systematic review of the evidence underlying the association between mineral metabolism disturbances...
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Systematic Review of the Evidence Underlying the Association BetweenMineral Metabolism Disturbances and Risk of Fracture and Need for
Parathyroidectomy in CKD
David Goldsmith, MA, FRCP,1 Prajesh Kothawala, MD, MPH,2 Arpi Chalian, MD,2
Myriam Bernal, MD, MPH,2 Sean Robbins, MS,3 and Adrian Covic, MD, PhD, FRCP4
Background: Chronic kidney disease (CKD) is associated with such complications as fractures andthe need for parathyroidectomy. Mineral metabolism control in patients with CKD has been poor.Studies have assessed fractures and parathyroidectomy risk with mineral disturbances, but withconsiderable diversity in methods. Thus, a systematic review was conducted to assess method orclinical heterogeneity by comparing the design, analytical techniques, and results of studies.
Study Design: Systematic review of the MEDLINE, EMBASE, and Cochrane databases between1980 and December 2007.
Setting & Population: Patients with CKD or dialysis patients.Selection Criteria for Studies: Observational and clinical trials investigating the risk of fractures or
parathyroidectomy with mineral disturbances.Predictor: Mineral metabolism variables (phosphorus, calcium, and parathyroid hormone [PTH]
levels).Outcomes: Fractures, need for parathyroidectomy.Results: 9 studies were identified that assessed fractures (n � 6) or need for parathyroidectomy (n �
3). Data for fractures or parathyroidectomy risk in predialysis patients are absent. Diversity acrossstudies was observed in populations, methods of exposure assessment, adjusted covariates, andreference mineral levels used in risk estimation. A significant fracture risk was observed with increasingPTH levels. However, additional data are required to understand fracture risk with changes inphosphorus or calcium levels. Data supported greater parathyroidectomy risk with increasing PTH,phosphorus, or calcium levels.
Limitations: Clinical and method heterogeneity across studies precluding the quantitative synthesisof data.
Conclusions: Serious limitations were observed in the number, quality, and method rigor of studies.Despite heterogeneity across studies, data suggest a significant parathyroidectomy risk with mineraldisturbances and a fracture risk with increasing PTH levels in dialysis patients. Additional high-qualitydata for risk of fractures or parathyroidectomy with changes in phosphorus, calcium, or PTH levels isrequired to highlight the importance of managing such common, but subclinical, conditions as mineralmetabolism disturbances.Am J Kidney Dis 53:1002-1013. © 2009 by the National Kidney Foundation, Inc.
INDEX WORDS: Mineral metabolism disturbances; chronic kidney disease; fracture; parathyroidectomy.
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hronic kidney disease (CKD) is a wide-spread problem present in approximately
3% of the US population and 16% in Europe.1
revalences of end-stage renal disease in 2005 inmerican and European adults were 1,569 and08 per million people, respectively.2,3 Five-year
From 1Guy’s Hospital, London, UK; 2Cerner LifeSciences,everly Hills, CA; 3Amgen (Europe) GmbH, Zug, Switzer-
and; and 4C.I. Parhon University Hospital, Iasi, Romania.Received December 3, 2008. Accepted in revised form
ebruary 13, 2009.Address correspondence to David Goldsmith, MA, FRCP,
uy’s Hospital, London, UK. E-mail: [email protected] or [email protected]
© 2009 by the National Kidney Foundation, Inc.0272-6386/09/5306-0014$36.00/0
wdoi:10.1053/j.ajkd.2009.02.010
American Journal of K002
urvival rates in dialysis patients are low (Unitedtates, 55.2%; Europe, 40.5%) and have re-ained constant during the past decade.2,3
CKD appears to be associated strongly withuch common complications as fractures andeed for parathyroidectomy.4-6 Furthermore, theisk of these complications appears to be multi-lied by the presence and severity of CKD. Therevalence of fractures is very high, developingn 5.2% of patients with CKD.7 Similarly, dialy-is patients also have a high rate of fractures2.9/1,000 patients/y)8 and at an earlier age thann the general population.9 US Renal Data Sys-em data identified a 4-fold greater hip fractureisk in dialysis patients than in the general popu-ation.6 The development of fractures in patients
ith CKD has severe economic and clinicalidney Diseases, Vol 53, No 6 (June), 2009: pp 1002-1013
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Risk of Fractures, Parathyroidectomy With Mineral Disturbances in CKD 1003
mplications. Medical costs of fractures are high,anging from $14,000 to $20,000/event.10 Hipractures place dialysis patients at a 2-fold greaterortality risk than the general population.11
Increased fracture risk may be attributed toactors unique to patients with CKD, such asitamin D deficiency, low calcium levels, alteredone morphological characteristics, and in-reased susceptibility to falls.12-14 Patients withKD are at increased risk of high-turnover and
ow-turnover bone disease, including the lowone mineral density seen in patients withoutKD with osteoporosis.15 Finally, the elderlyKD population is susceptible to malnutrition
hat is inversely associated with risk of frac-ures.16
Despite advances in the medical managementf CKD and associated secondary hyperparathy-oidism, defined as excessive secretion of para-hyroid hormone (PTH) in response to disrup-ions in the control of phosphorus, calcium, anditamin D, parathyroidectomy is necessary in aignificant proportion of dialysis patients. Para-hyroidectomy rates have increased progres-ively from 6.8/1,000 patient-years in 1998 to1.8/1,000 patient-years in 2002.5
Changes in mineral metabolism, which in-lude low vitamin D and increased phosphorusnd PTH levels, begin to develop early with onlylight impairment in renal function.17,18 How-ver, mineral control has been consistently poor.19
chievement of targets defined by the Nationalidney Foundation’s Kidney Disease Outcomesuality Initiative (KDOQI) has been difficultith vitamin D and calcium-binder treatment.ewer therapies that target all mineral parame-
ers are expensive, thus warranting a need tonderstand the true relationship between mineralisturbances (surrogate end points) and clinicalutcomes (hard end points) to implement treat-ent recommendations. Better understanding of
he clinical impact of changes in phosphorus,alcium, and PTH levels also is required tomprove clinical management and simplify clini-al decision making for these mineral abnormali-ies, which are commonly observed subclinicalonditions in patients with CKD.20
Our recent review examined the risk of all-ause and cardiovascular mortality and cardiovas-ular events with mineral abnormalities in pa-
ients with CKD.21 This study applies a method eimilar to our previous analysis to examine theisks of fractures and parathyroidectomy withineral disturbances in the CKD population. The
pecial objective of this study is to address methodr clinical diversity in designs, populations, andnalytical approaches among studies. This ap-roach differentiates our study from previouseviews.
METHODS
iteratureReview
The MEDLINE, EMBASE, and Cochrane databases wereystematically searched for English-language articles pub-ished from January 1980 to December 2007. The searchtrategy was composed of the following medical subjecteadings and key words from 3 categories: population (renalialysis, kidney failure chronic, dialysis, kidney failure,nd-stage renal disease, chronic kidney disease, hemodialy-is, peritoneal dialysis), mineral metabolism parametersphosphorus, calcium, parathyroid hormone), and outcomesfractures, parathyroidectomies).
The search strategy consisted of 3 components. The firstart of the search combined key words from the population,ineral parameters, and outcomes categories to capture
rticles about clinical risk with mineral disturbances inatients with CKD. The second component consisted ofxcluding all duplicates. The last component consisted ofimiting the search to English-language articles publishedetween 1980 and 2007.Published articles were included in the review if they met
hese criteria: participants were adults with CKD or onialysis therapy, outcomes were risk of fractures or parathy-oidectomy with mineral disturbances (phosphorus, calcium,nd PTH), and the study design was observational or alinical trial. Case series, editorials, reviews, and non–nglish-language articles were excluded.Using these criteria, 2 reviewers reviewed an identical
0% random sample of abstracts identified by using theearch strategy and evenly distributed the remaining ab-tracts on attainment of inter-rater agreement, assessed bysing � statistic (� � 0.7). The full-text publication wasbtained for each accepted abstract, and the review processas repeated for all articles.
ata Synthesis
Qualitative data analysis was performed to summarizeesults of the identified studies. Studies were categorized byype of outcome analyzed. The number of studies reportingignificantly increased risk (P � 0.05) of each outcome withbnormalities in every mineral parameter was calculated.he threshold mineral level above which the risk signifi-antly increased was ascertained. Also, fracture and parathy-oidectomy risk in patients with mineral levels beyond theDOQI targets was measured. Clinical and method homoge-eity across studies was explored in the populations studiedCKD stage, type [incident versus prevalent], and mode ofialysis [hemodialysis (HD) versus peritoneal dialysis (PD)]),
xposure assessments (continuously, categorically, or di-![Page 3: Systematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD](https://reader036.vdocuments.us/reader036/viewer/2022081807/5750763e1a28abdd2e9d9bcc/html5/thumbnails/3.jpg)
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hotomously), risk assessments (risk ratio [RR], hazard ratioHR], or odds ratio), types of covariates adjusted, andeference mineral levels used in risk measurement. Table 1ists baseline characteristics of studies.
Types of adjusted covariates were assessed to gain insightsf the ability to compare results. We captured covariates thatere controlled in Table 2, then compared them across studies
o assess the extent of heterogeneity. Quality of the observa-ional studies was assessed by using the Strengthening theeporting of Observational Studies in Epidemiology (STROBE)
tatement, a checklist of 22 items22 (Table 3). We created aating score and classified the quality of each publication asood (met criteria listed by at least 17 items; 75%), moderate11 to 16 items; 50%), or poor (�10 items).
RESULTS
iteratureReview
The search strategy identified 1,162 refer-nces, of which 235 abstracts were selected forull-text review. Nine of these met the criteria fornclusion in the review. The majority of rejectedrticles failed to assess the outcomes of interestFig 1). All 9 studies were observational inature and assessed fractures (n � 6) or parathy-oidectomy (n � 3).
ractures
Data for fracture risk with mineral distur-ances are limited (n � 6). Furthermore, muchiversity was observed in study populations,ethods, and outcomes.9,10,13,23-25 Five stud-
es9,10,13,24,25 were retrospective cohorts and 1tudy23 was cross-sectional. The dialysis methodor patients was HD only (n � 4)13,23-25 or bothD and PD (n � 2).9,10 Evidence for fractures inredialysis patients is absent. Only 1 study13 wasated as good based on the STROBE criteria. Theuality of the methods and reporting of data wereood in only 1 study,13 but moderate (n � 4) oroor (n � 1) in the remainder. No study reportedTH assays, an important source of heteroge-eity. Fracture types assessed varied from hipn � 4),9,10,13,25 vertebral (n � 2),10,23 long bonen � 1),24 and pelvic (n � 1)10 to any fracture (n �).25 Evidence for risk of common fractures ofhe femoral neck and wrist is absent.
Three studies13,23,24 treated mineral parame-ers categorically: 1 study,9 dichotomously; 1tudy,10 continuously; and 1 study,25 both cat-gorically and continuously, with reference lev-ls defined inconsistently. Fracture risks were
xpressed as RR (n � 3),13,23,25 HR (n � 1),24 Ta
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Risk of Fractures, Parathyroidectomy With Mineral Disturbances in CKD 1005
nd rate ratio (n � 1)10 to correlation coefficientn � 1).9 Of a set of 19 considered covariates,nly demographics was controlled uniformly.mportant risk factors for fractures, such as frac-ure history (n � 2),10,25 body mass index (n �),24,25 dialysis vintage (n � 2),24,25 comedica-ions (steroids [n � 1]),24 and comorbiditiesdiabetes [n � 1)],10 were rarely adjusted. Only 1tudy assessed the effect of controlling mineralarameters within KDOQI targets on fractureisk.25 Table 4 lists results of studies.
Phosphorus
Four studies10,13,24,25 evaluated fracture riskith high phosphorus levels in dialysis patients;one showed a significant relationship. Also, riskstimates varied across studies because of differ-nces in methods of phosphorus assessment andype of fractures studied. Analyzing phosphorusevel continuously, the relative risk of any frac-ure increased nonsignificantly by 4% for every-mg/dL increase (RR, 1.04; 95% confidencenterval [CI], 0.98 to 1.11).25 In addition, nohange in risk was observed on continuous anal-sis of hip fractures (RR, 0.99; 95% CI, 0.89 to.1).25 Two studies used categorical models; nei-her reported a significant association.24,25 Theelative risk of hip fracture was 1.26 (95% CI,.78 to 2.04)25 at levels of 4.5 to 5.49 mg/dLreference, 3.5 to 4.49 mg/dL), but no change inisk was seen for any fractures25 or long-boneractures.24 In addition, 2 other studies also ob-erved no significant change in risk of hip,10,13
ertebral,10 or pelvic10 fractures, but did noteport the method of phosphorus assessment.
Two studies24,25 assessed low phosphorus levelategorically, but did not identify a significantisk of hip, long-bone, or any fractures.
Calcium
Four studies10,13,24,25 evaluated fracture riskith high calcium levels in dialysis patients.nalyzing continuously, 1 study reported a non-
ignificant increase in risk of any fracture by0% (RR, 1.1; 95% CI, 0.97 to 1.25) and nohange in hip fracture risk with every 1-mg/dLncrease in calcium level.25 Two studies24,25 as-essed calcium categorically and found no evi-ence of significant risk. Categorical analysis ofalcium with the KDOQI target (8.4 to 9.5 mg/dL)
as the reference did not yield a significant increase
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n risk of hip (RR, 0.91; 95% CI, 0.6 to 1.36) or anyractures (RR, 0.96; 95% CI, 0.74 to 1.23) withevels of 9.6 to 10.1 mg/dL.25 Risk also was nonsig-ificant for long-bone fractures at levels of 9 mg/dLr greater (reference, 8.4 to 8.9 mg/dL).24 In addi-ion, 2 studies reported no significant risk of hip,10,13
ertebral,10 and pelvic fractures,10 but did not re-ort the method of calcium evaluation.
Two studies assessed the risk of fractures withow calcium levels,24,25 but did not observe aignificant relationship for hip, any fracture, orong-bone fractures.
Parathyroid Hormone
Five studies10,13,23-25 assessed high PTH lev-ls in dialysis patients; 3 studies10,23,25 identifiedsignificant relationship. Data supported a sig-
ificant risk of vertebral fracture, followed byip, pelvic, and long-bone fractures. As a continu-us variable, a 200-pg/mL increase in PTH levelignificantly increased the risk of any fracturesy 9%, but no change was observed for hipractures (RR, 0.95; 95% CI, 0.79 to 1.14).25 A00-pg/mL increase in PTH level was associatedith a significant risk of both vertebral and hip
rate ratios, 1.33 [95% CI, 1.06 to 1.66] and 1.1595% CI, 1.01 to 1.31]), but not pelvic fracturesrate ratio, 0.91; 95% CI, 0.71 to 1.16) within theange of 300 to 800 pg/mL, but not within 1 to00 pg/mL and greater than 800 pg/mL, resultingn a U-shaped relationship.10
The importance of controlling PTH levelsithin the KDOQI target was confirmed by a
ategorical analysis that identified a thresholdevel greater than 900 pg/mL (reference, 150 to00 pg/mL), at which the risk of any fracturencreases significantly (RR, 1.72; 95% CI, 1.02o 2.9).25 Vertebral fracture risk was significantt a threshold of 62 to 202 pg/mL (reference, 5 to1 pg/mL; RR, 2.4).23 With respect to longones, a significant decrease in risk was ob-erved at a cut-off level of 227.1 to 538 pg/mLreference, �39 pg/mL; HR, 0.68; 95% CI, 0.48o 0.95).24 However, risk of hip fractures wasonsignificant in 2 studies at levels of 301 to 600g/mL (reference, 150 to 300 pg/mL)25 andreater than 300 pg/mL (reference, 100 to 300g/mL).13
Two studies9,25 assessed low PTH levels; 1bserved a significant relationship. The correla-
ion of low PTH level (�195 pg/mL) and hip wracture risk was significant (reference, �195g/mL; r � 0.128).9 However, categorical assess-ent did not identify a significant risk of hip or
ny fractures at levels less than 150 pg/mLelative to the reference KDOQI target.25
arathyroidectomy
Only 3 studies26-28 assessed parathyroidec-omy risk with mineral disturbances. All26-28
ere retrospective and enrolled prevalent HDatients only (n � 2)27,28 or incident HD or PDatients (n � 1).26 Evidence for parathyroidec-omy risk in predialysis patients is absent. Twotudies were rated as moderate quality and 1 wasated poor based on the STROBE criteria.
One study27 assessed mineral parameters cat-gorically, whereas the rest26,28 used a continu-us variable. Risks were calculated as RR (n �)26,28 or HR (n � 1).27 None measured thessociation between KDOQI targets and risk ofarathyroidectomy. Of 12 covariates considered,nly sex was adjusted uniformly. It is vital toontrol for dialysis vintage because parathyroid-ctomy risk appears to peak after 5 to 10 years ofialysis therapy,27 but only 1 study adjusted fort.27 Other established risk factors, such as hemo-lobin level (n � 2)27,28 and comorbidities (dia-etes [n � 1]27) were adjusted inconsistently.ne study27 assessed a population of HD and PDatients, but did not adjust for dialysis modality.ype of PTH assays used, an important source ofeterogeneity, was reported by only 1 of the 3tudies (immunoradiometric assays test). Table 5ists study results.
Phosphorus
Three studies26-28 assessed phosphorus levelsn dialysis patients; all reported a significantelationship. Two studies26,28 using continuousodels reported significant increases in relative
isk by 17% (RR, 1.17; 95% CI, 1.09 to 1.25)28
nd 10.7% (RR, 1.07; 95% CI, 1.05 to 1.09)26 forvery 1-mg/dL and 0.1-mmol/L increase in phos-horus levels, respectively. Categorically, 1tudy27 reported a threshold of 5.4 to 6.3 mg/dL,t which the risk increased significantly (HR,.07, 95% CI, 1.43 to 2.98; reference, �4.4g/dL). Evidence for parathyroidectomy risk
ith low phosphorus level is absent.![Page 6: Systematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD](https://reader036.vdocuments.us/reader036/viewer/2022081807/5750763e1a28abdd2e9d9bcc/html5/thumbnails/6.jpg)
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Risk of Fractures, Parathyroidectomy With Mineral Disturbances in CKD 1007
Calcium
Two studies27,28 analyzed parathyroidectomyisk with high calcium levels in dialysis patients.n 1 study28 using a continuous model, every-mg/dL increase in calcium level was associ-ted with a 58% (RR, 1.58; 95 CI, 1.35 to 1.85)ignificantly greater relative risk of parathyroid-ctomy. Categorical analysis of calcium identi-ed a threshold of 8.8 to 9.2 mg/dL (HR, 1.73;5% CI, 1.2 to 2.49; reference, �8.7 mg/dL), athich risk increased significantly.27 Data forarathyroidectomy risk with low calcium levelsre absent.
ParathyroidHormone
Three studies26-28 assessed PTH levels in dialy-is patients; all showed significant risk with highevels. Continuous assessment of PTH levelshowed significant increases in relative risk by.8%26 (RR, 1.018; 95% CI, 1.01 to 1.027) and%28 (RR, 1.07; 95% CI, 1.05 to 1.09) for every-pmol/L and 100-pg/mL increase in PTH level.nalyzing categorically,27 risk of parathyroidec-
omy increased in a stepwise fashion with greaterTH levels. A significant increase in parathyroid-ctomy risk was observed at PTH levels of 38 to8 pg/mL compared with the reference level of
Table 3. Assessment of the Quality of ObservationalAbnormalities Based
Reference
Introduction
Abstract Rationale ObjectiveStudy-Design
tsumi et al,23 1999 ● ● ●
oco and Rush,9 2000 ● ● ● ●
anese et al,10 2006 ● ● ● ●
adoul et al,25 2006 ● ● ● ●
orna et al,26 2004 ● ● ● ●
aneko et al,24 2006 ● ● ● ●
linin et al,27 2007 ● ● ● ●
tehman-Breen et al,13 2000 ● ● ● ●
oung et al,28 2005 ●
Note: Items of good quality are added to achieve a totaitle/abstract: reporting study design and a balanced sucientific rationale behind the study has been reported;eported; (4) study design: key elements of the study detudy, relevant dates, including periods of enrollment, exarticipants: eligibility criteria and source/method of sxposure, predictors, potential confounders, and effecteasons for its adjustment were reported; (8) data sourceethod of assessment are described; (9) bias: efforts undf how the study size was arrived at; (11) quantitative var
n the analyses; (12) statistical methods: description of met
7 pg/mL or less (HR, 2.41; 95% CI, 1.2 to 4.84) p
hat increased in a stepwise fashion to 13.8195% CI, 7.47 to 24.5) with PTH levels greaterhan 480 pg/mL relative to the reference of 37g/mL or less. Evidence for parathyroidectomyisk with low PTH is lacking.
DISCUSSION
Our review is the first systematic appraisal ofhe evidence for risks of fractures and parathy-oidectomy associated with mineral disturbancesn patients with CKD. The quality of evidenceelating mineral parameters and clinical out-omes poses serious limitations. Very few stud-es have focused on fractures (n � 6) and parathy-oidectomy (n � 3) in dialysis patients.ssessments of predialysis patients for risk of
hese outcomes are absent, which raises concernn view of the role of CKD in multiplying theisk of clinical outcomes.29
Studies were diverse in designs, populations,nd analytical techniques used. Study designsere only retrospective or cross-sectional and
ssessed prevalent or incident HD or PD patientsr sometimes both. Important method heteroge-eity was observed across techniques of mineralarameter assessment, risk calculation, adjustedovariates, and reference mineral levels. Mineral
s Assessing Risk of Clinical Outcomes With MineralSTROBE Statement
Methods
InclusionCriteria Variable
DataSource Bias
StudySize
QuantitativeVariable
StatisticalMethods
●
● ● ● ●
● ● ● ● ● ●
● ● ● ●
● ● ●
● ● ●
● ● ●
● ● ● ● ● ● ●
● ●
out of 22. The description of each item is as follows: (1)y of method and results; (2) background/rationale: thejectives: specific objectives and hypotheses have beenresented early in the report; (5) setting: location of the, follow-up, and data collection have been described; (6)n of participants described; (7) variables: outcomes,rs have been clearly defined; type of confounders andsurement: for each variable of interest, data source andn to address source of bias; (10) study size: explanationexplanation of the handling of the quantitative variablesed to control confounding, sensitivity analyses, and (cont’d)
Studieon the
Setting
●
●
●
l scoremmar(3) obsign p
posureelectiomodifies/meaertake
iables:
arameters were assessed categorically, continu-
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usly, or dichotomously. Although categoricalvaluation is a rigorous technique that captureshe range of mineral levels associated with signifi-ant risk, the reference mineral levels used foreasuring risk lacked uniformity, thus further
imiting the comparability of results. Continuousssessment does not allow identification of thehreshold level at which risk begins to increasend tends to force a linear relationship betweenineral parameters and outcome risk; neverthe-
ess, many studies used continuous models (n �
Table 3 (Cont’d). Assessment of the Quality of ObserMineral Abnormalities Ba
Reference
Results
ParticipantDescriptive
DataOutcome
Data Res
tsumi et al,23 1999 ●
oco and Rush,9 2000 ● ●
anese et al,10 2006 ● ● ●
adoul et al,25 2006 ●
orna et al,26 2004 ● ●
aneko et al,24 2006 ● ●
linin et al,27 2007 ● ●
tehman-Breen et al,13 2000 ● ●
oung et al,28 2005 ●
ow missing data and loss to follow-up were addressed;f study, eg, numbers potentially eligible, examined forollow-up, and analyzed; (14) descriptive data: characteriocial; (15) outcome data: time-dependent informationpplicable, confounder-adjusted estimates and their preensitivity analysis; (18) key results: key results were sutudy discussed key limitations, taking into account theautious overall interpretation was given considering theneralizability: the external validity of results were disunders was provided.
Abbreviation: STROBE, Strengthening the Reporting of O
sFigure 1. Flow chart of results of the literature review.
). Finally dichotomous analysis also preventshe comparability of results across studies. Riskalculations included RR (n � 6), HR (n � 1),ate ratio (n � 1), or correlation coefficient (n �). Although most studies did not report the PTHssays used, PTH concentrations can vary de-ending on type of assay, which in turn cannfluence risk measurement of fractures or para-hyroidectomy.30 Thus, variations in PTH assaysan be another potential source of method heter-geneity.Despite this heterogeneity, the review identi-
ed a significant relationship between mineralarameters and parathyroidectomy in dialysisatients. With respect to fractures, risk was sig-ificant with high PTH levels. However, inabil-ty to conduct a meta-analysis because of enor-
ous data heterogeneity precluded us fromrawing a conclusion about the relationship be-ween fracture risk and changes in calcium orhosphorus levels because appropriate poolingf additional uniform data might have yielded aignificant result. Thus, data for fracture riskith abnormal calcium or phosphorus levels areeterogeneous and unclear, warranting addi-ional evidence to derive a conclusion about the
al Studies Assessing Risk of Clinical Outcomes Withthe STROBE Statement
Discussion
Totalyult
OtherAnalyses Limitation Interpretation
ExternalValidity Funding
● ● ● 9/22● 13/22
● ● 16/22● ● ● 13/22
● ● 12/22● ● ● 13/22● ● ● ● 14/22● ● ● ● 18/22● ● 8/22
rticipants: number of individuals reported at each stageity, confirmed eligible, included in the study, completedf study participants, including demographic, clinical, andcomes; (16) main results: unadjusted estimates and, if(17) other analyses: reporting of subgroup analysis ored with respect to study objectives; (19) limitations: the
e of potential bias or imprecision; (20) interpretation: atives, limitations, and results from similar studies; (21)
d; and (22) funding: the source of funding and role of
ational Studies in Epidemiology.
vationsed on
ultKe
Res
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●
●
●
●
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(13) paeligibilstics ofor outcision;mmarizsourc
e objeccusse
ignificance of the relationship. Of 5 studies, 3
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Risk of Fractures, Parathyroidectomy With Mineral Disturbances in CKD 1009
Table 4. Summary of Results of Studies Evaluating Risk of Fractures With Changes in MineralMetabolism Parameters
StudyType ofDialysis Fractures Variable Variable Levels
Risk Ratio(95% CI)
CorrelationCoefficient (r) P
adoul et al,25 2006 HD Any Phosphorus (mg/dL) Categorical �3.5 1.29 (0.93-1.77) NS3.5-4.49 1 (reference) NS4.5-5.49 0.98 (0.76-1.29) NS
�5.5 0.98 (0.77-1.31) NSContinuous Risk/1-mg/dL increase 1.04 (0.98-1.11) NS
Calcium (mg/dL) Categorical �8.4 0.86 (0.58-1.34) NS8.4-9.5 1 (reference) NS9.6-10.1 0.96 (0.74-1.23) NS�10.2 1.2 (0.92-1.59) NS
Continuous Risk/1-mg/dL increase 1.1 (0.97-1.25) NSPTH (pg/mL) Categorical �150 1.05 (0.8-1.38) NS
150-300 1 (reference)301-600 1.24 (0.88-1.76) NS601-750 0.86 (0.41-1.77) NS751-900 1.03 (0.35-3.08) NS�900 1.72 (1.02-2.9) �0.05
Continuous Risk/200-pg/mL increase 1.09 (1.01-1.17) �0.05adoul et al,25 2006 HD Hip Phosphorus (mg/dL) Categorical �3.5 1.62 (0.94-2.81) NS
3.5-4.49 1 (reference)4.5-5.49 1.26 (0.78-2.04) NS
�5.5 1.29 (0.81-2.06) NSContinuous Risk/1-mg/dL increase 0.99 (0.89-1.1) NS
Calcium (mg/dL) Categorical �8.4 0.93 (0.46-1.87) NS8.4-9.5 1 (reference)9.6-10.1 0.91 (0.6-1.36) NS�10.2 1.08 (0.69-1.68) NS
Continuous Risk/1-mg/dL increase 1 (0.82-1.22) NSPTH (pg/mL) Categorical �150 1.27 (0.78-2.06) NS
150-300 1 (reference) NS301-600 1.19 (0.63-2.26) NS601-750 0.33 (0.05-2.37) NS751-900 0.62 (0.08-4.87) NS�900 1.14 (0.34-3.8) NS
Continuous Risk/200-pg/mL increase 0.95 (0.79-1.14) NStehman-Breen et al,13
2000HD Hip Phosphorus NR NR 1.02 (0.92-1.13) 0.7
Calcium NR NR 0.93 (0.78-1.1) 0.4PTH (pg/mL) Categorical �100 1.17 (0.66-2.08) 0.6
100-300 1 (reference)�300 1.16 (0.6-2.26) 0.7
oco and Rush,9 2000 NR Hip PTH (pg/mL) Dichotomous �195 1 (reference)�195 0.128 0.006
Study Type ofDialysis
Fractures Variable Variable Levels Hazard Ratio(95% CI)
Rate Ratio(95% CI) Risk Ratio
aneko et al,24
2006HD Long bone Phosphorus
(mg/dL)Categorical �4.4 NR NS
4.5-5.4 1 (reference)5.5-6.4 NR NS6.5-7.7 NR NS
�7.7 NR NSCalcium
(mg/dL)Categorical �8.4 NR NS
8.5-8.9 1 (reference) NS9-9.4 NR NS
9.4-10 NR NSPTH (pg/mL) Categorical �39 1 (reference)
39.1-105 NR NS105.1-227 NR NS227.1-538 0.68 (0.48-0.95) 0.03
�538 NR NSanese et al,10
2006HD and PD Hip, vertebral
or pelvicPhosphorus NR NR NSCalcium NR NR NS
Hip PTH (pg/mL) Continuous (risk/100-pg/mLincrease in everycategory)
1-300 0.91 (0.75-1.1) NS300-800 1.15 (1.01-1.31) 0.03�800 0.99 (0.97-1.02) NS
Vertebral 1-300 0.74 (0.51-1.05) NS300-800 1.33 (1.06-1.66) 0.03�800 0.99 (0.95-1.04) NS
(Continued)
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howed significant fracture risk with high PTHevels. Risk estimates varied depending on frac-ure type, mineral assessment technique, andeference mineral levels. Risk of any fracturencreased significantly by 9% with a 200-mg/dLncrease in PTH level and by 72% with a PTHevel greater than 900 pg/mL (reference, 150 to00 pg/mL). The risk of hip fracture was signifi-ant for every 100-pg/mL increase in PTH levelithin the category of 300 to 800 pg/mL, but
ailed to reach significance in categorical mod-ls.10 Also, hip fracture risk increased signifi-antly in patients with PTH levels less than 195g/mL (reference, �195 pg/mL).9 Risk esti-
Table 4 (Cont’d). Summary of Results of StudiesMetabolis
Study Type ofDialysis
Fractures Variable Variabl
Pelvic
tsumi et al,23
1999HD Vertebral PTH (pg/mL) Categorical
Note: Conversion factors for units: serum phosphorus in0.2495; serum PTH levels expressed in pg/mL and ng/L aAbbreviations: CI, confidence interval; HD, hemodialysi
TH, parathyroid hormone.
Table 5. Summary of Results of Studies Evaluating Risk
ReferenceType ofDialysis
MineralVariable
Type ofVariable
linin et al,27
2007HD Phosphorus
(mg/dL)Categorical
Calcium (mg/dL) Categorical
PTH (pg/mL) Categorical
oung et al,28
2005HD Phosphorus Continuous Risk/
Calcium Continuous Risk/PTH Continuous Risk/
orna et al,26
2004HD and PD Phosphorus Continuous Risk/
PTH Continuous Risk/
Note: Conversion factors for units: serum phosphorus in0.2495; serum PTH levels expressed in pg/mL and ng/L aAbbreviations: CI, confidence interval; HD, hemodialysi
ormone.
ates for vertebral fractures varied from 1.33every 100-pg/mL increase within 300 to 800g/mL) to 2.4 (62 to 202 versus 5 to 61 pg/L).10,22 This finding is consistent with previous
rticles that reviewed only selected studies.31
he high risk of fractures with secondary hyper-arathyroidism may be attributed to uncontrolledTH-induced high-turnover bone lesions as aesult of uremic osteodystrophy and osteitis fi-rosa.15,32 The significant relationship betweenTH level and parathyroidectomy was expectedecause increased PTH level is a consequence ofyperfunctional parathyroid glands. The strongssociation between phosphorus level and para-
ating Risk of Fractures With Changes in Mineralameters
Levels Hazard Ratio(95% CI)
Rate Ratio(95% CI) Risk Ratio
1-300 1.02 (0.75-1.37) NS300-800 0.91 (0.71-1.16) NS
�800 1.01 (0.98-1.03) NS5-61 1 (reference)
62-202 2.4 �0.05203-1,818 1.6 �0.05
to mmol/L, �0.3229; serum calcium in mg/dL to mmol/L,ivalent.not reported; NS, not significant; PD, peritoneal dialysis;
athyroidectomy With Mineral Metabolism Disturbances
elsHazard Ratio
(95% CI)Risk Ratio(95% CI) P
4.4 1 (reference)-5.3 1.34 (0.89-2.01) NS-6.3 2.07 (1.43-2.98) �0.001-7.5 2.17 (1.52-3.11) �0.0017.5 2.92 (2.06-4.15) �0.0018.7 1 (reference)
-9.2 1.73 (1.2-2.49) 0.004-9.6 2.6 (1.84-3.66) �0.001-10.3 3.38 (2.41-4.73) �0.00137 1 (reference)-98 2.41 (1.2-4.84) 0.01-210 3.5 (1.8-6.83) 0.002-480 6.5 (3.44-12.28) �0.00180 13.81 (7.47-25.55) �0.001
increase 1.17 (1.09-1.25) �0.001increase 1.58 (1.35-1.85) �0.001
/dL increase 1.07 (1.05-1.09) �0.001ol/L increase 1.107 (1.035-1.183) 0.002L increase 1.018 (1.01-1.027) �0.001
to mmol/L, �0.3229; serum calcium in mg/dL to mmol/L,ivalent.not significant; PD, peritoneal dialysis; PTH, parathyroid
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hyroidectomy may be explained by the hyper-hosphatemia-associated increase in parathyroidransforming growth factor levels, which resultsn hyperplastic growth in parathyroid glands.33
Identification of the threshold mineral level athich clinical risk starts to increase significantly
s important for clinical practice. However, thresh-ld levels varied considerably. In 1 study, theTH threshold level at which fracture risk signifi-antly increased was 62 to 202 pg/mL (reference,to 61 pg/mL), which is lower than the KDOQI
arget range. Conversely, patients with PTH lev-ls greater than 900 pg/mL had a greater fractureisk than those in the category of 150 to 300g/mL. Based on these large differences, theDOQI guidelines, developed empirically andased on opinion, may appear somewhat conser-ative.34 However, randomized controlled trialsf secondary hyperparathyroidism interventionfficacy in ameliorating fracture or parathyroid-ctomy risk are long overdue and urgently neededo establish a causal relationship between min-ral parameters and patient outcomes. However,he randomized controlled trials will need toave a large sample size, long duration, and goodeasures (skeletal surveys and clinical examina-
ion) to improve the diagnosis of fractures andarathyroidectomy, which are relatively infre-uent events.The KDIGO (Kidney Disease: Improving
lobal Outcomes) foundation has commissionedhe development of practice guidelines for theanagement of mineral disturbances in patientsith CKD to address the gap of heterogeneity in
he classification of these disorders, improveomparability of results, and provide clinicalnsights about threshold mineral levels associ-ted with significant fracture risk. Our study inhe future climate of post-KDIGO guidelinesay help nephrologists understand the strengths
nd weaknesses of the current literature on clini-al risk with mineral disturbances, highlight themportance of mineral control, and emphasizehe importance of clinical examination for signsf fractures in patients with mineral abnormali-ies.
Our review has limitations. Results could note quantitatively meta-analyzed because of theignificant clinical and method heterogeneity ob-erved across studies with respect to study popu-
ations and techniques of risk estimation and aineral parameter assessment. Lack of uniformontrol of such covariates as dialysis vintage alsos an important limitation to the validity of theignificance of results across studies. Further-ore, need for parathyroidectomy also may have
een influenced by uncontrolled local factorsgeographic location and access to nephrologyare)35 and use of cinacalcet,36 which can delayhe need for parathyroidectomy through betterTH level control. In particular, homogenousata are required for testing risk of fractures withhanges in calcium or phosphorus levels, forhich the current evidence is unclear and pre-
ludes us from drawing conclusions. Therefore,esults of this systematic review should be re-iewed keeping in mind the serious limitationsbserved in the method quality of studies. Confir-ation of the significance of clinical risk withineral abnormalities requires high-quality stud-
es with homogenous populations and analyticalechniques and control of all important covari-tes.
Serious limitations were observed in the num-er, quality, and methods of studies that assessedisk of fractures or parathyroidectomy with min-ral metabolism disturbances. Despite these draw-acks, the data showed significant parathyroidec-omy risk with mineral disturbances. The dataupported greater fracture risk with high PTHevels, but the evidence for fracture risk withhanges in calcium or phosphorus levels is notlear. Additional high-quality data for risks ofractures or parathyroidectomy with changes inhosphorus, calcium, or PTH levels are requiredo improve the comparability of results acrosstudies and thus aid in highlighting the impor-ance of managing such common, but subclini-al, conditions as mineral metabolism distur-ances.
ACKNOWLEDGEMENTSAntonia Panayi of Amgen Europe provided editing assis-
ance. Previously presented in abstract form at the Europeanenal Association-European Dialysis Transplant Associa-
ion (ERA-EDTA) conference in Sweden, May 10-18, 2008.Support: Information on funding sources is listed in the
inancial Disclosure.Financial Disclosure: This study was funded by Amgen
Europe) GmbH. Dr Goldsmith has served as a speaker orember of an advisory board for Amgen, Genzyme, andhire Pharmaceuticals. Drs Kothawala, Bernal, and Chalian
re employees of Cerner LifeSciences, a consulting com-![Page 11: Systematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD](https://reader036.vdocuments.us/reader036/viewer/2022081807/5750763e1a28abdd2e9d9bcc/html5/thumbnails/11.jpg)
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actors for hip fracture in white women. Study of Osteoporotic
ractures Research Group. N Engl J Med 332:767-773, 1995 D17. Levin A, Bakris GL, Molitch M, et al: Prevalence ofbnormal serum vitamin D, PTH, calcium, and phosphorusn patients with chronic kidney disease: Results of the studyo evaluate early kidney disease. Kidney Int 71:31-38, 2007
18. Zehnder D, Landray MJ, Wheeler DC, et al: Cross-ectional analysis of abnormalities of mineral homeostasis,itamin D and parathyroid hormone in a cohort of pre-ialysis patients. The Chronic Renal Impairment in Birming-am (CRIB) Study. Nephron Clin Pract 107:c109-c116,00719. Young EW, Akiba T, Albert JM, et al: Magnitude and
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Risk of Fractures, Parathyroidectomy With Mineral Disturbances in CKD 1013
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