Comparison of calcium carbonate and aluminium hydroxide as phosphate binders on biochemical bone markers, PTH(1-84), and bone mineral content in dialysis patients.

Bone mineral content, estimated by single-photon absorptiometry of the forearm, serum values of intact parathyroid hormone (PTH(1-84], osteocalcin, alkaline phosphatase, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), and aluminium were determined during treatment with calcium carbonate (CaCO3) or aluminium hydroxide (Al(OH)3) in 11 dialysis patients participating in a randomised cross-over study. Each treatment period lasted 6 months. Serum phosphorus was maintained in the range 1.5-2.0 mmol/l. During Al(OH)3 treatment bone mineral content (BMC) decreased by 11% per half-year (mean), but only by 3% per half-year during CaCO3 treatment (P less than 0.05). Comparing the CaCO3 and Al(OH)3 periods the following differences were found: serum calcium increased during CaCO3 treatment, PTH(1-84) decreased (79% of initial values during CaCO3 versus 196% during Al(OH)3, mean area under curve, P less than 0.05), osteocalcin decreased (89% versus 117%, P less than 0.01), alkaline phosphatase decreased (92% versus 116%, P less than 0.05), and aluminium decreased (56% versus 189%, P less than 0.05). 1,25(OH)2D3 remained unchanged in both periods. No increase in soft-tissue calcification was demonstrated on X-ray of the shoulders in any of the periods. Thus, CaCO3 treatment seems to slow down loss of bone mineral content, and using CaCO3 as phosphate binder may have a more beneficial effect on the progression of uraemic bone disease than Al(OH)3 due to the reduction of hyperparathyroidism and bone turnover.     

Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis

BACKGROUND: Bone mineral density (BMD) is reduced among patients with idiopathic hypercalciuria (IH) and nephrolithiasis. To disentangle effects of diet, stone formation, and physiology upon BMD, we studied vertebral and femoral neck BMD among relatives of hypercalciuric stone formers, and contrasted those with to those without stones. METHODS: Among 59 subjects from 11 families, vertebral and femoral neck BMD, diet calcium intake, urine excretions of calcium, sodium, ammonium, titratable acid, sulfate, urea nitrogen, and serum levels of calcitriol and markers of bone turnover were studied. RESULTS: Stone formers (SF) consumed less calcium than non-stone formers (NSF). Spine and femoral neck BMD z-scores varied inversely with urine calcium loss and urine ammonium excretion among SF but not NSF. No correlations of BMD z-score were found for bone markers, calcitriol, or any of the other measurements. CONCLUSION: SF consumed less calcium, presumably to prevent more stones, and displayed a bone mineral responsiveness to calcium loss and ammonium excretion not present among NSF, who ate more calcium. Lowered calcium consumption in IH, perhaps in response to stone formation, alters bone responses in a direction that can predispose to mineral loss and eventual fracture.     

Serum osteocalcin and bone mineral metabolism following successful renal transplantation

Serum osteocalcin (bone gla protein, BGP), a vitamin K-dependent non-collagenous bone protein and its relationship to other markers of bone and mineral metabolism were studied cross-sectionally in varying numbers of patients before and over 240 days following renal transplantation. Marked elevation of serum creatinine (11.9 +/- 0.76 mg/dl), osteocalcin (216.9 +/- 7 ng/ml), parathyroid hormone (PTH, mid-molecule fragment) (24.5 +/- 3.6 ng/ml), alkaline phosphatase (255.2 +/- 54.7 IU/l) and phosphorus (5.6 +/- 0.3 mg/dl) were noted preoperatively. Serum calcium levels remained normal throughout the study period while phosphate levels normalized within one week after transplantation. PTH levels progressively decreased postoperatively over the study period but were still elevated well above normal. Serum osteocalcin decreased to near normal values at 60-90 days after surgery. Both PTH and alkaline phosphatase correlated significantly with osteocalcin preoperatively and postoperatively. The relatively depressed values of osteocalcin in the face of still elevated PTH levels post-transplantation was attributed to the effect of immunosuppressive corticosteroid therapy. The significant correlation between PTH and osteocalcin suggests that osteocalcin may be as or more sensitive a measurement of bone turnover than alkaline phosphatase pre- and post-transplantation.     

Biochemical Indicators of Bone Metabolic Activity in Buffalo (Bubalus bubalis) During Late Pregnancy and Early Lactation*

Blood levels of calcium, inorganic phosphorus, magnesium, osteocalcin, intact parathyroid hormone, calcitonin, alkaline phosphatase activity, creatinine and thyroid hormones were estimated in 10 healthy buffalo during late pregnancy (30, 15 days and 7 days before calving), within 12 h after calving and 7–15–30–45 and 60 days after calving. The almost constant serum levels of calcium, phosphorus, intact parathyroid hormone, and the low calcitonin concentration indicate that these buffalo need to utilize only a little of their endogenous mineral resources. Bone‐turnover could be demonstrated by variations in the serum levels of osteocalcin and alkaline phosphatase activity. A study of these bone markers could be useful for other research purposes and for future clinical application in pathological conditions.     

The Relation Between Bone and Stone Formation

Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total-body calcium. The source of this additional urinary calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD), which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone, we utilized our genetic hypercalciuric stone-forming (GHS) rats, which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls, and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption, and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and that their bones are more fracture-prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve the bone health of patients with kidney stones.     

Biochemical variables associated with bone density in patients with primary hyperparathyroidism.

OBJECTIVE--To clarify the association between primary hyperparathyroidism and cortical osteopenia. DESIGN--Open study. SETTING--Department of Surgery, University of Lund, Sweden. SUBJECTS--38 patients with primary hyperparathyroidism. OUTCOME MEASURES--Correlation between bone density (measured by single photon absorption) and age; sex; serum concentrations of parathyroid hormone and ionised calcium; serum alkaline phosphatase activity; and serum concentration of calcium, phosphate, creatinine, urea, osteocalcin, 25 hydroxycholecalciferol, and 1,25 dihydroxycholecalciferol. RESULTS--There was no difference in bone density between men and women. There was no correlation between bone density and severity of hypercalcaemia or age. No biochemical abnormality was peculiar to the seven patients whose bone density was more than two SD below the population mean. Serum concentrations of 1,25 dihydroxycholecalciferol and osteocalcin both correlated significantly with bone density (p < 0.05) and there was a strong correlation between serum osteocalcin and serum intact parathyroid hormone (p < 0.001). Serum osteocalcin had the strongest correlation with bone density of any of the biochemical variables. CONCLUSION--There is little association between bone density and serum concentration of parathyroid hormone.     

Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers. The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 27 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml. The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K2 therapy, there was a significant increase of alkaline phosphatase after vitamin K2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study. These changes of bone metabolism markers suggested that vitamin K2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels.     

Late Calcium Metabolic Consequences of Jejuno-ileal Bypass

Seventeen patients with previous jejuno-ileal bypass operation (JIB) for obesity were included in a follow-up study 11 to 19 years after JIB. Evaluation of calcium-parathyroid hormone axis was performed by a highly sensitive two-site IRMA assay for serum intact parathyroid hormone and serum ionized calcium. Evidence of a varying degree of secondary hyperparathyroidism was found. The observed hyperparathyroidism was of clinical significance in a subpopulation characterized by increased bone turnover and reduced bone mineral content. As a consequence, the calcium metabolism with special attention to the parathyroid function must be carefully monitored in JIB patients. Serum ionized calcium alone and vitamin D metabolites do not identify patients at risk of bone loss.     

Evaluation of serum osteocalcin in patients with urolithiasis

Serum osteocalcin, also called bone gla protein, is one of sensitive and specific markers for metabolic bone diseases. Current evidence suggests that the protein may be involved in the regulation of calcium homeostasis in bone. We measured serum osteocalsin levels by radioimmunoassay in 100 patients with urolothiasis, especially in calcium containing stone formers and evaluated the influence of bone metabolism on the formation of calcium-containing stones. Although serum osteocalcin levels in most patients were normal, those of two male and four female patients were high. We considered that they were patients with renal hypercalciuria and secondary hyperparathyroidism and in them the formation of calcium containing stones were influenced by disorder of bone metabolism. In addition, we suggest that serum osteocalcin levels may be available index for the effect of treatment in stone formers with renal hypercalciuria and bone disease.     

原发性甲状旁腺机能亢进症手术治疗后骨量和骨代谢指标的变化

目的 了解甲状旁腺切除术对原发性甲状旁腺机能亢进症病人的骨矿密度及骨代谢指标变化的影响。方法 ４０例病人,其中３０例未治疗组（男：女＝３：２７）;１０例已手术治疗组（男：女＝３：７）,手术后时间１～２４月（平均５．３±７．９月）。用ＤＥＸＡ测量腰椎及股骨颈的骨矿密度,同时,测定血清中的甲状旁腺素（ＰＴＨ）,骨钙素（ＯＣ）,及骨唾液酸蛋白（ＢＳＰ）。结果 在已手术组病人其腰椎及股骨颈骨矿密度再没有明     

Polymorphism of vitamin D receptor gene start codon in patients with calcium kidney stones

BACKGROUND: A linkage has been detected between vitamin D receptor (VDR) locus and calcium kidney stone disease. In order to assess the eventual role of VDR gene start codon polymorphisms in stone production, we analyzed the genotype-phenotype association in a group of patients with calcium kidney stones. METHODS: One hundred and fifty-five patients were studied. VDR genotypes were characterized at the translation start site by restriction fragment length polymorphism analysis, using endonuclease FokI. Phenotypes of calcium-phosphate metabolism were compared in patients with different genotypes: strontium enteral absorption (used as a surrogate marker for calcium absorption), bone mineral density (BMD), calcium and phosphate excretion were measured. RESULTS: Genotype distribution was not different in hypercalciuric and normocalciuric stone formers. Enteral strontium absorption, calcium excretion and BMD did not vary with the patient's genotype. Serum concentrations of phosphate (p=0.022) and renal threshold for phosphate excretion (p=0.026) were lower in patients with genotype FF (homozygous for the absence of the FokI site) than in those with genotype ff (homozygous for the presence of the FokI site). The lower phosphatemia was confirmed in FF hypercalciuric patients, but not in normocalciuric ones. Serum concentrations of phosphate and calcitriol in the group of hypercalciuric patients were inversely correlated with the genotype FF. CONCLUSIONS: The FokI genotype does not appear to be involved in the causes of idiopathic hypercalciuria and kidney stones. Hypercalciuric patients with FF genotype may be a subgroup with low plasma concentrations of phosphate, predisposed to tubular leakage of phosphate.     

Clinical studies on recurrence of urolithiasis. (2) Hypercalciuria and recurrence of urolithiasis

According to the dynamics of the urinary calcium excretion mechanism, we have classified the patients with urolithiasis into 4 groups, namely group I (normocalciuria; urinary calcium excretion of 270 mg/day or less for male patients and 210 mg/day or less for female patients), group II (absorptive hypercalciuria; hypercalciuric with urinary calcium excretion of 200 mg/day or less under the low calcium diet), group III (renal hypercalciuria; hypercalciuric with urinary calcium excretion exceeds 200 mg/day even under a low calcium diet), and group IV (hyperparathyroidism; hypercalciuric patients as in group III with high serum calcium). Of the 97 stone formers, 77 were classified into group I, 9 into group II, 8 into group III and 3 into group IV. Both under the restricted diet and under the ambulatory free diet, urinary calcium excretion of groups II, III and IV was significantly higher than that of the group I patients. It was noteworthy, however, that some of the patients in group I excreted much calcium without restriction of their diet. Although no difference in excretion of oxalate, magnesium and phosphate was observed between the 4 groups, the patients in groups II, and III excreted more uric acid into their urine than group I patients. As for stone recurrence rate, no difference was noted between group I and group II, III or IV. Based on these findings, we conclude that hypercalciuria has no significant role in the stone forming mechanism. However, lowering of urinary calcium and other stone forming constituents is mandatory in preventing stone recurrence until the mechanism of stone formation is elucidated more precisely.     

Ovarian hormone status,life-style factors,and markers of bone metabolism in women aged 50 years

Fifty-year-old women (n=519) attending a health examination were divided by their ovarian hormone status into four groups: premenopausal, perimenopausal, postmenopausal without ovarian hormone replacement therapy (HRT), and postmenopausal with HRT. Information on lifestyle factors was obtained with interviews and questionnaires. Bone mineral density at the calcaneus was assessed with single-photon absorptiometry, and several serum and urine markers of bone metabolism were measured. Postmenopausal women without HRT had significantly higher levels of fasting serum alkaline phosphatase, osteocalcin, total and ionized calcium, phosphate, and fasting urinary hydroxyproline than those in the three other study groups. No difference was found in bone mineral density between the premenopausal and postmenopausal groups. Postmenopausal women without HRT showed a marked correlation between serum osteocalcin and urine hydroxyproline. Both markers showed significant correlations with serum calcium, phosphate, and alkaline phosphatase. Multivariate analyses showed a statistically significant association of ovarian hormone status and body mass index with most measured markers of bone metabolism. The association between alcohol consumption and serum osteocalcin was highly significant. Cigarette smoking was associated with levels of serum alkaline phosphatase and total and ionized calcium. A weak association was found between coffee drinking and serum alkaline phosphatase.     

Genetic hypercalciuric stone-forming rats

PURPOSE OF REVIEW: We will describe the pathophysiology of hypercalciuria and the mechanism of the resultant stone formation in a rat model and draw parallels to human hypercalciuria and stone formation. RECENT FINDINGS: Through inbreeding we have established a strain of rats that excrete 8-10 times more urinary calcium than control rats. These genetic hypercalciuric rats absorb more dietary calcium at lower 1,25-dihydroxyvitamin D3 levels. Elevated urinary calcium excretion on a low-calcium diet indicated a defect in renal calcium reabsorption and/or an increase in bone resorption. Bone from hypercalciuric rats released more calcium when exposed to 1,25-dihydroxyvitamin D3. Bisphosphonate significantly reduced urinary calcium excretion in rats fed a low-calcium diet. Clearance studies showed a primary defect in renal calcium reabsorption. The intestine, bone and kidneys of the hypercalciuric rats had increased numbers of vitamin D receptors. When hydroxyproline is added to their diet they form calcium oxalate stones, the most common stone type in humans. Increased numbers of vitamin D receptors may cause hypercalciuria in these rats and humans. SUMMARY: Understanding the mechanism of hypercalciuria and stone formation in this animal model will help clinicians devise effective treatment strategies for preventing recurrent stone formation in humans.     

Postoperative Elevated Serum Levels of Intact Parathyroid Hormone after Surgery for Parathyroid Adenoma: Sign of Bone Remineralization and Decreased Calcium Absorption

Increased levels of intact parathyroid hormone (PTH) have been documented after surgery for primary hyperparathyroidism (pHPT) despite normocalcemia. The pathogenesis remains to be elucidated. Seventeen consecutive patients operated on for solitary parathyroid adenoma were investigated before and at 8 weeks and 1 year after surgery with serum levels of intact PTH, biochemical variables known to reflect PTH activity, and bone mineral content (BMC). In addition, an oral calcium loading test was performed 8 weeks after the operation. All patients had low or normal serum calcium levels during follow-up. Eight weeks after operation six patients (35%) had an increased serum PTH level. These patients (group I) preoperatively had higher serum levels of PTH and alkaline phosphatase than patients with normal PTH levels (group II). They also had lower BMC and larger parathyroid adenomas. They did not differ in renal function. At 8 weeks after operation group I showed higher mean serum levels of osteocalcin and propeptide of type I procollagen but lower urinary calcium excretion. In contrast to patients in group II, they also showed a lower calciuric response and a trend to a lower calcemic response during the oral calcium load. The two groups showed similar parathyroid sensitivity for calcium. Patients in group I demonstrated a significant increase in BMC the first year after the operation. Increased serum PTH 8 weeks after surgery for sporadic parathyroid adenoma was not due to persistent pHPT or impaired renal function. Instead, the results imply there is diminished calcium absorption and increased bone turnover with cortical bone remineralization.     

Pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen in uremic hyperparathyroidism

SUMMARY: We compared the serum level of the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (I-CTP) with clinical parameters of bone formation and skeletal symptoms to investigate whether I-CTP can predict the degree of renal osteodystrophy. Serum I-CTP was measured in 41 patients with secondary hyperparathyroidism who underwent total parathyroidectomy and autoimplantation (PTx). Measurement was done by using radioimmunoassay. Blood samples were collected before surgery and at 1, 3, 6, 9, 12, 15, and 18 months afterwards for the measurement of bone formation parameters. Serum I-CTP levels were significantly higher in patients with Jensen grade 3–5 renal osteodystrophy than in patients with grade 0–2 renal osteodystrophy. the I-CTP levels were also significantly higher in patients with bone or joint pain compared with patients without pain. There was a significant negative correlation between the serum I-CTP level and the lumbar vertebral (L2-4) bone mineral density. Serum I-CTP was significantly correlated with the serum levels of alkaline phosphatase, calcium, and phosphate, as well as the serum calcium x phosphate product, and the intact parathyroid hormone level. These findings suggest that serum I-CTP could be used as a marker for evaluating osteodystrophy in uremic hyperparathyroidism.     

Lithium's effect on bone mineral density

Lithium salts are widely used in treating psychiatric patients. Lithium may be associated with hyperparathyroidism, a risk factor for osteoporosis. However, the data on the effect of lithium on bone mass are conflicting. We assessed bone mineral density with dual-energy X-ray absorptiometry at the hip and lumbar spine in 75 lithium treated outpatients and 75 normal subjects matched for age, sex and body mass index. Serum total calcium, intact parathyroid hormone (PTH), estradiol, osteocalcin, total alkaline phosphatase (ALP) and C-telopeptide (CTX) in addition to fasting urinary calcium excretion were also determined in both groups. The mean (+/-SD) bone density in lithium treated patients was 4.5% higher at the spine (P<0.05), 5.3% higher at the femoral neck (P<0.05) and 7.5% higher at the trochanter (P<0.05). In addition, lithium treated patients had lower serum total ALP (P<0.005), lower serum osteocalcin (P<0.005) and lower serum CTX (P<0.05) but the total calcium, PTH and urinary calcium excretion did not differ significantly between patients and controls. In conclusion, our results suggest that maintenance therapy with lithium carbonate may preserve or enhance bone mass. These data also suggest a lower bone turnover state in those receiving lithium.     

Persistence of hypercalciuria after successful surgical treatment for primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) causes hypercalciuria and stone disease in a subset of patients. Hypercalciuria typically normalizes after surgery, although the risk of stone formation may persist up to 10?years. There are few reports in the literature that show persistent hypercalciuria despite normalization of serum calcium after parathyroid surgery. We retrospectively analyzed 111 patients with PHPT from the osteoporosis, and stone clinics seen between 1999 and 2006. We selected only patients who had a complete metabolic profile that included 24-hour collections before and at least 3?months after parathyroidectomy. We excluded patients who had creatinine clearance <60?ml/min/1.73?m². Fifty-four patients were selected for further analysis, 46 with baseline hypercalciuria and 8 with normocalciuria. Changes in filtered load of calcium and fractional excretion of calcium were evaluated before and after parathyroid surgery. Total and ionized calcium and phosphorus normalized in all patients after surgery (24?±?19?months); fractional excretion of calcium decreased, but did not normalize. Hypercalciuria persisted after surgery in 30.7% (n?=?12/39) of the women and 50% (n?=?4/8) of men. Of the patients in whom calciuria normalized after parathyroidectomy, 43.3% (n?=?13/30) had kidney stones before surgery, whereas kidney stones were present in 87.5% (n?=?14/16) in those in whom hypercalciuria persisted postsurgery. In hypercalciuric men and women before surgery in whom hypercalciuria persisted after surgery, fractional excretion of calcium was significantly higher than that in patients with normocalciuria. Conclusions: Persistently increased fractional excretion of calcium could explain the sustained increased risk of stone disease in patients with PHPT for many years after successful parathyroidectomy.     

Low calcium diet in idiopathic urolithiasis: a risk factor for osteopenia as great as in primary hyperparathyroidism

The bone mineral content of the radius was measured in 32 male renal stone formers, 18 of them presenting with idiopathic urolithiasis and 14 with primary hyperparathyroidism, a disease known to disturb bone metabolism. The idiopathic stone formers had been on regular treatment with a low calcium diet. The bone mineral content of the radius was reduced to a similar level in both groups of patients. The data suggest that idiopathic stone formers on a low calcium diet are at risk of osteopenia; the factors which could lead to a negative calcium balance included uncompensated renal hypercalciuria, hypophosphataemia and exaggerated serum levels of 1,25-dihydroxyvitamin D. To treat idiopathic hypercalciuria, thiazide diuretics, which reduce the renal excretion of calcium and have been shown to be beneficial for bone, seem safer than a low calcium diet.