sahota et. al 2006 - mg vit d e pth b2

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Osteoporos Int (2006) 17: 10131021DOI 10.1007/s00198-006-0084-3

O RIG IN A L A RTICLE

Vitamin D insufficiency and the blunted PTH response

in established osteoporosis: the role of magnesium deficiency

O. Sahota . M. K. Mundey . P. San .

I. M. Godber . D. J. Hosking

Received: 6 May 2005 / Accepted: 26 January 2006 / Published online: 5 April 2006# International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Abstract Introduction: Vitamin D insufficiency is com-mon, however within individuals, not all manifest the

biochemical effects of PTH excess. This further extends to

patients with established osteoporosis. The mechanismunderlying the blunted PTH response is unclear but may berelated to magnesium (Mg) deficiency. The aims of this studywere to compare in patients with established osteoporosis anddiffering degrees of vitamin D and PTH status : (1) the

presence of Mg deficiency using the standard Mg loading test(2) evaluate the effects of Mg loading on the calcium-PTHendocrine axis (3) determine the effects of oral, short term Mgsupplementation on the calcium-PTH endocrine axis and boneturnover. Methods: 30 patients (10 women in 3 groups) wereevaluated prospectively measuring calcium, PTH, Mg reten-tion (Mg loading test), dietary nutrient intake (calcium,vitamin D, Mg) and bone turnover markers (serum CTX &

P1CP). Multivariate analysis controlling for potential con-founding baseline variable was undertaken for the measuredoutcomes. Results: All subjects, within the low vitamin D

and low PTH group following the magnesium loading testhad evidence of Mg depletion [mean(SD) retention 70.3%(12.5)] and showed an increase in calcium 0.06(0.01) mmol/l

[95% CI 0.03, 0.09, p=0.007], together with a rise in PTH13.3 ng/l (4.5) [95% CI 3.2, 23.4, p=0.016] compared to

baseline. Following oral supplementation bone turnoverincreased: CTX 0.16 (0.06) mcg/l [95%CI 0.01, 0.32

p=0.047]; P1CP 13.1 (5.7) mcg/l [95% CI 0.29, 26.6p=0.049]. In subjects with a low vitamin D and raised PTHmean retention was 55.9%(14.8) and in the vitamin repletegroup 36.1%(14.4), with little change in both acute markersof calcium homeostasis and bone turnover markers follow-ing both the loading test and oral supplementation.Conclusions: This study confirms that in patients withestablished osteoporosis, there is also a distinct group with alow vitamin D and a blunted PTH level and that Mg

deficiency (as measured by the Mg loading test) is animportant contributing factor.

Keywords Functional hypoparathyroidism . Magnesium .

Osteoporosis . Secondary hyperparathyroidism . Vitamin D

Introduction

Vitamin D insufficiency is well documented in the frail andinstitutionalised elderly but it is becoming increasinglyrecognised among the healthy, community-dwelling elderlyand middle-aged subjects [13]. Furthermore, a high

prevalence of vitamin D insufficiency has been reportedin patients with established osteoporosis presenting tosecondary care [46]. Biochemically, the increase in

parathyroid hormone (PTH) [710] maintains calciumhomeostasis but at the expense of a further increase in

bone turnover [11], significant bone loss and increased riskof fracture [12, 13]. However, within individuals, it isevident from a number of studies that not all patients withvitamin D insufficiency manifest the biochemical or bonehistomorphometric effects of PTH excess [4, 1417], andmore recently, in patients with established osteoporosis, thishas been defined as functional hypoparathyroidism [18].

Funding Sources This work was supported by a Research andDevelopment (R & D ) grant, Nottingham City Hospital and aneducational grant from Lamberts Pharmaceuticals Ltd.

O. Sahota (*)Department of Health Care of the Elderly,Queens Medical Centre, University Hospital,B Floor South Block,Nottingham, NG7 2UH, UKe-mail: [email protected].: +44-115-9249924Fax: +44-115-8754619

M. K. MundeySchool of Biomedical Sciences,Queens Medical Centre, University Hospital,Nottingham, UK

P. San . D. J. HoskingDivision of Mineral Metabolism, City Hospital,Nottingham, UK

I. M. GodberClinical Laboratories, Wishaw General Hospital,Wishaw, Lanarkshire, UK


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The mechanism underlying the defect in PTH synthesisis unclear but may be related to magnesium (Mg)deficiency, which is known to inhibit PTH synthesis/regulation related to a decrease in Mg-dependent enzymeactivity [19]. The aims of the study were in patients withestablished osteoporosis and (a) low vitamin D and raisedPTH (vitamin D insufficiency); (b) low vitamin D and low/low normal PTH (functional hypoparathyroidism);

(c) normal vitamin D and normal PTH (vitamin D replete)to:

1. Investigate the presence of Mg deficiency using thestandard Mg loading test

2. Evaluate the effects of Mg loading on the calciumPTH endocrine axis

3. Determine the effects of oral, short-term (4 weeks) Mgsupplementation on the calciumPTH endocrine axisand bone turnover

Materials and methods

Screening

Postmenopausal women aged 60 years referred to theosteoporosis clinic with a vertebral fracture were screenedover a 12-month period. Housebound, residential andnursing home patients were excluded, as were patients with

diseases or medication known to affect bone metabolism(including patients taking corticosteroids and bisphos-

phonates) (Fig. 1). All subjects underwent a full physicalexamination, blood investigations (including antiendo-mysial antibody screening), bone densitometry and elec-trocardiogram testing.

Following physical and biochemical screening and bonedensitometry, patients found with other diseases known toaffect bone metabolism but not identified on initial

Baseline Screening

Postmenopausal women 60 Yrs presenting with

a vertebral fracture

Exclusion Group

Women with diseases /medication know to affect bonemetabolism/ Mg homeostasis

Women living in residential homes/housebound

Personal reasons/Not willing to have a Mginfusion

Normal /osteopenic BMD

Physical/Biochemical

Screening

Low calcium and raised alk phos

Creatinine clearance

50 ml/min

Other diseases/ECG abnormalities foundon examination &/or following routine

blood tests

Vitamin D Insufficiency Functional Hypoparathyroidism Vitamin D replete

[10] [10] [10]

Patients Recruited

into the Study

169

12

120

4

4

15

2

12

30

12 16 73

21

Fig. 1 Flow diagram of patientsrecruited into the study

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presentation were also excluded, as were patients with acreatinine clearance 50 ml/min and patients with normal/osteopenic bone density (Fig. 1). Creatinine clearance wasestimated from plasma creatinine (see below). A thresholdvalue of 50 ml/min was taken, below which renal functionimpairs hydroxylation of 25-hydroxy-vitamin D (25OHD)to 1,25(OH)2D [20]. Subjects were also excluded if foundto have a serum calcium below the laboratory reference

range with a raised alkaline phosphatase, together withpatients found to have moderate to severe cardiac diseasefollowing electrocardiogram examination. The study pro-tocol was approved by the Nottingham City Hospital EthicsCommittee, and all patients gave written, informedconsent.

From the pool of vitamin D replete subjects identified asbeing suitable to take part in the study, ten patients wererecruited, matched as closely as possible for age and bodymass index (BMI) to the patients with vitamin D insuffi-ciency. Similarly, from the pool of patients with functionalhypoparathyroidism, ten were matched to patients withvitamin D insufficiency (Fig. 1). Similar proportions of

patients within each season were included in each of thevitamin D groups.

Vitamin D insufficiency was defined arbitrarily in thisstudy as 25OHD 30 nmol/l and a PTH above the uppertertile of the laboratory reference range (>57 ng/l; range1272); functional hypoparathyroidism was defined arbi-trarily as 25OHD 30 nmol/l and PTH 57 ng/l; andvitamin D replete was defined as 25OHD >30 nmol/l, PTH1272 ng/l based on previous work we have undertaken inthis area [11, 18].

Biochemistry

Biochemical measurements were standardised with bloodcollected between 0900 and 1130 hours (nonfasting). Serumcalcium (corrected for albumin binding), phosphate, mag-nesium and creatinine were measured by automated standardlaboratory methods. Intact PTH was measured by DPCImmulite (Diagnostic Products Corporation, Los Angeles,CA, USA) and 25OHD by radioimmunoassay (Diasorin,MN, USA). The intra- and interassay variations for PTHwere 2.9%/3.5% and for 25OHD 2.1%/4.5%, respectively.Creatinine clearance was estimated from plasma creatinine[21].

Bone mineral density

Bone mineral density (BMD) was measured on the LunarExpert densitometer (Lunar Corp Ltd.). All patients had aT-score 2.5 [standard deviation (SD) units related to theyoung normal mean value; World Health Organisation(WHO) classification of osteoporosis] at either the antero-

posterior L2L4 spine (lumbar spine), total hip or bothsites.

Intervention

All 30 subjects recruited were invited to the metabolicresearch unit and underwent three study phases:

1. Pre-Mg infusion assessment2. Post-Mg infusion assessment3. Oral Mg therapy assessment (4 weeks post-Mg

infusion)

Premagnesium infusion assessment

Blood specimens were collected in the fasting statebetween 0800 and 0900 hours for: calcium, 25OHD, PTH,Mg and bone turnover markers (described below). Pre-infusion urine Mg and creatinine were calculated from a10-ml urine sample (second-void morning sample follow-ing an overnight fast) using the methods as described byRyzen et al. [22] who reported a highly significant cor-relation between the measured 24-h urinary Mg preinfusion

and the calculated value based on a preinfusion spot urineMg/creatinine ratio.

Bone turnover markers comprised:

1. Bone formation: Serum C-terminal propeptide of type1 collagen (P1CP) (ELISA, Prolagen-C: Metrabiosys-tems , Palo Alto, CA, USA).

2. Bone resorption: Serum carboxy terminal cross-linkingtelopeptide of bone collagen (CTX) (ELISA, SerumCrosslaps, Osteoemeter Biotech, Denmark).

These assays were performed with an automated device(Elecsys; Roche Diagnostics, Switzerland). All routineassays were measured within 24 h of sampling. Bone

turnover markers were separated, refrigerated and thenanalysed at a later date in batched pairs (baseline andweek 4) by a single technician. The inter-/intraassayvariations for CTX were 7.3%/ 2.1% and for P1CP4.9%/1.9%, respectively.

Magnesium loading testThe Mg loading test was based onthe method described by Ryzen et al. [22]. Following alight breakfast, subjects were given 2.4 mg/kg (0.1 mmol/kg) of Mg sulphate in 50 ml 5% dextrose infused over 4 h.This dose has been shown not to exceed the renal tubularmaximum of Mg reabsorption [23]. Patients wereevaluated in groups of four. All infusions were com-

menced simultaneously at 1000 hours, and blood pressureand heart rate monitored every hour. During the last 2 h ofthe infusion, subjects were allowed to eat a light lunch.

Postmagnesium infusion assessment

Serum calcium, PTH and Mg were measured postinfusion.Postinfusion Mg retention was measured from a 24-h urinecollection, which was started following the infusion. All

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subjects were given detailed verbal instructions supple-mented by written guidance on how to collect the 24-hurine specimen accurately. The percentage of Mg retentionwas calculated using the formula:

1 post infusion Mg excretion basal Mg excretion

total Mg infused

100

basal Mg excretion

pre infusion urine Mg

pre infusion urine Creatinine

post infusion 24 hour urine

Creatinine

Mg status [22]: 50% retention at 24 h = deficiency;>25% to 30, PTH 1272)

Age (years) 67.1 (7.7) 67.8 (9.8) 66.4 (6.9)

BMI (kg/m2) 27.2 (3.6) 26.8 (3.0) 26.1 (4.1)

Dietary vitamin D Intake (mcg) 2.9 (4.1) 2.8 (3.3) 3.1 (2.9)

Dietary calcium Intake (mg) 924.5 (314.6) 984.3 (399.2) 921.9 (401.1)

Dietary magnesium intake (mg) 321.1 (145.9) 305.9 (165.7) 316.2 (135.4)

Creatinine clearance (lab ref 70120 ml/min) 71.2 (10.3) 74.6 (11.4) 73.2 (9.8)

Calcium (2.22.6 mmol/l) 2.40 (0.05) 2.33 (0.07) 2.45 (0.07)

Total alk phosphatase (40120 IU/l) 151.9 (54.5) 109.5 (36.2) 105.2 (31.7)Magnesium (lab ref 0.81.2 mmol/l) 0.8 (0.03) 0.8 (0.02) 0.8 (0.02)

Phosphate (lab ref 0.81.2 mmol/l) 1.1 (0.2) 1.0 (0.1) 1.0 (0.2)

Spine BMD (g/cm2) 0.82 (0.13) 0.84 (0.17) 0.85 (0.19)

Total hip BMD (g/cm2) 0.69 (0.11)* 0.74 (0.10)* 0.77 (0.09)

25OHD 25-hydroxy-vitamin D, PTH parathyroid hormone, BMI body mass index, BMD bone mineral density*p


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oral supplements). BMD was significantly lower at the hipsite (p25%to


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Discussion

The presence of Mg depletion in subjects with establishedosteoporosis was high as defined by the Mg loading test.This has been suggested in previous studies [24, 25],however, in the absence of the more formal Mg loading testor by dividing patients into different states of baselinevitamin D and PTH status, as in this study. Furthermore,detection of Mg depletion is often attempted clinicallyusing the more convenient serum assays, but as shown, thisis unreliable. In all patients with Mg depletion (as defined

by the loading test), serum levels of Mg were in the normal

range.

The cause of this level of depletion remains unclear.Mean Mg intake was within the recommended nutrientintake for women for UK, so nutritional deficiency as a

primary cause does not appear likely. With a normal dietaryintake of approximately 300350 mg/day, fractionalabsorption is 3050%, but this varies in the presence ofother nutrients, particularly high dietary fibre, phytate,oxalate and phosphate [26]. It may have been possible thatthese type of food products were consumed at the time food

products rich in Mg were taken. Similarly, certain foodproducts may also affect renal Mg excretion. High sodium,calcium or protein diets, as well as caffeine, have been

shown to increase renal Mg excretion. Interestingly, our

50

25

%MgRetention

Vit D Replete

mean 55.9 (14.8)

mean 70.3 (12.5)

mean 36.1 (14.4)

Vitamin D Insufficiency

Functional

hypoparathyroidism

100

75

0

Fig. 3 Magnesium (Mg)retention within each group(mean SD). Dotted linesrepresent 25% and 50%insufficient and deficient ranges,respectively

Table 2 Biochemical changes at 4 weeks following oral magnesium (Mg) supplementation (mean SEM) analysis of variance (ANOVA)comparison between groups

Vitamin D insufficiency

(25OHD 30, PTH >57)

Functional hypoparathyroidism

(25OHD 30, PTH 57)

Vitamin D replete

(25OHD >30, PTH 1272)

ANOVA

p value

Serum calcium (mmo/l)

Preinfusion 2.45 (0.03) 2.39 (0.03) 2.49 (0.02) 0.163

4 weeks 2.49 (0.03)* 2.51 (0.02)** 2.50 (0.02)*

Parathyroid hormone (ng/l)

Preinfusion 85.1 (5.0) 41.1 (3.4) 44.3 (3.4) 0.0023

4 weeks 73.7 (6.1)*** 56.7 (4.1)*** 45.4 (3.2)*Serum magnesium (mmo/l)

Preinfusion 0.81 (0.02) 0.79 0.03) 0.80 (0.02) 0.72

4 weeks 0.83 (0.03)* 0.84 (0.02)* 0.83 (0.02)*

Carboxy terminal cross-linking telopeptide of bone collagen (mcg/l)

Preinfusion 0.23 (0.07) 0.20 (0.07) 0.19 (0.07) 0.042

4 weeks 0.30 (0.07)* 0.36 (0.09)*** 0.23 (0.06) *

C-terminal propeptide of type 1 collagen (mcg/l)

Pre-infusion 35.5 (5.1) 31.2 (7.6) 32.9 (6.7) 0.059

4 weeks 38.9 (5.8)* 45.1 (7.9)** 34.1 (5.4)*

*Not significant (values compared to baseline), ** p


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group had a mean calcium intake of about 950 mg, which is

considerably higher than the national average for post-menopausal women, and this may have had an effect.


Mg deficiency is known to inhibit PTH synthesis, and thefindings from our study are consistent with early publishedreports showing a high presence of Mg deficiency in

patients with functional hypoparathyroidism [27] but withestablished osteoporosis. The mechanism underlying the

defect in PTH synthesis is unclear but may be related to a

decrease in enzyme activity associated with PTH synthesis/regulation. These defects have been shown to correctwithin minutes following an intravenous Mg load [28],which is consistent with the findings from our study.However, within individuals, two of the ten patients failedto show an increase in PTH secretion, which implies thatother mechanisms may be involved. Regulation of PTHsynthesis occurs at several levels, including transcription ofthe PTH gene and stability of PTH mRNA. Therefore,abnormalities at any of these levels will affect PTHsynthesis. Abnormalities may also be present in the

2.20

2.40

2.60

2.80

0

40

80

120

PTHng/l

2.20

2.40

2.60

2.80

0

40

80

120

Pre-infusion Pre-infusion


Pre-infusion Pre-infusion Pre-infusion Pre-infusion



PTHng/l

Vitamin D Replete

Ca

2+mmol/l

2.20

2.40

2.60

2.80

0

40

80

120

PTHng/l

Ca

2+mmol/l

Vitamin D Insufficiency


Ca

2+mmol/l

Fig. 4 Change in baseline parathyroid hormone (PTH) and calcium following the magnesium (Mg) loading test

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calcium-sensing receptor, which is the main focus ofcontrol in PTH expression [29]. Clearly, further studies arenecessary to investigate these pathways.

The increase in PTH restores calcium homeostasis, andwith further oral supplementation, leads to a significantincrease in bone turnover. While these changes arecorrective with respect to calcium homeostasis, the effectsof increased bone turnover, particularly if increased to the

levels as those seen in patients with vitamin D insufficien-cy, may not be wholly beneficial. Thus, in clinical practice,it may be appropriate to cosupplement these patients with acombination of calcium, magnesium, vitamin D and

possibly a bisphosphonate to offset any increase in boneturnover and treat the underlying osteoporosis although it isaccepted that further studies are needed to define optimaltreatment strategy. Eskiyurt et al. [30] showed that dailysupplementation of calcium (1,000 mg), Mg citrate(300 mg) and vitamin D (800 IU) significantly reduced

bone turnover markers and increased BMD over a 12-month period. However, it is unclear from this studywhether any of these patients suffered from vitamin D

insufficiency and/or Mg deficiency.

Vitamin D insufficiency

In patients with vitamin D insufficiency, the Mg loadingtest confirmed the presence of Mg deficiency in a subgroupof patients. Mg repletion resulted in an increase in PTH inthree out of five of these subjects, which suggests that their

baseline PTH level may have reflected a suboptimalparathyroid response. Similar findings were seen in thestudy by Rude et al. [31] where six patients who were Mgdeficient with underlying secondary hyperparathyroidism

showed an increase in PTH following the Mg loading testalthough none of the patients had established osteoporosisas in that study.

Vitamin D replete

In the vitamin D replete group, there was no effect on meanserum calcium or PTH following the Mg loading test orchange in bone turnover following oral supplementation,which is in keeping with previous studies, [31] althoughextending this further to patients with established osteo-

porosis. With respect to baseline differences in BMD found

between the groups, this has been shown and discussed indetail in one of our previous studies [18].In summary, in patients with a low vitamin D and

established osteoporosis, there is a high presence of Mgdeficiency. In patients with functional hypoparathyroidism,Mg repletion leads to an increase in PTH, restoration ofcalcium homeostasis and an increase in bone turnover.Whether this is detrimental to the skeleton if levels increaseto those seen in patients with vitamin D insufficiency andthe optimal treatment requires further assessment. In

patients with vitamin D insufficiency, Mg loading leads

to a transient suppression in PTH but has no effect oncalcium homeostasis and no effect on bone turnoverfollowing oral supplementation. However, there is asubgroup of patients in whom PTH increases followingthe Mg loading test, which suggests an inability in these

patients to initially secrete PTH maximally. This studyconfirms that in patients with established osteoporosis,there is a distinct group of patients with functional

hypoparathyroidism and that Mg deficiency is an importantcontributing factor, further extending to the understandingin PTH and vitamin D physiology.

A number of caveats are recognised in this study. 1,25(OH)2D resistance has been reported in Mg-depletedhumans and animals [32], and furthermore, studies havealso shown low 1,25(OH)2D in the Mg-deficient state. 1,25(OH)2D was not measured in this study and would have

been useful. Secondly, the duration of the Mg replacementphase of the study was only 4 weeks. It is recognised thatbone turnover markers take 36 months to reach a steadystate following the introduction of treatment. However, arecent study by Bjarnasson and Christiansen [33] showed

that the suppression of serum CTX at 2 weeks followingtreatment with HRT significantly correlated with bonemarker changes at 6 months and BMD changes at 3 years.Furthermore, although CTX and P1CP may not be theoptimal markers, recent studies have shown less variabilityand stronger correlation between changes in these markersin response to long-term therapy compared with othermeasures of bone turnover currently available [33, 34].Additionally, with respect to PTH, only a single fasting wastaken, and it would have been interesting to see whether afasting sample on two consecutive days was essentiallyidentical, which may have explained some of the variationseen in the study, within the groups. Thirdly our cutoff

values defining

functional hypoparathyroidism

werearbitrary. We took the lower two tertiles of the laboratoryreference range. Further studies are necessary to definethese absolute thresholds.

Acknowledgements The authors are grateful to the research nursesin the Metabolic Unit for their help in collating data. We are alsograteful to Isabel Fowler in the Department of Clinical Chemistry forher support in preparing/analysing some of the biochemical samples,and Vincent Crosby for his advice on undertaking the Mg studies.

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sahota et. al 2006 - mg vit d e pth b2

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