(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis

ar3224ARJ Research article (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis den UylDebbyd.denuyl@vumc.nl NurmohamedTMikemt.nurmohamed@planet.nl van TuylHDLilianl.vantuyl@vumc.nl RatermanGHennieh.raterman@vumc.nl LemsFWillemwf.lems@vumc.nl

Department of Rheumatology, VU Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

Department of Internal Medicine, VU Medical Centre, De Boelelaan 1117, 1081 NV Amsterdam, The Netherlands

Department of Rheumatology, Jan van Breemen Research Institute/Reade, Dr Jan van Breemenstraat 2, 1056 AB Amsterdam, The Netherlands

Arthritis Research & Therapy 1478-6354 2011 13 1 R5 http://arthritis-research.com/content/13/1/R5 10.1186/ar322421241491 17620101211201017120111712011 2011den Uyl et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms.

Methods

A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized.

Results

Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation.

Conclusions

The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.

Introduction

Cardiovascular (CV) disease and osteoporosis are both important causes of morbidity and mortality in aging men and women. They share common risk factors, such as increased age and inactivity, and are frequently found in the same individuals, suggesting a possible relationship. Results from epidemiological studies indicate an association between CV disease and osteoporosis. Prevalent CV disease and subclinical atherosclerosis have been found to be related to low bone mass and increased fracture risk 1 2 3 4 . Similarly, low bone mineral density (BMD) has been related to increased cardiovascular risk 5 6 7 8 . This relationship is often regarded as a result of aging; however, recent evidence suggests a direct association, independent of age and traditional cardiovascular risk factors and accumulating evidence from experimental research indicates a shared pathogenesis. A variety of factors that influence bone metabolism are involved in the development of vascular disease, for example, atherosclerosis and vascular calcification. Interestingly, several bone-related proteins are implicated in the calcification process resulting in mineral deposition 9 . This is important as calcification of the arterial wall may be a marker for CV disease and was shown to predict CV events 10 . Given the importance of identifying a person at risk for CV events or fractures, evidence for an association of CV disease with osteoporosis might have implications for screening decisions in patients with low bone mass and vice versa. This review aims to summarize all the present clinical literature about the association between CV disease and osteoporosis and to describe common pathophysiological mechanisms. The results of this review are grouped into two topics: clinical results, discussing the relationship between 1) cardiovascular disease and osteoporosis and 2) vice versa. In addition, the possible pathophysiological links of CV disease and osteoporosis will be discussed.

Materials and methods

Search strategy

A systematic search (in Medline, Pubmed and Embase) was conducted to identify all clinical studies from 1966 to January 2010 (last updated 8 June 2010) that investigated the association between cardiovascular disease and osteoporosis. The following search terms for cardiovascular disease were used: cardiovascular diseases, cerebrovascular diseases and peripheral vascular diseases. These searches were each combined with an osteoporosis search block and duplicates were removed. Searches were limited to human studies in the English, Dutch and German languages. The complete Medline search is available in Additional file 1. In addition, references from the retrieved articles were scanned for additional relevant studies.

Additional file 1

Medline search. Complete medline search on 8 June 2010.

Click here for file

Selection criteria

Abstracts were screened by one reviewer (DdU) and studies were included in the review if they fulfilled the following inclusion criteria: epidemiological studies (including prospective, cross-sectional, case-control, or retrospective studies) reporting the association between CV disease and osteoporosis in the general population or in patients with prevalent CV disease or low bone mass. Cardiovascular disease was defined as coronary heart disease (CHD) (myocardial infarction, angina pectoris, coronary insufficiency or ischemic heart disease), cerebrovascular disease (stroke, transient ischemic attacks), peripheral arterial disease (PAD) (lower extremity claudication, arterial thrombosis/embolism, ankle brachial index (ABI) <0.90) or subclinical atherosclerosis measured as intima media thickness (IMT) or vascular calcification. In addition, bone mass had to be assessed as bone mineral density or bone quality, and osteoporosis was defined as low bone mass (T-score ≤-2.5) or increased fracture risk (vertebral and non-vertebral). Exclusion criteria were: reviews, letters, case-reports, intervention studies and biomechanical studies. Studies in patients with co-morbidity other than osteoporosis or CV disease were also excluded. Finally, investigations using risk factors of CV disease or osteoporosis as outcome measurements, such as hypertension, metabolic syndrome, atrial fibrillation, bone markers, and calcium supplementation were not included.

Assessment of study quality

The quality of each manuscript was systematically assessed with a checklist for cohort studies as proposed by the Dutch Cochrane Collaboration 11 (Additional file 2). Quality assessment included a scoring of the following components: definition of study population, the likelihood of bias, adequate blinding, the accuracy of outcome measurements, duration of follow-up and selective loss-to follow-up, the appropriateness of the statistical analysis and the clinical relevance. All items had the following answer options: yes/no/too little information to answer the question. We considered incomplete information or data important criteria for study quality. Therefore, if the answer could not be given because the study provided too little information, a negative score (for example, "no") was given. Each "no" was scored and an equal weight was given to each item. A maximum of 10 points could be given. The scores of each study are given in Tables 1 and 2.

Additional file 2

Quality assessment cohort studies. List of quality assessment of cohort studies as proposed by the Dutch Cochrane Collaboration.

Click here for file

Table 1

Prospective studies investigating relationship CV disease and low BMD

Study

Study population (years follow-up)

Number of cases (% women)

Postmenopausal women

CV disease excluded

Mean age

Outcome CV disease

Outcome bone mass

Results #

Quality

Sennerby, 2009 13

Population-based

(20)

31,936

(NA)

Yes

67.9 to 74.4

CV disease by National patient registry, ICD 9 codes

Incident hip fracture by National patient registry, ICD 9 codes

Women:

HR: 4.42 (95% CI 3.49 to 5.61)

Men:

HR: 6.65 (95% CI 4.82 to 9.19)

Szulc, 2008 14

Population-based

(10)

781

(0%)

AC by X-spine

Incident fracture by hospital records or X-ray

OR: 2.54 to 3.04 (P < 0.005 to 0.001)

Naves, 2008 4

Population-based

(4)

624

(51%)

AC by X-spine

BMD lumbar spine and femur by DXA

Incident fracture by hospital record or X-ray

Change BMD spine in progression AC vs no progression AC:

-1.48% vs 1.43% (P <.0001)

Change BMD hip in progression AC and no progression AC:

-0.48% vs 0.23% (P = 0.315)

Incident fracture:

OR: 2.13 (95% CI 0.85 to 5.31)

Von Muhlen, 2009 15

Population-based

(4)

1,332

(60%)

73.8

PAD by ABI

BMD lumbar spine and hip by DXA and incident fracture by X-ray

Women:

Change BMD in PAD vs no PAD:

59.2% vs 43.5% (P < 0.05)

Incident non-vert fracture:

OR: 0.84 (95% CI 0.31 to 2.26)

Men :

Change BMD in PAD vs no PAD :

43.5% vs 35.5% (P = 0.20)

Incident non-vert fracture:

OR: 1.52 (95% CI 0.30 to 7.45)

Collins, 2009 2

Population-based

(5.4)

4,302

(0%)

73.5

PAD by ABI

BMD hip by DXA

Incident fractures by x-ray and hospital records

Change BMD in PAD vs no PAD:

-0.60% vs -0.32% (P < 0.001

PAD and non-vert fracture risk: HR = 1.47 (95% CI 1.07 to 2.04)

Hak, 2000 3

Population-based

(9)

236

(100%)

No (100%)

AC by X-spine

MCA by radiogrammetry

MCA in patients with AC progression vs no AC progression

-3.5 mm vs -2.0 mm (P < 0.01)

Samelson, 2007 12

Population-based

(21)

2,499

(58%)

AC by X-spine

Incident hip fracture by hospital records and death certificates

Women:

HR: 1.4 (0.8 to 2.3)

Men:

HR: 1.2 (0.2 to 5.7)

Bagger, 2006 1

Population-based

(7.5)

2,262

(100%)

Yes (100%)

AC by X-spine

BMD lumbar spine and hip and incident fractures by hospital records or X-ray

Change hip BMD AC score ≥3 vs <3:

-0.38% vs -0.25% (P < 0.001)

AC and hip fracture:

OR: 2.3 (95% CI 1.1 to 4.8)

AC and vert fracture:

OR: 1.2 (95% CI 1.0 to 1.5)

Schulz, 2004 17

Clinic-based

(8)

228

(100%)

Yes

65.2

AC by CT-scan of spine

BMD spine by CT-scan

Change BMD AC vs no AC:

-5.3% vs -1.3% (P < 0.001)

#adjusted for confounders; NA, not available; AC, aortic calcification; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; PAD, peripheral arterial disease; ABI, ankle brachial index; MCA, metacarpal cortical area.

Table 2

Prospective studies investigating relationship low BMD and CV disease

Study

Study population (years follow-up)

Number of cases (% women)

Postmenopausal women

CV disease excluded

Mean age (years)

Race

Outcome osteoporosis

Outcome CV disease

Results #

Quality (x nee)

Mussolino, 2007 69

Population-based

(9)

5,272 (NA)

Yes

60.9 to 69.4

Caucasian (NA%), black and Mexican-American

BMD proximal femur by DXA

CV and stroke mortality by death certificates

Women:

BMD and CV mortality RR: 1.26 (95% CI 0.88 to 1.80)

BMD and stroke mortality: RR: 1.34 (95% CI 0.86 to 2.07)

Men:

BMD and CV mortality: RR: 1.05 (95% CI 0.79 to 1.39)

BMD and stroke mortality: RR; 0.73 (95% CI 0.43 to 1.23)

Farhat, 2007 6

Population-based

(5.4)

2,310 (55%)

Yes

73.5

Caucasian (58%) and black

BMD total hip, femoral neck and trochanter by DXA

BMD spine by CT-scans

Incident CV disease by hospital records and death certificates

Women: BMD fem neck and incident CV disease: HR: 1.24 (95% CI 1.02 to 1.52)

Men: BMD fem neck and incident CV disease:

HR: 1.04 (95% CI 0.89 to 1.21)

Tamaki, 2009 75

Population-based

(10)

609 (100%)

Yes (60%)

55.9

Japanese

BMD lumbar spine and total hip by DXA

IMT values

<10 YSM:

IMT OP vs normal bone mass: 1.55 vs 1.19 (P < 0.05)

≥YSM:

IMT OP vs normal bone mass: 1.53 vs 1.28 (P < 0.05)

Browner, 1991 5

Population-based

(2.8)

9,704 (100%)

Yes

Caucasian (99%) and Asian

BMD distal radius, prox radius and calcaneus by single photon absorptiometry

Overall mortality and CV mortality by death certificates

BMD and risk overall mortality: RR: 1.22 (95% CI 1.01 to 1.47)

BMD and stroke mortality: RR: 1.75 (95% CI 1.15 to 2.65)

BMD and CV mortality: RR: 1.17 (95% CI 0.92 to 1.51)

Trone, 2007 68

Population-based

(7.6)

1,580 (60%)

Yes (NA %)

71.9

Caucasian

Prevalence vertebral fracture by lateral spine radiographs

Overall mortality by death certificates

Women: prevalent vertebral fracture and overall mortality: HR: 1.15 (95% CI 0.83 to 1.59)

Men: prevalent vertebral fracture and overall mortality: HR: 0.98 (95% CI 0.55 to 1.46)

Kado, 2000 64

Population-based

(3.5)

6,018 (100%)

Yes

76.5

Caucasian

BMD total hip by DXA

Overall and CV mortality by death certificates

BMD and overall mortality: RH: 1.3 (95% CI 1.1 to 1.4)

BMD and CV mortality: RH: 1.3 (95% CI 1.0 to 1.9)

Trivedi, 2001 67

Population-based

(6.7)

1,002 (0%)

No women included

69.7

BMD total hip by DXA

Overall and CV mortality by death certificates

BMD and overall mortality: RR: 0.79 (95% CI 0.65 to 0.97)

BMD and CV mortality: RR: 0.72 (95% CI 0.56 to 0.93)

Tanko, 2005 76

Clinic-based

(4)

2,576 (100%)

Yes

66.5

BMD lumbar spine and femoral neck by DXA

Incidence CV events self-reported and confirmed by primary documents

HR: 3.9 (95% CI 2.0 to 7.7)

Pinheiro, 2006 66

Population-based

(5)

208 (100%)

Yes

75.1

Caucasian

BMD lumbar spine, femoral neck and trochanter by DXA

Overall and CV mortality by death certificates

BMD and overall mortality: HR: 1.44 (95% CI 1.06 to 2.21)

BMD and CV mortality: HR: 1.28 (95% CI 1.08 to 2.26)

Johansson, 1998 7

Population-based

(7)

1,468 (56%)

Yes

74.0

Caucasian

BMD calcaneus by DPA

Overall mortality by death certificates

Women: RR: 1.19 (95% CI 1.02 to 1.39)

Men: RR: 1.23 (95% CI 1.10 to 1.41)

Mussolino, 2003 65

Population-based

(18.5)

3,402 (NA)

Yes

Caucasian (87%) and black

BMD phalangeal by single photon absorption

Stroke mortality by death certificates

Women: RR: 1.01 (95% CI 0.86 to 1.19)

Men: RR: 1.13 (95% CI 0.93 to 1.38)

Blacks: RR : 0.93 (95% CI 0.72 to 1.21)

Samelson, 2004 70

Population-based

(30)

2,059 (60%)

Yes (85,3-94%)

Yes

60.2

Second MCA by radiogrammatry

Incidence coronary heart disease by hospital records and death certificates

Women: HR: 0.73 (95% CI 0.53 to 1.00)

Men: HR: 1.14 (95% CI 0.84 to 1.56)

Kiel, 2001 77

Population-based

(25)

554 (66%)

54.4

Second MCA by radiogrammetry

AC by radiograph of the lumbar spine

Women: Sign association % change in MCA and change AC index (P = 0.01)

Men: No association % change MCA and change AC index (P = 0.50)

Browner, 1993 62

Population-based

(1.98)

4,024 (100%)

Yes

Caucasian

BMD distal radius and calcaneus by single photon absorptiometry

Incident strokes by hospital records and death certificates

HR: 1.31 (95% CI 1.03 to 1.67)

Von der Recke, 1999 8

Clinic-based

(17)

1,063 (100%)

Yes

50 and 70

BMD distal forearm by single photon absorptiometry with ¹²⁵I source

CV mortality by death certificates, hospital records and autopsy reports

Early menopause: RR: 2.3 (95% CI 1.0 to 5.3)

Late menopause: RR: 1.3 (95% CI 0.9 to 1.8)

Silverman, 2004 71

Clinic-based

(3)

2,565 (100%)

Yes

Caucasian (95.8%)

Prevalence vertebral fracture by lateral spine radiographs

Incident CV event self-reported and confirmed by primary documents

CV event rate women with prevalent vertebral fracture vs no vertebral fracture: 15.1 vs 8.3 (P = 0.55)

Varosy, 2003 73

Clinic-based

(4.1)

2,763 (100%)

Yes

Prevalent and incident skeletal fracture self-reported. Incident fractures were confirmed by radiological reports

Incident coronay event by hospital records

HR: 0.75 (95% CI 0.57 to 0.98)

Gonzales-Macias, 2009 63

Clinic-based

(3)

5,201 (100%)

Yes

72.3

Caucasian

eBMD calcaneus by QUS

Overall and CV mortality by medical records

eBMD and overall mortality: HR: 1.19 (95% CI 0.97 to 1.45)

eBMD and CV mortality: HR: 1.39 (95% CI 1.15 to 1.66)

#adjusted for age; AC, aortic calcification; BMD, bone mineral density; DPA, dual photon absorptiometry; DXA, dual-energy x-ray absorptiometry; IMT, intima media thickness; MCA, metacarpal relative cortical area; NA, not available; QUS, quantitative ultrasonography; YSM, years since menopause.

Statistical analysis

A formal meta-analysis of the prospective studies investigating the association between bone mass and risk for cardiovascular events and mortality was not possible due to extended heterogeneity between studies with respect to the study population and methods used. Furthermore, the number of prospective studies that were eligible for pooling was too small for analysis. For this reason, narrative summaries are provided in the results section and quantitatively presented in Tables 1 and 2. The heterogeneity between studies in terms of study population and outcome measures is shown in Tables 1 and 2. Moreover, cross-sectional studies are shown in Table 3.

Table 3

Cross-sectional studies investigating relationship CV disease and low BMD

Study

Study population

Number of cases

% women

Outcome bone mass

Outcome CV disease

Main results #

Frye, 1992 35

Population-based

200

100%

BMD lumbar spine and hip by single photon absorptiometry

AC by x-ray

Association AC and BMD lumbar spine: β-2.213 (P < 0.05)

Association AC and BMD hip: β-0.661 (NS)

Barengolts, 1998 32

Clinic-based

100%

BMD lumbar spine and hip by DXA

Coronary calcium score by EBT

Correlation BDM hip and calcium score: r-0.34 (P = 0.022)

Correlation BMD spine and calcium score: r-0.28 (P = 0.056)

Jorgensen, 2001 27

Clinic-based

52%

BMD femoral neck by DXA

Incident stroke

Women:

OR: 6.6 (95% CI 1.8 to 24.8)

Men:

OR: 0.6 (95% CI 0.1 to 2.3)

Aoyagi, 2001 40

Population-based

524

100%

BMD distal and proximal radius, calcaneus single photon absorptiometry by sinlge photon absorptiometry

AC by x-ray

BMD distal radius and AC: OR: 1.1 (95% CI 0.9 ro 1.3)

BMD calcaneus and AC: OR: 1.1 (0.9 to 1.3)

Van der Klift, 2002 29

Population-based

5,268

57%

BMD lumbar spine and hip by DXA

PAD by ABI

Women:

PAD and BMD hip: OR: 1.35 (95% CI 1.02 to 1.79)

Men:

PAD and BMD hip: OR: 0.89 (95% CI 0.64 to 1.23)

Tanko, 2003 39

Population-based

963

100%

BMD hip and lumbar spine by DXA

AC by x-ray

AC and BMD hip: β-0.10, 9 (P = 0.004)

Hirose, 2003 56

Clinic-based

7,865

OSI calcaneus

baPWV

Women: β-0.11 (P < 0.01)

Men: β-0.07 (P < 0.01)

Pennisi, 2004 50

Clinic-based

44%

BMD total body, lumbar spine, and hip by DXA and calcaneus by QUS

IMT and presence of plaque in carotid artery

63% patients with BMD spine T <-1

93% patients with BMD hip T <-1

Jorgensen, 2004 47

Population-based

5,296

52%

BMD distal radius by single x-ray absorptiometry

IMT and prevalent plaque

BMD and IMT: NS

BMD and prevalent plaque: OR: 0.90 (95% CI 0.75 to 1.07)

BMD and echogenic plaque: OR: 0.51 (95% CI 0.31 to 0.83)

Montalcini, 2004 49

Clinic-based

157

100%

BMD calcaneus by QUS

IMT

BMD and IMT: NS

Magnus, 2005 23

Population-based

5,050

36%

BMD hip by DXA

Self reported CV events

Women:

OR: 1.22 (0.80 to 1.86)

Men:

OR: 1.39 (95% CI 1.03 to 1.87)

Bakhireva, 2005 31

Population-based

366

51%

BMD lumbar spine and hip by DXA

CAC by CT scan

Women:

BMD hip and CAC: OR: 0.69 (95% CI 0.51 to 0.93)

Men:

BMD hip and CAC: OR: 1.03 (0.75 to 1.41)

Wong, 2005 30

Population-based

3,998

50%

BMD lumbar spine and hip by DXA

PAD by ABI

Per SD increase in ABI sign associated with hip BMD:

0.5 (95% CI 0.02 to 0.9)

Yamada, 2005 53

Clinic-based

260

59%

BMD lumbar spine by DXA and OSI calcanues

IMT carotid artery and femoral artery

BMD lumbar spine and FA-IMT: ρ-0.117 (P < 0.005)

Farhat, 2006 34

Population-based

490

100%

vBMD spine by CT scan

AC and CAC by CT scan

AC and BMD: OR: 1.68 (95% CI 1.06 to 2.68)

CAC and BMD: OR: 1.19 (95% CI 0.81 to 1.74)

Farhat, 2006 19

Population-based

1,489

51%

BMD hip by DXA

vBMD lumbar spine by QCT

Prevalent CV disease self reported Prevalent PAD by ABI

Women:

Prevalent CV disease and BMD hip: OR: 1.22 (95% CI 1.03 to 1.43)

PAD and BMD hip: NS Men:

Prevalent CV disease and BMD hip: NS

PAD and BMD hip: OR: 1.39 (95% CI 1.03 to 1.84)

Yamada, 2006 54

Population-based

149

100%

BMD lumbar spine by DXA and vBMD calcaneus by QCT

IMT and PWV

FA-IMT and BMD spine: β-0.067 (P < 0.05)

PWV and BMD spine: NS

Sumino, 2006 60

Clinic-based

315

100%

BMD lumbar spine by DXA

baPWV

Association baPWV and BMD: β-0.265 (P = 0.002)

Sinnot, 2006 43

Clinic-based

480

65%

BMD lumbar spine by QCT

Calcium score by CT-scan

No correlation CAD and BMD in women and men

Shaffer, 2007 51

Population-based

870

61%

BMD lumbar spine, hip and distal radius by DXA

IMT

Women >60 years:

IMT and BMD spine: β-73.0 (P < 0.001)

IMT and BMD hip: β-62.4 (P < 0.001)

Men >60 years:

IMT and BMD radius: β-27.0 (P < 0.001)

Sumino, 2007 61

Clinic-based

100%

BMD lumbar spine by DXA

Brachial arterial endothelial function (FMD)

Correlation FMD and BMD: r .034 (P < 0.01)

Association FMD and BMD: β 0.40 (P < 0.01)

Hyder, 2007 36

Clinic-based

365

64%

BMD lumbar spine by CT-scan

Atherosclerotic calcium in carotid, coronary and iliac arteries by CT-scan

Women:

Calcium score aorta and BMD: OR: 3.14 (95% CI 1.55 to 6.38) Calcium score iliac arteries and BMD: OR: 2.20 (95% CI 1.13 to 4.29)

Men:

Calcium score carotid and BMD: OR: 2.85 (95% CI 1.02 to 7.96)

Calcium score aorta and BMD: OR: 5.90 (95% CI 1.78 to 19.6)

Shen, 2007 42

Population-based

682

56%

BMD lumbar spine and hip by DXA

CAC by CT scan

CAC and BMD spine: -0.105 ± 0.132 (NS)

CAC and BMD hip: 0.022 ± 0.142 (NS)

Sioka, 2007 24

Clinic-based

BMD lumbar spine and hip by DXA

CAD by angiography

BMD in severe CAD vs no CAD: 77.8% vs 37.5%, P =?

Sumino, 2008 52

Clinic-based

175

100%

BMD lumbar spine by DXA

IMT

BMD and IMT β-0.313 (P = 0.001)

Kim, 2008 48

Clinic-based

194

100%

BMD lumbar spine and hip by DXA

Prevalent vertebral fracture

IMT and prevalent plaque

BMD and IMT: NS

BMD and plaque: NS

Vertebral fracture and plaque: OR: 2.8 (95% CI 1.17 to 7.12)

Frost, 2008 45

Clinic-based

100%

Lumbar spine and hip by DXA

IMT and PWV

BMD spine and IMT: r -.025 (P = 0.26)

BMD hip and IMT: r-0.17 (NS)

BMD and PWV: NS

Mangiafico, 2008 57

Clinic-based

182

100%

BMD lumbar spine and hip DXA

PWA (AIx and PWV)

BMD hip and AIx: β-5.46 (P < 0.0001)

BMD spine and Aix: β-3.29 (P < 0.0001)

Tekin, 2008 25

Clinic-based

227

100%

BMD lumbar spine by DXA

Prevalence CAD

CAD and low BMD: OR: 0.68 (95% CI 0.39 to 1.28)

Broussard, 2008 18

Population-based

3,881

51%

BMD total femur by DXA

Framingham CHD risk score by Framingham CHD prediction model

Women:

moderate CHD risk and low BMD: OR: 1.45 (95% CI 1.03 to 2.06)

high CHD risk and low BMD: OR: 1.73 (95% CI 1.12 to 2.66)

Men: NS

Chow, 2008 41

Population-based

693

54%

vBMD lumbar spine and hip by QCT and vBMD distal radius by HRpQCT

AC by CT-scan

Women: NS

Men: NS

Hyder, 2009 37

1,909

50%

vBMD lumbar spine by CT scan

CAC and AAC score

Women:

vBMD and CAC (P-trend <0.002) vBMD AND AAC (P-trend <0.004)

Men:

vBMD and CAC (P-trend <0.034)

vBMD and AAC (P-trend <0.001)

Hmamouchi, 2009 46

Clinic-based

100%

BMD lulmbar spine and hip by DXA

IMT in carotid artery and femoral artery

CA-IMT and BMD hip: r-0.330 (P < 0.05)

FA-IMT and BMD hip: NS

IMT and BMD lumbar spine: NS

Mikumo, 2009 58

Clinic-based

143

100%

BMD lumbar spine by DXA

PWV

BMD and PWV: r-99.78 (NS)

Marcowitz, 2005 20

Clinic-based

209

88%

Lumbar spine, hip and distal radius by DXA

CAD

Osteoporosis: OR: 5.58 (95% CI 2.59 to 12.0) for CAD

Ness, 2006 38

Clinic-based

1,000

100%

Diagnosis osteoporosis or osteopenia by electronic medical records

AVD

Prevalence AVD osteoporotis vs osteopenia:

60% vs 35% (P < 0.001)

Prevalence AVD osteoporis vs normal bone mass:

60% vs 22% (P < 0.001)

Gupta, 2006 78

Clinic-based

101

100%

BMD lumbar spine and total hip by DXA

Prevalent CV disease

Prevalent CV disease in low BMD vs normal BMD:

61% vs 38% (P < 0.025)

Mangifico, 2006 28

Clinic-based

345

100%

BMD lumbar spine and femoral neck by DXA

PAD by ABI

PAD and BMD lumbar spine: OR: 1.01 (95% CI 0.97 to 1.05)

PAD and BMD hip: OR: 0.20 (95% CI 0.05 to 0.70)

Erbilen, 2007 33

Clinic-based

BMD lumbar spine and hip by DXA

CAD

Association BMD and CAD:

OR: 5.4 (95% CI 1.66 to 17.49)

Sennerby, 2007 21

Clinic-based

1,327

100%

Incident hip fracture by X-ray and hospital record

Prevalent CV disease by questionnaire

OR: 2.38 (95% CI 1.92 to 2.94)

Varma, 2008 22

Clinic-based

198

74%

Lumbar spine and hip by DXA

Obstructive CAD

Prevalence CAD osteoporosis vs osteopenia:

76% vs 68% (P < 0.01)

Prevalence CAD osteoporosis vs normal bone mass:

76% vs 47% (P < 0.005)

Seo, 2009 59

Clinic-based

253

100%

BMD lumbar spine and hip by DXA

baPWV

Sign association BMD hip and baPWV:

Β-0.123 (P < 0.05)

Pouwels, 2009 16

Clinic-based

6,763

73%

Incident hip fracture

Incident stroke by ICD 9 code

Risk hip fracture after stroke

Women: OR: 2.12 (95% CI 1.73 to 2.59)

Men: OR: 1.63 (95% CI 1.17 to 2.28)

#adjusted for confounders; BMD, bone mineral density; AC, aortic calcification; DXA, dual-energy x-ray absorptiometry; PAD, peripheral arterial disease; ABI, ankle brachial index; OSI, osteosono assessment index; baPWV, brachial-ankle pulse wave velocity; IMT, intimal medial thickness; CAC, coronary artery calcium; QCT, quantitative computerized tomography; PWV, pulse wave velocity; CAD, coronary artery disease; PWA, pulse wave analysis; AIx, augmentation index; CHD, coronary hearth disease; AVD, atherosclerotic vascular disease.

Results

Studies included

Our search strategy resulted in 2,886 references. The search strategy resulted in 70 relevant articles, including 9 studies prospectively assessing the relationship between CV disease and osteoporosis and 18 prospective studies about the inverse relationship. Figure 1 shows the flow-chart of included and excluded studies.

Figure 1

Flow-chart of the systematic review

Flow-chart of the systematic review.

Study results

The relationship between CV disease and osteoporosis

Cardiovascular disease and fracture risk

Seven population-based cohort studies assessed the relationship between CV disease and fracture risk 1 2 4 12 13 14 15 (Table 1). An increased risk of incident fractures was observed in four studies with risk rates ranging from 1.2 to 6.7 1 2 13 14 .

The largest study included more than 30,000 twins with a follow-up duration of 20 years 13 . In this study, twins, without prevalent CV disease, were included at the age of 50 years and followed up until a first hip fracture, death or end of follow-up period. Twins were considered unexposed until the first CV event. An increased hip fracture risk was found after all diagnoses of CV disease in both men (hazard ratio (HR) 6.65; 95% CI 4.82 to 9.19) and women (HR 4.42; 95% CI 3.49 to 5.61).

Furthermore, this study showed that CHD was associated with an increased fracture risk (HR 2.32; 95% CI 1.91 to 2.84) as was cerebral vascular disease (HR 5.09 95% CI 4.18 to 6.20) 13 . This was confirmed in a large population case-control study. This case-control study was conducted using the Dutch PHARMO Record Linkage System database. Patients (n = 6,763) with a hip fracture were compared with age- and sex-matched patients without a hip fracture (n = 26,341), with the objective to evaluate the association between stroke and risk of hip fracture 16 . The prevalence of stroke was 3.3% in cases versus 1.5% in control patients. The risk for a hip fracture was increased in patients who experienced a stroke before the index date (OR 1.96; 95% CI 1.65 to 2.33).

Three studies looked at the association between PAD and fracture risk. PAD was associated with increased risk for non-vertebral fractures (HR 1.47; 95% CI 1.07 to 2.04) 2 and hip fractures (HR 3.20; 95% CI 2.28 to 4.50) 13 . In contrast, a smaller study in men and women, with shorter follow-up time, did not find an association between PAD and non-vertebral fracture risk 15 . Time of follow-up might be an important factor explaining different results, for the risk of fractures was highest more than 10 years after the diagnosis of PAD 13 .

Longitudinal analysis in healthy postmenopausal women (n = 2,262) showed that aortic calcifications (AC) represented a strong predictor for fragility fractures: AC predicted a 2.3-fold increased risk for hip fracture 1 . Not only women, but also men with advanced AC have a two- to three-fold increased fracture risk 14 . However, a large population-based study with 21 years follow-up, found no evidence that severity of vascular calcification, measured as AC, is associated with an increased risk of incident hip fracture 12 . Conflicting results might be due to differences in population and methodology. The incident fracture rates were equal in comparison to the other studies.

Hence, although heterogeneity makes it difficult to draw firm conclusions, there is evidence that subjects with atherosclerotic disease are at an increased risk for frailty fractures. There are insufficient data to draw conclusions about fracture risk in patients with prevalent coronary or cerebral CV disease.

Cardiovascular disease and bone loss

Longitudinal data about CV disease and bone loss were available from six studies 1 2 3 4 15 17 . All studies showed that prevalent CV disease was associated with an increased bone loss during follow-up, independent of age and traditional risk factors. In addition, several cross-sectional studies similarly reported that prevalent CV disease is associated with low BMD 18 19 20 21 22 . In the next section the results are presented per subcategory of CV disease.

The association of CHD and BMD was only addressed in cross-sectional studies and all but one found an association with low BMD 20 22 23 24 25 . Several studies reported increased bone loss after an incident stroke. Particularly patients who are wheelchair-bound or have paretic limbs as a result of the stroke have significant bone loss within months after the stroke 26 . These studies were not included in this review, for the underlying pathogenesis is obvious. One study looked at bone density immediately after the stroke and found that female stroke patients have lower BMD than controls 27 . Since the BMD measurement was assessed within six days after the stroke, one may assume that the possible differences are not a result of immobilisation.

A large prospective study found that men with prevalent PAD had an increased rate of hip bone loss compared with men without PAD (-0.6% vs -0.3%, P < 0.001) 2 . In another, smaller, study the association between PAD and bone loss in women was weaker and not observed in men 15 . In addition, a number of cross-sectional studies showed that women and/or men with PAD have decreased BMD 19 28 29 30 .

Numerous reports have looked at the association between subclinical atherosclerosis and osteoporosis. Men and women with progression of AC have significantly higher bone loss in the lumbar spine compared with subjects without AC progression (-1.5% vs 1.4%) 4 . This is in line with other studies where AC progression is associated with higher rates of bone loss in the proximal femur and metacarpal bones 1 3 . Furthermore, several studies confirmed the prospective data and showed that subjects with calcifications in the aorta, coronary arteries, carotid arteries or femoral arteries have significant lower BMD compared with controls 31 32 33 34 35 36 37 38 39 . Only a few studies fail to find an association 40 41 42 43 . In recent years, many studies have examined the association between atherosclerosis and osteoporosis. An increased IMT has been associated with severity of atherosclerosis and increased cardiovascular risk and considered useful in identifying subjects with increased risk 44 . An association between IMT and BMD was studied intensively and most of the studies reported an association of increased IMT with low bone density 45 46 47 48 49 50 51 52 53 54 . Endothelial dysfunction is considered to be an early phase of atherosclerosis and one way to measure this is to focus on arterial compliance. The endothelium plays an important role in determining vascular tone and dysfunction will result in increased arterial stiffness 55 . In line with earlier discussed results, an increased arterial stiffness is associated with low BMD 45 54 56 57 58 59 60 61 .

Altogether, the results strongly suggest that subjects with subclinical atherosclerosis and early CV disease are at increased risk of bone loss. Again, there were insufficient data to reach conclusions about bone loss in patients with prevalent coronary or cerebral CV disease.

The relationship between osteoporosis and CV disease

Eighteen studies, most of moderate quality, reporting about the relationship between osteoporosis and CV disease were included. Results will be discussed per subcategory of CV disease, when possible.

Low bone mineral density and cardiovascular mortality

The association of osteoporosis with CV mortality was studied in 10 prospective studies 5 7 8 62 63 64 65 66 67 68 (Table 2). Low bone mass was inversely related with CV mortality in seven studies 5 7 8 62 63 64 66 67 . Postmenopausal women with a low BMD had a 1.2- to 2.3-fold increased risk of dying from CV events, independent of traditional CV risk factors 7 8 66 . Similar results were found in elderly men 7 67 . Studies in postmenopausal women with relative short follow-up periods (around three years) showed no or minimally significant elevated mortality rates 5 63 64 . Two large population-based studies in elderly men and women did not reveal a significant association between low bone mass and CV mortality 65 69 . The most recent and largest study determined the risk of CV mortality in 5,272 persons 69 . Women with low BMD had higher risk for CV mortality; however, this did not reach significance (relative risk (RR) 1.26; 95% CI 0.88 to 1.80). No association was found in men.

Focusing on the few studies that reported the results per CV subcategory, women with low bone mass had no or a small increased risk for mortality by coronary heart disease (RR 1.17; 95% CI 0.92 to 1.51) and (relative hazard 1.3; 95% CI 1.0 to 1.8), respectively 5 64 and two out of three studies showed that men and women with low BMD had a 1.3- to 1.7-fold increased risk for stroke mortality 5 62 65 .

Low bone mineral density and incident cardiovascular disease

A total of six studies assessed the risk of incident CV events in persons with osteoporosis 6 62 70 71 72 73 . Most of them show a significant inverse relationship between BMD and incident CV events in women (HR 1.23 to 3.9) 6 39 62 70 but not in men 6 70 . Two studies related the prevalence of vertebral fractures with future CV events and were unable to find any association 68 71 . Surprisingly, one study showed that women with prevalent fractures and known CHD had a reduced risk for CV events 73 .

Few articles assessed incident CV events separated per CV category. Three studies assessed the risk for CHD. Two studies showed an association with increased risk for CHD in postmenopausal women 72 73 . One study could not find an association in elderly men and women 70 . Cerebrovascular events were studied in two articles. Both found an increased risk for stroke in postmenopausal women with low BMD with hazard ratios of 1.31 and 4.1 62 72 .

There was a considerable heterogeneity in measurement of osteoporosis. It is shown that the specificity and sensitivity of the densitometry tests differs greatly, and the site of measurement plays an important role in diagnosing osteoporosis as well 74 . Only six studies used dual energy absorptiometry (DXA) measurements to assess BMD 6 64 66 67 69 75 76 , while in the other studies BMD was measured with older techniques such as single photon absorptiometry, dual photon absorptiometry (DPA) or quantitative ultrasonography (QUS). Most studies measured BMD of the hip and lumbar spine, but also distal radius and heel were measured and in some the phalangeals.

Low bone mineral density and subclinical atherosclerosis

In addition to associations with CV events, low BMD has also been shown to be associated with surrogate markers of CV disease, such as vascular calcification. In women with the largest decrease in metacarpal cortical area during a 25-year follow-up, the most severe progression of aortic calcification was observed 77 and women with a prevalent vertebral fracture had a higher IMT measured 10 years later 75 . Moreover, results from several cross-sectional studies confirmed that both women and men with low bone mass, compared to subjects with normal bone mass, have significantly more subclinical atherosclerosis 20 28 31 32 33 34 37 38 45 48 49 51 52 78 79 , increased risk of peripheral arterial disease 28 29 34 54 and other surrogate end markers for CV disease 57 60 61 .

Taken together, there is some evidence that persons with low BMD are at increased risk for CV events and subsequent CV mortality. However, variations in study design, for example, study population and outcome measures, limits interpretation. Since only a few studies assessed the CV outcome divided per CV subcategory, no conclusions can be drawn concerning a relationship between osteoporosis and specific categories of CV disease.

Links between CV disease and osteoporosis

Common pathogenesis

CV disease is preceded by atherosclerosis, for example, arterial disease. Atherosclerosis is a long-term process in which deposits of cholesterol, cellular waste products and calcium accumulates in the arterial wall causing it to thicken. Clinically, atherosclerosis is manifested by coronary heart disease, cerebrovascular disease and peripheral arterial disease. Endothelial dysfunction is the first step in the pathogenesis of atherosclerosis and predicts future CV events 80 . Calcification in the aorta and coronary arteries, for example, vascular calcification, may be a surrogate marker for atherosclerosis and increased CV risk 81 . In a recent meta-analysis patients with calcifications were found to have an increased risk for CV mortality and events 10 . Presently, vascular calcification is regarded as an active process, regulated by factors known to be involved in the process of osteogenesis, such as bone morphogenetic protein (BMP), alkaline phosphatase (ALP), osteopontin (OPN) and matrix GLA protein (MGP) 82 83 84 85 (Figure 2). Accumulating evidence suggests that calcification is a consequence of active bone formation by osteoblast-like cells 86 . Vascular smooth muscle cells (VSMCs) are able to re-differentiate towards osteoblast-like cells and a subpopulation, that is, calcifying vascular cells (CVCs), were shown to form nodules and mineralisation spontaneously 87 . In vitro, these osteoblastic cells produce hydroxyapatite, a mineral important in bone formation 88 . In the following paragraphs some of the bone-related factors that are involved in vascular calcification will be discussed in more detail.

Figure 2

Vascular calcification

Vascular calcification. Vascular calcification is an active process regulated by factors known to be involved in the process of osteogenesis. Vascular smooth muscle cells are able to differentiate towards osteoblast-like cells, promoted by a variety of stimuli, including BMP, RANKL, oxidative stress, inflammation and estrogen deficiency. These osteoblastic cells produce osteocalcin and ALP, important factors in mineralisation. ^#Excessive vitamin D promotes mineralisation. * It is not clear whether OPN promotes or inhibits calcification in the arterial wall, in bone mineralisation it is a known mineralisation inhibitor. Abbreviations: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; Cbfa1, core binding factor-α1; MGP, matrix GLA protein; Msx2, msh homeobox 2; OPG, osteoprotegerin; OPN, osteopontin; ox-LDL, oxidized low density lipoprotein; RANKL, receptor activator of nuclear factor-B ligand; VSMC, vascular smooth muscle cell; Wnt, combination of wingless and Int.

BMPs are members of the transforming growth factor-β superfamily and important factors in the regulation of osteoblast differentiation. BMP acts through upregulation of transcription factors important in bone metabolism, such as core binding factor-α1 (Cbfα1), also known as runt-related transcription factor 2 (Runx2), and msh homeobox 2 (Msx2). BMP appears to be an important mediator in vascular calcification. An increased expression of BMP2 and BMP4 is found in atherosclerotic lesions in endothelial cells, foam cells and VSMCs 88 89 . In vitro studies showed that several factors that are known to induce CV disease, such as oxidative stress, oxidized low-density lipoprotein (ox-LDL) and tumor necrosis factor alpha (TNF-α), are able to upregulate BMP expression in endothelial cells 90 91 .

MGP is a calcium-binding protein and requires vitamin K to function. MGP is found to be expressed in areas with arterial calcification 92 and may be an important calcification inhibitor. MGP knock-out mice developed extensive calcification in coronary arteries 93 . Recently the mechanism by which MGP inhibits calcification has become clear. In vitro, MGP has been shown to inhibit calcification by binding to BMP2, thereby blocking the induction of osteoblasts 94 .

OPN is a glycoprotein that accumulates in the extracellular matrix of bone tissue where it binds to hydroxyapatite and calcium. In bone, OPN is expressed by (pre-) osteoblasts and osteoclasts and is also found to be highly expressed in the atherosclerotic artery 89 92 . Whether it promotes or inhibits calcification in the arterial wall is not completely clear 95 . While high OPN serum levels are associated with vascular calcification 96 and vitamin increases OPN and subsequent calcification in bovine VSMC's 97 , OPN is also shown to inhibit calcification by inhibiting de novo hydroxyapatite production 98 .

ALP is found on the surface of osteoblasts and is often used as a marker for bone turnover. ALP is an enzyme that catalyses the hydrolysis of phosphate esters. Hydrolysis of pyrophosphate, which is an inhibitor of hydroxyapatite formation, is especially needed to facilitate normal mineralisation 99 . In vitro studies in VSMC's showed that the ALP expression is increased in response to inflammatory markers, LDL and oxidative stress and this increased expression was associated with increased mineralisation 100 101 102 .

The recent identification of receptor activator of nuclear factor-kB (RANK), osteoprotegerin (OPG) and RANK ligand (RANKL) provides more insight into bone metabolism 103 . Most interestingly, there is increasing evidence that OPG is a key regulator in the pathogenesis of osteoporosis and vascular calcification. OPG production by osteoblastic cells is regulated by a number of factors, including BMP-2, inflammation, estrogen, vitamin D and oxidative stress 104 . OPG is expressed in various tissues, including the skeleton and vascular wall, and serves as a soluble decoy for RANKL 105 . Interestingly, OPG knock-out mice show, in addition to early-onset osteoporosis, increased vascular calcification 106 . In vitro studies have shown that OPG appears to be important for endothelial cell survival 107 and may inhibit active calcification 108 . Surprisingly, while experimental studies showed that OPG might protect against vascular calcification, OPG levels appear to be elevated in patients with CV disease. Several, but not all, clinical studies found a correlation of high OPG serum levels and more severe CV disease 45 50 62 109 110 111 . Other pathways interacting with OPG might explain this discrepant finding. Estrogen deficiency results in an increased vascular OPG/RANKL ratio with subsequent increased calcification in an animal model 112 . Furthermore, pro-inflammatory cytokines are shown to elevate OPG levels in patients with CV disease 113 . Thus, while OPG appears to play a role in the pathogenesis of atherosclerosis, the exact mechanism remains to be elucidated.

Another important mechanism linking CV disease and osteoporosis is Wnt signalling, a combination of the genes Wg (wingless) and Int. Animal models showed the important role of Wnt signalling in bone formation through lipoprotein receptor-related protein 5 (LRP5), lipoprotein receptor-related protein 6 (LRP6) and β-catenin 114 . Wnt signalling is suggested to play an important role in bone formation and bone adaptation to mechanical loading 115 116 . Interestingly, TNF-α 117 , oxidative stress 118 and vitamin D 119 are shown to promote vascular calcification through the Wnt signalling pathway and this supports the hypothesis that Wnt signalling is an interesting new molecular mechanism that influences bone and vascular metabolism.

Common risk factors

CV disease and osteoporosis are both common diseases in elderly men and women. While the increased prevalence of both conditions is often attributed to aging, most of the associations found in observational studies remain significant after adjustment for age. Other important traditional risk factors are also shared, such as inactivity, smoking, estrogen deficiency and chronic inflammation, explaining part of the link between CV disease and osteoporosis 9 .

Estrogen deficiency is considered an important risk factor for osteoporosis 120 and some studies suggest estrogen deficiency to be a cardiovascular risk factor 121 122 123 . Estrogen regulates bone turnover and the CV system directly and indirectly through the effects on the immune system, antioxidant system and other risk factors. After menopause, estrogen levels decrease rapidly resulting in an upregulated osteoclast formation and differentiation, inducing high bone turnover and accelerated bone loss 124 . Furthermore, following estrogen withdrawal the production and secretion of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1 and TNF-α is increased 116 125 .

Presently, inflammation is considered to play an important role in the process of atherosclerosis 126 127 . Both cellular and humoral pathways of the immune response contribute to an important part in the pathogenesis of atherosclerosis 128 . Markers of inflammation, such as pro-inflammatory cytokines and C-reactive protein (CRP), are involved in the development of atherosclerosis and CRP predicts cardiovascular events independently of other CV risk factors 129 130 . There is accumulating evidence that inflammation influences bone metabolism and is considered to be the most important cause of postmenopausal osteoporosis. Pro-inflammatory cytokines enhance bone resorption directly through an induction of osteoclastogenesis or through the OPG pathway 116 131 .

Recent research has identified new common mediators for vascular calcification and bone loss, such as hyperlipidemia, oxidative stress and vitamin D deficiency. An abnormal lipid profile, that is, high levels of total cholesterol, LDL and triglycerides and low levels of high-density lipoprotein (HDL), is known to play a key role in development of atherosclerosis and CV disease 132 133 . Interestingly, HDL is able to regulate the calcification of VSMCs 134 . HDL inhibited the spontaneous and cytokine induced osteogenic differentiation of CVCs in vitro. The role of lipids in the regulation of bone mass is more complicated. While experimental studies showed that ox-LDL influences bone metabolism 135 , results in observational studies are contradictory 1 136 137 138 .

Oxidative stress is believed to increase with age and is associated with hypertension and atherosclerosis 139 . Free radicals have important effects on osteoclast differentiation and function 140 and oxidative stress markers are significantly associated with BMD 141 . In vitro, minimally oxidized low-density lipoprotein (MM-LDL) enhances the differentiation of VSMC's towards osteoblastic cells. Interestingly, antioxidants inhibited these effects 100 .

The prevalence of vitamin D deficiency is high among elderly men and women 142 and associated with osteoporosis and increased fracture risk 143 . Observational studies showed an inverse association of vitamin D deficiency with hypertension and CV events, suggesting a role for low vitamin D 144 145 146 147 148 . Proposed mechanisms are effects on myocardial gene expression, the renin-angiotensin axis or through secondary hyperparathyroidism. Important risk factors as physical condition and immobility were rarely assessed. Animal models and in vitro studies on the other hand, demonstrated that toxic levels of vitamin D induce vascular calcification 97 149 . Interestingly, osteoprotegerin has been shown to inhibit the vitamin-induced calcifications in an animal model 150 . It has been suggested that vitamin D has a biphasic relation with vascular calcification and that both vitamin D deficiency and vitamin D excess results in increased vascular calcification.

Genetic studies

In complex, multifactorial diseases genetic factors are believed to play an important role in the pathogenesis in addition to environmental influences. Identifying candidate genes offers opportunities to gain more insight into possible shared pathogenesis and common risk factors in CV disease and osteoporosis. Many candidate genes have been examined, mainly genes coding for known factors, such as cytokines, bone-associated factors and receptors. The genes that might be involved in both diseases will be discussed here.

Polymorphism in the IL-6 gene, a cytokine involved in bone metabolism and CV disease, might be an interestingly candidate gene. A G174C polymorphism in the promoter region of the IL-6 gene was shown to be associated with low bone mass in the radius in postmenopausal women 151 and with a high blood pressure and increased CV risk in men 152 .

Vitamin D receptor polymorphisms have been associated in many studies with bone density 153 154 . Although this could not be replicated in a large meta-analysis, it did show that the Cdx2 polymorphism was associated with risk for vertebral fractures 155 . In addition, the BsmI polymorphism was associated with IMT and myocardial infarction (MI) 156 157 , strengthening the possible role of vitamin D in linking CV disease and osteoporosis.

One of the most interesting candidate genes to mention is the OPG gene, located on chromosome 8 and several single nucleotide polymorphisms (SNPs) are identified in this gene. So far, studies were able to associate different SNPs with either bone density or vascular disease. SNPs A163G and T245G were associated with osteoporotic fractures 158 . The linked polymorphisms T950C and C1181C within the promoter region of the OPG gene were associated with an increased risk for CAD in men 159 . In addition, C1181C was also associated with first-ever intracerebral haemorrhage 160 . Furthermore, another SNP in the promoter region in the TATA box was related to vascular morphology and function 161 .

A genetic defect in the Wnt signalling pathway was recently discovered in a family with features of metabolic syndrome and early onset coronary artery disease 162 . This rare mutation in the LRP6 gene is associated with dyslipidemia, hypertension and diabetes. This finding supports further research for mutations in genes involved in the Wnt signalling pathway.

Collagen type I is an important protein in the mineralisation matrix and connective tissue. Mutations in this gene are associated with low BMD and fracture risk 163 . Interestingly, besides low BMD, individuals with a SNP in the COL1A gene (rs42524) had an increased prevalence of stroke and MI 164 .

The calcium-sensing receptor (CASR) is a receptor involved in the regulation of calcium homeostasis. A SNP in the CARS gene (A986S) was associated with higher serum calcium and increased prevalence of coronary artery disease (CAD) and MI 165 . This SNP was also associated with low BMD in premenopausal women 166 . However, the role in postmenopausal osteoporosis is not clear, since several studies showed no association of this SNP with BMD or fracture risk in postmenopausal women 167 168 .

An interesting candidate gene to mention is the klotho gene. Defects in the klotho gene have been shown to result in arteriosclerosis and increased IMT in klotho deficient mice 169 . A SNP in this gene (G395A) was associated with CAD. Surprisingly, this same SNP was associated with bone density 170 and was suggested to be involved in the pathophysiology of bone loss. This SNP in the promoter region resulted in impaired function of the gene. What makes this gene interesting is that it might offer a new treatment approach, because the abnormalities seen in klotho-deficient mice can be reversed by restoring the klotho expression 171 .

Finally, polymorphisms in the apolipoprotein E (APOE) gene has been studied intensively. It has been associated with hypertension, atherosclerotic disease and CV disease 172 173 174 . Furthermore, APOE gene polymorphisms have been suggested to be associated with low BMD and fracture risk. However, a recent meta-analysis was unable to show a strong and consistent association with BMD and fracture incidence 175 .

Discussion

Our study is the first to systematically review the epidemiological literature about the association between CV disease and osteoporosis. An extensive literature search yielded 27 prospective studies addressing this relationship. Due to considerable heterogeneity in study design and outcome measurements the results could not be pooled. Focusing on the methodologically strongest studies (those with minimal selection bias and the appropriate assessments, that is, a methodological score of more than 3), our review indicates that the prevalent subclinical CV disease predicts future fractures and bone loss 2 3 4 13 14 15 (Table 4).

Table 4

Summary of findings in high quality prospective studies

Association

No association

CV disease and OP

N = 6

N = 0

Bone mass and CV events

N = 3

N = 2

Furthermore, there is some evidence that low bone mass predicts CV mortality and CV events 6 62 68 69 75 .

Interestingly, several studies demonstrated shared risk factors, supporting the existence of a direct association between vascular calcification and bone biology.

Due to the substantial diversity of patients and study methods, pooled analysis was not considered appropriate. Although numerous efforts were made to investigate the association between CV disease and osteoporosis, a vast majority of studies used secondary outcome measurements, while a limited number of studies used primary outcome measurements such as incident CV events or osteoporosis. Furthermore, the population studied varied with respect to age, sex, baseline risk for CV events or fractures and ethnicity. Larger prospective studies in elderly persons, men and women, are needed to answer this question. To reduce heterogeneity we encourage that in new studies well-defined outcome measures should be incorporated, such as incident CV disease presented per subcategory of CV disease and measurement of BMD by DXA-scans on regular interval periods.

Conclusions

The current evidence indicates that individuals with prevalent (sub)clinical CV disease are at increased risk for bone loss and subsequent fractures. Presently, no firm conclusions can be drawn to which extent low BMD might be associated with increased cardiovascular risk. Age, estrogen deficiency and inflammation represent the most important common risk factors and the discovery of new pathways, for example, OGP/RANKL and Wnt signalling, might provide interesting new therapeutic options. Altogether our results suggest that bone density screening could be recommended in patients with prevalent CV disease.

Abbreviations

ABI: ankle brachial index; AC: aortic calcifications; ALP: alkaline phosphatase; APOE: apolipoprotein E; BMD: bone mineral density; BMP: bone morphogenetic protein; CAD: coronary artery disease; CASR: calcium-sensing receptor; Cbfa1: core binding factor-α1; CDH: coronary heart disease; CRP: C-reactive protein; CV: cardiovascular; CVC: calcifying vascular cells; DPA: dual photon absorptiometry; DXA: dual energy absorptiometry; HDL: high density lipoprotein; HR: hazard ratio; IL-6: interleukine-6; IMT: intima media thickness; LRP5: lipoprotein receptor-related protein 5; LRP6: lipoprotein receptor-related protein 6; MGP: matrix GLA protein; MI: myocardial infarction; MM-LDL: minimally oxidized low-density lipoprotein; Msx2: msh homeobox 2; OPG: osteoprotegerin; OPN: osteopontin; OR: odds ratio; ox-LDL: oxidized low density lipoprotein; PAD: peripheral arterial disease; QUS: quantitative ultrasonography; RANK: receptor activator of nuclear factor-B; RANKL: receptor activator of nuclear factor-B ligand; RR: relative risk; Runx2: runt-related transcription factor 2; SNP: single nucleotide polymorphism; TNF-α: tumour necrosis factor alpha; VSMC: vascular smooth muscle cell; Wnt: combination of wingless and Int.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

DU conducted the data collection, interpretation and analysis of the data and drafted the manuscript. LT participated in interpretation and analysis of the data and helped to draft the manuscript. WL conceived of the hypothesis of the manuscript and participated in study design and coordination. MT, HR and WL helped to draft the manuscript. All authors critically reviewed, contributed to and approved the final manuscript.

Acknowledgements

We would like to thank Hans Ket (Clinical Library, VU medical centre, Amsterdam) for his assistance in collecting the literature for this systematic review.

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