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.

Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials.

PURPOSE: To ascertain whether hypomagnesemia develops during short-term thiazide treatment in normal subjects and if it can be corrected by potassium-magnesium citrate (Relyte) supplementation. METHODS: Serum magnesium data were retrieved from 242 normal subjects from prior 4 trials. After 1-3 weeks of treatment with hydrochlorothiazide 50 mg/day, subjects received supplementation with Relyte or a related compound while continuing on thiazide for 3 weeks. RESULTS: Hypomagnesemia (< or =1.8 mg/dl) was disclosed in 19.4% of 242 subjects on thiazide alone. In such patients, Relyte treatment significantly increased serum magnesium concentration to the normal range, whereas supplementation with potassium citrate or potassium chloride did not. In the Relyte group comprised of 131 subjects, the frequency of hypomagnesemia decreased from 22.9% on thiazide alone to 4.6% after 4 weeks of Relyte supplementation. In contrast, the frequency of hypomagnesemia displayed a non-significant increase from 15.7% on thiazide alone to 20-24% on potassium citrate or potassium chloride. CONCLUSION: Mild hypomagnesemia develops in about one fifth of normal subjects during short-term thiazide treatment. Relyte can readily correct it.

Pharmacokinetics of calcium absorption from two commercial calcium supplements.

This study was conducted to compare pharmacokinetic indices of calcium absorption after a single oral (500 mg calcium) load of Citracal (calcium citrate) and Os-Cal (calcium carbonate). In 18 postmenopausal normal women, venous blood samples were obtained for the measurement of calcium before and hourly for 6 hours after an oral ingestion of Citracal, Os-Cal, or placebo with a breakfast meal. The change in area under the curve (delta AUC) in serum calcium from preload was 2.5-fold greater for Citracal than Os-Cal, and the peak-basal variation in serum calcium was 76% higher for Citracal than Os-Cal. The increment in serum calcium from preload after Citracal administration was significantly higher than that obtained after placebo load during most time periods and significantly higher than that of Os-Cal at 1, 4, and 5 hours after load. In contrast, delta AUC and peak basal variation of Os-Cal did not differ significantly from placebo and increment in serum calcium was significantly increased from placebo only at 6 hours. In conclusion, Citracal is much more bioavailable than Os-Cal.

Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magnesium loss.

The study was performed to ascertain the value of potassium magnesium citrate, magnesium citrate, and potassium citrate in overcoming thiazide-induced hypokalemia and magnesium loss. Sixty-two healthy subjects were first administered hydrochlorothiazide, 50 mg/d. After 3 weeks of thiazide treatment (or earlier for potassium level

The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.

This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.

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.

Effect of potassium-magnesium citrate on upper gastrointestinal mucosa.

BACKGROUND: Potassium supplements may cause mucosal damage of the gastrointestinal tract. AIM: To evaluate the effect of a new potassium supplement, potassium-magnesium citrate (K-Mag), on upper gastrointestinal mucosa and to compare it with an older potassium supplement, potassium citrate (Urocit-K). METHODS: A randomized and double-blind study was conducted utilizing 36 healthy adults. Subjects were randomized into three groups: K-Mag (70 mmol/day K, 35 mmol/day citrate and 17.6 mmol/day Mg); Urocit-K (70 mmol/day K and 23.4 mmol/day citrate), and placebo. All subjects took 5 tablets b.d. of the allocated drug and 2 mg t.d.s. of glycopyrrolate for 7 days. On day 8, stool was examined for occult blood, a symptom score was calculated and an oesophagogastroduodenoscopy was performed. Mucosal lesions were scored at five anatomic sites. RESULTS: Demographic characteristics and symptom score were similar in the three groups (< 10% with more than mild symptoms). There were no significant differences in the endoscopic scores at any site examined nor in the total scores among the three groups. Erosion or ulcers were found in 180% of K-Mag, 23% of Urocit-K and 17% of the placebo group. CONCLUSION: Short-term use of K-Mag does not appear to induce lesions in the upper gastrointestinal mucosa and its oral tolerance is similar to Urocit-K or placebo.

Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate.

The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

Physicochemical effects of a new slow-release potassium phosphate preparation (UroPhos-K) in absorptive hypercalciuria.

A new slow-release, neutral potassium phosphate salt (UroPhos-K) has been formulated in order to minimize gastrointestinal side effects and avoid sodium-induced calciuria. It was tested in a prospective randomized, double-blind trial in a group of 21 kidney stone patients with absorptive hypercalciuria type I (AH). Twelve patients allocated to the UroPhos-K group received four tablets twice daily with breakfast and an evening snack providing 1240 mg of phosphorus and 63.5 mEq of potassium daily. Nine patients assigned to the placebo group received placebo tablets of the same appearance containing excipient only. Subjects were studied during a 3-day period in the hospital while consuming a constant metabolic diet containing 400 mg Ca, 100 mEq Na, and 800 mg P per day before and after 3 months of treatment. Treatment with UroPhos-K did not cause any significant gastrointestinal side effects; nor did it raise fasting serum K or phosphorus, or reduce hemoglobin or creatinine clearance. It was associated with a rise in urinary K from 46 +/- 7 to 98 +/- 9 mEq per day and phosphorus from 744 +/- 185 to 1535 +/- 112 mg per day (p < 0.001 each). UroPhos-K treatment reduced urinary Ca from 288 +/- 63 to 171 +/- 49 mg/day (p < 0.001), without altering oxalate excretion. It reduced the urinary saturation of calcium oxalate without altering that of brushite. Moreover, by increasing urinary excretion of inhibitors (citrate and pyrophosphate), it reduced the propensity for spontaneous nucleation of brushite (increased formation product of brushite) and inhibited crystal agglomeration of calcium oxalate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of added citrate or malate on calcium absorption from calcium-fortified orange juice.

OBJECTIVE: Calcium absorption was determined from calcium-fortified diluted orange juice, which contained additional citrate or malate, in 16 normal subjects. METHODS: Each load of fortified orange juice with additional citrate (OJ+C) contained 300 mg Ca, 5.7 mEq malate, and 33.6 mEq citrate (10.4 mEq of which were added). Each load of orange juice with additional malate (OJ+M) had 300 mg Ca, 23.2 mEq citrate and 16.1 mEq malate (10.4 mEq of which were added). For each subject, fractional (intestinal) calcium absorption was measured by taking the ratio of fractional forearm radioactivity following an oral administration of OJ+C or OJ+M (labeled with 47Ca) and the fractional forearm radioactivity obtained after intravenous administration of trace 47Ca chloride on a separate occasion. RESULTS: There was no significant difference in fractional calcium absorption from the two calcium-fortified orange juice preparations (40.1 +/- 8.3% for OJ+C and 40.6 +/- 8.6% for OJ+M, p = 0.81). CONCLUSION: Calcium-fortified orange juice with additional citrate provides equivalent bioavailable calcium as the juice with additional malate.

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.

Citrate and renal calculi: an update.

Citrate is an inhibitor of the crystallization of stone-forming calcium salts. Hypocitraturia, frequently encountered in patients with nephrolithiasis, is therefore an important risk factor for stone formation. Potassium citrate provides physiological and physicochemical correction and inhibits new stone formation, not only in hypocitraturic calcium nephrolithiasis but also in uric acid nephrolithiasis. Inhibition of stone recurrence has now been validated by a randomized trial. Ongoing research has disclosed additional causes of hypocitraturia (sodium excess, low intestinal alkali absorption, but not primary citrate malabsorption). Moreover, new insights on potassium citrate action have been shown, notably that some of absorbed citrate escapes oxidation and contributes to the citraturic response, that ingestion with a meal does not sacrifice physiological or physicochemical action, that orange juice mimics but does not completely duplicate its actions, that potassium citrate may have a beneficial bone-sparing effect, that it may reduce stone fragments following ESWL, and that danger of aluminum toxicity is not great in subjects with functioning kidneys. Finally, the research on potassium citrate has led to two promising products, calcium citrate as an optimum calcium supplement and potassium-magnesium citrate which may be superior to potassium citrate in the management of stone disease.

Assessment by reflection ultrasound method of the effect of intermittent slow-release sodium fluoride-calcium citrate therapy on material strength of bone.

It has been suggested that fluoride therapy, while increasing bone mass, produces bone with inferior mechanical properties. In the present report this hypothesis was tested using a novel reflection ultrasound technique. Transiliac crest bone biopsies were obtained from 16 patients with osteoporosis and vertebral compression fractures (12 women and 4 men, mean age 56 years) before and after approximately 2 years of intermittent slow-release sodium fluoride therapy (25 mg twice a day) combined with continuous calcium citrate supplementation. Samples were analyzed by a reflection ultrasound method, which analyzes ultrasound velocity with a sample site resolution of 200 microns and thus provides a measure of the mechanical property of single trabeculae (material). For the group, mean fractional change in velocity increased 6.1 +/- 2.3% (SEM) from a mean value of 3303 +/- 80 to 3484 +/- 55 m/s (p = 0.028). A total of 13 patients (81%) demonstrated higher velocities after treatment. Thus reflection ultrasound analysis of bone appears to provide a sensitive means of assessing changes in the material property of bone. Furthermore, these results suggest that the treatment regimen utilized in these patients improves strength of bone at the material or trabecular level largely independently of change in bone mass. The combination therapy also increased spinal (L2-L4) bone density for the group as assessed by dual-photon absorptiometry (5.3 +/- 2.0%). There was no significant correlation between the change in ultrasound velocity and bone density (r = 0.0026, p = 0.996).(ABSTRACT TRUNCATED AT 250 WORDS)

Seasonal variations in urinary risk factors among patients with nephrolithiasis.

Twenty-four hour urine specimens from 5,677 stone-forming patients throughout the United States were analyzed for seasonal variations in urinary risk factors for nephrolithiasis. Determinations were performed for urine volume, pH, calcium, oxalate, phosphorus, sodium, magnesium, citrate, sulfate, uric acid, and the relative supersaturation (RS) of calcium oxalate, brushite, monosodium urate, and uric acid. Criteria for significant seasonal variation included a significant difference in monthly means of risk factors, seasonal grouping of the data by the Student-Newman-Keuls multiple range test, consistent year-to-year trends and a physiologically significant range. Minimum urine volume of 1.54 +/- 0.70 SD L/day occurred in October while a maximum urine volume of 1.76 +/- 0.78 SD L/day was observed during February. Minimum urine pH of 5.94 +/- 0.64 SD was observed during July and August while a maximum pH of 6.18 +/- 0.61 SD was observed during February. Daily urinary excretion of sodium was lowest during August, 158 +/- 74 SD mEq/day and highest during February 177 +/- 70 SD mEq/day. The RS of brushite and uric acid were found to display significant pH-dependent seasonal variation with a maximum RS of uric acid 2.26 +/- 1.98 SD in June and a low of 1.48 +/- 1.30 SD in February. Maximum RS of brushite 2.75 +/- 2.58 was observed during February. Minimum RS of brushite 1.93 +/- 1.70 SD was observed in June. Phosphorus excretion displayed seasonal variation about a spring-fall axis with a maximum value 1042 +/- 373 SD mg/day in April and a minimum value of 895 +/- 289 SD mg/day. Urine volume, sodium, and pH were significantly lower during the summer (June, July, August) than in the winter (December, January, February). The RS of uric acid was higher, but that of brushite and monosodium urate was lower in the summer than in the winter. The seasonal changes observed in urine volume, pH, sodium, and the RS of brushite and uric acid are consistent with summertime sweating and increased physical activity. Seasonal variations in phosphorus excretion are probably dietary in origin. The summertime was characterized by an increased propensity for the crystallization of uric acid but not of calcium oxalate or calcium phosphate.

A further study of oxalate bioavailability in foods.

We extended the study of oxalate bioavailability by testing 7 additional food items: brewed tea, tea with milk, turnip greens, okra, peanuts and almonds. Nine normal subjects ingested a large serving of each of these items. The bioavailable oxalate was calculated from the increment in urinary oxalate during 8 hours after ingestion and bioavailability was determined as the percentage of total oxalate content in a given food item represented by bioavailable oxalate. Brewed tea and tea with milk, with a high oxalate content, had a low bioavailable oxalate level (1.17 and 0.44 mg. per load) because of the low oxalate availability (bioavailability of 0.08 and 0.03%). Turnip greens, with a satisfactory oxalate bioavailability (5.8%), had a negligible effect on urinary oxalate excretion, since oxalate content was relatively low (12 mg. per load). Okra, with a moderate oxalate content (264 mg. per load) had a negligible bioavailable oxalate (0.28 mg. per load). Only peanuts and almonds provided a moderate increase in oxalate excretion (3 to 5 mg. per load) due to the modest oxalate content (116 and 131 mg. per load) and oxalate bioavailability (3.8 and 2.8%). Thus, the ability of various oxalate-rich foods to augment urinary oxalate excretion depends not only on oxalate content but on the bioavailability.

Similarity of urinary risk factors among stone-forming patients in five regions of the United States.

STUDY OBJECTIVE: To compare urinary biochemical risk factors among stone-forming patients in the Southeast (SE) or "stone belt" versus four other regions of the United States. DESIGN: Prospective biochemical survey for regional comparisons. SETTING: Referral-based nephrolithiasis clinics, urologists, nephrologists, and family practitioners. PATIENTS: Consecutive sample of 3473 stone-forming patients who submitted 24-hour urine collections for biochemical analyses of stone-forming risk factors. INTERVENTIONS: None. Subjects taking medication known to interfere with stone-forming risk factors were deleted from the final data compilation. MEASUREMENTS AND MAIN RESULTS: Overall, the mean values for each urinary parameter spanned a narrow range without significant difference between the five regions. Among "metabolic" factors, 40% in the SE had hypercalciuria (> 6.25 mmol/d), compared to 35%-43% in other regions, and hyperuricosuria (> 4.2 mmol/d) was found in 16% in the SE versus 17%-19% elsewhere. Among "environmental" factors, low urine volume ( < 2 L/d) was found in 77% patients in the SE compared to 69%-78% elsewhere, and high sodium was encountered in 27% in the SE versus 24%-29% elsewhere. No differences were noted in occurrence of other abnormal risk factors: hyperoxaluria, hypocitraturia, low pH, high sulfate, high phosphorus, or low magnesium. CONCLUSIONS: Despite expected regional differences in nutritional and environmental influences, the results of this study showed a striking similarity in urinary biochemical risk factor profiles of stone-formers in all five regions of the United States.

Effect of intermittent therapy with a slow-release fluoride preparation.

Long-term clinical effects of intermittent sodium fluoride (slow-release) therapy were assessed in 71 patients with primary osteoporosis. In Group I (receiving 1,25-(OH)2D3 2 micrograms/day for 2 weeks before 3 months of sodium fluoride treatment 25 mg twice a day, in each 5-month cycle), vertebral (L2-L4) bone mineral content did not change significantly. However, the L2-L4 bone mineral content significantly increased by 3.1% in Group II (those who did not receive 1,25-(OH)2D3 during 5-month cycle), 3.5% per patient year in Group III (combined NaF 25 mg twice a day with 1,25-(OH)2D3 0.5 micrograms/day for 12 months in each 13-month cycle), and by 7.8% per patient year in Group IV (combined NaF with calcium citrate for 12 months in each 13-month cycle). The rise in vertebral bone mineral content was sustained, with an annual increment of 4.2% during the third year compared with 4.4% during the first year. The vertebral fracture rate declined significantly from the pretreatment value in all groups, but comparison with a placebo control group was not available. There was no significant change in the bone density of the radial shaft or of the proximal femur. The rate of hip fracture (nontraumatic) during treatment was 1.8% per patient year, the same as before treatment. The drug was well tolerated with only minor infrequent gastrointestinal and rheumatic side effects. Thus, intermittent slow-release sodium fluoride treatment with adequate calcium supplementation augments spinal bone mass and apparently inhibits vertebral fractures, with a satisfactory safety of usage; however, it has no effect on appendicular bone mass or on hip fracture rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone mass and inhibition of fractures.

The value of intermittent slow release sodium fluoride treatment in the management of osteoporosis was studied by a comprehensive metabolic and clinical assessment during a long term trial. Its effect was compared with that of a large dose of 1,25-dihydroxyvitamin D [1,25-(OH)2D] given for a short period preceding each fluoride treatment period in another group of randomly selected patients. The 24 patients in group I (3 idiopathic and 21 postmenopausal) received cyclic treatment in repeated 5-month cycles; each cycle was initiated by 1,25-(OH)2D (2 micrograms/day) for 2 weeks, followed for 3 months by sodium fluoride (slow release, 25 mg twice daily) with 25-hydroxyvitamin D (50 micrograms twice weekly) and calcium supplements (to bring total calcium intake to 1500 mg/day), and was concluded by 6 weeks of 25-hydroxyvitamin D and calcium supplementation without sodium fluoride. The 21 patients in group II (3 idiopathic and 18 postmenopausal) received the same treatment, except for the omission of 1,25-(OH)2D. In both groups, the serum fluoride level was maintained within 5-10 mumol/L (95-190 ng/mL) during fluoride treatment, and serum osteocalcin concentrations correlated positively with the duration of treatment. However, vertebral bone mineral content (L2-L4) did not increase significantly in group I, whereas it rose significantly in group II (fractional change, +0.031/2.4 yr in group I vs. + 0.118/2.9 yr in group II; P less than 0.005). Although bone histomorphometric analyses disclosed overall improvement in both groups, only group II had significant increases in the mineral apposition rate [0.5 +/- 0.2 (+/- SE) to 1.4 +/- 0.2 micron/day; P less than 0.05] and the adjusted apposition rate (0.2 +/- 0.1 to 0.7 +/- 0.1 micron/day; P = 0.04). The vertebral fracture rate significantly declined in both groups, but more so in group II. Excluding the first year of treatment, the fracture rate during treatment in group II of 0.03/patient yr was significantly lower than that of 0.28/patient yr in group I (P less than 0.05). The treatment was well tolerated in both groups; only 16% of patients had either gastrointestinal or rheumatic complications. We conclude that intermittent sodium fluoride treatment without 1,25-(OH)2D provides safe and effective treatment of osteoporosis, marked by formation of new adequately mineralized bone, a rise in vertebral bone mass, and reduced frequency of vertebral fractures. The addition of 1,25-(OH)2D treatment before initiation of each fluoride phase yielded a less favorable response.