Evidence-based medicine in older patients: how can we do better?

Evidence-based medicine (EBM) aims to integrate three elements in patient care: the patient situation, scientific evidence, and the doctors' expertise. This review aims 1) to assess how these elements are systematically different in older patients and 2) to propose strategies how to improve EBM in older patients. The ageing process systematically affects all three elements that constitute EBM. First, ageing changes the physiology of the older body, makes the patient more vulnerable with more multimorbidity and polypharmacy and affects somatic, psychological and social function. The heterogeneity of older patients may lead to overtreatment of vulnerable and undertreatment of fit older patients. Second, representative older patients are underrepresented in clinical studies and endpoints studied may not reflect the specific needs of older patients. Third, adequate clinical tools and schooling are lacking to aid physicians in clinical decision-making. Strategies to improve elements of EBM include: first systematically acknowledging that physical, mental and social function may reveal patients vulnerability and specific treatment goals. Second, clinical studies specifically targeting more representative older patients and studying endpoints relevant to older patients are warranted. Finally, teaching of physicians may increase their experience and expertise in treating older patients. In conclusion, in older patients the same elements constitute EBM, but the elements need tailoring to the older patient. In the clinic, a thorough assessment of individual patient preferences and physical, mental and social functioning in combination with increased level of experience of the doctor can increase the quality of EBM in older patients.

APOE genotype modulates the effect of serum calcium levels on cognitive function in old age.

OBJECTIVE: The APOE genotype and serum calcium levels have both been associated with cognitive impairment. Animal studies have shown variation in apoE isoforms to play a critical role in intraneuronal calcium homeostasis, but the contribution of this interaction to cognitive function in man is unknown. Here, we studied whether the APOE genotype modulates the association between serum calcium levels and cognition. METHODS: Within the Leiden 85-plus Study, a prospective population-based study of 599 subjects aged 85 years, we measured serum calcium levels and APOE genotype at baseline. During a 5-year follow-up period, cognitive function was annually assessed using the Mini-Mental State Examination (MMSE) and a standardized neuropsychological test battery. RESULTS: Both at baseline and during follow-up, high serum calcium levels were associated with worse cognitive function in epsilon3epsilon4 carriers and to a lesser extent in epsilon3epsilon3 carriers, but not in epsilon2epsilon3 carriers. The MMSE score during the entire follow-up period differed between those with high and low serum calcium levels, with 5.5 points in epsilon3epsilon4 carriers (p < 0.001), 1.6 points in epsilon3epsilon3 carriers (p = 0.010), and 0.1 point in epsilon2epsilon3 carriers (p = 0.935). Formal testing showed an interaction between APOE genotype and serum calcium levels in relation to global cognitive function (p = 0.003). CONCLUSIONS: In old age, APOE genotype modulates the association between serum calcium levels and cognitive function. High serum calcium levels associate with worse cognitive function, especially in APOE epsilon4 allele carriers, but not in carriers of the epsilon2 allele.

[Causes of health and disease in old age: new insights from the Leiden Research Program on Ageing]. / Determinanten van ziekte en gezondheid op hoge leeftijd: nieuwe inzichten uit de Leidse verouderingsstudies.

The clinical research of the Department of Gerontology and Geriatrics of the Leiden University Medical Center focuses on the causes of health and disease in old age. We examine, amongst others, the genetic mechanisms of longevity by comparing children of long-living parents with their partners. At a mean age of 60 years, the children of the long-living parents have a lower prevalence of several cardiometabolic diseases, among which are myocardial infarction, diabetes, and hypertension. The children of the long-living parents also have a more favourable cardiometabolic risk profile, with lower values of glucose, insulin, triglycerides, and thyroid hormone, and a better insulin sensitivity. Moreover, over the past years we have shown that traditional cardiovascular risk factors, such as an increased cholesterol and hypertension, do not automatically apply to the very old. For the very old it must be taken into account that risk profiles for various diseases differ from those of younger populations. The choice of treatment must therefore be based on the 'best available evidence'. In absence of randomized clinical trials this is currently the knowledge on the pathofysiology of health and disease in old age.

Effects of the selective estrogen receptor modulator, raloxifene, on the somatotropic axis and insulin-glucose homeostasis.

Raloxifene is the first selective estrogen receptor modulator registered for the prevention and treatment of postmenopausal osteoporosis. In addition to direct effects on bone cells, estrogen and raloxifene may act indirectly via changes in hormonal homeostasis. However, the menopause-related decrease in serum insulin-like growth factor I (IGF-I) and the increase in insulin or glucose are not always reversed by estrogen replacement. Especially orally administered estrogen was reported to decrease serum IGF-I levels. Understanding the effects of estrogens and raloxifene on the GH-IGF axis and insulin-glucose homeostasis are important because of their link to bone metabolism and cardiovascular health. We investigated the effects of raloxifene on the GH-IGF-I axis and insulin-glucose homeostasis in a cross-sectional study in the third year of the Multiple Outcomes of Raloxifene Evaluation trial, a double blind, placebo-controlled, prospective study in postmenopausal women with osteoporosis (T-score of -2.5 or less or at least two moderate vertebral fractures). Patients with diabetes mellitus were excluded from this additional study. A fasting blood sample was obtained (0 h), and women received an sc injection of 0.05 mg recombinant human GH (Humatrope)/kg BW. The second blood sample was obtained 24 h later (24 h). GH, IGF-I, IGF-binding protein-3 (IGFBP-3), insulin, and glucose were measured. Group characteristics were tested by nonparametric ANOVA. The dose-response to raloxifene was tested by linear regression models, with age and body mass as covariates. Seven women were taking placebo, 16 were taking raloxifene (60 mg/day), and 9 were taking raloxifene (120 mg/day). Patients from the 60 mg raloxifene group were the oldest (mean +/- SD, 64.4 +/- 4.2 vs. 69.3 +/- 6.9 and 63.3 +/- 5.9 yr for placebo, 60 mg/day raloxifene, and 120 mg/day raloxifene, respectively; P = 0.05). Compared with placebo users, patients taking raloxifene had higher body mass index (24.7 +/- 1.7 vs. 25.0 +/- 3.1 and 28.8 +/- 5.8 kg/m(2); P = 0.03). At 0 h, raloxifene use was associated with lower IGF-I/IGFBP-3 ratio (4.3 +/- 0.7 vs. 2.9 +/- 0.7 and 3.0 +/- 0.7 nmol/mg; P = 0.001) and insulin/glucose ratio (13.7 +/- 5.2 vs. 11.9 +/- 5.9 and 9.5 +/- 2.3 pmol/mmol; P = 0.04). Similarly, raloxifene use was associated with lower IGF-I/IGFBP-3 and insulin/glucose ratios at 24 h (P = 0.01 and 0.07). Glucose, GH, and IGFBP-3 levels were similar among the groups (0.12 < P < 0.67). In conclusion, raloxifene use is associated with decreased serum IGF levels and insulin/glucose ratio before and 24 h after one rhGH injection in nondiabetic postmenopausal women with osteoporosis. Therefore, raloxifene may decrease liver sensitivity to GH. Other explanations are increased clearance or increased tissue sensitivity to IGF-I or insulin. The raloxifene-induced increases in bone mineral density do not appear to be mediated by reversing the age- and menopause-related decreases in IGF-I levels. The results of this small cross-sectional study need confirmation by longitudinal studies.

Effects of the selective oestrogen receptor modulator-raloxifene-on calcium and PTH secretory dynamics in women with osteoporosis.

OBJECTIVES: A possible mechanism for the maintenance of bone mass by oestrogens and the selective oestrogen receptor modulator (SERM)-raloxifene-is an interaction with calciotropic hormones. We studied the effects of raloxifene on calcium-PTH homeostasis. PATIENTS AND MEASUREMENTS: Calcium and EDTA infusions were performed in 32 post-menopausal women with osteoporosis (BMD T score < - 2.5). This cross-sectional study was performed in the third year of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, a double-blind, placebo-controlled study. After an overnight fast, calcium glubionate (5 mg/kg BW*h), and after 2.5 h of test-free interval, Na3EDTA (40 mg/kg BW*h) were given intravenously. The duration of infusions was based on individual plasma total calcium before the calcium infusion (t = 0), the target calcium (2.60 and 1.95 mmol/l, respectively), and desired mean calcium change (0.010 mmol/L*min). Blood samples were taken at 0 and every 5 minutes of both infusions. Plasma PTH levels were fitted into an inversed sigmoidal relation with plasma calcium. The effect of raloxifene on calcium-PTH homeostasis was tested in linear regression models adjusted for age and BMI. Nine patients used placebo, 13 raloxifene 60 mg/day and 10 raloxifene 120 mg/day. RESULTS: Raloxifene use was associated with lower plasma albumin (40.7 +/- 1.8 vs. 38.0 +/- 2.0 and 38.5 +/- 2.3 g/l, for placebo, raloxifene 60 mg/day and raloxifene 120 mg/day, respectively, P = 0.01), lower plasma total calcium at t = 0 (2.28 vs. 2.24 and 2.21; +/- 0.07 mmol/L; P = 0.03), lower plasma total calcium at 50% of maximal PTH secretion (PTH set-point: 2.23 +/- 0.06 vs. 2.18 +/- 0.07 and 2.16 +/- 0.08 mmol/l, P = 0.06), and lower plasma non-suppressible PTH (0.84 +/- 0.19 vs. 0.75 +/- 0.10 and 0.73 +/- 0.05 pmol/l, P = 0.02). After correction for plasma albumin, the differences for plasma calcium at t = 0 and at PTH set-point were no longer significant. In contrast, the difference in PTH suppression during calcium load was not explained either by differences in plasma albumin or calcium. CONCLUSION: Raloxifene did not have any detectable effect on the PTH set-point. An effect on non-suppressible PTH secretion cannot be excluded.

A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial.

Vitamin D deficiency leads to secondary hyperparathyroidism, increased bone turnover, and bone loss and, when severe, to osteomalacia. Vitamin D deficiency is common in elderly people, especially the institutionalized. The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D (25OHD), the main circulating metabolite. The international Multiple Outcomes of Raloxifene Evaluation study, a large prospective intervention trial in postmenopausal women with osteoporosis, offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world. For this study, baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents. All women had osteoporosis, i.e. bone mineral density (BMD) at femoral neck or lumbar spine was lower than t-score -2.5, or they had 2 vertebral fractures. Serum 25OHD was measured by RIA, and serum PTH was measured by immunoradiometric assay. BMD was measured by dual x-ray absorptiometry. The mean (+/-SD) serum 25OHD was 70.8 +/- 30.9 nmol/L. A low serum 25OHD (<25 nmol/L) was observed in 4.1% of all women in the Multiple Outcomes of Raloxifene Evaluation study, ranging from 0% in south east Asia (very few patients) to 8.3% in southern Europe. Serum 25OHD was between 25-50 nmol/L in 24.3% of the women. Serum 25OHD showed a significant seasonal relationship, with lower values in all regions in winter. Serum PTH correlated negatively with serum 25OHD (r = -0.25; P < 0.001). This significant negative correlation was observed in all regions. When serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, mean serum PTH levels were 4.8, 4.1, and 3.5 pmol/L, respectively (by ANOVA, P < 0.001). Similarly, mean alkaline phosphatase levels were 83.7, 79.1, and 75.7 U/L (P < 0.001), respectively, with increasing serum 25OHD. The effect of serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4% lower BMD. After 6 months of treatment with vitamin D(3) (400-600 IU/day) and calcium (500 mg/day), serum 25OHD increased from 70.8 +/- 29.8 to 92.3 +/- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment, and this decrease depended on baseline serum 25OHD. When baseline serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, serum PTH decreased by 0.8, 0.5, or 0.2 pmol/L, respectively (P < 0.001). In conclusion, serum 25OHD was less than 25 nmol/L in 4% of the women, and this was associated with a 30% higher serum PTH. In 24% of the women serum 25OHD was between 25-50 nmol/L, associated with a 15% higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter. Treatment with vitamin D(3) and calcium increased serum 25OHD and decreased serum PTH significantly; the effect was greater for lower baseline serum 25OHD.

Estrogen enhances mechanical stress-induced prostaglandin production by bone cells from elderly women.

Several studies indicate that estrogen may enhance the effects of mechanical loading on bone mineral density in elderly women. This stimulating effect of estrogen could be due to increased sensitivity of bone cells to mechanical stress in the presence of estrogen. The present study was performed to determine whether 17beta-estradiol (E2) enhances mechanical stress-induced prostaglandin production and cyclooxygenase (COX)-2 mRNA expression. We subjected bone cells from seven nonosteoporotic women between 56 and 75 yr of age for 1 h to pulsating fluid flow (PFF) in the presence or absence of 10(-11) M E2 and measured prostaglandin production and COX-1 and COX-2 mRNA expression. One hour of PFF stimulated prostaglandin (PGE2) production threefold, PGI2 production twofold, and COX-2, but not COX-1, mRNA expression 2.9-fold. Addition of E2 further enhanced PFF-stimulated PGE2 production by 1.9-fold but did not significantly affect PGI2 production or COX-2 or COX-1 mRNA expression. E2 by itself did not affect any of the parameters measured. These results suggest that estrogen modulates bone cell mechanosensitivity via the prostaglandin synthetic pathway independently of COX mRNA expression.

Bone structure in patients with low bone mineral density with or without vertebral fractures.

Vertebral fractures (VFX) are caused by low bone mass and microstructural deterioration of bone tissue. The latter is not well defined. We investigated bone structure in transiliac biopsy specimens from 88 volunteers. Biopsy specimens were obtained at baseline in the Multiple Outcomes of Raloxifene Evaluation trail, a prospective study in osteoporotic (BMD < or = -2.5 T score) postmenopausal women without or with VFX on standardized lateral spinal radiographs. Bone biopsy specimens were embedded in methylmethacrylate (MMA). Histomorphometry was done in 8 microns (U.S.A.) or 5 microns (Europe) Goldner stained sections. Vertebral fracture status (yes/no) was the outcome variable in logistic regression models adjusted for age and biopsy specimen origin (U.S.A. vs. Europe). Patients with and without VFX (26/62) were similar regarding age (69.2 +/- 5.2 years vs. 67.3 +/- 6.7 years), bone volume (BV/TV; 17.7 +/- 4.7% vs. 19.0 +/- 5.8%), and bone surface (BS/TV; 2.7 +/- 0.6 mm2/mm3 vs. 2.8 +/- 0.6 mm2/mm3). A lower cortical thickness (C.Th; 652 +/- 267 microns vs. 822 +/- 325 microns), total strut length (TSL; 826 +/- 226 microns/mm2 vs. 922 +/- 256 microns/mm2), node-to-loop (Nd-Lp) strut length (10.1 +/- 10.3% vs. 15.0 +/- 13.6%), together with a higher node-to-terminus (Nd-Tm) strut length (45.6 +/- 9.7% vs. 39.1 +/- 9.3%) were each associated with prevalent VFX (0.01 < p < 0.10). Differences in BV/TV did not explain these associations. In conclusion, cortical thinning and disruption of trabecular lattice are possible pathogenic mechanisms in patients with VFX.

Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures.

Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. As part of the baseline measurements of the Multiple Outcomes of Raloxifene Evaluation (MORE) study, HRQOL was assessed in 751 osteoporotic (bone mineral density [BMD] T score > or = -2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception, and mental function. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with 0 corresponding to the best HRQOL. In comparison with patients without VFX, those with VFX were older (66.2 +/- 5.9 years vs. 68.8 +/- 6.3 years; p < 0.001), had higher prevalence of nonvertebral fractures (25% vs. 36%; p = 0.002), and higher QUALEFFO scores (worse HRQOL; total score, 26 +/- 14 vs. 36 +/- 17; p < 0.001). QUALEFFO scores increased progressively with increasing number of VFX, especially lumbar fractures (p < 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores (p < 0.05). Similar, though weaker, associations were seen for NHP and EQ-5D scores. This study confirms decreased HRQOL for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is suitable for clinical studies in patients with postmenopausal osteoporosis.