The association between age and bone mineral density in men and women aged 55 years and over: the Rotterdam Study.

In this cross-sectional study, bone mineral density (BMD) measurements were performed in 1762 ambulatory subjects (678 men and 1084 women) aged 55 years and over from the Rotterdam Study, a population based study of diseases in the elderly. BMD measurements of the proximal femur and lumbar spine were performed using dual energy X-ray absorptiometry. No age-related decline in BMD could be observed in the lumbar spine. Yearly percentage BMD reduction in women and men was -0.6% and -0.3% in the femoral neck, -0.8% and -0.5% in the Ward's triangle, and -0.4% and -0.3% in the trochanter, respectively. Late menopause was associated with high BMD in Ward's triangle and lumbar spine. We conclude that: (1) accurate assessment of age-related bone reduction in the spine is impossible from cross-sectional studies since BMD measurements in the elderly may be influenced by spinal osteoarthritis; and (2) the rate of age-related bone reduction in the femoral neck appears to be approximately two times higher in women than in men.

Insulin-like growth factor-1: a prognostic factor of knee osteoarthritis.

During a population survey in 1975-1978 persons with radiological osteoarthritis (ROA) of the knee were identified. After 12 years a follow-up study was conducted to study the effect of circulating insulin-like growth factor-1 (IGF-1) on cartilage loss, osteophyte growth and overall progression in 141 persons with confirmed ROA of the knee. The outcome measures were scored by comparing the radiographs taken at baseline and at follow-up. Insulin-like growth factor-1 was measured by radioimmunoassay in serum taken at follow-up and in 79% of the baseline sera. After adjusting for age, gender and body mass index at baseline, IGF-1 concentration at follow-up was related to osteophyte growth and overall progression. The adjusted odds ratio of the highest vs the lowest tertile was 2.96 (95% CI: 1.15-7.60) for osteophyte growth and 2.58 (1.01-6.60) for overall progression. No clear relationship was found with cartilage loss. These results were confirmed when baseline IGF-1 was studied. We conclude that the circulating IGF-1 concentration has an effect on the course of knee OA by influencing osteophyte formation but a preventive effect on cartilage loss could not be shown.

A 12 year follow up study in the general population on prognostic factors of cartilage loss in osteoarthritis of the knee.

The natural history and prognostic factors of cartilage loss in osteoarthritis of the knee were studied in subjects from a general population survey on rheumatic diseases in 1975-8. Baseline data were collected by questionnaire, physical examination, and weightbearing anteroposterior knee radiographs. Follow up of the subjects aged 46-68 years with radiological osteoarthritis grade 2-4 (Kellgren) took place in 1988-9. Cartilage loss was assessed by two observers who scored the change in joint space width between two radiographs. Thirty four per cent had cartilage loss. Prognostic factors and adjusted odds ratios (ORs) (95% confidence intervals) were: body mass index OR = 11.1 (3.3 to 37.3) fourth v first quartile; body weight OR = 7.9 (2.6 to 24.0) third v first tertile; age OR = 3.8 (1.1 to 13.4) > 60 v < or = 49 years; Heberden's nodes OR = 6.0 (1.5 to 23.1); clinical diagnosis of generalised osteoarthritis OR = 3.3 (1.3 to 8.3); and previous bow legs or knock knees OR = 5.1 (1.1 to 23.1). The relation of age with cartilage loss was also confounded by the presence of Heberden's nodes or a diagnosis of generalised osteoarthritis. There was no statistically significant relation for gender, meniscectomy, injury, uric acid concentration, chondrocalcinosis, smoking, and occupation related factors, except possibly standing.

Cardiovascular determinants of carotid artery disease. The Rotterdam Elderly Study.

The objective of the present study was to assess the prevalence of moderate and severe stenosis of the right carotid artery in the elderly and its associations with smoking, blood pressure, serum lipid levels, and hemostatic factors. The Rotterdam Elderly Study is a recently started single-center prospective follow-up study of a cohort of 11,854 elderly people aged 55 years or more. In 1990, 954 participants of the Rotterdam Elderly Study underwent ultrasonic duplex examination of the right internal carotid artery. A reduction of the lumen diameter of 16-49% was found in 29 people (3.0%). Severe stenosis (50% or more) was observed in 13 people (1.4%). With differences in age, sex, and body mass index taken into account, subjects with moderate-to-severe carotid artery disease had, compared with participants without stenosis, lower mean high density lipoprotein cholesterol levels (mean difference, 0.10 mmol/l; 95% confidence interval, 0, 0.20) and higher mean fibrinogen levels (difference, 0.24 g/l; 0.04, 0.45). Among them were more people with hypertension (mean difference, 16%) and more current smokers (mean difference, 13%). Factor VIIc and factor VIIIc activity was higher in subjects with carotid artery disease, without, however, reaching statistical significance (mean difference, 0.06 IU/ml [-0.01, 0.12] and 0.21 IU/ml [-0.05, 0.47], respectively). Our data suggest that hypertension, smoking, and reduced serum high density lipoprotein cholesterol levels, combined with unfavorable increases in hemostatic factors, may be related to carotid artery disease in the elderly.

A community-based study of dementia: the Rotterdam Elderly Study.

The Rotterdam Elderly Study is designed as a community-based prospective follow-up study. The study population consists of almost 12,000 individuals aged 55 years and over who are living in an urban area in Rotterdam, the Netherlands. The objective of the study is to investigate the prevalence, incidence and determinants of neurogeriatric disorders, cardiovascular diseases, locomotor diseases and ophthalmologic diseases. In this paper we give a general outline of the Rotterdam Elderly Study, and a detailed description of the case finding and diagnostic procedures for the study of dementia. The risk factors for dementia that are assessed in the study are summarized.

Natural menopause, oophorectomy, hysterectomy and the risk of osteoarthritis of the dip joints.

The purpose of this study was to determine whether postmenopausal women have an increased risk of developing radiological osteoarthritis (ROA), bony enlargement or Heberden's nodes of the distal interphalangeal (DIP) joints. Secondly, the effects of the duration of the postmenopausal period, age at menopause or duration of the fertile period on the occurrence of DIP-OA were studied. Data from a population survey were used and 143 postmenopausal women with a natural menopause, 53 with a hysterectomy and 75 with a hysterectomy and bilateral oophorectomy were compared with 374 premenopausal women. There was no significant association of these postmenopausal states with ROA, bony swelling or Heberden's nodes. Age adjusted odds ratios and 95% confidence intervals were 1.14 (0.68-1.91), 1.30 (0.72-2.35), 1.92 (0.77-4.76), respectively for the women with a natural menopause. After adjusting for age there was a positive relationship of Heberden's nodes with age at menopause and duration of the fertile period for women with a natural menopause.

Determinants of disease and disability in the elderly: the Rotterdam Elderly Study.

In this paper the Rotterdam Elderly Study is presented. The aim of the study is to investigate determinants of disease occurrence and progression in the elderly. In addition to contributing to our understanding of the etiology of geriatric illnesses, the study is expected to lead to specific recommendations for intervention. The study focuses on causally related determinants of major diseases in the elderly. Fields of interest for the Rotterdam Elderly Study are conditions which interfere the most with the quality of life for the elderly. The aims of the Rotterdam Elderly Study are: (1) To investigate, by means of epidemiologic, clinical and basic research, the determinants of diseases in order to assess their etiologic significance. (2) To investigate potentially modifiable determinants in order to be able to develop preventive strategies by providing specific recommendations for intervention studies. The Rotterdam Elderly Study focuses on four primary areas of research: neurogeriatric diseases, cardiovascular diseases, locomotor diseases and ophthalmologic diseases. It is a prospective follow-up study, in which determinants of disease and determinants of progression of disease will be investigated in the total population of 55 years or over of the district of Ommoord in Rotterdam. It is anticipated that about 10,000 people will participate in the study and they will be examined in the period of 1991 to 1995.

Do clinical findings associate with radiographic osteoarthritis of the knee?

From a population survey of 2865 subjects, test characteristics of a number of clinical findings relating to knee osteoarthritis were calculated against the standard of radiographic diagnosis. The clinical findings included from the history were age, gender, current pain in the knee, swollen knee, pain in both hands, morning stiffness, osteoarthritis in any joint, pain or stiffness, or both, in knees or hips when rising from seated position, and pain in knees or hips while climbing stairs; and from the physical examination: Quetelet's index, Heberden's nodes, bony enlargement, palpable effusion, soft tissue swelling, limitation of knee function, pain with knee flexion, bony tenderness and, finally, the latex fixation test. Of 18 clinical variables, all but Heberden's nodes, palpable knee effusion, pain in both hands, and latex fixation test showed a significant association after adjustment for age. Neither one single variable nor a combination could predict radiographic osteoarthritis of the knee with reasonable accuracy and thus be applicable in clinical practice. The x ray film, therefore, keeps its place in the diagnosis of knee osteoarthritis in general practice as well as in epidemiological research.

Pharmacokinetics of rimexolone after intra-articular administration.

The pharmacokinetics of rimexolone were investigated after intra-articular injection into the knee joints of patients with rheumatoid arthritis. After a single dose of 40 mg rimexolone the drug could be detected in plasma over 3 months. The suspension dissolves in the synovia very slowly and provides a sustained release of the steroid in the joint. Pharmacokinetic analysis was performed on the assumption that the disposition of rimexolone after intra-articular administration is absorption limited ("flip-flop-case"). Dose linearity was studied in a range from 40 to 200 mg. Total body clearance averaged 106 L/h and was independent of dose. The mean residence time of rimexolone in the knee joint is very long and averaged 25 days. It could be shown that the mean residence time of different glucocorticoids correlates well with the duration of their clinical effectiveness.

Transcutaneous absorption of naproxen gel.

The kinetics of naproxen was studied in healthy volunteers after cutaneous application of gels containing 5 and 10% of the drug. Bioavailability was estimated from serum concentration and cumulative urinary metabolite excretion data, both determined up to 96 hours after drug administration. The mean bioavailability after the 10% gel was 1.1% (serum data) and 1.0% (urine data), and after the 5% gel it was 2.1% (serum data) and 1.8% (urine data). Despite the small amount of naproxen absorbed, a potential pharmacological effect, due to cutaneous accumulation of the drug following topical administration, may be suggested from the course of the serum concentration-time curves.

Pharmacokinetics of high-dosage naproxen in elderly patients.

After multiple oral doses of 500 mg naproxen twice daily, eight young healthy male volunteers and six male and female elderly patients participated in a pharmacokinetic study. Serum naproxen levels were measured by high-pressure liquid chromatography; protein-unbound drug was determined after equilibrium dialysis. A significantly lower maximal serum concentration (Cpeak), smaller area under the curve during one dose interval [AUC(0-12)], larger total body clearance (CL/F) and apparent volume of distribution (V/F body wt-1) were found for the total drug in elderly patients. The pharmacokinetics of the protein-unbound drug showed higher trough and peak concentrations, larger AUC(0-12)u, and smaller (CL/F)u and (V/F)u in the elderly patients. The unbound fraction (less than 1% of total naproxen) showed concentration dependency; in the elderly, a larger unbound fraction was found. Pharmacokinetic differences between the elderly and the young may be explained by a lower serum albumin concentration in the aged, together with a decrement in binding affinity of naproxen to albumin; moreover, the clearance of unbound drug was significantly reduced in the elderly (281 +/- 96 l/h) as compared with the young (713 +/- 164 l/h). We conclude that age-related factors increase serum unbound naproxen concentrations. It is, therefore, advisable to start treatment with naproxen in the elderly at a low dosage.

Congestive heart failure due to nonsteroidal anti-inflammatory drugs in the elderly.

Congestive heart failure in the elderly which might be due to treatment with nonsteroidal anti-inflammatory drugs was studied by means of a questionnaire sent to the participants of a postgraduate course on locomotor disease in the elderly, and also by analysis of the hospital records of 600 elderly subjects diagnosed with congestive heart failure. The questionnaire revealed 22 possible cases, reported by 20 physicians (84 physicians out of 243 responded). In the hospital population five probable cases were detected. Details of these patients are presented. In contrast with findings in the literature, solute retention was in no case the result of kidney function impairment. The specific problems regarding the attribution of this adverse effect are discussed. The results of our study provide further evidence that congestive heart failure due to nonsteroidal anti-inflammatory drug treatment is a probable adverse drug reaction in elderly individuals with or without a history of impaired cardiac performance. It may result from drug toxicity following (relative) overdosing in this age group, from reduced effectiveness of concomitant diuretic treatment or from effects on cardiovascular homoeostasis.

Naproxen kinetics and disease activity in rheumatoid arthritis: a within-patient study.

The effects of rheumatoid arthritis disease activity on the pharmacokinetics of the highly albumin-bound nonsteroidal anti-inflammatory drug naproxen were studied in six patients during chronic therapy. In the same patients, kinetics during active disease were compared with those in improvement. Active disease is commonly associated with hypoalbuminemia: 30 +/- 4 gm/L vs. 41 +/- 2 gm/L (mean +/- SD) at the time of improvement. Total naproxen concentrations were significantly lower in active disease, together with a larger apparent volume of distribution (10.6 +/- 1.8 L vs. 8.4 +/- 1.3 L; P less than 0.05) and total body clearance (0.79 +/- 1.8 L/hr vs. 0.59 +/- 0.14 L/hr; P less than 0.001). Peak unbound naproxen concentrations were 29% +/- 19% (P less than 0.05) lower at the time of improvement. The unbound clearance was found diminished during active disease (390 +/- 277 L/hr) in comparison with improvement (488 +/- 343 L/hr; P less than 0.05). Clinical implications of the alterations in naproxen kinetics induced by polyarticular inflammation in patients with rheumatoid arthritis are discussed.

Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation.

Patients with rheumatoid arthritis often have hypoalbuminaemia as a sign of disease activity. In view of the extensive binding of naproxen to albumin, the pharmacokinetics of total and unbound drug were studied in eight patients and eight healthy male volunteers during chronic intake of 500 mg twice daily. The area under the serum concentration-time curve of total naproxen during a dose interval, AUC (0,12), smaller in patients (641 +/- 101 mg l-1 h) than in volunteers (896 +/- 85 mg l-1 h; P less than 0.0001). The unbound naproxen AUCu (0,12) was larger in patients (1.9 +/- 0.9 mg l-1 h) than in volunteers (0.7 +/- 0.2 mg l-1 h; P less than 0.01). The higher unbound naproxen concentrations in patients were accompanied by an approximately 40% increase in apparent clearance/bioavailability (CL/F) and a 60% increase in volume of distribution (V/F). Both CL/F and V/F were inversely correlated with the individual serum albumin concentration (r = 0.76, P less than 0.001; r = -0.85, P less than 0.001, respectively). The high unbound naproxen concentration in the serum of patients with active rheumatoid arthritis and concomitant hypoalbuminaemia is not known to be accompanied by an increase in side effects and may be beneficial if anti-inflammatory effects correlate with unbound drug concentration.

Gastrointestinal blood loss during treatment with naproxen for rheumatoid arthritis.

In 9 patients with active rheumatoid arthritis we studied gastrointestinal blood loss during well tolerated therapy with the non-steroidal anti-inflammatory drug naproxen, 500 mg twice daily. The mean gastrointestinal blood loss, assessed with reinfused autologous 51Cr-labelled erythrocytes, was 1.4 +/- 0.6 ml/day (mean +/- SD) and did not exceed the upper normal level. No relationship was observed between individual gastrointestinal blood loss and serum concentrations of protein-unbound or of total naproxen, or of the duration of drug treatment, or of the degree of disease activity of rheumatoid arthritis. Two subjects developed peptic ulcer disease after the study, from which they had a blood loss of 0.9 and 1.9 ml/day, respectively.

Lymphapheresis as compared with rest period in treatment of severe rheumatoid arthritis.

In this study lymphapheresis over a 5-week period was compared with a period of rest in 8 patients with active severe rheumatoid arthritis. These patients failed to respond to gold or/and to D-penicillamine. All the patients treated by lymphapheresis improved in the first 2 or 3 weeks and one patient in the control group improved in 3 weeks. The laboratory findings and the 99mTc-pertechnetate uptake index of the joints were inconsistent. In this study lymphapheresis had a clinically modest beneficial effect which in 3 of 4 patients persisted even after 18 weeks.