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Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. P. Vestergaard. Received: 11 July 2006 ...
Osteoporos Int (2007) 18:427–444 DOI 10.1007/s00198-006-0253-4

ORIGINAL ARTICLE

Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis P. Vestergaard

Received: 11 July 2006 / Accepted: 6 October 2006 / Published online: 27 October 2006 # International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Abstract Introduction and hypothesis Diabetes affects bone metabolism. The hypothesis was that type 1 (T1D) and type 2 (T2D) affects BMD and fracture risk differently. Material and methods Pubmed, Embase, and Web of Science were searched using the terms “diabetes”, “fracture”, and “bone mineral”. Results Hip fracture risk was increased in T1D (RR=6.94, 95% CI: 3.25–14.78, five studies) and T2D (1.38, 95% CI: 1.25–1.53, eight studies) compared to subjects without diabetes. The increase in relative hip fracture risk was significantly higher in T1D than in T2D. BMD Z-score was decreased in the spine (mean±SEM −0.22±0.01) and hip (−0.37±0.16) in T1D and increased in the spine (0.41± 0.01) and hip (0.27±0.01) in T2D. A meta-regression showed that body mass index (BMI) was a major determinant for BMD in both the spine and hip. Glycated haemoglobin (HbA1C) was not linked to BMD. The increase in fracture risk was higher and BMD lower in patients with complications to diabetes. Conclusions Hip fracture risk is increased in both T1D and T2D, whereas BMD is increased in T2D and decreased in T1D. A common factor such as complications may explain the increase in fracture risk, whereas BMI may ameliorate the increase in fracture risk in T2D. Keywords Bone mineral density . Diabetes . Fracture . Meta-analysis

P. Vestergaard (*) The Osteoporosis Clinic, Aarhus Amtssygehus, Aarhus University Hospital, Tage Hansens Gade 2, 8000 Aarhus C, Denmark e-mail: [email protected]

Impaired glucose metabolism has a number of detrimental effects on bone metabolism, which have significant consequences for patients with diabetes in terms of decreased bone mineral density [1, 2] and increased risk of fractures [3]. The pathophysiological mechanisms can be divided into mechanisms that decrease bone mineral density (BMD) or weaken bone structure, and those which increase the likelihood of falls and other traumas. Among the mechanisms that decrease BMD are 1) an increased urine calcium excretion that leads to a negative calcium balance [1] (The increased urine calcium excretion is linked to hyperglycaemia [1]. Antidiabetic treatment reverses the urine calcium loss [4]), 2) a functional hypoparathyroidism [5] (The increased urine calcium loss should theoretically lead to secondary hyperparathyroidism, but this is not seen in patients with diabetes), 3) alterations in vitamin D metabolism, which is particularly prominent in patients with nephropathy [6], and 4) perhaps insulin itself and insulin like growth factors [7]. Insulin is an anabolic hormone, and patients with type 1 diabetes (T1D) have an absolute deficiency in insulin, whereas patients with type 2 diabetes (T2D) may have excess insulin levels. Mechanisms that lead to a decreased bone biomechanical competence besides decreases in BMD are alterations in glycosylation of collagen [8–14] brought about by hyperglycaemia in the same was as increased glycosylation of haemoglobin, which is expressed as HbA1C. These advanced glycation end products (AGE) and their receptors (RAGE) play an important role in bone metabolism and bone strength [8–14]. Other studies have also raised concern that diabetes through the impaired bone metabolism may delay fracture healing [15]. The complications of diabetes may also contribute to fracture risk, in particular in patients with renal failure and those undergoing renal transplantation [16, 17]. Neuropathy may perhaps also be involved through decreased mobility and increased

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bone mineral loss [18]. Angiopathy may also play a role as microangiopathy may alter blood flow to the bones through altered endothelial function although this is controversial [19], and macroangiopathy may also decrease blood supply to parts of the skeleton [20, 21]. However, besides the alterations related to BMD and bone strength, diabetes may be associated with an increased risk of falls [22] and other traumas [23]. This may be related to fits during hypoglycaemia [24, 25] or falls e.g., related to decreased eyesight following retinopathy or decreased postural balance related to neuropathy. Patients with T2D often have a higher body weight and body mass index (BMI) than patients with T1D. When they fall they sustain a greater traumatic load due to obesity, but on the other hand may the soft-tissue energy absorption upon impact be greater in obese patients with T2D than in thin T1D patients. This may lead to differences in fracture pattern. Prior studies have shown discrepant results for type 1 and type 2 diabetes with a decreased bone mineral density (BMD) in patients with T1D [26] and a normal to increased BMD in patients with T2D [27]. Prior studies in patients with T1D have shown an increase in fracture risk [3], whereas discrepant results have been reported for T2D [3, 27]. It is, thus, unclear if the increased BMD actually to some degree is protective against fractures in T2D or whether the increased BMD is just the result of the generally higher body mass index (BMI) in patients with T2D, the patients despite this having an increased risk of fractures stemming from the disturbances in bone metabolism with decreased bone strength. If the hyperglycaemia alone was responsible for the alterations in skeletal metabolism, the changes in BMD and fracture risk should theoretically be equal in T1D and T2D. However, if other factors such as insulin levels and BMI were also responsible, differences might be anticipated. Furthermore, if complications to diabetes were involved this could also contribute to the differences as patients with T2D may have complications at the diagnosis of their diabetes, whereas this is not the case in patients with T21. It is thus of interest to assess the degree of BMD changes and changes in fracture risk with particular respect to differences between T1D and T2D. We addressed the following research questions in this meta-analysis: 1) What were the changes in spine and hip BMD Z-scores in patients with T1D and T2D? 2) What were the changes in fracture risk in patients with T1D and T2D? 3) Did the changes in BMD explain the changes in fracture risk in T1D and T2D? 4) What were the effects of glycaemic control and complications on the risk of fracture and the changes in BMD in T1D and T2D?

Osteoporos Int (2007) 18:427–444

Material and methods A systematic search of Pubmed (1951–December 16, 2005), Embase (1974–December 16, 2005), and ISI Web of Science (1945–December 16, 2005) was performed. The search was divided into two. The first search used the terms “diabetes” and “fracture” and produced 1,499 papers, and among these 16 were included in the analysis. The second search used the terms “diabetes” and “bone mineral” and produced 889 papers, of which 65 were included in the analysis. Due to overlap of one paper between the two search strategies, the combined number of papers was 80. Inclusion criteria were epidemiological studies (cross sectional, cohort or case control) that provided data on fracture risk or BMD in patients with T1D or T2D compared to a control group without diabetes. Data for BMD data were expressed as Z-scores. Data could either be expressed as Zscores in patients with diabetes in relationship to a reference population or as a direct difference between patients and a control group. Only published results were used. Papers in all languages and abstracts were eligible. Diabetes was categorised as T1D or T2D depending on the information provided by the authors. Subgroups of patients (say patients who had to have T2D because they were diagnosed with diabetes and were not treated with insulin but rather with oral antidiabetics and/or diet) were also eligible. The studies were excluded if no clear definition of diabetes was given [28]. The studies were also excluded provided that the entire group of patients with diabetes were selected based on presence of complications known to be associated with fracture risk say renal failure. Studies with both groups of patients with and without complications to diabetes were eligible. If more than one study group presented data from the same study population [27, 29–31], the one with the longest duration of observation and the more complete reporting of data was chosen. BMD data had to be measured on modern scanners using DXA technique [32]. Only scans of the lumbar spine (L1–L4 or L2–L4) or hip (femoral neck or total hip) were eligible. No internationally accepted criteria for evaluating quality of epidemiological studies exist, as is the case for randomised controlled trials (e.g., the Jadad scale [33]). In the actual study ad hoc classification was attempted based on reporting of criteria for diagnosing diabetes, CV for BMD measurements, consecutive selection of cases, and random selection of controls. All risk estimates (relative risk, odds ratio, hazard ration, prevalence ratio etc.) were considered estimates of relative risk. The estimates had to be crude estimates of fracture risk in patients with diabetes compared to non-diabetics. If large age or gender differences between patients and controls were present, age- and gender adjusted risk estimates were used. Estimates adjusted for say BMI, smoking, BMD etc. were

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Table 1 Relative risk estimates of fractures in patients with diabetes N controls

Age BMI (years) (kg/cm2)

RR (95% CI)

12,639

45.4

25.0

12,639

64.0

28.0

12,639

61.2

28.6

89

12,639

66.7

27.3

29

14,065

43.5

24.3

198

14,065

68.2

29.3

78

14,065

65.7

30.5

120

14,065

69.7

28.6

52

12,639

45.4

25.0

Hip

175

12,639

64.0

28.0

Men

Hip

86

12,639

61.2

28.6

Men

Hip

89

12,639

66.7

27.3

Women

Hip

29

14,065

43.5

24.3

T2D

Women

Hip

198

14,065

68.2

29.3

T2D insulin treated T2D non insulin treated

Women

Hip

78

14,065

65.7

30.5

Women

Hip

120

14,065

69.7

28.6

3.06 (1.27–7.38) 1.19 (0.61–2.31) 1.10 (0.41–2.95) 1.28 (0.53–3.11) 3.03 (0.98–9.44) 0.89 (0.59–1.35) 0.87 (0.43–1.74) 1.39 (0.90–0.54) 17.79 (5.57– 56.75) 1.45 (0.53–3.99) 1.77 (0.43–7.22) 1.23 (0.30–5.03) 8.55 (1.19–61.49) 1.72 (0.97–3.02) 1.72 (0.64–4.64) 1.71 (0.87–3.36)

2,688

>65

N/A

Women

Hip Hip

316

T2D T2D oral antidiabetics T2D insulin

Women

Hip

Women

Hip

T2D

Men

Hip

T2D oral antidiabetics T2D insulin

Men

Hip

Men

Hip

T2D

Both Both

Reference

Type of diabetes

Gender

Fracture type

Ahmed [46] 2005, Norway, self report, screening of HbA1C and register data

T1D

Men

T2D

Men

T2D insulin treated T2D non insulin treated T1D

Men

Non 52 vertebral Non 175 vertebral Non vertebral 86

T2D

Women

T2D insulin treated T2D non insulin treated T1D

Women Women Men

Non vertebral Non vertebral Non vertebral Non vertebral Non vertebral Hip

T2D

Men

T2D insulin treated T2D non insulin treated T1D

Cortes-Sancho [48] 2004, Taiwan, screening, FPG and HbA1C

De Liefde [29] 2005, Netherlands, screening, OGTT)

Men Women

N DM

1.4 (1.1–1.7) 1.8 (1.3–2.6) 2.9 (1.9–4.5) 1.5 (1.1–2.0) 2.6 (1.7–4.1) 4.2 (2.0–8.6) 792

Both

Non vertebral Hip

Both

Wrist

5,863

73.8

26.8 1.09 (0.88–1.34) 1.16 (0.81–1.65) 1.08 (0.71–1.66)

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Table 1 (continued) Reference

Type of diabetes

Gender

Fracture type

N DM

N controls

Age BMI (years) (kg/cm2)

RR (95% CI)

Forsen [3] 1999, Norway, self report, screening of non-fasting blood glucose and HbA1C

T2D ≤5 years duration T2D ≤5 years duration T2D ≤5 years duration T2D ≤5 years duration T2D ≤5 years duration T2D ≤5 years duration T2D ≤5 years duration T1D

Women 50– 74 years Women 50– 74 years Women ≥75 years Women ≥75 years Men 50– 74 years Men ≥75 years Men ≥75 years Women 50– 74 years Men 50– 74 years Women

Hip

221

13,685

66

29

Hip

274

13,685

67

30

Hip

144

3,831

82

28

Hip

196

3,831

81

27

Hip

148

13,210

66

27

Hip

220

2,868

81

26

Hip

7

2,868

81

25

Hip

23

13,685

59

27

Hip

28

13,210

60

25

Any fracture 74

1,058

N/A

N/A

Women

Hip

74

1,058

N/A

N/A

Women

Wrist

74

1,058

N/A

N/A

Women

Spine

74

1,058

N/A

N/A

Women

Vertebral deformity Vertebral deformity Vertebral deformity Vertebral deformity Any fracture Wrist

63

5,156

67

N/A

35

5,156

63

N/A

347

1,970

67

N/A

182

1,970

63

N/A

147

3,450

N/A

N/A

N/A

N/A

0.7 (0.4–1.5) 1.7 (1.1–2.7) 0.9 (0.5–1.5) 1.4 (0.9–2.0) 1.0 (0.4–2.6) 1.8 (1.0–3.4) 1.1 (0.6–2.5) 5.7 (1.8–17.9) 4.0 (0.6–28.2) 0.83 (0.52–1.33) 0.54 (0.20–1.49) 0.62 (0.33–1.16) 0.52 (0.19–1.42) 1.24 (0.61–2.51) 0.97 (0.34–2.77) 0.92 (0.67–1.26) 0.77 (0.49–1.22) (0.4–3.0) 1.4 (0.2–10.2) 2.7 (0.3–21.7) 7.6 (5.9–9.6) 4.1 (2.7–6.0) 17.4 (12.5–23.5) 4.5 (3.2–6.3) 31.6 (21.7–44.3) 4.6 (3.3–6.4) 32.6 (22.3–46.0) 6.6 (5.0–8.5)

T1D Gerdhem [39] 2005, Sweden, self report

Hanley [49] 2003, Canada, self report

Ivers [42] 2001, Australia, self report

Miao [37] 2005, Sweden, register data

T2D, no insulin treatment T2D, no insulin treatment T2D, no insulin treatment T2D, no insulin treatment T1D T1D

Men

T2D

Women

T2D

Men

T2D diet or tablets

Both

T1D

Men

Proximal humerus 12,551

T1D no eye complications T1D eye complications T1D no nephropathy

Men

Hip

12,551

Population N/A

N/A

Men

Hip

12,551

Population N/A

N/A

Men

Hip

12,551

Population N/A

N/A

T1D nephropathy

Men

Hip

12,551

Population N/A

N/A

T1D no neurological complications T1D neurological complications T1D no cardiovascular complications

Men

Hip

12,551

Population N/A

N/A

Men

Hip

12,551

Population N/A

N/A

Men

Hip

12,551

Population N/A

N/A

Population N/A

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Table 1 (continued) Reference

Michaelsson [50] 1995, Sweden, self report Nicodemus [51] 2001, USA, self report

Poor [52] 1995, USA, files Seeley [53] 1996, USA, self report Strotmeyer [43] 2005, USA, self report or FPG screening Taylor [54] 2004, USA, self report Van Daele [27] 1995, Netherlands, drug use or OGTT Vestergaard [38] 2005, Denmark, register data

Type of diabetes

Gender

Fracture type

N DM

N controls

Age BMI (years) (kg/cm2)

T1D Cardiovascular complications T1D

Men

Hip

12,551

Population N/A

N/A

Women

Hip

12,054

Population N/A

N/A

T1D no eye complications T1D eye complications

Women

Hip

12,054

Population N/A

N/A

Women

Hip

12,054

Population N/A

N/A

T1D no nephropathy

Women

Hip

12,054

Population N/A

N/A

T1D nephropathy

Women

Hip

12,054

Population N/A

N/A

T1D no neurological complications T1D neurological complications T1D no cardiovascular complications T1D cardiovascular complications T2D dietary treatment

Women

Hip

12,054

Population N/A

N/A

Women

Hip

12,054

Population N/A

N/A

Women

Hip

12,054

Population N/A

N/A

Women

Hip

12,054

Population N/A

N/A

Women

Hip

27

1,066

N/A

N/A

T2D oral antidiabetics

Women

Hip

47

1,066

N/A

N/A

T1D

Women

Hip

47

30,377

60.9

25.8

T2D

Women

Hip

1,682

30,377

62.3

30.5

T2D ≤4 years duration T2D 5–12 years duration T2D 13–40 years duration T2D insulin treated

Women

Hip

N/A

N/A

N/A

N/A

Women

Hip

N/A

N/A

N/A

N/A

Women

Hip

N/A

N/A

N/A

N/A

Women

Hip

N/A

N/A

N/A

N/A

T2D oral antidiabetics

Women

Hip

N/A

N/A

N/A

N/A

T2D no pharmacological Women treatment T2D Men

Hip

N/A

N/A

N/A

N/A

Hip

42

190

78.5

N/A

T1D

Women

Foot

101

9,441

71.4

N/A

T2D

Both

Any fracture 566

2,236

73.5

28–30

T2D

Women

Hip

443

7,437

73.5

N/A

T2D

Women

Any fracture 335

3,115

72.3

27.8

T1D

Both

Any fracture 4,362

484,657

N/A

N/A

T2D

Both

Any fracture 9,598

484,657

RR (95% CI) 28.6 (15.2–48.8) 9.8 (7.3–12.9) 4.1 (2.3–6.9) 20.5 (14.5–28.3) 6.4 (4.3–9.2) 32.6 (20.4–49.4) 5.7 (3.7–8.3) 41.6 (26.9–61.4) 8.1 (5.8–11.0) 29.2 (15.1.51.1) 1.09 (0.41–2.91) 2.04 (1.09–3.82) 14.1 (5.85–34.20) 1.75 (1.25–2.43) 1.47 (0.81–2.67) 1.82 (1.05–3.16) 1.21 (0.68–2.14) 2.79 (1.61–4.85) 1.82 (1.05–3.16) 1.21 (0.68–2.14) 0.9 (0.5–1.7) 2.36 (0.97–5.73) 1.23 (0.82–1.86) 1.52 (1.14–2.02) 0.63 (0.44–0.90) 1.30 (1.16–1.46) 1.19 (1.11–1.27)

432

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Table 1 (continued) Reference

Type of diabetes

Gender

Fracture type

N DM

N controls

T1D

Both

Hip

4,362

484,657

T2D

Both

Hip

9,598

484,657

T1D

Both

Wrist

4,362

484,657

T2D

Both

Wrist

9,598

484,657

T1D

Both

Spine

4,362

484,657

T2D

Both

Spine

9,598

484,657

Age BMI (years) (kg/cm2)

RR (95% CI) 1.70 (1.31–2.21) 1.38 (1.18–1.60) 1.04 (0.76–1.44) 1.21 (1.01–1.45) 2.48 (1.33–4.62) 1.34 (0.97–1.86)

The mode of diagnosis of diabetes is mentioned under reference. Under reference, country of origin, date of publication, and method of diagnosis of diabetes has been mentioned. OGTT: Oral glucose tolerance test, FPG: fasting plasma glucose. N DM is number of patients with diabetes, N controls is number of control subjects, BMI: Body mass index, RR: relative risk with 95% confidence intervals (95% CI).

excluded. A common weighted risk estimate for relative fracture risk was calculated as a derSimonian and Laird estimator using a random effects model [34]. Tests for heterogeneity were performed. Publication bias was tested using funnel plots. Sensitivity analyses were performed excluding large studies. For BMD a weighted mean difference (WMD) estimate was calculated for Z-score in the spine or hip [34]. Analyses of pooled relative fracture risk and WMD were only performed providing that at least three studies were available. The observed BMD was converted into an expected relative fracture risk using the estimates of Marshall et al. [35]. The expected relative fracture risk was calculated as c−z, where z is the observed zscore, and c is a constant. To assess the effects of diabetes type, age, disease duration, BMI and average glucose level (HbA1C) a meta-regression analysis was performed using STATA 8.0 [36].

Results Fracture risk Table 1 shows details of studies on fracture risk in patients with diabetes compared to controls. Most studies focused on hip fracture risk. A trend towards an increased fracture risk was reported at most skeletal sites for T1D, whereas for T2D many studies also reported a trend towards an increased fracture risk at most skeletal sites, although some studies also reported a trend towards a decreased fracture risk. There was a marked trend towards a higher relative fracture risk with the presence of complications in T1D (study by Miao et al. [37]). No studies on the effect of complications were present for T2D. Table 2 shows the combined results for relative fracture risk. Only for hip fractures were the studies numerous enough to allow analysis in T1D. There was a highly

Table 2 Observed risk of fractures. Only studies with all treatment modalities represented Diabetes type

Fracture type

RR (95% CI)

P

Number of studies

T1D

Hip Hip

6.94 (3.25–14.78)* 8.65 (7.26–10.30)*