The effects of smoking on bone metabolism.

Osteoporosis is a common, morbid and costly disorder characterized by deterioration in bone strength. Cigarette smoking is associated with reduced bone mineral density (BMD) and increased fracture risk. There are basic, clinical, and observational studies that define several of the underlying pathophysiologic mechanisms that predispose smokers to bone loss. Such mechanisms include alterations in calciotropic hormone metabolism and intestinal calcium absorption, dysregulation in sex hormone production and metabolism, alterations in adrenal cortical hormone metabolism and in the receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) system (RANK-RANKL-OPG system), and direct cellular effects of cigarette use on bone cells. In addition, there is evidence of reversibility in the aforementioned mechanisms with smoking cessation. In summary, cigarette smoking is a reversible risk factor for osteoporosis and osteoporotic fractures through diverse pathophysiologic mechanisms.

Comparison of the absorption of calcium carbonate and calcium citrate after Roux-en-Y gastric bypass.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) restricts food intake. Consequently, patients consume less calcium. In addition, food no longer passes through the duodenum, the main site of calcium absorption. Therefore, calcium absorption is significantly impaired. The goal of this study is to compare two common calcium supplements in gastric bypass patients. METHOD: Nineteen patients were enrolled in a randomized, double-blinded, crossover study comparing the absorption of calcium from calcium carbonate and calcium citrate salts. Serum and urine calcium levels were assessed for peak values (C (max)) and cumulative calcium increment (area under the curve [AUC]). Serum PTH was assessed for minimum values (PTH(min)) and cumulative PTH decrement (AUC). Statistical analysis was performed using a repeated analysis of variance model. RESULTS: Eighteen subjects completed the study. Calcium citrate resulted in a significantly higher serum C (max) (9.4 + 0.4 mg/dl vs. 9.2 + 0.3 mg/dl, p = 0.02) and serum AUC (55 + 2 mg/dl vs. 54 + 2 mg/dl, p = 0.02). Calcium citrate resulted in a significantly lower PTH(min) (24 + 11 pg/ml vs. 30 + 13 pg/ml, p = 0.01) and a higher AUC (-32 + 51 pg/ml vs. -3 + 56 pg/ml, p = 0.04). There was a non-significant trend for higher urinary AUC in the calcium citrate group (76.13 + 36.39 mg/6 h vs. 66.04 + 40.82, p = 0.17). CONCLUSION: Calcium citrate has superior bioavailability than calcium carbonate in RYGB patients.

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.

Is there an optimal parathyroid hormone level in end-stage renal failure: the lower the better?

Skeletal resistance to parathyroid hormone is well defined in patients with chronic renal failure. In recent years, with the increased frequency of development of adynamic bone disease, it has been recognized that secondary hyperparathyroidism must exist as a 'trade off' mechanism to maintain skeletal bone remodeling in this patient population. An optimal level of intact parathyroid hormone to maintain the normal skeletal bone turnover is believed to be between 2.0 and 2.5 times the upper limit of normal parathyroid hormone. It has very recently been argued that the optimal parathyroid hormone level for maintenance of skeletal bone remodeling may be insufficient to prevent the extraskeletal complications of coronary artery calcifications, calcific valvular heart disease, and cardiac death. To provide optimal health care for these patients several new treatments have been developed, including use of new vitamin D analogs, calcimimetic agents, and noncalcium-based phosphorus binders. It is anticipated that with lower suppression of parathyroid hormone by these vitamin D analogs, intermittent suppression of parathyroid hormone with calcimimetic agents, and the use of noncalcium phosphorus binders (Renageltrade) by regulating serum calcium, the resultant phosphorus concentrations will provide an optimal parathyroid hormone activity to maintain skeletal bone remodeling, while preventing extraskeletal complications.

A comparison of fluoride bioavailability from a sustained-release NaF preparation (Neosten) and other fluoride preparations.

Twelve normal subjects completed a crossover study with sustained-release sodium fluoride (Neosten, 11.3 mg F), monofluorophosphate (MFP, 10 mg F), and plain sodium fluoride (P-NaF, 11.3 mg F). After each preparation was given with 400 mg calcium, serum fluoride (Fser) was measured for 24 hours, and pharmacokinetic data were calculated. Fluoride absorption in the Neosten group, as measured by change in the area under the curve (delta AUC) of Fser, was less than 33% of that in the MFP and P-NaF treated groups. Both peak Fser (Cmax) and peak-basal variation in the Neosten group were 25% that found in the other groups. t1/2 was nearly twofold greater after Neosten. MFP and P-NaF showed greater bioavailability than Neosten and much higher Cmax that exceeded the toxic threshold of Fser (190 ng/ml). These findings could explain the ineffectiveness of MFP and P-NaF observed in recent clinical trials.

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.

Meta-analysis of calcium bioavailability: a comparison of calcium citrate with calcium carbonate.

OBJECTIVE: To perform a meta-analysis of data from available published trials comparing the bioavailability of calcium carbonate with that of calcium citrate. DATA SOURCES: The whole set was comprised of 15 studies involving 184 subjects who underwent measurement of calcium absorption from calcium carbonate and calcium citrate. Category A excluded four studies for lack of physiological relevance, use of a mixed preparation with low content of calcium carbonate, or wide variability in results. Category B was comprised of five studies (from Category A) involving 71 subjects who took calcium supplements on an empty stomach. Category C was comprised of six studies (from Category A) involving 65 subjects who took calcium preparations with meals. METHOD: The meta-analysis of calcium absorption data from calcium carbonate and calcium citrate, with calculation of effect size and 95% confidence intervals. RESULTS: Calcium absorption from calcium citrate was consistently significantly higher than that from calcium carbonate by 20.0% in the whole set, by 24.0% in Category A, by 27.2% on an empty stomach, and by 21.6% with meals. CONCLUSION: Calcium citrate is better absorbed than calcium carbonate by approximately 22% to 27%, either on an empty stomach or co-administered with meals.

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.

Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia.

BACKGROUND: Angiotensin II stimulates the proximal tubular Na/H antiporter and increases proximal tubular cell pH. Because intracellular pH may affect urinary citrate excretion and enzymes responsible for renal citrate metabolism, the present studies examined the effect of enalapril, an angiotensin converting enzyme inhibitor, on the activity of renal cortical ATP citrate lyase and urinary citrate excretion. METHODS: Enalapril was given to rats (15 mg/kg/day) for seven days and to humans (10 mg twice daily) for 10 days. Blood and 24-hour urine samples were obtained in both groups. Renal cortical tissue from rats was analyzed for enzyme activity. RESULTS: In rats, enalapril decreased urinary citrate excretion by 88%. The change in urinary citrate was not associated with a difference in plasma pH, bicarbonate nor potassium concentration. However, similar to metabolic acidosis and hypokalemia, enalapril caused a 42% increase in renal cortical ATP citrate lyase activity. When given to humans, enalapril significantly decreased urinary citrate excretion and urine citrate concentration by 12% and 16%, respectively, without affecting plasma pH or electrolytes. CONCLUSIONS: Enalapril decreases urinary citrate in rats and humans. This is due, at least in part, to increases in cytosolic citrate metabolism through ATP citrate lyase in rats similar to that seen with chronic metabolic acidosis and hypokalemia. The effects of enalapril on urinary citrate and renal cortical ATP citrate lyase occur independently of acidosis or hypokalemia but may be due to intracellular acidosis that is common to all three conditions.

Mutations in the genomic deoxyribonucleic acid for SLC3A1 in patients with cystinuria.

Cystinuria is an inherited transport disorder characterized by defective renal resorption of cystine and other dibasic amino acids. We have studied the occurrence of mutations in the SLC3A1 gene, which codes for a dibasic amino acid transporter-like protein, in 33 unrelated cystinurics. We found mutations in 34 of the 66 chromosomes studied. There were 14 different mutations in our study population, 8 of which had not been previously described. Of these new mutations, 4 were missense mutations: G1934C, C1259G, T1607G, and G1373A. The other 4 mutations consisted of a single base insertion mutation (2022 ins T), a single base deletion mutation (163 del C), a 23-base deletion mutation (del 782A-804A), and a complex mutation that consisted of a 36-base deletion (del C431-3 to T463) and a duplication insertion of 468 T to 474 A after nucleotide 474.

Dietary sulfate regulates the expression of the renal brush border Na/Si cotransporter NaSi-1.

Dietary inorganic sulfate (Si) intake is an important factor in the regulation of renal proximal tubular sodium-dependent Si transport (Na/Si cotransport). The purpose of the present study was to determine whether modulation of Na/Si cotransport activity by dietary Si is mediated through regulation of the renal expression of the recently cloned NaSi-1 protein located in the apical brush border membrane (BBM) of the proximal tubule. It was found that rats fed a high Si diet had a marked increase in the renal excretion of Si and a concomitant decrease in BBM Na/Si cotransport activity when compared with rats on a control Si diet. The 43% decrease in BBM Na/Si cotransport activity was associated with a 33% decrease in BBM NaSi-1 protein abundance, as determined by Western blotting, and a 2.7-fold decrease in cortical NaSi-1 mRNA abundance, as determined by Northern blotting. Furthermore, cortical mRNA from rats fed a high Si diet when injected into Xenopus laevis oocytes led to a 2.2-fold decrease in Na/Si cotransport activity compared with mRNA isolated from control Si diet rats. This study indicates that adaptation to a high Si diet is accompanied by a decrease in renal cortical NaSi-1 mRNA abundance, which results in reduced expression of the NaSi-1 protein at the level of the proximal tubular BBM.

Primary hyperparathyroidism and ALS: is there a relation?

BACKGROUND: An association between primary hyperparathyroidism (PHP) and amyotrophic lateral sclerosis (ALS) has been noted; however, a causal relation between these disorders has not been confirmed. PATIENTS/METHODS: We report five patients (three men, two women) meeting El Escorial criteria for ALS who also had PHP. In three patients, the diagnosis of PHP was made during the laboratory evaluation for motor neuron disease, and in one patient, the diagnosis of PHP preceded the onset of weakness by 5 months and in another by 2 years. Serum calcium levels in all five patients were elevated, ranging from 11.2 to 12.8 mg/dL (normal, <10.4 mg/dL), as were levels of parathyroid hormone (PTH). RESULTS: All five patients underwent parathyroid adenoma resection with subsequent normalization of serum calcium and PTH levels. Each patient had progressive weakness resulting in death 1 to 3 years following parathyroidectomy. CONCLUSION: Resection of parathyroid adenomas in patients meeting El Escorial criteria for ALS did not alter the course of ALS. PHP and ALS appear to be coexisting but unrelated disorders.

The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity.

Chronic metabolic acidosis is a process whereby an excess nonvolatile acid load is chronically placed on the body due to excess acid generation or diminished acid removal by normal homeostatic mechanisms. Two common, often-overlooked clinical conditions associated with chronic metabolic acidosis are aging and excessive meat ingestion. Because the body's homeostatic response to these pathologic processes is very efficient, the serum HCO3- and blood pH are frequently maintained within the "normal" range. Nevertheless, these homeostatic responses engender pathologic consequences, such as nephrolithiasis, bone demineralization, muscle protein breakdown, and renal growth. Based on this, the concept of eubicarbonatemic metabolic acidosis is introduced. Even in patients with a normal serum HCO3- and blood pH, it is important to treat the acid load and prevent pathologic homeostatic responses. These homeostatic responses, as well as the mechanisms responsible for their initiation, are reviewed.