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Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine (H.D., J.C.P.-S., M.R., B.O.-P., E.M., P.M., C.S., A.F.-P.), and Center for Medical Research (A.T., A.S.), Medical University of Graz, A-8036 Graz, Austria
Address all correspondence and requests for reprints to: Harald Dobnig, M.D., Professor of Internal Medicine, Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: harald.dobnig{at}meduni-graz.at.
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Abstract |
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Objective: The objective of this study was to investigate whether type 2 DM affects bone mass, bone turnover, or prospective fracture rates in frail, elderly women living in nursing homes.
Design, Setting, and Participants: This study was a prospective cohort of 583 patients with type 2 DM and 1081 control (CTR) individuals above age 70 recruited from 95 nursing homes in Austria. Patients were enrolled and followed up by mobile study teams.
Main Outcome Measures: We performed quantitative bone ultrasound measurements at the calcaneus, radius, and proximal third phalanx, measurements of quadriceps strength, and biochemical parameters of mineral metabolism and bone turnover. Patients were prospectively followed for hip and other nonvertebral fractures over 2 yr.
Results: Patients with type 2 DM had significantly higher age-, weight-, and mobility score-adjusted calcaneal stiffness (P < 0.0001), radial speed of sound (P < 0.005), and phalangeal speed of sound (P < 0.05) measurements when compared with CTRs. Mean serum PTH (–20.7%) and osteocalcin levels (–22.3%) were significantly lower (both P < 0.0001) in patients with treated type 2 DM despite comparable low serum 25-hydroxyvitamin D levels and slightly higher adjusted total serum calcium levels compared with CTRs. Important independent determinants of bone turnover in both patient groups were PTH, creatinine clearance, alanine aminotransferase, as well as glycosylated hemoglobin levels, together accounting for 30–40% of its variance. A total of 110 hip fractures occurred during the observation period, corresponding to a hip fracture rate of 3.1% (in CTRs) and 3.4% (in type 2 DM) per 100 patient years; this was not significantly different for CTRs and diabetics.
Conclusions: Decreased PTH levels and higher levels of glycemia independently contribute to lower bone turnover in elderly nursing home patients with type 2 DM. Despite higher bone mass and lower bone turnover, hip fracture risk is comparable with women without DM.
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Introduction |
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It is well known that diabetics show an increased propensity to fall due to visual impairment and neuropathy, as well as foot problems (13, 14) and presumably accelerated cognitive decline (15). Such diabetes-associated complications tend to become clinically more significant over the years and may increase the risk for falls and fractures. At the same time, potential fracture preventive effects of DM on bone turnover and bone mass may overlap with a time period in which diabetes-related morbidity increases. Looking at diverse populations of diabetics at different ages may thus generate conflicting results because the time dependency of negative as well as positive effects on fracture risk may develop differently over the years. One would need large longitudinal studies of well-defined patient populations to control for these confounders.
Because on the one hand, according to the National Center for Health Statistics, the prevalence of DM in nursing homes is estimated to be around 17% (16), and on the other, the effects on bone mass are quite substantial in the cohorts reported to date, we intended to look for any diabetes-related effects on bone metabolism and fracture rate in institutionalized individuals. Here, the scope of the problem is especially large because 3–5% of these patients develop a hip fracture annually (17). These fractures are triggered by physical and cognitive handicaps, malnutrition, vitamin D deficiency, and increased bone turnover, by numerous comorbidities in most cases, and finally by high intake of the most various medications. Because it would be too strenuous for most of these patients to participate in a study demanding transportation and an extended hospital stay, we chose to visit nursing home patients with study teams equipped with ultrasound devices for measuring bone density and equipment for obtaining high-quality blood specimens.
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Patients and Methods |
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Inclusion and exclusion criteria
The female patients, all Caucasian because of the ethnic composition of that age group in Austria, had to be able to walk a short distance independently, with the use of canes or a walker, or with the support of a nurse. Physical activity was graded as follows (adopted from Ref. 18): mobility score 1, walking outside the institution, walking independently; score 2, walking inside nursing home, majority using a walking aid but not a wheelchair; score 3, staying in bed less than 50% of the time during daytime, majority requiring a wheelchair; and score 4, staying in bed more than 50% of the time during daytime.
Exclusion criteria were known current malignancies or completed treatment for any type of malignancy during the past year, hypercalcemia (>2.6 mmol/liter), advanced kidney and liver dysfunction (defined as serum creatinine levels above 1.9 mg/dl and liver transaminases more than 3.5 times higher than the upper limit of normal), bilateral hip replacements, history of total gastrectomy, decompensated heart failure (New York Heart Association class 4), chronic alcoholism, known osteomalacia, untreated thyroid disease, or chronic steroid treatment with more than 5 mg prednisolone equivalent/d.
All subjects were followed from their baseline visit until death, first hip fracture, or the last follow-up visit, whichever occurred first.
Type 2 DM
Patients were assigned to the group of diabetics if they had a diagnosis of DM in their medical chart, had antidiabetic drugs prescribed, or were found to have glycosylated hemoglobin (HbA1c) levels of more than 5.9% (19). Treatment for DM was classified as follows: 1) diabetes diet alone and no antidiabetic drugs prescribed, 2) oral antidiabetic therapy alone, or 3) insulin either alone or in combination with an oral hypoglycemic agent. This classification was also used for analyses between DM subgroups.
Bone ultrasound measurements
Bone status in the present study was measured by Achilles Express at the calcaneus (GE LUNAR Corp., Madison, WI) and by Sunlight Omnisense ultrasound bone sonometer (Sunlight Ultrasound Technologies Ltd., Rehovot, Israel) at the distal one third of the radius and the proximal phalanx of the third finger on the nondominant side. The Achilles Express is a fluid-coupled system that automatically calculates the patient’s stiffness index (SI), which is derived from a combination of speed of sound (SOS; m/sec) and broadband ultrasound attenuation (decibels per megahertz) and calculated as follows: SI = 0.67 x broadband ultrasound attenuation + 0.28 x SOS – 420. Intra- and interobserver coefficients of variation (CV) for SI were 1.5 and 2.3%, respectively. The Omnisense system measures axially transmitted SOS. Here, the intra- and interobserver CV were 0.6 and 0.9% for the radius and 1.0 and 1.3% for the phalanx. Three Achilles Express and three Omnisense systems were used by the study teams at a given time. Quantitative ultrasound systems of both brands were cross-calibrated at the beginning of the study, and quality control checks were performed by the study teams every 2 wk. In vivo and in vitro results on CV were communicated to both companies to decide whether a recalibration might be necessary. Both systems, however, ran stable over the time used.
Determination of muscle strength
Quadriceps muscle strength was measured as knee extensor strength in kiloponds (kp), with a validated, hand-held isometric device (model DPPH, Industrial Scale Inc., Houston, TX) on the nondominant side (20). The participants were seated in an adjustable, straight-back chair with the pelvis fixed by a strap. The highest score obtained during three attempts was recorded. Verbal encouragement was given each time to obtain the maximal score. Intra- and interobserver CV were 1.5 and 1.7%, respectively.
Handling and processing of blood samples and laboratory analysis
Nonfasting blood samples were drawn and specimens allowed to clot at room temperature for 15 min. They were then immediately centrifuged with a Heraeus Biofuge (Thermo Electron, Waltham, MA), aliquoted, and placed in an ice-water bath before they were finally transferred to the electric cooler. When the study teams returned to the study center, serum and plasma samples were immediately stored at –70 C until further analysis. Routine serum parameters were measured by an autoanalyzer (Hitachi-747, Hitachi Software Engineering, Yokohama, Japan). Bone turnover was assessed by measuring C-terminal telopeptide cross-links (ß-CTxs; Elecsys ß-CrossLaps) and osteocalcin [intact osteocalcin (1–49) and large N-MID fragments (1–43); Elecsys N-MID Osteocalcin]. PTH was analyzed using Elecsys Intact PTH that recognizes PTH (1–84) and the PTH (7–84) fragment (all Elecsys systems from Roche Diagnostics, Indianapolis, IN). Serum 25-hydroxyvitamin D was measured by RIA after extraction (Immunodiagnostic Systems, Boldon, UK). HbA1c was measured using HPLC.
Follow-up
Depending on the size of the nursing home, at least two staff nurses were responsible for reporting fracture incidents by fax to the study center at the beginning of each month. For 2 yr, all participating centers were additionally visited by one and the same physician on a regular basis. This physician searched the medical charts for new fracture cases and radiology reports. All fatalities that had occurred since the previous visit were also recorded.
The study was performed under the terms of Good Clinical Practice guidelines (http://www.wma.net/e/policy/b3.htm) and was carried out in accordance with the ethical principles laid down in the revision of the Declaration of Helsinki (http://www.wma.net/e/policy/b3.htm). The study protocol was approved by the local research ethics committees, and written informed consent and willingness to participate were required for all participants. Patients whose physical handicaps prevented them from signing the informed consent form were assigned an impartial witness unconnected to the study. This witness was present during the entire informed consent discussion. After the subject had orally consented to participate in the study, the witness’s signature on the form attested that the information in the consent form had been accurately explained and understood. Residents also had the option of participating in a subprotocol requiring collection of blood samples and bone ultrasound measurements. Patients without a legal representative were not enrolled when impaired cognitive function was obvious.
Statistical analyses
Power analysis was performed using an online service of DSS Research, Inc. (http://www.dssresearch.com). All other analyses were conducted using SPSS version 12.0 (SPSS Inc., Chicago, IL). Our prestudy assumption of hip fracture incidence in the control (CTR) group was 7% over the observation period. In one study performed in elderly community-dwelling Mexican-Americans, the relative risk for hip fracture in individuals with DM was 1.5-fold increased (21). With a final observed hip fracture rate of 6.3% in CTR, the number of individuals enrolled in the present study would have been large enough to demonstrate a minimum 1.6-fold increase in the relative risk for hip fractures between the groups with a statistical power of 83%. Differences in fracture rates were calculated by 
2 test as well as by Cox proportional regression analysis. Hazard ratios (HRs) estimated from Cox models are reported as relative risks, with corresponding 95% confidence intervals (CIs).
Normality of data was checked by Kolmogorov-Smirnov and Shapiro-Wilk testing in the overall population as well as for both study groups separately. With the exception of radial and phalangeal bone ultrasound measurements that were log-transformed, all other variables were normally distributed. Potential differences between CTR and DM in continuous variables were tested using the Student’s t test and in the case of categorical variables, the 2 test. Differences in bone ultrasound measurements, body mass index (BMI), knee extensor strength, and various biochemical parameters in CTR, DM, or DM subgroups were calculated by analysis of covariance and adjusted for age and other important variables (given in table and figure legends) that were significantly correlated to the dependent variable in univariate analysis. Likewise, we looked for differences in the PTH to total serum calcium ratio between CTR and DM after adjustment for age, BMI, glomerular filtration rate (GFR), serum 25-hydroxyvitamin D, and magnesium levels using analysis of covariance. Step-wise multiple linear regression models were performed to determine relevant independent determinants of bone ultrasound measurements and bone turnover (osteocalcin) in CTR and patients with DM. Coefficients of correlations between bone turnover markers and HbA1c levels were calculated by the Spearman rank sum method. A two-way ANOVA was performed to explore interactions between HbA1c and PTH concentrations on calcaneal stiffness and osteocalcin levels.
P < 0.05 was considered significant. Data are presented as mean (SD).
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Results |
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Anthropometric and clinical characteristics of CTR and diabetic subjects are given in Table 1
. Of 677 CTR patients for whom blood specimens were available, 77 (11.3%) had an HbA1c level of 6.0% or above and were thus diagnosed as having DM (19). For further analyses, these patients were assigned to the DM group. Close to half of all patients with DM were treated with diet alone; one third received additional treatment with oral antidiabetic agents, and the remainder had insulin treatment either alone or in combination with an oral antidiabetic drug. Patients with DM were slightly younger than CTR subjects. A statistically significant difference in height was no longer present when data were adjusted for age. Slightly fewer patients with DM had a full degree of mobility (P = 0.08), but quadriceps strength was similar between the two groups.
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summarizes relevant comorbidities and medications taken by the patients. Medications were grouped by pharmacological classes. Differences in the clinical diagnoses mainly reflect the higher prevalence of cardiovascular disease and associated pharmacological treatment regimens in a diabetic patient cohort. Slightly fewer patients with DM carried a diagnosis of osteoporosis (P = 0.07). The mean (SD) observation period was 24.7 ± 9.7 months (median, 30 months) for both patient groups. Total patient years were 2222 for the CTR and 1199 for the DM group. During the observation period, 378 patients (35.0%) in the CTR and 216 (37.0%) in the DM group died (P = 0.39).
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Bone ultrasound measurements
Because bone ultrasound measurements were generally better correlated to weight than to BMI, analyses used weight as a confounder. Patients with lower mobility scores had lower calcaneal (but not radial or phalangeal) ultrasound values after adjustment for age and weight. Mean calcaneal SI for mobility score 1 was –0.08; for mobility score 2, –0.46 (P < 0.0001 vs. mobility score 1); for score 3, –0.80 (P < 0.0001 vs. score 1); and score 4, –1.16 (P = 0.08 vs. score 1). Consequently, all presented data on bone ultrasound measurements were also normalized for mobility score.
Diabetic patients taken as a single group had higher age-, weight-, and mobility score-adjusted calcaneal stiffness (–0.03 ± 0.06 in DM vs. –0.52 ± 0.04 in CTR, P < 0.0001) as well as peripheral radial (–0.49 ± 0.07 in DM vs. –0.81 ± 0.05 in CTR, P < 0.005) and phalangeal (–0.65 ± 0.05 in DM vs. –0.79 ± 0.03 in CTR, P < 0.05) SOS measurements. Results on bone ultrasound measurements for all three DM subgroups are given in Fig. 1.
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), significant independent determinants of calcaneal stiffness in both patient groups were age, mobility status, osteocalcin levels, and quadriceps strength.
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Phalangeal SOS measurements in diabetic subgroups tended to be lower, but this difference was not significant. Similar to radial measurements, osteocalcin was the only parameter that remained a significant determinant in a step-wise regression analysis.
Bone turnover
Osteocalcin was elevated above the upper limit of the postmenopausal normal range in 81% of all patients. There was a good overall correlation to ß-CTx levels (r = 0.66, P < 0.0001). In patients with DM, serum osteocalcin was lower, and this was especially the case in patients treated with oral antidiabetic agents or insulin (Table 4). Here, the multivariate adjusted mean value was 18.5% (oral antidiabetic group) and 24.2% (insulin group) lower than the mean values of the CTR group. Osteocalcin (r = –0.21, P < 0.0001) as well as ß-CTx concentrations (r = –0.13, P < 0.0001) were correlated to HbA1c levels in univariate analysis (Fig. 2).
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). In medically treated diabetics, HbA1c followed PTH as the second most important determinant of osteocalcin concentrations (standardized ß for HbA1c, –0.26, P < 0.0001) (data not shown). Similar results could be obtained with ß-CTx (data not shown).
A separate two-way ANOVA was performed to better illustrate the independent effects of HbA1c and PTH levels on calcaneal bone ultrasound measurements as well as on bone turnover (Fig. 3). Independent of serum PTH, patients with higher HbA1c levels had higher calcaneal bone mass and lower bone turnover markers with no significant interaction between PTH and HbA1c levels.
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The advanced age of the nursing home residents was also reflected in low creatinine clearance rates (Table 4). According to the clinical practice guidelines for chronic kidney disease (CKD), 4% of the patients fulfilled CKD stage 2 (GFR, 60–89 ml/min·1.73 m2), 68% CKD stage 3 (GFR, 30–59), and 27% CKD stage 4 (GFR, 15–29) criteria.
Vitamin D deficiency was a problem of global dimensions in all study participants. Only 3% of the residents had 25-hydroxyvitamin D levels of more than 28 ng/ml, suggesting vitamin D sufficiency. The majority (58%) of the nursing home patients had 25-hydroxyvitamin D levels less than 8, 74% less than 10, and 82% less than 12 ng/ml. There was no difference in 25-hydroxyvitamin D level between CTR and DM patient groups. As a consequence, secondary hyperparathyroidism was very common, with 51% of the patients having elevated PTH levels of more than 65 pg/ml. One in every five patients had PTH levels more than 100 pg/ml. Mean adjusted PTH concentration was 22% lower in both patient groups receiving pharmacological treatment for DM. They also had slightly higher adjusted serum calcium concentrations. A PTH to total serum calcium ratio adjusted for possible major confounders such as age, BMI, GFR, 25-hydroxyvitamin D, and serum magnesium levels was 21.4% lower in medically treated diabetics than in CTR (26.3 vs. 33.5, P < 0.001).
Fracture data (Table 5)
Absolute prospective fracture risk in the groups was high. Cox proportional hazard regression revealed a HR for hip fracture in subjects with DM compared with those without DM of 0.90, with a 95% CI of 0.60–1.34 when adjusted for age and weight. Higher weight was associated with a HR of 0.97 (0.96–0.99; P = 0.01) per kilogram increase in body weight for hip fractures. For each SD decrease in calcaneal stiffness, there was an increase in the risk for hip fractures of 30% [HR, 1.3 (1.16–1.48; P = 0.002)]. When calcaneal bone mass was included as a confounder for fracture risk, the HR for hip fractures in patients with DM increased significantly to 1.46 (1.25–1.81; P = 0.01), and weight was no longer a significant confounder.
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Discussion |
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Our results carry forward previous observations in diabetics on this special elderly patient cohort and for the first time use detailed laboratory analyses to shed some light on the mechanisms underlying this increase in bone mass. Diabetic individuals had lower serum PTH levels and lower bone turnover markers than nondiabetic individuals. Bone turnover constituted an important difference between the two cohorts. Because osteocalcin was a significant independent determinant of bone mass at all measurement sites, it is reasonable to assume that lower bone turnover partially protected patients with type 2 DM from bone loss related to aging, secondary hyperparathyroidism, and likely other insults to bone turnover.
Interestingly, serum PTH was not only lower, but at the same time, corrected total serum calcium levels were slightly but significantly higher in DM. This small increase in serum calcium, however, seems unlikely to be the sole reason for decreased PTH levels. Despite the possibility that magnesium deficiency may have contributed somewhat to inhibition of PTH secretion in patients with DM (24), there still remained an unexplained difference of 21% (P = 0.001) in the PTH to total serum calcium ratio between diabetics and nondiabetics after multivariate adjustment. The data suggest a form of hypoparathyroidism in diabetics that is either linked to impaired PTH secretion or caused by a calcium-sensing defect of the parathyroid glands. Our findings are supported by previous smaller studies (3, 25, 26, 27) but not all studies (4), suggesting overall lower PTH secretion than may be expected for homeostatic needs. In the present study, there was a weak but significant negative correlation between HbA1c and PTH in DM (r = –0.14, P < 0.01) that would basically support such a direct relationship between degree of glycemia and impairment of PTH secretion. However, the discrepancy between the finding of clearly decreased PTH levels in medically treated DM on the one hand and the overlap of HbA1c levels between all diabetic subgroups on the other hand may suggest that duration of DM apart from the present degree of glycemia determines the magnitude of relative hypoparathyroidism.
Another important PTH-independent modulator of bone turnover in nursing home patients was glycemia itself, especially in patients treated with oral antidiabetics and insulin. Here, HbA1c was the second most important determinant of bone turnover among the variables tested. However, even in nondiabetic CTRs, HbA1c within the normal range showed a correlation with osteocalcin and serum cross-laps concentrations, suggesting a role for glucose modulation of bone turnover within a physiological range of glycemia.
Diabetics with HbA1c levels above the median exhibited a significant reduction in bone turnover and had higher mean bone mass values than those with HbA1c levels below the median, especially when secondary hyperparathyroidism was quite substantial. With increasing bone turnover, hyperglycemia may thus provide a protective momentum against bone loss. Previous smaller studies have also proposed an inverse correlation between HbA1c and osteocalcin or ß-CTx levels (28). Histomorphometric studies in DM described a low recruitment of osteoblasts and a diminished mineral apposition rate (29, 30). Apart from above-mentioned mechanisms, bone turnover may have also been influenced by other factors such as leptin or osteoprotegerin that contribute to bone homeostasis and may be altered in DM (31, 32).
The overall incidence of hip and other nonvertebral fractures was exceedingly high in the present study, as was the prevalence of vitamin D deficiency and secondary hyperparathyroidism. Only one of 20 nursing home patients received calcium and/or vitamin D supplements. These results once more point to the widespread problem of calcium and vitamin D deficiency, especially in nursing home patients, despite the known beneficial effects of appropriate supplements to decrease bone turnover and hip fracture rates over at least 3 yr (33).
Of seven large trials investigating hip fracture incidence in elderly Caucasian community-dwelling diabetic women (average ages between 66 and 82 yr), four showed unchanged (5, 34, 35, 36), two an increased (10, 37), and one a decreased (38) rate of hip fractures compared with nondiabetics. Results of the present study strongly suggest that hip and nonvertebral fracture risks in general in nursing home patients with DM are not increased when compared with nondiabetic residents, although the absolute fracture risk is two to six times higher compared with elderly individuals living independently (39). The favorable effects on bone mass and bone turnover on the other hand do not translate into a reduced fracture rate as might be anticipated. This discrepancy may be explained by the increased risk of falls that has been reported for nursing home patients with DM (23, 40). Because hip fracture risk after normalization for baseline calcaneal stiffness increased significantly by 46% in patients with DM [HR, 1.46 (95 CI, 1.25–1.81)], it seems reasonable to assume that the advantage of elevated bone mass on hip fracture risk is counterbalanced by an increased incidence in falls of patients with type 2 DM.
In this study, various aspects of bone quality ranging from assessment of fractures to determination of bone mass and turnover have for the first time been comprehensively investigated in institutionalized elderly with type 2 DM. Another important strength of the study is its size and therefore associated statistical power that allowed analyses even between diabetic subgroups. Limitations of this study should also be noted. Based on the HbA1c determinations, it can be calculated that approximately 44 (11%) of the remaining 404 CTR patients for whom HbA1c analyses were not available had undiagnosed DM. This misclassification, however, likely led to an underestimation of the effects we found on bone metabolism. For the fracture data, it is doubtful that such a number of patients would have changed the final result appreciably. Furthermore, blood samples could not be obtained from all patients and sometimes not in a fasting state. Both hip fracture and mortality rates were higher in those patients for whom blood samples were not available. This, however, was independent of prevalent diabetic status.
We conclude that our study demonstrates that in type 2 DM, bone loss seems to be halted or delayed by lower bone turnover. This decrease in bone turnover is primarily caused by a derangement in calcium sensing or by another form of hypoparathyroidism in medically treated DM. Glycemia is another independent modulator of bone turnover, and higher HbA1c levels confer a protective effect on bone turnover and bone mass. DM does not increase the risk for hip or other nonvertebral fractures in nursing home patients. We believe that DM confers a relative protective effect on fracture development in such patients.
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Acknowledgments |
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Footnotes |
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The authors have nothing to disclose.
First Published Online May 30, 2006
Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; CTR, control; ß-CTx, C-terminal telopeptide cross-links; CV, coefficient(s) of variation; DM, diabetes mellitus; GFR, glomerular filtration rate; HbA1c, glycosylated hemoglobin; HR, hazard ratio; kp, kilipond; SI, stiffness index; SOS, speed of sound.
Received February 28, 2006.
Accepted May 18, 2006.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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