretion, will provide novel insights into the pathogenesis of uric acid stones, and open the way for new therapeutic strategies.

Nephrolithiasis in children.

A metabolic etiology is the most common cause for pediatric kidney stones. Appropriate evaluation of affected children should include assessment of stone type, if available, and assessment of predisposing factors in all cases. This review discusses the metabolic disorders that lead to nephrolithiasis with respect to the development of calcium, uric acid, struvite, and cystine stones. Environmental and hereditary factors are summarized to provide a guide in the evaluation of pediatric stone formers.

Nephrolithiasis as a systemic disorder.

Purpose of reviewNephrolithiasis is a prominent public health issue. It imposes a substantial burden on human health and is a considerable financial expenditure for the nation. Numerous epidemiologic studies have shown a significant association between nephrolithiasis, obesity, hypertension and chronic kidney disease. The review highlights many of those emerging studies and sheds light on the importance of our recognition of kidney stones as a systemic illness. Recent findingsSeveral cross-sectional retrospective studies have investigated the relationship between kidney stones and the metabolic syndrome. The various silent features of the metabolic syndrome, including type 2 diabetes, increased BMI, hypertension and dyslipidemia, are becoming progressively more recognized and independently associated with an increased risk of kidney stone formation. SummaryOur further understanding of the underlying mechanisms in the connection between nephrolithiasis and the metabolic syndrome will stimulate the development of more effective preventive and therapeutic measures.