Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday.

UNLABELLED: In a retrospective analysis of 208 osteoporotic patients followed during a bisphosphonate holiday, lower body weight and risedronate use were associated with a more rapid decline in bone mineral density during the bisphosphonate holiday, while bone mineral density (BMD) trends were similar in patients who sustained vs. did not sustain a fracture. INTRODUCTION: A drug holiday has been suggested for some bisphosphonate-treated patients with osteoporosis to minimize potential side effects from prolonged use. However, there is limited information on the evolution of BMD during a bisphosphonate holiday. Our study analyzed the longitudinal course of BMD following bisphosphonate discontinuation and assessed its determinants. METHODS: Retrospective single-center cohort study of osteoporosis patients treated with alendronate or risedronate for at least 2 years and then discontinued their bisphosphonate for a drug holiday. Patients were stratified by bisphosphonate type and by fracture occurrence during drug holiday. RESULTS: A total of 208 patients were included in this analysis (87.5 % female). At the time of bisphosphonate cessation, mean ± SD age was 66.9 ± 8.9 years and BMI 24.5 ± 4.4 kg/m(2). Duration of bisphosphonate treatment was 5.2 ± 2.3 years, and follow-up during holiday was 3.3 ± 1.7 years. During the first 2 years of the holiday, BMD remained stable at the lumbar spine and femoral neck, but declined significantly at the total hip. BMD declined significantly at all sites thereafter. Significant predictors of BMD decline during bisphosphonate holiday included lower BMI at the start of the holiday and change in body weight during the holiday. BMD decline was more pronounced in former risedronate compared to former alendronate users. BMD trends were similar in patients who sustained vs. did not sustain a fracture during the holiday. CONCLUSIONS: BMD at the total hip declines significantly within 1 year of bisphosphonate discontinuation, particularly in lean patients. Additional studies are needed to identify predictors of fracture incidence during a bisphosphonate holiday.

Biochemical profile of idiopathic uric acid nephrolithiasis.

BACKGROUND: The objective of this study was to elucidate a biochemical profile of patients with idiopathic uric acid nephrolithiasis, without secondary causes (such as dehydration or diarrhea). Study subjects comprised 56 patients with idiopathic uric acid nephrolithiasis (UA stone group) who underwent a full outpatient evaluation. The control group was composed of 54 with absorptive hypercalciuria and 2 normal subjects, matched with the UA stone group according to age, body mass index, and gender. METHODS: Urinary pH and ammonium and serum and urinary uric acid were measured. The fractional excretion of urate was calculated. RESULTS: Compared with the control group, the UA stone group had a significantly higher serum uric acid and significantly lower urinary uric acid, pH (5.34 +/- 0.23 vs. 6.17 +/- 0.36, P < 0.001), and fractional excretion of urate (0.052 +/- 0.028 vs. 0.080 +/- 0.029, P < 0.001), but individual values overlapped considerably between the two groups. Discriminant analysis of the relationship between urinary pH and fractional excretion of urate yielded a "discriminant score," which provided a much better separation between the two groups, with a correct classification in 95.5% of subjects. In contrast, urinary ammonium, citrate, sulfate, and potassium did not differ between two groups. CONCLUSIONS: In idiopathic uric acid nephrolithiasis, urinary pH and fractional excretion of urate are significantly lower than in control subjects, suggestive of defects in urinary acidification and urate excretion. Since these impairments are believed to be associated with primary gout, the underlying disturbance in idiopathic uric acid nephrolithiasis may be primary gout.

Adequacy of a single stone risk analysis in the medical evaluation of urolithiasis.

PURPOSE: We tested the hypothesis that a single 24-hour urine sample for stone risk analysis would be sufficient for the simplified medical evaluation of urolithiasis. MATERIALS AND METHODS: We retrospectively analyzed stone risk profile data on 24-hour urine samples obtained during random and restricted diets in 225 patients with recurrent urolithiasis. RESULTS: In 2 random samples we noted no significant difference in urinary calcium, oxalate, uric acid, citrate, pH, total volume, sodium, potassium, sulfate or phosphorus. For these risk factors there was a highly significant positive correlation in the 2 random samples (r > or = 0.68, p <0.0003) and the value of each was abnormal or normal in at least 81% of patients. Urinary magnesium and ammonium were significantly lower in random sample 2 than 1, the former by 4%. After calcium, sodium and oxalate dietary restriction mean urinary calcium and sodium plus or minus standard deviation decreased significantly by 25% from 251 +/- 125 to 187 +/- 98 mg. daily and by 38% from 183 +/- 87 to 113 +/- 57 mEq. daily, respectively. Other risk factors had a slight or no significant change. Correcting random urinary calcium for the excessive urinary excretion of sodium brought urinary calcium to 210 +/- 108 mg. daily, similar to the value on the restricted diet. CONCLUSIONS: The reproducibility of urinary stone risk factors is satisfactory in repeat urine samples. A single stone risk analysis is sufficient for the simplified medical evaluation of urolithiasis.

Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women.

This randomized crossover study compared the single-dose bioavailability and effects on parathyroid function of two commercially formulated calcium supplements containing 500 mg of elemental calcium. Twenty-five postmenopausal women underwent three phases of study wherein they each took a single dose of calcium citrate with a standard breakfast (as Citracal 250 mg + D), calcium carbonate (as Os-Cal 500 mg + D), or placebo at 8 a.m. Blood samples were drawn at baseline and hourly for 4 or 6 hours after each dose. Fasting and postload urine samples were also collected. Compared with calcium carbonate, calcium citrate provided a 46% greater peak-basal variation and 94% higher change in area under the curve for serum calcium and a 41% greater increment in urinary calcium. Moreover, the decrement in serum parathyroid hormone concentration from baseline was greater after calcium citrate. In conclusion, calcium citrate is more bioavailable than calcium carbonate when given with a meal.

In situ reproductive rate of freshwater Caulobacter spp.

Electron microscope grids were submerged in Lake Washington, Seattle, Wash., in June 1996 as bait to which Caulobacter sp. swarmers would attach and on which they would then reproduce in situ. Enumeration of bands in the stalks of attached cells implied that the caulobacters were completing approximately three reproductive cycles per day. A succession of morphological types of caulobacters occurred, as well as an episode of bacteriovore grazing that slowed the accumulation of caulobacters and prevented the aging of the population.

Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia.

BACKGROUND: The purpose of this study was to compare the value of potassium-magnesium citrate (KMgCit) with potassium chloride in overcoming thiazide-induced hypokalemia. METHODS: Sixty normal subjects first took hydrochlorothiazide (HCTZ; 50 mg/day). After three weeks of treatment (or earlier if hypokalemia developed), they were randomized to take KMgCit (42 mEq K, 21 mEq Mg, and 63 mEq citrate/day) or potassium chloride (42 mEq/day) for three weeks while continuing on HCTZ. RESULTS: KMgCit significantly increased the serum potassium concentration from 3.42 +/- 0.30 mEq/L on HCTZ alone to about 3.8 mEq/L (P < 0.001). Potassium chloride produced a similar increase in serum potassium concentration from 3.45 +/- 0.44 mEq/L to about 3.8 mEq/L (P < 0. 001). KMgCit significantly increased the serum magnesium concentration by 0.11 to 0.12 mEq/L (P < 0.01), whereas potassium chloride produced a marginal decline or no significant change. KMgCit was less effective than potassium chloride in correcting HCTZ-induced hypochloridemia and hyperbicarbonatemia. KMgCit, but not potassium chloride, significantly increased urinary pH (by about 0.6 unit), citrate (by about 260 mg/day), and urinary magnesium. CONCLUSIONS: KMgCit is equally effective as potassium chloride in correcting thiazide-induced hypokalemia. In addition, KMgCit, but not potassium chloride, produces a small but significant increase in serum magnesium concentration by delivering a magnesium load, and it confers alkalinizing and citraturic actions.

The effect of varying molar ratios of potassium-magnesium citrate on thiazide-induced hypokalemia and magnesium loss.

This study was conducted to compare the value of an older formulation of potassium-magnesium citrate (K4MgCit2) with newer formulations (K3MgHCit2 and K5MgCit2Cl) with respect to the correction of thiazide-induced hypokalemia and magnesium loss, alkalinizing effect, and citraturic action. Sixty-two healthy volunteers first took hydrochlorothiazide 50 mg/day. After 3 weeks of thiazide treatment (or earlier if hypokalemia developed), they were randomized to take one of three drugs for 3 weeks while continuing thiazide: K4MgCit2 (49 mEq K, 25 mEq Mg, and 74 mEq citrate/day), K3MgHCit2 (49 mEq K, 33 mEq Mg, and 98 mEq citrate/day), and K5MgCit2Cl (49 mEq K, 20 mEq Mg, 10 mEq Cl and 59 mEq citrate/day). Outcome measures were changes in serum potassium and magnesium, and urinary potassium, magnesium, pH, and citrate. The three drugs were equally effective in correcting thiazide-induced hypokalemia. K3MgHCit2 and K4MgCit2 produced a small but significant increase in serum magnesium concentration, whereas K5MgCit2Cl did not. Although all three supplements significantly increased urinary pH and citrate, these effects were more marked with K3MgHCit2 and K4MgCit2 than with K5MgCit2. All three supplements were generally well tolerated, with the lowest side effect profile obtained with K4MgCit2. The new formulation of K3MgHCit2 exerts similar correction of thiazide-induced hypokalemia and magnesium loss, and enhancement of urinary pH and citrate, compared with the older K4MgCit2. However, it is less well tolerated. The new formulation of K5MgCit2Cl does not avert magnesium loss, and has less prominent alkalinizing and citraturic effects than the older preparation.

Caulobacter and Asticcacaulis stalk bands as indicators of stalk age.

The prosthecae (stalks) of dimorphic caulobacters of the genera Caulobacter and Asticcacaulis are distinguished among such appendages by the presence of disk-like components known as stalk bands. Whether bands are added to a cell's stalk(s) as a regular event coordinated with the cell's reproductive cycle has not been settled by previous studies. Analysis of the frequency of stalks with i, i + 1, i + 2, etc. bands 'among more than 7,000 stalks of Caulobacter crescentus revealed that in finite (batch) cultures (in which all offspring accumulate), the proportion of stalks with i + 1 hands was regularly 50% of the proportion of stalks with i bands. This implied that the number of bands correlated with the number of reproductive cycles completed by a stalked cell. In chemostat-maintained perpetual cultures, the proportion was greater than 50% because stalked cells, with their shorter reproductive cycle times, contributed a larger proportion of offspring to the steady-state population than did their swarmer siblings. In Asticcacaulis biprosthecum cells, which bear twin prosthecae, the twins on a typical cell possessed the same number of bands. For both genera, stalk bands provide a unique morphological feature that could be employed in an assessment of age distribution and reproductive dynamics within natural populations of these caulobacters.

Quantitation of incident spinal fractures: comparison of visual detection with quantitative morphometry.

The value of quantitative morphometry in detection of new spinal fractures was assessed in serial radiographs from 83 patients with osteoporosis. From vertebral landmarks on lateral spine radiographs, a computer program allowed calculation of vertebral heights and area. By comparing vertebral dimensions in the two sets of films, incident spinal fractures could be quantitated based either on the minimum criteria of 15% reduction in vertebral height (CM2) or a fall in height and area of 20% and 10% (CM1). The results of quantitative morphometry were compared with those of the consensus and individual readings of visual detection by three experienced investigators in the same paired sets of spinal films. For incident new fractures, the visual consensus method (V-C) showed a very good agreement with individual visual detection (kappa of 0.794 to 0.916) as well as with CM1 (kappa of 0.821). However, there was a poor agreement between the results of consensus reading and of detection by CM2 (kappa of 0.341), due to excessive number of fractures identified by CM2, but not by the visual method. For incident recurrent fractures, there was a poor agreement between V-C and individual visual detection, and between V-C and quantitative morphometry (kappa of 0.306 to 0.496). It was due to severe compression fractures at baseline, which caused further changes in vertebral dimensions difficult to measure accurately by either visual or quantitative morphometry. Thus, if the visual detection of fractures by a consensus of experienced investigators is considered as the "gold standard," quantitative morphometry, based on minimum reduction in vertebral height of 20% accompanied by a minimum decline in area of 10%, provides an objective detection of incident new spinal fractures but not of recurrent fractures.

Treatment of postmenopausal osteoporosis with slow-release sodium fluoride. Final report of a randomized controlled trial.

OBJECTIVE: To test whether slow-release sodium fluoride inhibits spinal fractures and is safe to use. DESIGN: Placebo-controlled randomized trial. INTERVENTIONS: Slow-release sodium fluoride, 25 mg twice daily, in four 14-month cycles (12 months receiving sodium fluoride followed by 2 months not receiving it) compared with placebo. Calcium citrate, 400 mg calcium twice daily, continuously in both groups. PATIENTS: 48 of 54 patients who received sodium fluoride and 51 of 56 patients who received placebo completed at least 1 year of the study. All patients had postmenopausal osteoporosis. RESULTS: Compared with the placebo group, the fluoride group had a lower individual vertebral fracture rate (0.064 +/- 0.182 per patient-year compared with 0.205 +/- 0.297 per patient-year; P = 0.002), a higher unadjusted fracture-free rate (85.4% compared with 56.9%; P = 0.001), and a greater survival estimate (relative risk, 0.3 [95% CI, 0.12 to 0.76]) for new fractures. The recurrent spinal fracture rate did not differ between the two groups. The fluoride group had a substantial increase in L2-L4 bone mass of 4% to 5% per year for 4 years, a mean increase in femoral neck bone density of 2.38% +/- 3.33% per year, and no change in radial shaft bone density. The frequency with which minor side effects and appendicular fractures occurred was similar in the two groups; no patients developed microfractures or gastric ulcers. CONCLUSION: Slow-release sodium fluoride and calcium citrate administered for 4 years inhibits new vertebral fractures (but not recurrent fractures), augments spinal and femoral neck bone mass, and is safe to use.

Limited risk of kidney stone formation during long-term calcium citrate supplementation in nonstone forming subjects.

The physiological and physicochemical effects of long-term calcium citrate supplementation (25 mmol. calcium per day) were assessed in 7 normal premenopausal women. Calcium citrate increased urinary calcium from 3.27 +/- 0.42 mmol. per day (standard deviation) before treatment to 5.16 +/- 0.75 mmol. per day after 1-month of treatment (p < 0.0125). After 3 months of treatment urinary calcium decreased from the 1-month value to 4.54 +/- 0.67 mmol. per day (p < 0.0125) but remained higher than the pretreatment value (p < 0.0125). Fractional intestinal calcium absorption and serum 1,25-dihydroxyvitamin D levels decreased marginally at 1 month of calcium citrate therapy, from 0.457 +/- 0.092 to 0.374 +/- 0.035 (p < 0.05) and from 103 +/- 7 to 77 +/- 14 pmol./l. (p < 0.05), respectively. After 3 months of treatment fractional intestinal calcium absorption decreased further to 0.341 +/- 0.061 (p < 0.0125 compared to pretreatment), whereas serum 1,25-dihydroxyvitamin D remained unchanged at 82 +/- 14 pmol./l. Calcium citrate treatment decreased urinary phosphorus levels significantly from 18.9 +/- 3.3 to 15.0 +/- 2.5 mmol. per day (p < 0.0125) and 14.0 +/- 2.5 mmol. per day (p < 0.05) at 1 and 3 months, respectively. Mean urinary oxalate decreased by 15 to 20% and urinary citrate increased marginally during treatment. Urinary saturation of calcium oxalate and brushite did not change during calcium citrate therapy, except at 1 month when the saturation of calcium oxalate increased marginally. The inhibitory activity of urine against spontaneous nucleation of calcium oxalate and brushite (formation product) did not change during treatment. In conclusion, long-term calcium citrate supplementation in normal subjects does not increase the propensity for crystallization of calcium salts in the urine. This protective effect is probably due to the attenuated increase in urinary calcium excretion (from a decrease in fractional intestinal calcium absorption), a decrease in urinary phosphorus and an increase in urinary citrate.

Slow-release sodium fluoride in the management of postmenopausal osteoporosis. A randomized controlled trial.

OBJECTIVE: To test whether intermittent treatment with slow-release sodium fluoride and continuous calcium citrate supplementation inhibits vertebral fractures without causing fluoride complications. DESIGN: A placebo-controlled, randomized trial. SETTING: Outpatient setting of specialty clinics in Dallas and Temple, Texas. INTERVENTIONS: Slow-release sodium fluoride (25 mg twice daily) in repeated 14-month cycles (12 months on treatment followed by 2 months off treatment) compared with placebo. Both groups took calcium citrate (400 mg calcium twice daily) continuously. PATIENTS: 110 patients with postmenopausal osteoporosis were randomly assigned to two groups. In the slow-release sodium fluoride group, 48 of 54 patients completed more than 1 cycle of treatment (mean, 2.44 cycles/patient), whereas 51 of 56 patients in the placebo group completed at least 1 cycle (mean, 2.14 cycles/patient) in this interim analysis. MEASUREMENTS: Vertebral fracture rate and lumbar bone mineral content. Vertebral fractures were quantified from yearly radiographs. Bone mass was determined annually by densitometry. RESULTS: In the sodium fluoride group, the mean L2 to L4 bone mineral content increased by 4% to 6% in each cycle and the mean femoral neck bone density increased by 4.1% and 2.1% during the first two cycles, but the radial bone density did not change. The placebo group showed no statistical change in bone mass at any site. Compared with the placebo group, the sodium fluoride group had a lower individual new vertebral fracture rate (0.057/patient cycle compared with 0.204/patient cycle, P = 0.017), a higher fracture-free rate (83.3% compared with 64.7%, P = 0.042), and a lower group fracture rate (0.085/patient cycle compared with 0.239/patient cycle, P = 0.006). The side-effect profile was similar for the two groups; no patient developed microfractures, hip fractures, or blood loss anemia. CONCLUSIONS: Intermittent slow-release sodium fluoride plus continuous calcium citrate, administered for about 2.5 years, inhibits new vertebral fractures, increases the mean spinal bone mass without decreasing the radial shaft bone density, and is safe to use.

A surgical approach to a vascular malformation in the plantar medial foot.

Vascular malformations are infrequent findings in the foot, especially the plantar medial foot. Deeper vascular malformations may be more difficult to diagnose due to the depth and oblique course of the medial neurovascular structures into plantar aspect of the foot. The authors present an interesting case report of a vascular anomaly mimicking a heel spur syndrome and describe a surgical approach for the resection of this type of lesion with a 10-month follow-up.

Metabolic effects of thiazide and 1,25-(OH)2 vitamin D in postmenopausal osteoporosis.

It was previously shown that the stimulation of intestinal calcium absorption by exogenous 25-hydroxyvitamin D (25-OHD) in postmenopausal women with osteoporosis was attenuated when thiazide was added, probably due to the suppression of endogenous synthesis of 1,25-(OH)2 vitamin D (1,25-(OH)2D). To test whether the above attenuation could be averted if exogenous 1,25-(OH)2D replaced 25-OHD, 10 women with postmenopausal osteoporosis participated in a three-phase study comprising control (pretreatment), treatment with 1,25-(OH)2D 0.5 microgram/day for 4 weeks, and combined 1,25-(OH)2D and trichlormethiazide (TZ) 2 mg/day for 4 weeks. The 1,25-(OH)2D treatment significantly increased serum 1,25-(OH)2D from 60 +/- 7.2 (SD) to 154 +/- 48 pmol/l, fractional intestinal calcium absorption (alpha) from 0.386 +/- 0.055 to 0.613 +/- 0.081, and urinary calcium from 3.7 +/- 0.8 to 6.6 +/- 1.9 mmol/day. Addition of TZ significantly reduced urinary calcium from 6.6 +/- 1.9 to 4.8 +/- 1.3 mmol/day, without changing alpha (0.613 +/- 0.081 to 0.584 +/- 0.070), serum calcium or 1,25-(OH)2D (154 +/- 48 to 154 +/- 38 pmol/l). Thus, estimated calcium balance (absorbed minus urinary calcium, increased marginally to +5.6 mmol/day on 1,25-(OH)2D alone (p = 0.028) and significantly to +6.8 mmol/day on 1,25-(OH)2D+TZ, from the control value of +4.0 mmol/day. Seven patients who were treated long-term with combined 1,25-(OH)2D and TZ for 11-29 months maintained their alpha (0.593 +/- 0.099) and a marginally more positive estimated calcium balance (+6.4 mmol/day, p = 0.025 from the control phase). Moreover, there was a stability of bone density of radial shaft, femoral neck, and lumbar spine.(ABSTRACT TRUNCATED AT 250 WORDS)

Calculation of titratable acidity from urinary stone risk factors.

Using urine samples and standard solutions, this study demonstrates that the existing procedure for measuring titratable acidity in the urine is not reliable and may result in overestimates of up to 25%. The accuracy is affected by loss of CO2, the presence of uric acid crystals, and the precipitation of calciumphosphate phases during the titration. A method is presented for calculating titratable acidity, using a number of routinely-measured urine components and a computer program for calculating complex equilibria in the urine. The calculated titratable acidity is shown to be more reliable then the measured one. The results are compiled in a nomogram from which the titratable acidity can be directly read. When the parameters of urine pH, PO4 content and pCO2 are used, the accuracy of the nomogram is > 96% for urine samples with a pH value above 6.0 and > 89% for urine samples with a pH value below 6.0. For all samples, the accuracy is improved to > 97% when the nomogram using uric acid and citrate content is used in additionally.

Calcium citrate without aluminum antacids does not cause aluminum retention in patients with functioning kidneys.

It has been suggested that calcium citrate might enhance aluminum absorption from food, posing a threat of aluminum toxicity even in patients with normal renal function. We therefore measured serum and urinary aluminum before and following calcium citrate therapy in patients with moderate renal failure and in normal subjects maintained on constant metabolic diets with known aluminum content (967-1034 mumol/day, or 26.1-27.9 mg/day, in patients and either 834 or 1579 mumol/day, or 22.5 and 42.6 mg/day, in normal subjects). Seven patients with moderate renal failure (endogenous creatinine clearance of 43 ml/min) took 50 mmol (2 g) calcium/day as effervescent calcium citrate with meals for 17 days. Eight normal women received 25 mmol (1 g) calcium/day as tricalcium dicitrate tablets with meals for 7 days. In patients with moderate renal failure, serum and urinary aluminum were normal before treatment at 489 +/- 293 SD nmol/l (13.2 +/- 7.9 micrograms/l) and 767 +/- 497 nmol/day (20.7 +/- 13.4 micrograms/day), respectively. They remained within normal limits and did not change significantly during calcium citrate treatment (400 +/- 148 nmol/l and 600 +/- 441 nmol/day, respectively). Similarly, no significant change in serum and urinary aluminum was detected in normal women during calcium citrate administration (271 +/- 59 vs 293 +/- 85 nmol/l and 515 +/- 138 vs 615 +/- 170 nmol/day, respectively). In addition, skeletal bone aluminum content did not change significantly in 14 osteoporotic patients (endogenous creatinine clearance of 68.5 ml/min) treated for 24 months with calcium citrate, 10 mmol calcium twice/day separately from meals (29.3 +/- 13.9 ng/mg ash bone to 27.9 +/0- 10.4, P = 0.727). In them, histomorphometric examination did not show any evidence of mineralization defect. Thus, calcium citrate given alone without aluminum-containing drugs does not pose a risk of aluminum toxicity in subjects with normal or functioning kidneys, when it is administered on an empty stomach at a recommended dose of 20 mmol calcium/day.