A Slight Decrease in Renal Function Further Impairs Bone Mineral Density in Primary Hyperparathyroidism

A Slight Decrease in Renal Function Further Impairs Bone Mineral Density in Primary Hyperparathyroidism
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   A Slight Decrease in Renal Function Further ImpairsBone Mineral Density in Primary Hyperparathyroidism Laura Gianotti, Francesco Tassone, Flora Cesario, Anna Pia, Paola Razzore, Giampaolo Magro, Alessandro Piovesan, and Giorgio Borretta  Division of Endocrinology and Metabolism (L.G., F.T., F.C., A.Pia, P.R., G.M., G.B.), S. Croce and Carle Hospital, 12100Cuneo, Italy; and Division of Endocrinology and Oncology (A.Pio.) S. G. Battista Hospital, 10126 Turin, Italy Background: Theimpairmentofrenalfunctioncanaffecttheclinicalpresentation of primary hyperparathyroidism (PHPT), increasing cardiovascular morbidity, fracture rate, and the risk of mortality.  Aim: Theaimofthestudywastoassessthedifferencesinbonestatusin a series of consecutive patients affected by PHPT without overtrenal failure at diagnosis grouped according to creatinine clearance(Ccr). Methods:  A total of 161 consecutive patients with PHPT were stud-ied.TheyweredividedintotwogroupsbasedonCcr.GroupAhadCcr70 ml/min or less (n    49), and group B had Ccr greater than 70ml/min (n    112). PTH, total and ionized serum calcium; urinarycalcium and phosphate; serum 25-hydroxyvitamin D3; serum andurinary bone markers; lumbar, forearm, and femoral bone mineraldensity (BMD) were evaluated. Results:  Patients in group A were older than those in group B (  P  0.0001). PTH levels did not differ in the two groups, whereas bothurinary calcium and phosphorus were lower in group A than group B(  P  0.01). Lower BMD was evident in group A at lumbar spine (  P  0.002), forearm (  P  0.0001), and femur (  P  0.01). In asymptomaticPHPT,thosewithCcr70ml/minorlesshadlowerforearmBMDthanpatients with higher Ccr (  P  0.00001). When adjusting for age andbody mass index in PHPT, BMD at each site persisted being lower(  P  0.05) in group A than group B. In all PHPT subjects, Ccr (beta  0.29,  P  0.0005), age (beta  0.27,  P  0.00001), and PTH levels(beta    0.27,  P    0.0005) were all independently associated withforearm BMD. Conclusions:  In PHPT a slight decrease in renal function is asso-ciated with more severe BMD decrease, independent of age, bodymassindex,andPTHlevels.Thisassociationisalsopresentinasymp-tomatic PHPT and strengthens the National Institutes of Healthrecommendations for surgery in patients with mild PHPT.  (  J Clin Endocrinol Metab  91: 3011–3016, 2006) T HECLASSICALCLINICALpresentationofprimaryhy-perparathyroidism (PHPT) as a symptomatic diseaseassociated with kidney stones, bone disease, and hypercal-cemicsymptomsisrarenowadays.Infact,thecurrentclinicalpresentation of PHPT is usually without overt symptoms,and the diagnosis is often made during routine biochemicalevaluation (1–3). Hence, the indications for surgical treat-ment are less obvious (4, 5). Two successive conferences attheNationalInstitutesofHealth(NIH)in1990and2002wereheld to clarify and define these indications (4, 5). Thus, be-sidesothercriteria,ithasbeensuggestedthatsurgeryshould be advised in asymptomatic patients who have a reductionof 30% or more in creatinine clearance (Ccr), compared withage- and sex-matched reference values (4, 5).Theimpactofrenalfunctiononthebiochemicalexpressionof PHPT has been well documented (6–10). In mild PHPT,glomerular filtration rate (GFR) has been reported to be in-versely correlated to the preoperative serum levels of intactPTH, ionized calcium, and osteocalcin (6). More recent dataconfirm the association between a slight reduction in GFRmeasured as Ccr and increased bone turnover reflected byhigher levels of PTH, calcium, and osteocalcin in both symp-tomatic and asymptomatic disease (7). Other findings (7–9)strengthened the impact of reduced renal function, on theclinicalexpressionofPHPT.Inparticular,preoperativerenalfunction was associated with increased prevalence of hyper-tension and diabetes (7) and was linked to the risk of deathat long-term follow-up in PHPT (8, 10). The recovery fromPHPT is associated with improvement of renal function, andsurgery generally leads to a substantial increase of renalconcentration capacity (9).Although all these studies indicate a relationship betweenrenal function and clinical features of PHPT, including boneimpairment, to the best of our knowledge, no data on theimpact of slight renal failure on bone mineral density (BMD)values are currently available. BMD levels, measured bydual-energyx-rayabsorption(DEXA),representthepresent-day gold standard to define osteopenia or osteoporosis andpredict the risk of fracture (11, 12). They also represent oneof the key elements to consider as surgical indications inasymptomatic PHPT (4, 5). Therefore, we thought it would be of interest to study the impact of slight renal failure onBMD and bone turnover in this condition. In particular, wedefined the effect of a mild decline of Ccr on bone status,measured in terms of BMD as well as on the basis of serum First Published Online May 30, 2006 Abbreviations: ALP, Alkaline phosphate; aPHPT, asymptomaticPHPT; BMD, bone mineral density; BMI, body mass index; Ca u , urinarycalcium; Ccr, creatinine clearance; CRF, chronic renal failure; DEXA,dual-energy x-ray absorption; GFR, glomerular filtration rate;25(OH)D3, 25-hydroxyvitamin D3; OPG, osteoprotegerin; PHPT, pri-mary hyperparathyroidism; RANKL, receptor activator of nuclear fac-tor-  B ligand.  JCEM is published monthly by The Endocrine Society (, the foremost professional society serving the en-docrine community. 0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(8):3011–3016  Printed in U.S.A.  Copyright © 2006 by The Endocrine Societydoi: 10.1210/jc.2006-0070 3011  and urinary bone markers in a large series of consecutivepatients with PHPT without overt renal failure at the time of the diagnosis. Patients and Methods  Patient selection One hundred seventy-three consecutive patients affected by PHPTwere studied from 1993 through 2003.PHPT was diagnosed by the concomitant elevation of total and ion-ized serum calcium coupled with elevated or inappropriately elevatedlevels of intact PTH. None of the patients had hepatic or overt renalfailure or active thyroid disorder (TSH levels    0.2 or    4   U/mlrepresented exclusion criteria). To exclude overt renal failure, we eval-uatedthatnoneofthepatientshadapreviousdiagnosisofchronicrenalfailureorhadcreatininelevelsgreaterthan1.4orgreaterthan1.5mg/dl(depending on whether female or male) according to the guidelines of the European Society of Hypertension 2003, which indicated these val-ues as a sign of early renal damage (13). For the latter reason, fourpatientswithcreatininelevelshigherthan1.4–1.5mg/dlwereexcluded.Ccr was available for 161 of the remaining 169 patients. Thus, 161patients represented the study group.Ccr was assessed using the Cockroft and Gault formulae (14) asfollows: Ccr (milliliters per minute) in males    (140    age)    weight(kilograms)/72    creatinine (milligrams per deciliter); in females   (140  age)  weight (kilograms)/72  creatinine (milligrams per de-ciliter)  0.85.None of the patients had been taking medications that are known tointerferewithcalciumandvitaminDmetabolisminthe6monthsbeforethe study.Eighty-three of 161 patients (51%) were classified as having mild/asymptomatic PHPT (aPHPT). The criteria used to define this groupwere chosen according to the summary statement by Bilezikian  et al.  (5), basedontheNIHConsensusconferenceonasymptomaticPHPTof1991(4).A history of kidney stone disease was present in 30% of the patients,whereas classical bone manifestations, such as osteitis fibrosa, cysticlesions, subperiostal resorptions of phalanges, or brown tumors, wererecorded in 19% of the patients. Osteoporosis was diagnosed accordingtotheWorldHealthOrganizationclassification(11)in67.6%ofallPHPTpatients, whereas 26.6% of the patients showed osteopenia.All biochemical and hormonal data as well as the results of neckultrasound, parathyroid scintigraphy, and DEXA were progressivelyreported in a database.  Study ThepatientswerestudiedattheDivisionofEndocrinologyofS.CroceHospital,Cuneo,Italy,from1993through2003.Alltheevaluationswereperformed during a single hospitalization at the time of the diagnosis.The patients underwent a screening that included the following: 1)complete family and personal medical history; 2) physical examinationincluding body weight, body mass index (BMI) and blood pressure; 3) biochemical evaluation of general blood and urinary parameters, in-cluding: total and ionized serum calcium, serum phosphate, serumcreatinine, plasma fibrinogen, serum immunoreactive intact PTH, totalalkaline phosphate (ALP) and bone isoenzyme serum ALP, serum os-teocalcin,urinarycross-links,serum25-hydroxyvitaminD3[25(OH)D3]24 h-urinary calcium (Ca u ), and urinary phosphate; 4) neck ultrasound,parathyroid scintigraphy; 5) x-ray evaluation of the phalanxes and theskull; and 6) densitometric evaluation of lumbar spine, total proximalfemur, and forearm.Patients consented to these investigations as part of their normalmedical care.The patients were divided into two groups according to Ccr values:groupAwithCcrof70ml/minorlessandgroupBwithCcrgreaterthan70 ml/min. This value was chosen because it was already assumed byother authors to represent the cut-off value between slight renal failureand normal renal function in PHPT (7). Moreover, it is known that inchronic renal failure (CRF), secondary hyperparathyroidism may de-velop in early stages of GFR reduction (15). We thus hypothesized thatthis Ccr level could make for an easier identification of the possiblenegative effect of secondary hyperparathyroidism on bone metabolismin PHPT.  Methods and measurements Biochemical analysis.  Total serum calcium, serum phosphate, and serumcreatinine as well as Ca u  were analyzed by a standard autoanalyzerusing colorimetric and enzymatic methods, whereas ionized serum cal-cium was analyzed by a specific probe after correction for pH.Total serum ALP was measured by a colorimetric assay and serumosteocalcin by a fluorometric assay (TRACE; Kryptur, Brahms, Ger-many), whereas urinary cross-links were measured by an immuno-chemiluminometric assay (Diagnostic Products Corp., Los Angeles,CA).Serum immunoreactive intact PTH was measured by an immuno-chemiluminometric assay (Diagnostic Products Corp.) with intra- andinterassay coefficients of variation of 4.2–5.7 and 6.3–8.8%, respectively.Serum 25(OH)D3 levels were measured by RIA (Biosource Europe,Nivelles, Belgium) with intra- and interassay coefficients of variation of 6.1–7.9 and 7.1–8.2%, respectively. Densitometric measurements.  The BMD of the lumbar spine (L2-L4), prox-imal femur, and distal third of the nondominat radius was measured byDEXA QDR-4500 (Hologic, Bedford, MA). The data on bone density arereported as absolute measurements of BMD (grams per square centi-meter), T score ( sd  from mean BMD of young adult population), or Zscore ( sd  from mean BMD of age-matched population).  Statistical analysis Data are expressed as mean  sd .All analyses were performed using Statistica (version 7.0 for Win-dows; StatSoft Inc., Tulsa, OK).StatisticaldifferencesinmeanlevelsofthevariableswereassessedbyMann Whitney  U   test and ANCOVA (with age and BMI as covariates)followed by LSD  post hoc  test.SpearmanrankcorrelationtestwascalculatedbetweenCcrandBMDor PTH or serum/Ca u  or bone markers. Multiple linear regression anal-ysis (all variables entered model) was used to determine whether Ccr orPTH or age were independently related to forearm BMD. Results Clinical data of the whole group of patients and A and Bsubgroups are reported in Table 1. PHPT patients weremostly asymptomatic (83 of 161) and female (120 of 161).Their mean Ccr was 86.0  29.4 ml/min with a range from30 to 168 ml/min and a median of 83 ml/min.Patients in group A (n  49, Ccr 53.9  11.9 ml/min, age66.6  12.4 yr) were older ( P  0.0001) than those in groupB (n  112, GFR 100.05  22.9 ml/min, age 57.2  12.5 yr)and obviously had creatinine levels higher than group B. Onthe other hand, BMI levels were not significantly different inthe two groups (Table 1).PTH levels did not differ significantly in the two groups(197.4  148.4 and 184.4  132.1 pg/ml, in groups A and B,respectively) with the following details: group A, range 58–630, median level 148, lower quartile 96, higher quartile 241pg/ml;groupB,range42–723,medianlevel140,lowerquar-tile 90, higher quartile 226 pg/ml.No significant differences were present in total and ion-ized serum calcium in the two groups, whereas Ca u  andurinary phosphate were lower in group A than B ( P  0.01).Serum or urinary bone markers as well as serum 25(OH)D3levels were not significantly different in the two groups,althoughatrendofhigherosteocalcinlevelswasobservedingroup A ( P  0.09). Among biochemical parameters evalu- 3012  J Clin Endocrinol Metab, August 2006, 91(8):3011–3016 Gianotti  et al.  • Renal Function and Bone Density in PHPT  ated, plasma fibrinogen was higher in group A than groupB ( P  0.03).BMD as well as T score at lumbar spine ( P  0.002), femur( P  0.01), and forearm ( P  0.0001) were lower in group Athan B (Fig. 1). Even Z score at forearm was lower in groupA than group B ( P  0,01). All biochemical, hormonal, andBMD data are reported in Table 2.Considering patients with aPHPT, BMD ( P  0.0001) andT score ( P  0.03) at the forearm were lower in patients withCcr 70 ml/min or less (n  24, Ccr  50.4  10.1 ml/min)than in patients with Ccr greater than 70 ml/min (n    59,Ccr  100.1  24.9 ml/min).Adjusting for age or BMI in all PHPT patients, both BMDand T score at each bone site persisted being lower in groupAthangroupB.Similarly,inaPHPTforearmBMDpersisted, being lower in patients with lower Ccr levels, independentlyof age or BMI (0.38  0.1  vs.  0.49  0.1 g/cm 2 ,  P  0.0001).InPHPT,therewasapositivecorrelationbetweenCcrandforearmBMD(r  0.54, P  0.00005)(Fig.2)aswellaslumbarBMD (r  0.32,  P  0.05). Moreover, we noticed a positiveassociation between Ccr and Ca u  (r  0.3,  P  0.02), whereaswe did not find any significant association either betweenCcr and PTH or between Ccr and bone markers. A negativecorrelation between Ccr and plasma fibrinogen was found(r  0.2,  P  0.05) in the whole group of patients.The multiple regression analysis showed that Ccr (beta  0.29,  P  0.0005), age (beta  0.27,  P  0.00001), and PTHlevels (beta    0.27,  P    0.0005) were all independentlyassociated with forearm BMD. Discussion Our findings indicate that in a large group of patientsaffected by PHPT without overt renal failure, a slight de-crease in renal function is associated with lower BMD atforearm, lumbar spine, or femur, and this association is in-dependent of age or BMI or PTH levels. The negative impactof decreased renal function on BMD is also evident in pa-tients with aPHPT.Thelinkamongrenalfunction,PTH,andbonemetabolismis well known in both physiological and pathological con-ditions (6, 7, 15–17).In CRF the progressive reduction of GFR is commonlyassociated with an increase in PTH, leading to progressive bonedamageandfinallyrenalosteodystrophy(15–17).How-ever, skeletal changes begin even at an early stage of CRFwhen reduced BMD, increased levels of PTH, and biochem-ical markers of bone turnover can be found (15–17). Never-theless, recent analysis from the Third National Health andNutrition Examination Survey (18) demonstrated that al-though adult subjects with worse renal function have sig-nificantly lower femoral BMD, this association can be ex-plainedbyconfoundingfactors,namelysex,age,andweight.Thus, the negative effects of reduced renal function on BMDcould be minimal or subclinical, at least among persons withmild CRF (18).In mild PHPT even a mild decrease of renal function rep-resents a further indication for surgery (4, 5). This indicationis based on the fact that a decline of renal function caninfluence the clinical expression of PHPT and worsen bonestatus.However,tothisdayclearevidenceoftherelationship between renal function and bone impairment, in terms of BMD decrease, is still lacking.We studied a large group of subjects affected by PHPTwith normal or slightly decreased renal function, and wechosethevalueofCcr70ml/minasthelimitbetweennormal TABLE 1.  Clinical data of PHPT patients PHPT(n  161)Group A (n  49)Group B(n  112)  Age (yr) 60.05  13.2 66.65  12.36 57.16  12.54 a Sex (female/male) 120/41 40/9 80/32BMI (kg/m 2 ) 25.86  4.92 24.57  3.95 26.38  5.19Symptomatic/asymptomatic 78/83 21/28 57/55PAS (mm Hg) 145.7 150.4 143.7 b PAD (mm Hg) 85.1 87.2 86.4Bone disease (%) 19 24.5 16.9 b Stone (%) 29.9 30.6 43.7 b Osteoporosis (%) 67.6 83.8 29.9 a PAS, Systolic arterial pressure; PAD, diastolic arterial pressure. a  P  0.05  vs.  group A. b  P  0.0001  vs.  group A.F IG . 1. Mean (  SD ) levels of BMD (grams per square centimeter) atlumbar spine, femur, and forearm of the whole group of PHPT pa-tients( blackcolumns ),PHPTpatientswithlowerCcr(groupA, whitecolumns ), and PHPT patients with higher Ccr levels (group B,  graycolumns ).  P  values refer to comparisons between groups A and B. Gianotti  et al.  • Renal Function and Bone Density in PHPT J Clin Endocrinol Metab, August 2006, 91(8):3011–3016  3013  renalfunctionandearlyCRF,inaccordwithpreviousstudies(7, 15–17).Anegativeinfluenceofrenalfunctiononbonemetabolismhad already been reported in PHPT (6, 7). In fact, serumlevels of calcium, PTH, and osteocalcin were reported sig-nificantly higher and 24-h Ca u  and phosphate significantlylower in patients with concomitant PHPT and renal functionslightly decreased in comparison with patients with normalrenal function (7). Our results confirmed a decrease in Ca u and phosphate in PHPT patients with lower Ccr. The re-ducedexcretionofCa u inpatientswithdecreasedrenalfunc-tion suggests that the evaluation of this parameter may bemisleading in the clinical assessment of these patients. Ac-cording to the NIH Consensus Development Conferencestatement(4,5),surgeryisrecommendedwhenCa u excretionis higher than 400 mg in 24 h. Ca u excretion, however, can bereduced in patients with slight decrease of renal function,hence limiting the role of hypercalciuria as a marker of moreaggressive disease that might require surgery.We did not observe any significant difference in serumPTH and total and ionized calcium between patients withpreservedrenalfunctionandpatientswithreducedfunction.Neither serum nor urinary bone markers were significantlydifferent in the two groups, although a trend of higher os-teocalcin levels was present in patients with reduced Ccr.Furthermore, no significant association between Ccr andPTH or serum calcium was found in the whole group of patients.These findings are different from previous reports (7) andcanbeduetotheverystrictcriteriaofinclusionofourstudy.Infact,weconsideredpatientswithmostlynormalcreatininelevels, whereas in other studies (7), these criteria were notclearlydefinedandpatientswithgreatervariabilityofserumcreatinine could have been studied. Accordingly, most pa-tientsinourstudyhadCcrvalueshigherthan60ml/minandmorehomogeneouslydistributedlevelsofcalciumandPTH.The lack of difference in PTH in the two groups may berelated to the similarly low serum phosphate levels becausetheincreaseofserumphosphateisoneofthemostimportantand precocious stimuli of PTH secretion in the early stagesof CRF (19, 20).The trend toward higher osteocalcin levels in the groupwith reduced renal function could reflect an increased boneturnover. However, this finding could also be explained bya prolongation of osteocalcin half-life due to the decrease of GFR, which leads to an increase of osteocalcin levels as de-tected by immunometric assay (21). Therefore, the slightlyhigher osteocalcin levels in patients with reduced Ccr mightsimply reflect a reduced excretion rate or an interference of  F IG . 2. LinearcorrelationbetweenCcrandBMDlevelsatforearminthe whole group of PHPT patients. TABLE 2.  Biochemical, hormonal, and densitometric details in PHPT patients Normal range PHPT(n  161)Group A (n  49)(Ccr  70 ml/min)Group B(n  112)(Ccr  70 ml/min) PTH (pg/ml) 10.0–65.0 188.19  136.83 197.42  148.44 184.40  132.10Serum calcium (mg/dl) 8.4–10.2 11.13  0.98 11.14  1.13 11.12  0.92Ionized calcium (mmol/liter) 1.13–1.32 1.47  0.15 1.48  0.18 1.47  0.13Serum creatinine (mg/dl) 0.7–1.2 0.85  0.19 0.92  0.20 0.82  0.18 a Creatinine clearance (ml/min)   70 86.0  29.39 53.89  11.90 100.05  22.90Plasma fibrinogen (mg/dl) 150–450 349.10  89.10 380.40  88.40 336.70  86.90 b Urinary calcium (mg/24 h) 100–250 248.90  183.62 183.30  161.20 273.30  186.30 a Urinary phosphorus (mg/24 h) 100–300 480.70  291.50 351.30  227.70 526.1  298.9 a 25(OH)D3 (ng/ml) 20–70 26.77  22.16 34.14  33.60 23.68  14.40 ALP (U/liter) 38–126 135.41  86.78 128.02  75.84 138.50  91.20Osteocalcin (ng/ml) 1.5–11 39.28  33.0 46.05  38.24 36.50  30.30Bone ALP (  g/liter) 3–20.5 27.55  28.43 21.91  18.48 30.10  31.70Urinary cross-links (n M  /m M  cr) 3–7.4 11.86  11.56 9.38  4.20 13.10  13.60Femoral BMD (g/cm 2 ) 0.74  0.15 0.67  0.15 0.77  0.15 a Femoral T score   2.04  1.18   2.55  1.14   1.78  1.12 a Femoral Z score   0.84  1.20   1.21  1.34   0.68  1.11Radial BMD (g/cm 2 ) 0.44  0.11 0.37  0.09 0.47  0.11 d Radial T score   2.44  1.57   3.33  1.38   2.00  1.48 d Radial Z score   1.14  1.29   1.62  1.32   0.92  1.22 a Lumbar BMD (g/cm 2 ) 0.79  0.25 0.65  0.37 0.84  0.16 c Lumbar T score   2.46  1.40   3.16  1.61   2.16  1.19 c Lumbar Z score   1.13  1.41   1.41  1.94   1.01  1.10 a  P  0.01  vs.  group A. b  P  0.03  vs.  group A. c  P  0.002  vs.  group A. d  P  0.0001  vs.  group A. 3014  J Clin Endocrinol Metab, August 2006, 91(8):3011–3016 Gianotti  et al.  • Renal Function and Bone Density in PHPT  fragments of degradation on the assay (17, 21) rather than anincrease of bone turnover. Thus, the biochemical determi-nation of bone markers may be limited in the presence of reduced GFR and in some cases may be unreliable.The analysis of the relationships between renal functionand BMD in PHPT indicated a negative impact of Ccr de-crease on BMD that, to the best of our knowledge, has never been described before in this condition. In particular, a moresevere decrease in mineral density at each bone site wasrecorded in patients with lower Ccr, independently of PTHlevels. Also in asymptomatic patients, forearm BMD waslower in those with reduced renal function, and again thisrelationship was independent of PTH.To rule out the impact of age or BMI, both of which in-dependently influence BMD levels (11, 12, 18, 22), we eval-uated the same results, considering age or BMI as covariatesand the analysis confirmed the findings. Furthermore, con-sidering all PHPT patients, we observed a positive associa-tionbetweenCcrandBMDatlumbarspineandforearm.Thelatterisalmostentirelymadeofcorticalboneandshowedthestrongest association with Ccr level (lower BMD at forearmin patients with lower Ccr levels). Thus, a slight decrease of renal function can represent a further risk for bone diseaseand fracture in PHPT, mainly at the cortical level. This is aninteresting finding if we consider that in this condition cor-tical bone is commonly more impaired than trabecular bone(23, 24).It is hard to explain the lower BMD in the group withreduced renal function, PTH, and bone markers being notsignificantly different. Indeed, even in overt renal failure,many manifestations of bone damage cannot be explainedexclusively by PTH excess (25). Other factors, such as im-mune factors, endothelial dysfunction and inflammation, ordecreased calcitriol activity, can exert major influences on bone metabolism and can be involved in the pathogenesis of  bone damage in CRF (25–29).The increased levels of plasma fibrinogen in patients withreduced Ccr could suggest the presence of subclinical in-flammation, which has been implicated in the pathophysi-ology of bone damage during early renal failure (28, 29). Themechanism of inflammation-induced bone loss could in-volve cytokines and growth factors system. For instance, theimbalance in the signaling system consisting of receptor ac-tivator of nuclear factor-  B ligand (RANKL), its receptorRANKL, and its decoy receptor osteoprotegerin (OPG) has been reported in both PHPT and CRF (25, 30, 31). However,recent studies indicate that the measurement of circulatingOPG may not reflect the local activity of the OPG/RANKLsystematbonecells(30,31).Thus,furtherstudiesareneededtoclarifythemechanismsbywhichamildCRFamplifiesthePHPT-induced bone damage.Whatever the pathogenetic mechanism, the importance of ourfindingsisremarkable,consideringtheprimaryrolethatBMD measurement has in both the clinical assessment andtreatmentofthemodernformofPHPT,inwhichtypicalbonediseaseisrare,whereasosteoporosisiscommon(1–5,23,24).In fact, a BMD decrease may influence the therapeuticalapproach to mild PHPT (4, 5).In conclusion, our findings indicate that in PHPT a slightdecrease in renal function is associated with more severe bone damage, in particular by a more severe decrease inBMD at each bone site and especially at cortical bone sites.This association is independent of age or PTH or BMI and isalso present in patients with mild PHPT. Some mechanisms,in addition to PTH excess, such as subclinical inflammation,maybeclaimedtoexplaintherelationshipbetweenrenalandBMD impairment in this condition.As a whole these data strengthen the NIH recommenda-tions for surgery in patients with mild PHPT who have aslight decrease of renal function.  Acknowledgments Received January 12, 2006. Accepted May 22, 2006.Address all correspondence and requests for reprints to: GiorgioBorretta,M.D.,DivisionofEndocrinologyandMetabolism,Departmentof Internal Medicine, A.S.O. S. Croce and Carle, Via M. Coppino, 26,12100 Cuneo, Italy. E-mail: References 1.  Bilezikian JP, Silverberg SJ  2004 Asymptomatic primary hyperparathyroid-ism. N Engl J Med 350:1746–17512.  Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ  2005 Primary hyperpara-thyroidism: new concepts in clinical, densitometric and biochemical features. J Int Med 257:6–173.  Silverberg S, Bilezikian JP  2003 Incipient primary hyperparathyroidism: a“forme fruste” of an old disease. J Clin Endocrinol Metab 88:5348–53524. 1991 National Institutes of Health Conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development confer-ence statement. Ann Intern Med 114:593–5975.  Bilezikian JP, Potts JT, Fuleihan GH, Kleerekoper M, Neer R, Peacock M,RastadJ,SilverbergSJ,UdelsmanR,WellsSA 2002Summarystatementfroma workshop on asymptomatic primay hyperparathyroidism: a perspective forthe 21st century. J Clin Endocrinol Metab 87:5353–53616.  Valdemarsson S, Lindergard B, Tibblin S, Bergenfelz A  1998 Increased biochemical markers of bone formation ans resorption in primary hyperpara-thyroidism with special reference with mild disease. J Intern Med 243:115–1227.  Yamashita H, Noguchi S, Uchino S, Watanabe S, Muratami T, Ogawa T,MasatsuguT,TakamatsuY,MiyatakeE,YamashitaH 2003Influenceofrenalfunctiononclinico-pathologicalfeaturesofprimaryhyperparathyroidism.Eur J Endocrinol 148:597–6028.  Hedback G, Oden A  1998 Death risk factor analysis in primary hyperpara-thyroidism. Eur J Clin Invest 28:1011–10189.  Hedback G, Abrahamsson K, Oden A  2001 The improvement of renal con-centration capacity after surgery for primary hyperparathyroidism. Eur J ClinInvest 31:1048–105310.  HedbackGM,OdenAS 2002 Cardiovascular disease, hypertension and renalfunction in primary hyperparathyroidism. J Intern Med 25:476–48311.  Fulton JP  1999 New guidelines for the prevention and treatment of osteopo-rosis. National Osteoporosis Foundation. Med Health RI 82:110–11112.  Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW, Johnston Jr CC, Kleerekoper M, Lindsay R, Luckey MM, McClung MR,NankinHR,PetakSM,ReckerRR,AndersonRJ,BergmanDA,BloomgardenZT,DickeyRA,PalumboPJ,PetersAL,RettingerHI,RodbardHW,Ruben-stein HA; AACE Osteoporosis Task Force  2003 American Association of Clinical Endocrinologists medical guidelines for clinical practice for the pre-vention and treatment of postmenopausal osteoporosis: 2001 edition, withselected updates for 2003. Endocr Pract 9:544–56413.  European Society of Hypertension-European Society of Cardiology Guide-linesCommittee 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hyper-tens 21:1011–105314.  Cockroft D, Gault MK  1976 Prediction of creatinine clearance from serumcreatinine. Nephron 16:31–4115.  ElderG 2002Pathophisiologyandrecentadvancesinthemanagementofrenalosteodystrophy. J Bone Miner Res 17:2094–210516.  Silver J, Kilav R, Naveh-Many T  2002 Mechanisms of secondary hyperpara-thyroidism. Am J Physiol Renal Physiol 283:F367–F37617.  RixM,AndreassenH,EskildenP,LangdahlB,OlgaardK 1999 Bone mineraldensityandbiochemicalmarkersofboneturnoverinpatientswithpredialysischronic renal failure. Kidney Int 56:1084–109318.  Hsu CY, Cummings SR, McCulloch CE, Chertow GM  2002 Bone mineraldensity is not diminished by mild to moderate chronic renal insufficiency.Kidney Int 61:1814–1820 Gianotti  et al.  • Renal Function and Bone Density in PHPT J Clin Endocrinol Metab, August 2006, 91(8):3011–3016  3015
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