Bone metabolism and intensive care

Bone metabolism on the ICU

Ard Struijs Internist intensivist

Erasmus Medisch Centrum

Wat doet een intensivist als voorzi=er van de IWO

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Dr. A. Struijs

Waarom doe?e het nou

•  PromoAe onderzoek naar GIOP in de dagelijkse prakAjk 2000

•  Keuze endocrinologie. Intensive care, beide? •  Voorbeelden opleiders H.Mulder, A. Fischer •  Thoraxcentrum, hartchirurgie, longchirurgie •  Beademing, ARDS, Hart-‐longmachine, long als motor inlammatoire response

•  ASBMR NO in bo=en vs NO op de IC

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Dr. A. Struijs

HibernaAon

•  Disuse causes imbalance in bone formaAon and bone resorpAon.

•  In bears hibernate the bone volume fracAon and Assue mineral density do not differ from acAve bears,

•  Indices of cellular level like mineral apposiAon rate and ostoid thickness decreased.

•  Bears maintain coupling between in bone turnover

McGEE Bone 21 Aug Epub J Biomech 2009:42;1378

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Dr. A. Struijs

Wat is de relaAe IC en bo=en ??

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Dr. A. Struijs

© 2011 by the Society of CriAcal Care Medicine and Lippinco= Williams & Wilkins. Published by Lippinco= Williams & Wilkins, Inc.

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Bone loss during cri.cal illness: A skeleton in the closet for the intensive care unit survivor? *. Griffith, David; MBChB, FRCA; Walsh, Tim; FRCP, FRCA; MD, MRes CriAcal Care Medicine. 39(6):1554-‐1556, June 2011. DOI: 10.1097/CCM.0b013e318215beb4

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Dr. A. Struijs

Examples of Causes of Immobilisa.on Bone Loss ▶ Damage to the vertebral bone marrow with deleterious effects on the bone ▶ Hemiplegia aker cerebrovascular incidents ▶ Paraplegia of the lower half of the body ▶ ImmobilisaAon aker fracture of the lower extremiAes (rapid bone loss especially in children) ▶ ImmobilisaAon aker operaAons on the legs or feet with subsequent reduced mobility for prolonged periods ▶ ImmobilisaAon due to muscular diseases or neurological disorders, e.g. mulAple sclerosis

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Dr. A. Struijs

Bone loss due to immobilisaAon •  Insufficient physical ac0vity is one of the most important overall risk factors for

osteoporosis.

•  This is especially true for young bed-‐ridden pa0ents who can loose up to 30% of their bone density within a few months while years are required for its replacement – that is for restora0on of density as it was before, i.e. “res0tu0o ad integrum” (see also Bartl and Frisch: Atlas of Bone Biopsy in Internal

Medicine).

•  For example, when an arm is enclosed in plaster for 3 weeks aker a fracture, the immobilised bones may loose up to 6% of their bone mass during this short

period. •  A study of paAents confined to bed has shown that, on average, trabecular

bone decreases by about 1% a week. When physical acAvity is resumed, bone density increases by 1% a month – considerably slower than its loss.

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Bone hyperresorpAon: Laboratory evaluaAon • 24-‐hr urine within 48 hours of RCU admission, • Urine N-‐telopepAde (NTx) measured, Osteomark® assay • Serum Intact PTH, 25-‐vitamin D, 1,25-‐vitamin D • Elevated serum intactPTH level diagnosAc of physiologically significant vitamin D deficiency • Elevated Urine NTx = Abnormal Bone ResorpAon • If NTx elevated, then: – Low PTH = ImmobilizaAon – High PTH = Vitamin D deficiency – Normal PTH = Both

Bone HyperresorpAon • CCI pts are at risk for accelerated bone loss due to: – Vitamin D deficiency – Prolonged immobility • IdenAficaAon and treatment of bone loss may prevent debilitaAng fractures aker recovery Nierman DM, Mechanick JI. Chest. 1998;114:1122-‐8

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Diagram of proposed metabolic pathways that lead to bone hyperresorption with elevated urine NTx levels.

Nierman D M, Mechanick J I Chest 2000;118:761-766

©2000 by American College of Chest Physicians

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© Williams & Wilkins 1997. All Rights Reserved. Published by Lippinco= Williams & Wilkins, Inc. 4

Urinary pyridinium cross-‐link excre.on is increased in cri.cally ill surgical pa.ents. Shapses, Sue; Weissman, Charles; Seibel, Markus; Chowdhury, Hasina CriAcal Care Medicine. 25(1):85-‐90, January 1997.

Figure 1 . ExcreAon of urinary pyridinoline (PYD/CreaAnine, top) and deoxypyridinoline (DPD/CreaAnine, bo=om) in healthy age-‐matched subjects and in criAcally ill paAents during their first 2 days in the intensive care unit (ICU). Solid bars, healthy subjects (n = 17); shaded bars, paAents who stayed in the ICU 5 days (n = 5). *Differs from healthy subjects, p t differs from paAents with a <or=to5-‐day stay in the ICU, p < .02. copyright

Dr. A. Struijs

Kenmerken metabole botziekten op IC

•  ImmobilisaAe •  Ontkoppeling aanmaak awraak gekenmerkt door hyperresorpAe

•  Secundaire hyper parathyreoidie •  Vitamine D deficienAe •  SIRS •  GlucocorAcoiden

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paAents, 19 months, retrospecAve review • 131 (83%) pts had ↑ urine NTx • 55 pts: – ↑ NTx levels at RCU admission – Treated with either calcitriol alone (n = 44) or calcitriol + pamidronate (n = 11) – NTxs remeasured aker treatment • All pts received calcitriol (1,25-‐dihydroxyvitamin D3) 0.25 mcg/day enterally (Rocaltrol®) or IV (Calcijex®) • At endocrinologist’s discreAon, pamidronate, 30 mg IVSS qD x 3 consecuAve days given (~ $532) • IndicaAons for pamidronate: – Elevated PTH + hypercalciuria – Very elevated urine NTx suggesAng severe bone hyperresorpAon Nierman DM, Mechanick JI. Chest 2000; 118:761-‐6

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Changes of basic bone turnover parameters in short-‐term and long-‐term paAents with spinal cord injury Autor(es) Reiter Andreas Ludwig, Volk Andreas, Vollmar Jens,

Fromm Bernd, Gerner, Hans Juergen

The bone mineral density (BMD), the cross-‐ links (PYD, DPD and NTx) and the bone specific alcaline phosphatase (BAP) was

invesAgated in a cross-‐sec.onal study in 62 male pa.ents with spinal cord injury (SCI), n = 28 short-‐term (0�1 year aQer

SCI) and n = 34 long-‐term SCI pa.ents (> 5 years aQer SCI).

LiVle is known regarding the extend of the osteoporosis as well as the causaAve factors.

Measurements of the BMD in the proximal femur and the lumbar spine (DEXA), of the osteoblast marker BAP from

serum, the osteoclast markers PYD (pyridinoline), DPD (desoxy-‐pyridinoline) and NTx (N-‐telopepAde of collagen type I)

from urine.

a significant decrease of BMD in the proximal femur and no relevant change in the lumbar spine (Z-‐score) in short-‐term

and long-‐term SCI paAents. a significant bone loss at the proximal femur, whereas at the lumbar spine the BMD even

slightly increases.

Bone resorpAon (cross-‐links) was increased in both groups, though in long-‐term SCI paAents it is significantly decreased

compared to short-‐term SCI paAents (DPD from 211.7 u/g creaAnine to 118.1 u/g creaAnine; NTx from 215.1 nmol/mmol

creaAnine to 83,6 nmol/mmol creaAnine). The bone formaAon marker BAP is slightly below normal range in both groups

(12.3 U/l in short-‐term, 9.7 U/l in long-‐ term SCI paAents). Only the proximal femur is affected by the immobilisa.on

osteoporosis of SCI pa.ents, therefore the BMD measurements in these pa.ents should be performed at the lower

limb. The problem of the immobilisaAon osteoporosis in SCI paAents is the striking increase of bone resorpAon and the

missing reacAon of the bone formaAon.

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Table 1 Urinary pyridinium cross-‐link excre.on is increased in cri.cally ill surgical pa.ents. Shapses, Sue; Weissman, Charles; Seibel, Markus; Chowdhury, Hasina CriAcal Care Medicine. 25(1):85-‐90, January 1997.

Table 1 . PaAent characterisAcs (mean +/-‐ SD)

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Table 2 Urinary pyridinium cross-‐link excre.on is increased in cri.cally ill surgical pa.ents. Shapses, Sue; Weissman, Charles; Seibel, Markus; Chowdhury, Hasina CriAcal Care Medicine. 25(1):85-‐90, January 1997.

Table 2 . Serum biochemical values (mean +/-‐ SD)

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Figure 2 Urinary pyridinium cross-‐link excre.on is increased in cri.cally ill surgical pa.ents. Shapses, Sue; Weissman, Charles; Seibel, Markus; Chowdhury, Hasina CriAcal Care Medicine. 25(1):85-‐90, January 1997.

Figure 2 . Daily urinary excreAon of pyridinoline (PYD/CreaAnine, top) and deoxypyridinoline (DPD/CreaAnine, bo=om) in criAcally ill paAents (n = 9). Solid lines, paAents who stayed in the intensive care unit 5 days.

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Table 1. Skeletal morbidity among survivors of cri.cal illness *. Orford, Neil; MBBS, FCICM; Saunders, Kym; MBBS, FCICM; Merriman, Elizabeth; Henry, Margaret; Pasco, Julie; Stow, Peter; MBBS, FCICM; Kotowicz, Mark; MBBS, FRACP CriAcal Care Medicine. 39(6):1295-‐1300, June 2011. DOI: 10.1097/CCM.0b013e318211ff3d

Table 1. DescripAve characterisAcs of all ICU admissions and admissions venAlated for >=48 hrs during 8-‐yr study period (data are shown as median [IQR] or no. [%])

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Table 2. DescripAve data of ICU survivors with >=48 hrs venAlaAon by gender (as above median [IQR] or no. [%])

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Table 3. Number of fractures post-‐ICU by age in adult males

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Table 4. Number of fractures in adult females by age in post-‐ICU and GOS samples

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Table 5. Comparison of female ICU survivors by post-‐ICU fracture status (data are shown as median [IQR] or no. [%])

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Table 6. Comparison of male ICU survivors by post-‐ICU fracture status (data are shown as median [IQR] or no. [%])

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Table 7. Unadjusted and adjusted fracture rates and hazard raAos for females (20-‐94 yrs of age) post-‐ICU compared with populaAon-‐based females (GOS)

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Figure 1. Skeletal morbidity among survivors of cri.cal illness *. Orford, Neil; MBBS, FCICM; Saunders, Kym; MBBS, FCICM; Merriman, Elizabeth; Henry, Margaret; Pasco, Julie; Stow, Peter; MBBS, FCICM; Kotowicz, Mark; MBBS, FRACP CriAcal Care Medicine. 39(6):1295-‐1300, June 2011. DOI: 10.1097/CCM.0b013e318211ff3d

Figure 1. Time to fracture of the wrist, hip, humerus, or vertebral fracture aker intensive care unit (ICU) compared with the random populaAon-‐based sample in older age group (>= 60 yrs) females. HR, hazard raAo; CI, confidence interval; GOS, Geelong Osteoporosis Study.

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1. J Clin Endocrinol Metab. 2008 Oct;93(10):3927-35. Epub 2008 Aug 5.

Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H.

Source

Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. [email protected]

Comment in

• J Clin Endocrinol Metab. 2009 Feb;94(2):418-20.

Abstract

CONTEXT:

Vitamin D has been shown to influence cardiac contractility and myocardial calcium homeostasis.

OBJECTIVES:

We aimed to elucidate whether insufficient vitamin D status is associated with heart failure and sudden cardiac death (SCD).

DESIGN, SETTING, AND PARTICIPANTS:

We measured 25-hydroxyvitamin D [25(OH)D] levels in 3299 Caucasian patients who were routinely referred to coronary angiography at baseline (1997-2000).

MAIN OUTCOME MEASURES:

The main outcome was cross-sectional associations of 25(OH)D levels with measures of heart failure and Cox proportional hazard ratios for deaths due to heart failure and for SCD according to vitamin D status.

RESULTS:

25(OH)D was negatively correlated with N-terminal pro-B-type natriuretic peptide and was

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1. Am J Med. 2009 Sep;122(9):793-802.

Vitamin D: bone and beyond, rationale and recommendations for supplementation. Stechschulte SA, Kirsner RS, Federman DG.

Source

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Fla, USA.

Comment in

• Am J Med. 2010 Feb;123(2):e17; author reply e19.

Abstract

Adequate vitamin D status is necessary and beneficial for health, although deficiency plagues much of the world's population. In addition to reducing the risk for bone disease, vitamin D plays a role in reduction of falls, as well as decreases in pain, autoimmune diseases, cancer, heart disease, mortality, and cognitive function. On the basis of this emerging understanding, improving patients' vitamin D status has become an essential aspect of primary care. Although some have suggested increased sun exposure to increase serum vitamin D levels, this has the potential to induce photoaging and skin cancer, especially in patients at risk for these conditions. Vitamin D deficiency and insufficiency can be both corrected and prevented safely through supplementation.

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1. Mol Nutr Food Res. 2010 Aug;54(8):1103-13.

Vitamin D deficiency and myocardial diseases. Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W.

Source

Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria. [email protected]

Abstract

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.

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1. Curr Drug Targets. 2011 Jan;12(1):88-96.

Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. Pilz S, Tomaschitz A, Drechsler C, Zittermann A, Dekker JM, März W.

Source

Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Austria. [email protected]

Abstract

Vitamin D deficiency is highly prevalent due to lifestyle and environmental factors which limit sunlight induced vitamin D production in the skin. This "pandemic" of vitamin D deficiency is of concern because low levels of 25-hydroxyvitamin D (25[OH]D) have been associated with cardiovascular, musculoskeletal, infectious, autoimmune and malignant diseases. Epidemiological studies have largely but not consistently shown that vitamin D deficiency is a risk factor for strokes. This is supported by associations of low 25(OH)D levels with cerebrovascular risk factors, in particular with arterial hypertension. Vitamin D has also been shown to exert neuroprotective, neuromuscular and osteoprotective effects which may reduce cognitive and functional impairments in poststroke patients. Hence, the current literature favours the notion that vitamin D supplementation is a promising approach for the prevention and treatment of strokes but accurate data from interventional studies are missing. Randomized controlled trials are therefore urgently needed to evaluate whether vitamin D supplementation reduces the incidence of strokes and improves the outcome of poststroke patients. We do, however, believe that currently published data on the multiple health benefits of vitamin D and the easy safe and inexpensive way by which it can be supplemented already argue for the prevention and treatment of vitamin D deficiency in order to reduce stroke associated morbidity and mortality.

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1. Kidney Int. 2009 Nov;76(9):931-3.

Chronic kidney disease and vitamin D: how much is adequate? Ruggiero M, Pacini S.

Source

Department of Experimental Pathology and Oncology, University of Firenze, Firenze, Italy. marco.ruggiero@unifi .it

Comment on

• Kidney Int. 2009 Nov;76(9):977-83.

Abstract

Mehrotra et al. demonstrate that there still is hypovitaminosis D in adults with chronic kidney disease (CKD) in the United States, and this defect is associated with increased risk for death. Definition of the adequate amount of vitamin D, however, is still uncertain; polymorphisms of the gene encoding the vitamin D receptor might be responsible for this uncertainty. People carrying less efficient variants of the receptor might need higher amounts of vitamin D.

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1. Mol Nutr Food Res. 2010 Aug;54(8):1103-13.

Vitamin D deficiency and myocardial diseases. Pilz S, Tomaschitz A, Drechsler C, Dekker JM, März W.

Source

Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Graz, Austria. [email protected]

Abstract

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.

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1. Eur Heart J. 2010 Sep;31(18):2253-61. Epub 2010 Aug 5.

Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, Dekker F, Brandenburg V, März W, Ritz E, Wanner C.

Source

Department of Internal Medicine 1, Division of Nephrology, University of Würzburg, Oberdürrbacher Str. 6, D-97080 Würzburg, Germany. [email protected]

Abstract

AIMS:

Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients.

METHODS AND RESULTS:

25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28-55). Patients with severe vitamin D deficiency [25(OH)D of ≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39-6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18-2.69, and HR: 1.74, 95% CI: 1.22-2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected.

CONCLUSION:

Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D

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1. Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):634-9.

Vitamin D deficiency and mortality. Zittermann A, Gummert JF, Börgermann J.

Source

Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westfalia, Ruhr University Bochum, Georgstrsse 11, D-32545 Bad Oeynhausen, Germany. [email protected]

Abstract

PURPOSE OF REVIEW:

To summarize recent findings on vitamin D deficiency and mortality. The serum concentration of 25-hydroxyvitamin D [25(OH)D], the metabolic precursor of the vitamin D hormone calcitriol, is the standard for assessing vitamin D status. Deficient 25(OH)D concentrations (<25 nmol/l) are prevalent in Europe and North America.

RECENT FINDINGS:

Several large nonrandomized studies indicate that different from adequate 25(OH)D concentrations (>75 nmol/l), deficient 25(OH)D concentrations are associated with excess mortality in the general population and in patients with increased cardiovascular disease risk. Results support an earlier meta-analysis of controlled trials that were not primarily designed to assess mortality showing a survival benefit of vitamin D supplementation over no supplementation in middle-aged and elderly persons. In patients with advanced chronic diseases such as end-stage heart failure, however, circulating calcitriol predicts mid-term mortality better than 25(OH)D does. Available data indicate that these patients may enter a vicious cycle of low calcitriol, increased inflammation markers, and renal impairment, which may be difficult to escape by simple vitamin D supplementation.

SUMMARY:

Accumulating evidence suggests that vitamin D deficiency is linked to excess mortality. However, future studies should clarify to which extent vitamin D supplementation can improve survival in the aging population and in specific patient groups.

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1. Kidney Int. 2009 Nov;76(9):977-83. Epub 2009 Aug 5.

Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Mehrotra R, Kermah DA, Salusky IB, Wolf MS, Thadhani RI, Chiu YW, Martins D, Adler SG, Norris KC.

Source

Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, California 90502, USA. [email protected]

Comment in

• Kidney Int. 2009 Nov;76(9):931-3.

Abstract

Low serum 25-hydroxy vitamin D (25OHD) predicts a higher cardiovascular risk in the general population. Because patients with chronic kidney disease are more likely to have low serum 25OHD, we determined the relationship between hypovitaminosis D and death in this group. Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease but were not on dialysis and who had a mean follow-up of 9 years. In analyses adjusted for demographics, cardiovascular risk factors, serum phosphorus, albumin, hemoglobin, stage of chronic kidney disease, albuminuria, and socioeconomic status, individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml. This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups. The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment. The trend for higher mortality in patients with 25OHD levels 15-30 ng/ml was not statistically significant. Our results indicate there is a graded relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis. Randomized, controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality.

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1. Clin J Am Soc Nephrol. 2009 Sep;4(9):1515-22. Epub 2009 Aug 20.

Vitamin D and the cardiovascular system. Artaza JN, Mehrotra R, Norris KC.

Source

Charles Drew University of Medicine & Science, Los Angeles, CA 90059, USA.

Abstract

Several epidemiologic and clinical studies have suggested that there is a strong association between hypovitaminosis D and cardiovascular disease (CVD). Hypovitaminosis D was reported as a risk factor for increased cardiovascular events among 1739 adult participants in the Framingham Offspring Study. Analysis of more than 13,000 adults in the Third National Health and Nutrition Examination Survey (NHANES III) showed that even though hypovitaminosis D is associated with an increased prevalence of CVD risk factors, its association with all-cause mortality is independent of these risk factors. Importantly, epidemiologic studies suggested that patients who had chronic kidney disease and were treated with activated vitamin D had a survival advantage when compared with those who did not receive treatment with these agents. Mechanistically, emerging data have linked vitamin D administration with improved cardiac function and reduced proteinuria, and hypovitaminosis D is associated with obesity, insulin resistance, and systemic inflammation. Preliminary studies suggested that activated vitamin D inhibits the proliferation of cardiomyoblasts by promoting cell-cycle arrest and enhances the formation of cardiomyotubes without inducing apoptosis. Activated vitamin D has also been shown to attenuate left ventricular dysfunction in animal models and humans. In summary, emerging studies suggest that hypovitaminosis D has emerged as an independent risk factor for all-cause and cardiovascular mortality, reinforcing its importance as a public health problem. There is a need to advance our understanding of the biologic pathways through which vitamin D affects cardiovascular health and to conduct prospective clinical interventions to define precisely the cardioprotective effects of nutritional vitamin D repletion.

Free Article

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1. Intensive Care Med. 2009 Dec;35(12):2028-32. Epub 2009 Sep 15.

Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality? Lee P, Nair P, Eisman JA, Center JR.

Source

Department of Endocrinology, St Vincent's Hospital, Sydney, NSW 2010, Australia. [email protected]

Abstract

The association between vitamin D deficiency and chronic illness is well-known. Vitamin D deficiency has been associated with increased mortality in the general population. Despite this knowledge, vitamin D insufficiency is seldom considered and rarely replaced adequately, if at all, in critically ill patients in intensive care. We present a hypothetic model demonstrating how vitamin D deficiency may be an unrecognized contributor to adverse outcome in intensive care patients.

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1. Crit Care. 2011;15(2):154. Epub 2011 Apr 19.

How deficient are vitamin D deficient critically ill patients? Lee P.

Source

Department of Diabetes and Endocrinology, Princess Alexandra Hospital, School of Medicine, University of Queensland, 199 Ipswich Road, Woolloongabba, Brisbane, Queensland, Australia 4102. [email protected]

Comment on

• Crit Care. 2011;15(2):R104.

Abstract

Vitamin D deficiency is highly prevalent among critically ill patients and may be associated with adverse outcomes. Failure of conventional vitamin D supplementation in correcting deficiency has called for studies to evaluate the efficacy and safety of a high-dose regime in critically ill patients. High-dose vitamin D supplementation that corrects a deficient state effectively and safely allows for intervention studies to be undertaken to determine the impact of vitamin D on morbidity and mortality in critically ill patients.

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1. Crit Care. 2011;15(2):R104. Epub 2011 Mar 28.

Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study. Amrein K, Sourij H, Wagner G, Holl A, Pieber TR, Smolle KH, Stojakovic T, Schnedl C, Dobnig H.

Source

Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Metabolism, Auenbruggerplatz 15, 8036 Graz, Austria.

Comment in

• Crit Care. 2011;15(2):154.

Abstract

INTRODUCTION:

Vitamin D deficiency is encountered frequently in critically ill patients and might be harmful. Current nutrition guidelines recommend very low vitamin D doses. The objective of this trial was to evaluate the safety and efficacy of a single oral high-dose vitamin D3 supplementation in an intensive care setting over a one-week observation period.

METHODS:

This was a randomized, double-blind, placebo-controlled pilot study in a medical ICU at a tertiary care university center in Graz, Austria. Twenty-five patients (mean age 62 ± 16 yrs) with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤ 20 ng/ml] and an expected stay in the ICU >48 hours were included and randomly received either 540,000 IU (corresponding to 13.5 mg) of cholecalciferol (VITD) dissolved in 45 ml herbal oil or matched placebo (PBO) orally or via feeding tube.

RESULTS:

The mean serum 25(OH)D increase in the intervention group was 25 ng/ml (range 1-47 ng/ml). The highest 25(OH)D level reached was 64 ng/ml, while two patients showed a small (7 ng/ml) or no response (1 ng/ml). Hypercalcemia or hypercalciuria did not occur in any patient. From day 0 to day 7, total serum calcium levels increased by 0.10 (PBO) and 0.15 mmol/L (VITD; P < 0.05 for both), while ionized calcium levels increased by 0.11 (PBO) and 0.05 mmol/L (VITD; P < 0.05 for both). Parathyroid hormone levels decreased

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Vitamin D intake in the two study groups.

Van den Berghe G et al. JCEM 2003;88:4623-4632

©2003 by Endocrine Society

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Effect of 200 IU and 500 IU of vitamin D supplement on vitamin D metabolism.



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Dr. A. Struijs

Effect of 200 IU and 500 IU of vitamin D supplement on markers of bone formation.



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Dr. A. Struijs

Aggravation of bone hyperresorption with time in ICU. A time-dependent increase in serum βCTX (all patients) and urine DPD (normalized for urine creatinine in those patients who did

not require dialysis or hemofiltration) levels, both already elevated on IC...



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Dr. A. Struijs

Antiinflammatory effects of vitamin D in the critically ill.



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Dr. A. Struijs

Circulating cytokine levels with time in ICU. Elevated serum IL-6 levels, observed on ICU admission, decreased significantly with time in ICU, whereas elevated levels of TNFα and low

IL-1 remained unaltered.



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Dr. A. Struijs

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Dr. A. Struijs


Figure 3 Urinary pyridinium cross-‐link excre.on is increased in cri.cally ill surgical pa.ents. Shapses, Sue; Weissman, Charles; Seibel, Markus; Chowdhury, Hasina CriAcal Care Medicine. 25(1):85-‐90, January 1997.

Figure 3 . Nitrogen (N) balance in two groups of criAcally ill paAents. Solid circles, paAents who stayed in the intensive care unit 5 days (n = 5). *Differs from zero nitrogen balance, p < .05.

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Dr. A. Struijs

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Dr. A. Struijs

Prevalence of bone hyperresorpAon in CCI • 49 CCI paAents • Median age 73 yrs, M/F = 28/21 • 22 Medical, 27 Surgical • Median ICU LOS = 20 days • Post-‐tracheotomy All RCU transfer = 7 days • 92% of popula0on found to have Abnormal Bone Resorp0on DistribuAon of PTH levels among Subjects with high urine NTX Nl PTH 49% Low PTH 9% High PTH 42% copyright

Dr. A. Struijs

Response to Treatment p value 0.02 NS PTH Post Rx 40 ± 28 53 ± 51 PTH Pre Rx 93 ± 145 36 ± 29 p value NS < 0.01 Urine NTX Post Rx 178 ± 123 100 ± 85 Urine NTX Pre Rx 187 ± 146 329 ± 238 Calcitriol + Calcitriol Pamidronate NTX Units = BCE/mmol Cr; PTH Units = pg/mL

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Dr. A. Struijs

Bone metabolism and intensive care

Health & Medicine

Transcript of Bone metabolism and intensive care