Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria
2007; Elsevier BV; Volume: 71; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5002181
ISSN1523-1755
AutoresH Heller, Joseph E. Zerwekh, Frank Gottschalk, C. Y. C. Pak,
Tópico(s)Magnesium in Health and Disease
ResumoAbsorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8±2.1 vs 3.0±1.5%, P=0.04; wall thickness 35.8±6.9 vs 47.2±7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4±0.2 vs 0.2±0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14±0.06 to 0.06±0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute. Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8±2.1 vs 3.0±1.5%, P=0.04; wall thickness 35.8±6.9 vs 47.2±7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4±0.2 vs 0.2±0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14±0.06 to 0.06±0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute. Absorptive hypercalciuria (AH), a common cause of calcareous renal stones, is characterized by hypercalciuria primarily driven by intestinal hyperabsorption of calcium.1.Pak C.Y.C. Ohata M. Lawrence E.C. et al.The hypercalciurias: causes, parathyroid functions, and diagnostic criteria.J Clin Invest. 1974; 54: 387-400Crossref PubMed Scopus (363) Google Scholar We have previously separated AH into type I (AH-I), in which hypercalciuria decreases but persists after restriction of dietary calcium, and type II (AH-II), in which hypercalciuria resolves with restriction of dietary calcium. Although fasting hypercalciuria, a crude marker of bone resorption, was reported to be absent in the original description of AH-1,1.Pak C.Y.C. Ohata M. Lawrence E.C. et al.The hypercalciurias: causes, parathyroid functions, and diagnostic criteria.J Clin Invest. 1974; 54: 387-400Crossref PubMed Scopus (363) Google Scholar we have since observed it in patients with higher urinary calcium and intestinal calcium absorption.2.Reed B.Y. Gitomer W.L. Heller H.J. et al.Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density.J Clin Endocrinol Metab. 2002; 87: 1476-1485Crossref PubMed Scopus (101) Google Scholar,3.Pak C.Y.C. Kidney stones: pathogenesis diagnosis and therapy.in: Avioli L.V. Krane S.M. Metabolic Bone Disease and Clinically Related Disorders. Academic Press Inc., San Diego1998: 739-758Crossref Google Scholar However, we attributed the fasting hypercalciuria to delayed calcium absorption because it corrected after treatment with sodium cellulose phosphate, a poorly absorbed calcium binder.4.Preminger G.M. Peterson R. Pak C.Y.C. Differentiation of unclassified hypercalciuria utilizing a sodium cellulose phosphate trial.in: Walker V.R. Sutton R.A.L. Bert Cameron E.C. Urolithiasis. New York, Plenum Press1989: 325-328Crossref Google Scholar Several lines of evidence suggest that the bone may also contribute to the hypercalciuric phenotype of AH. Bone mineral density (BMD) of the spine tends to be reduced in AH-I especially if fasting hypercalciuria is also present.5.Pietschmann F. Breslau N.A. Pak C.Y.C. Reduced vertebral bone density in hypercalciuric nephrolithiasis.J Bone Min Res. 1992; 7: 1383-1388Crossref PubMed Scopus (182) Google Scholar BMD at the lumbar spine has been noted to correlate inversely with both urinary calcium6.Asplin J.R. Bauer K.A. Kinder J. et al.Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis.Kidney Int. 2003; 63: 662-669Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar and intestinal calcium absorption in stone formers.7.Vezzoli G. Rubinacci A. Bianchin C. et al.Intestinal calcium absorption is associated with bone mass in stone-forming women with idiopathic hypercalciuria.Am J Kidney Dis. 2003; 42: 1177-1183Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Moreover, two studies have found that stone-formers are at higher risk of skeletal fracture.8.Melton III, L.J. Crowson C.S. Khosla S. et al.Fracture risk among patients with urolithiasis: A population-based cohort study.Kidney Int. 1998; 53: 459-464Abstract Full Text PDF PubMed Scopus (132) Google Scholar,9.Lauderdale D.S. Thisted R.A. Wen M. et al.Bone mineral density and fracture among prevalent kidney stone cases in the third national health and nutrition examination survey.J Bone Min Res. 2001; 16: 1893-1898Crossref PubMed Scopus (122) Google Scholar Finally, hypercalciuria is associated with osteoporosis.10.Orwoll E.S. Klein R.F. Osteoporosis in Men.Endocr Rev. 1995; 16: 87-116Crossref PubMed Scopus (419) Google Scholar The exact cause of the low BMD in AH-I is unknown. Most of the past work had been done in stone-formers with 'idiopathic hypercalciuria,' in which the key tests (such as intestinal calcium absorption) had not been measured and the various components of hypercalciuria had not been differentiated. Fuss et al.11.Fuss M. Pepersack T. Van Geel J. et al.Involvement of low-calcium diet in the reduced bone mineral content of idiopathic renal stone formers.Calcif Tissue Int. 1990; 46: 9-13Crossref PubMed Scopus (52) Google Scholar implicated an iatrogenic cause of bone loss; unlike stone-formers who were on unrestricted diet, radial BMD was lower in stone-formers who had been subjected to dietary calcium restriction. Other reports suggested that the bone loss may have been intrinsic to the underlying cause of hypercalciuria in stone-formers. For example, several investigators suggested that various factors, including IL-1, IL-6, tumor necrosis factor-α, granulocyte macrophage colony stimulation factor, prostaglandins, and fatty acids, may have instigated both hypercalciuria and bone loss.12.Pacifici R. Rothstein M. Rifas L. et al.Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria.J Clin Endocrinol Metab. 1990; 71: 138-145Crossref PubMed Scopus (140) Google Scholar, 13.Weisinger J.R. Alonzo E. Bellorin-Font E. et al.Possible role of cytokines on the bone mineral loss in idiopathic hypercalciuria.Kidney Int. 1996; 49: 244-250Abstract Full Text PDF PubMed Scopus (108) Google Scholar, 14.Ghazali A. Fuentes V. Desaint C. et al.Low bone mineral density and peripheral blood monocytes activation profile in calcium stone formers with idiopathic hypercalciuria.J Clin Endocrinol Metab. 1997; 82: 32-38Crossref PubMed Scopus (84) Google Scholar, 15.Buck A.C. Lote C.J. Sampson W.F. The influence of renal prostaglandins on urinary calcium excretion in idiopathic urolithiasis.J Urol. 1983; 129: 421426Google Scholar, 16.Baggio B. Budakovic A. Fatty acids and idiopathic calcium nephrolithiasis.Urol Int. 2005; 75: 97-101Crossref PubMed Scopus (8) Google Scholar Pediatric hypercalciuric stone-formers had low BMD at the time of diagnosis, before dietary restrictions had been imposed.17.Garcia-Nieto V. Ferrandez C. Monge M. et al.Bone mineral density in pediatric patients with idiopathic hypercalciuria.Pediatr Nephrol. 1997; 11: 578-583Crossref PubMed Scopus (72) Google Scholar,18.Penido M.G. Lima E.M. Marino V.S. et al.Bone alterations in children with idiopathic hypercalciuria at the time of diagnosis.Pediatr Nephrol. 2003; 18: 133-139PubMed Google Scholar Gitomer et al.2.Reed B.Y. Gitomer W.L. Heller H.J. et al.Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density.J Clin Endocrinol Metab. 2002; 87: 1476-1485Crossref PubMed Scopus (101) Google Scholar found that base substitutions in the putative AH gene were associated with low BMD. Cumulative evidence suggests that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) may play a role in the phenotype of AH and idiopathic hypercalciuria. At high dose, this primary hormonal regulator of intestinal calcium absorption may increase bone resorption and decrease collagen synthesis.19.Raisz L.G. Kream B.E. Smith M.D. et al.Comparison of the effects of vitamin D metabolites on collagen synthesis and resorption of fetal rat bone in organ culture.Calcif Tissue Int. 1980; 32: 135-138Crossref PubMed Scopus (88) Google Scholar Administration of calcitriol in normal volunteers recapitulates the AH phenotype.20.Broadus A.E. Erickson S.B. Gertner J.M. et al.An experimental human model of 1,25-dihydroxyvitamin D-mediated hypercalciuria.J Clin Endocrinol Metab. 1984; 59: 202-206Crossref PubMed Scopus (18) Google Scholar 1,25(OH)2D3 is elevated in 30–80% of patients with AH and its regulation is disordered.21.Broadus A.E. Insogna K.L. Lang R. et al.A consideration of the hormonal basis and phosphate leak hypothesis of absorptive hypercalciuria.J Clin Endocrinol Metab. 1984; 58: 161-169Crossref PubMed Scopus (65) Google Scholar, 22.Broadus A.E. Insogna K.L. Lang R. et al.Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria.New Engl J Med. 1984; 311: 73-80Crossref PubMed Scopus (153) Google Scholar, 23.Breslau N.A. Preminger G.M. Adams B.V. et al.Use of ketoconazole to probe the pathogenetic importance of 1,25-dihydroxyvitamin D in absorptive hypercalciuria.J Clin Endocrinol Metab. 1992; 75: 1446-1452Crossref PubMed Scopus (32) Google Scholar Vitamin D-receptor concentrations are increased in idiopathic hypercalciuric patients and in an animal model of hypercalciuric nephrolithiasis, genetic hypercalciuric stone-forming rats;24.Favus M.J. Karnauskas A.J. Parks J.H. et al.Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria.J Clin Endocrinol Metab. 2004; 89: 4937-4943Crossref PubMed Scopus (86) Google Scholar,25.Karnauskas A.J. van Leeuwen J.P. van den Bemd G.J. et al.Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats.J Bone Miner Res. 2005; 20: 447-454Crossref PubMed Scopus (58) Google Scholar thus, hypercalciurics may be more sensitive to normal serum 1,25(OH)2D3. In fact, cultured calvariae from neonatal genetic hypercalciuric stone-forming rats demonstrate increased bone resorption after calcitriol exposure unlike normal rat calvariae.26.Krieger N.S. Stathopoulos V.M. Bushinsky D.A. Increased sensitivity to 1,25 (OH)2 D3 in bone from genetic hypercalciuric rats.Am J Physiol. 1996; 271: C130-C135PubMed Google Scholar Finally, treatment with ketoconazole, which decreases serum 1,25(OH)2D3, reduces both urinary calcium and intestinal calcium absorption in most patients with AH.23.Breslau N.A. Preminger G.M. Adams B.V. et al.Use of ketoconazole to probe the pathogenetic importance of 1,25-dihydroxyvitamin D in absorptive hypercalciuria.J Clin Endocrinol Metab. 1992; 75: 1446-1452Crossref PubMed Scopus (32) Google Scholar We hypothesized that in the subset of patients with AH-I, bone formation may be inappropriately low relative to bone resorption, contributing to bone loss. Accordingly, we compared bone histomorphometric presentation of AH with matched normal subjects and examined the physiological effect of a short-term blockade of bone resorption by alendronate in AH-I. Overall, stone-formers displayed a lower bone formation and higher bone resorption compared with matched normal volunteers (Table 1, Figure 1a and b). Two parameters of bone formation (osteoblast surface or Ob.S/BS, P=0.04; wall thickness, P=0.008) were significantly decreased in stone-formers. Median bone formation rate (BFR/BS) also tended to be lower in stone-formers, but did not reach significance owing to the high variance between subjects (0.34). One parameter of bone resorption (osteoclast surface) was significantly increased in stone-formers (0.047). Eroded surface tended to be higher in stone-formers (0.30). Activation frequency was not significantly different between groups. Bone volume per tissue volume (BV/TV) tended to be lower in stone-formers than control subjects but the difference did not reach significance (P=0.25, Table 1, Figure 1c). Trabecular thickness (Tb.Th) was significantly decreased in stone-formers (P=0.008), but there was no difference in trabecular number (Tb.N) or trabecular separation (Tb.Sp) (Table 1, Figure 1c). There was no evidence of a mineralization defect in any stone-former. All patients demonstrated normal trabecular lamellar structure as seen with polarized light.Table 1Histomorphometric analysis of cancellous boneAHNormalP-valueMean±SDMedianMinimumMaximumMean±s.d.BV/TV (%)14.6±4.915.28.823.217.2±3.90.25Tb.Th (μm)96±169384134121±220.008Tb.N, No/(mm)1.5±0.41.60.92.11.4±0.20.44Tb.Sp (μm)617±2325173781066597±1190.67Ob.S/BS, %1.8±2.11.70.17.13.0±1.50.04W.Th (μm)35.8±6.934.829.246.847.2±7.60.008OS/BS (%)6.0±5.75.00.419.45.4±2.00.65BFR/BS (mm3/mm2/year)0.012±0.0140.0070.0020.0470.014±0.0070.34ES/BS (%)3.6±1.83.11.77.22.6±1.60.30Oc.S/BS (%)0.4±0.20.50.10.70.2±0.20.05Ac.f, (cycles/year)0.4±0.40.20.041.30.3±0.10.80O.Th (μm)8.0±2.08.25.110.711.6±2.90.01Mlt (days)24.2±20.415.911.576.827.1±15.30.39Ac.f, activation frequency; AH, absorptive hypercalciuria; BFR/BS, bone formation rate; BS, bone surface referent (½ single labeled+all double labeled surfaces); BV/TV, bone volume per tissue volume; ES/BS, eroded surface; Mlt, mineralization lag time; Ob.S/BS, osteoblast surface; Oc.S/BS, osteoclast surface; OS/BS, osteoid surface; O.Th, osteoid thickness; Tb.Th, trabecular thickness; Tb.N, trabecular number; Tb.Sp, trabecular separation; W.Th., wall thickness. Open table in a new tab Ac.f, activation frequency; AH, absorptive hypercalciuria; BFR/BS, bone formation rate; BS, bone surface referent (½ single labeled+all double labeled surfaces); BV/TV, bone volume per tissue volume; ES/BS, eroded surface; Mlt, mineralization lag time; Ob.S/BS, osteoblast surface; Oc.S/BS, osteoclast surface; OS/BS, osteoid surface; O.Th, osteoid thickness; Tb.Th, trabecular thickness; Tb.N, trabecular number; Tb.Sp, trabecular separation; W.Th., wall thickness. In AH patients, clustering below the standardized mean reference range was observed for BMD at the spine and hip, but not at the radius. Mean and median Z-scores of the L2–L4 vertebrae were -0.7 and -1.0 s.d., respectively, in the AH group (Figure 2). BMD was below the standardized mean reference range matched for age and sex in seven patients (including four with Z-score ≥1 s.d. below the mean reference range and one other subject with Z-score of -2.5 s.d.). At the femoral neck in AH patients, BMD was below the standardized mean in seven, but only two demonstrated Z-score ≥1 s.d. below the mean. At the distal radius in AH patients, only one patient had Z-score approaching -1 s.d. Compared with the normal volunteers group, mean and median BMD in AH patients trended lower at the spine and hip, but did not achieve statistical significance (Z-score for the L-spine, P=0.49; Z-score for the femoral neck, P=0.22). Unlike the BMD in AH patients, which clustered below the reference mean at the spine and hip, BMD in the normal volunteers was evenly distributed at the spine and hip. During treatment with alendronate, markers of bone resorption but not bone formation decreased significantly (Table 2). At baseline, mean fasting urinary calcium was elevated at 0.14 mg/mg Cr (normal 200 mg/day) (Table 2).1.Pak C.Y.C. Ohata M. Lawrence E.C. et al.The hypercalciurias: causes, parathyroid functions, and diagnostic criteria.J Clin Invest. 1974; 54: 387-400Crossref PubMed Scopus (363) Google Scholar,27.Levy F.L. Adams-Huet B. Pak C.Y.C. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol.Am J Med. 1995; 98: 50-59Abstract Full Text PDF PubMed Scopus (279) Google Scholar Following alendronate treatment, urinary calcium declined marginally (P=0.06; difference -48 mg/day, -1.2 mmol/day; 95% CI -143 to 14 mg/day, -3.6 to 0.4 mmol/day) and normalized in three subjects. Yet, mean urinary calcium remained slightly elevated. The mean decrement in urinary calcium tended to be greater in patients with fasting hypercalciuria (71±79 mg vs 22±35 mg), but this difference did not reach statistical significance (P=0.29). In patients with AH-1, we found that excess bone loss may contribute to the hypercalciuria. We documented histomorphometrical evidence of low bone formation and relatively increased bone resorption in patients with AH compared with a matched control group. A physiologic blockade of bone resorption with alendronate restored the originally described biochemical presentation of AH-11.Pak C.Y.C. Ohata M. Lawrence E.C. et al.The hypercalciurias: causes, parathyroid functions, and diagnostic criteria.J Clin Invest. 1974; 54: 387-400Crossref PubMed Scopus (363) Google Scholar, 27.Levy F.L. Adams-Huet B. Pak C.Y.C. Ambulatory evaluation of nephrolithiasis: an update of a 1980 protocol.Am J Med. 1995; 98: 50-59Abstract Full Text PDF PubMed Scopus (279) Google Scholar, 28.Pak C.Y.C. Kaplan R. Bone H. et al.A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias.New Engl J Med. 1975; 292: 497-500Crossref PubMed Scopus (375) Google Scholar by normalizing fasting urinary calcium. Prior studies examined bone histomorphometric picture among patients with kidney stones.29.Bordier P. Ryckewart A. Gueris J. et al.On the pathogenesis of so-called idiopathic hypercalciuria.Am J Med. 1977; 63: 398-409Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 30.Malluche H.H. Tschoepe W. Ritz E. et al.Abnormal bone histology in idiopathic hypercalciuria.J Clin Endocrinol Metab. 1980; 50: 654-658Crossref PubMed Scopus (94) Google Scholar, 31.De Vernejoul M.C. Hioco D. Villiaumey J. et al.tude histomorphométrique osseuse au tours de l'hypercalciurie idiopathique.Rev Rhum Mal Osteoartic. 1981; 48: 389-395PubMed Google Scholar, 32.Steiniche T. Mosekilde L. Christensen M.S. et al.A histomorphometric determination of iliac bone remodeling in patients with recurrent renal stone formation and idiopathic hypercalciuria.APMIS. 1989; 97: 309-316Crossref PubMed Scopus (58) Google Scholar, 33.Pfeferman Heilberg I. Martini L.A. et al.Bone disease in calcium stone forming patients.Clin Nephrol. 1994; 42: 175-182PubMed Google Scholar, 34.Misael da Silva A.M. Dos Reis L.M. Pereira R.C. et al.Bone involvement in idiopathic hypercalciuria.Clin Nephrol. 2002; 57: 183-191Crossref PubMed Google Scholar, 35.Fournier A. Ghazali A. Bataille P. et al.Bone involvement in idiopathic calcium-stone formers.in: Coe F.L. Favus M.J. Pak C.Y.C. Kidney Stones: Medical and Surgical Management. Philadelphia, PA, Lippincott-Raven1996: 921-938Google Scholar However, most reports involved patients with idiopathic hypercalciuria without a clear identification of AH, used differing definitions of hypercalciuria, employed control groups that were not matched for age and weight, and did not label the bone with tetracycline or provide complete data. In two articles, only subjects with low BMD were evaluated.33.Pfeferman Heilberg I. Martini L.A. et al.Bone disease in calcium stone forming patients.Clin Nephrol. 1994; 42: 175-182PubMed Google Scholar,35.Fournier A. Ghazali A. Bataille P. et al.Bone involvement in idiopathic calcium-stone formers.in: Coe F.L. Favus M.J. Pak C.Y.C. Kidney Stones: Medical and Surgical Management. Philadelphia, PA, Lippincott-Raven1996: 921-938Google Scholar Not surprisingly, the published results of bone histomorphometry have yielded conflicting results. Although most studies found a tendency toward low bone formation without a mineralization defect, two articles reported high bone formation and resorption.29.Bordier P. Ryckewart A. Gueris J. et al.On the pathogenesis of so-called idiopathic hypercalciuria.Am J Med. 1977; 63: 398-409Abstract Full Text PDF PubMed Scopus (139) Google Scholar,34.Misael da Silva A.M. Dos Reis L.M. Pereira R.C. et al.Bone involvement in idiopathic hypercalciuria.Clin Nephrol. 2002; 57: 183-191Crossref PubMed Google Scholar One study found a mineral defect with increased osteoid thickness and increased mineralization lag time, but serum 25-OHD was not provided.34.Misael da Silva A.M. Dos Reis L.M. Pereira R.C. et al.Bone involvement in idiopathic hypercalciuria.Clin Nephrol. 2002; 57: 183-191Crossref PubMed Google Scholar Another study reported hyperosteoidosis, but osteoid thickness and mineralization lag-time were omitted, leaving the possibility that the hyperosteoidosis may have been a manifestation of increased bone turnover rather than a mineralization defect.30.Malluche H.H. Tschoepe W. Ritz E. et al.Abnormal bone histology in idiopathic hypercalciuria.J Clin Endocrinol Metab. 1980; 50: 654-658Crossref PubMed Scopus (94) Google Scholar Among six studies that reported bone volume per tissue volume,30.Malluche H.H. Tschoepe W. Ritz E. et al.Abnormal bone histology in idiopathic hypercalciuria.J Clin Endocrinol Metab. 1980; 50: 654-658Crossref PubMed Scopus (94) Google Scholar, 31.De Vernejoul M.C. Hioco D. Villiaumey J. et al.tude histomorphométrique osseuse au tours de l'hypercalciurie idiopathique.Rev Rhum Mal Osteoartic. 1981; 48: 389-395PubMed Google Scholar, 32.Steiniche T. Mosekilde L. Christensen M.S. et al.A histomorphometric determination of iliac bone remodeling in patients with recurrent renal stone formation and idiopathic hypercalciuria.APMIS. 1989; 97: 309-316Crossref PubMed Scopus (58) Google Scholar, 33.Pfeferman Heilberg I. Martini L.A. et al.Bone disease in calcium stone forming patients.Clin Nephrol. 1994; 42: 175-182PubMed Google Scholar, 34.Misael da Silva A.M. Dos Reis L.M. Pereira R.C. et al.Bone involvement in idiopathic hypercalciuria.Clin Nephrol. 2002; 57: 183-191Crossref PubMed Google Scholar, 35.Fournier A. Ghazali A. Bataille P. et al.Bone involvement in idiopathic calcium-stone formers.in: Coe F.L. Favus M.J. Pak C.Y.C. Kidney Stones: Medical and Surgical Management. Philadelphia, PA, Lippincott-Raven1996: 921-938Google Scholar only three reports (two of which limited enrollment to osteopenic patients) found it reduced at 13–20%.31.De Vernejoul M.C. Hioco D. Villiaumey J. et al.tude histomorphométrique osseuse au tours de l'hypercalciurie idiopathique.Rev Rhum Mal Osteoartic. 1981; 48: 389-395PubMed Google Scholar, 33.Pfeferman Heilberg I. Martini L.A. et al.Bone disease in calcium stone forming patients.Clin Nephrol. 1994; 42: 175-182PubMed Google Scholar, 35.Fournier A. Ghazali A. Bataille P. et al.Bone involvement in idiopathic calcium-stone formers.in: Coe F.L. Favus M.J. Pak C.Y.C. Kidney Stones: Medical and Surgical Management. Philadelphia, PA, Lippincott-Raven1996: 921-938Google Scholar Trabecular thickness was normal in the sole study that examined it.34.Misael da Silva A.M. Dos Reis L.M. Pereira R.C. et al.Bone involvement in idiopathic hypercalciuria.Clin Nephrol. 2002; 57: 183-191Crossref PubMed Google Scholar In this study, we performed a comprehensive histomorphometric analysis of trabecular bone among patients with well characterized AH and compared the results with those of a matched control group. We found low bone formation with reduced osteoblast surface and wall thickness. Although bone resorption based on osteoclast surface was significantly higher in AH, our patients and controls demonstrated normal bone resorption when compared with reported osteoclast surface in normal young men and premenopausal women.36.Malluche H.H. Meyer W. Sherman D. et al.Quantitative bone histology in 84 normal American subjects. Micromorphometric analysis and evaluation of variance in iliac bone.Calcif Tissue Int. 1982; 34: 449-455Crossref PubMed Scopus (125) Google Scholar,37.Han Z.H. Palnitkar S. Rao D.S. et al.Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss.J Bone Miner Res. 1997; 12: 498-508Crossref PubMed Scopus (200) Google Scholar Moreover, we observed markedly decreased trabecular thickness despite normal trabecular number and separation, which is more consistent with chronic low bone formation than chronic high bone resorption. The low bone formation we observed may have resulted from decreased osteoblast recruitment, lifespan, or function. Although the underlying cause of our histomorphometrical observations is not clear, it is compatible with endogenous excess calcitriol effect.19.Raisz L.G. Kream B.E. Smith M.D. et al.Comparison of the effects of vitamin D metabolites on collagen synthesis and resorption of fetal rat bone in organ culture.Calcif Tissue Int. 1980; 32: 135-138Crossref PubMed Scopus (88) Google Scholar Our histomorphometric finding of a relative excess of bone resorption over bone formation is supported by prior physiological–metabolic studies in idiopathic hypercalciuria. Utilizing calcium balance studies, Liberman et al.38.Liberman U.A. Sperling O. Atsmon A. et al.Metabolic and calcium kinetic studies in idiopathic hypercalciuria.J Clin Invest. 1968; 47: 2580-2590Crossref PubMed Google Scholar reported negative calcium balance in five of nine patients. Coe et al.39.Coe F.L. Favus M.J. Crockett T. et al.Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects.Am J Med. 1982; 72: 25-32Abstract Full Text PDF PubMed Scopus (218) Google Scholar found that during severe
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