J.C. Birkenhäger

Vertebral deformities and functional impairment in men and women

The objective of this study was to assess the prevalence and health effects of vertebral deformities in men and women. The study was carried out as part of the cross‐sectional baseline phase of The Rotterdam Study, a prospective population‐based cohort study of residents aged 55 years or over of a district of Rotterdam, The Netherlands. The prevalence of vertebral deformities according to a modification of the Eastell method and concomitant functional impairment were assessed in a random sample of 750 men and 750 women. The prevalence of moderate (grade I) vertebral deformities was 8 and 7% in men and women, respectively. For severe deformities (grade II), these percentages were 4 and 8%. In men, the prevalence of both moderate and severe deformities increased with age. In women, however, the prevalence of moderate vertebral deformities remained constant, opposite to a marked increase in severe deformities. Moderate vertebral deformity was significantly associated with impaired rising in men only. Severe vertebral deformity was associated with a significantly increased risk of general disability and the use of a walking aid in both men and women, impaired bending in men, and impaired rising in women. It is concluded that (1) vertebral deformities are only slightly less common in men than in women from the general population and (2) severe progression with age occurs in women only and (3) severe vertebral deformity is, particularly in men, related to functional impairment.

Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study

Several factors besides bone mineral mass have been related to the risk of hip fracture. Bone quality, the rate of bone loss, and non-skeletal factors have been identified as important.1 2 High rates of bone resorption may be associated with disruption of the trabecular network as well as with an increased rate of bone loss. Furthermore, immobility associated with disability induces bone resorption not followed by increased bone formation.3 Urinary pyridinium crosslinks are markers of bone resorption. We investigated whether these were associated with the risk of hip fracture and also whether such an association was attributable to disability. This nested case-control analysis was conducted as part of the Rotterdam study, a prospective cohort study of the incidence of and risk factors for chronic disabling diseases.4 Briefly, all 10275 residents of a district of Rotterdam aged 55 or over were invited to participate. The study consisted of an initial home interview followed by a series …

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 Wards triangle, and -0.4% and -0.3% in the trochanter, respectively. Late menopause was associated with high BMD in Wards 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.

Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee.

Osteoporosis and osteoarthritis are age-related disorders of the skeleton with genetic components. Low bone density is a risk factor for osteoporotic fracture while osteoarthritis is associated with increased bone density. The 1,25-dihydroxyvitamin D3 receptor (VDR) gene locus was previously found to be associated with bone density. We therefore studied the relationship between radiographic osteoarthritis at the knee and VDR genotype in a population-based sample (n = 846), using molecular haplotyping of anonymous intragenic DNA polymorphisms. Radiographic osteoarthritis was defined using the Kellgren score, which is based on the assessment of osteophytes and joint space narrowing (JSN). We show that one VDR haplotype allele is significantly overrepresented in individuals with knee osteoarthritis and associated with a 2.27-fold increased relative risk (95% confidence interval 1.46, 3.52). Adjustment for bone density at the femoral neck did not change these results, indicating that the association is not mediated by bone density. The association appeared to be largely explained by the presence of osteophytes rather than JSN. Our results indicate a role of the VDR gene in the pathogenesis of osteophytes while linkage disequilibrium with another nearby gene, i.e., the collagen type IIa1 gene encoding the most abundant protein in cartilage, might contribute to the association.

Hyperinsulinemia and bone mineral density in an elderly population: The Rotterdam study

We studied the association between insulin and glucose levels and bone mineral density (BMD) in a population based study of 5931 elderly men and women. Serum insulin was measured 2 h after a nonfasting oral glucose load in subjects not using antidiabetes medication. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine and the proximal femur. In addition, the participants were asked about fractures in the preceding 5 years. Higher bone mass was associated with higher glucose and postload insulin levels at all sites, as well as with increased waist/hip ratio and body mass index. In men, the mean age-adjusted BMD at the lumbar spine (in mg/cm2) increased 4.64 per mmol/L serum glucose (95% CI 1.46-7.82) and 0.35 per mU/L postload insulin (0.17-0.53). In women, these values were 6.88 (4.37-9.39) for glucose and 0.25 (0.11-0.39) for insulin (for all analyses: p < 0.01). The relations were essentially the same with BMD measured in the femur, as well as after adjustment for waist/hip ratio. After adjustment for body mass index, the associations were reduced and lost statistical significance in women. After excluding subjects with diabetes mellitus, the results remained the same. Subjects with a history of nonvertebral fractures had a lower BMD and lower postload insulin levels than those without. The difference in insulin levels was statistically significant in men only (12.5 mU/L, p < 0.001). Excluding men with diabetes mellitus or further adjustment for waist/hip ratio, body mass index or BMD did not change this difference. These results suggest that increased insulin levels are associated with an increased BMD and might be related to a lower fracture rate.

Evidence for Involvement of 17β-Estradiol in Intestinal Calcium Absorption Independent of 1,25-Dihydroxyvitamin D3 Level in the Rat

The sex steroid 17β‐estradiol (17β‐E2) has a broad range of actions, including effects on calcium and bone metabolism. This study with 3‐month‐old Brown Norway rats was designed to investigate the role of 17β‐E2 in the regulation of calcium homeostasis. Rats were divided in four groups, sham‐operated, ovariectomized (OVX), and OVX supplemented with either a 0.025‐mg or 0.05‐mg 17β‐E2 pellet implanted subcutaneously. After 4 weeks, in none of the groups was serum calcium, phosphate, or parathyroid hormone altered compared with the sham group, while only in the OVX rats was a significant reduction in urinary calcium found. Bone mineral density and osteocalcin were modified, as can be expected after OVX and 17β‐E2 supplementation. OVX resulted in a nonsignificant increase in serum 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3). Supplementation with either one of the 17β‐E2 dosages resulted in an 80% reduction of 1,25(OH)2D3 and only a 20% reduction in 25‐hydroxyvitamin D3 levels. OVX, as well as supplementation with 17β‐E2, did not affect serum levels of vitamin D binding protein. As a consequence, the estimated free 1,25(OH)2D3 levels were also significantly decreased in the 17β‐E2‐supplemented group compared with the sham and OVX groups. Next, the consequences for intestinal calcium absorption were analyzed by the in situ intestinal loop technique. Although the 1,25(OH)2D3 serum level was increased, OVX resulted in a significant decrease in intestinal calcium absorption in the duodenum. Despite the strongly reduced 1,25(OH)2D3 levels (18.1 ± 2.1 and 16.4 ± 2.2 pmol/l compared with 143.5 ± 29 pmol/l for the OVX group), the OVX‐induced decrease in calcium absorption could partially be restored by supplementation with either 0.025 mg or 0.05 mg of 17β‐E2. None of the treatments resulted in a significant change in calcium handling in the jejunum, although the trends were similar as those observed in the duodenum. 17β‐E2 did not change the VDR levels in both the intestine and the kidney. In conclusion, the present study demonstrates that 17β‐E2 is positively involved in intestinal calcium absorption, and the data strengthen the assertion that 17β‐E2 exerts this effect independent of 1,25(OH)2D3. In general, 17β‐E2 not only affects bone turnover but also calcium homeostasis via an effect on intestinal calcium absorption.

Vitamin D: A modulator of cell proliferation and differentiation

1,25-Dihydroxyvitamin D3, [1,25(OH)2D3], the biologically most active metabolite of vitamin D3, is involved in the regulation of calcium homeostasis and bone metabolism. Recently, receptors for 1,25(OH)2D3 have also been shown in cells and tissues not directly related to calcium homeostasis. Experimental data obtained with leukaemic and cancer cell lines, both in vitro and in vivo, showed the effects of 1,25(OH)2D3 on cell differentiation and proliferation. However, high doses of the sterol have to be used to observe these effects. Additional studies are needed to establish whether 1,25(OH)2D3 or suitable analogues have a therapeutic potential in malignant diseases without unacceptable toxicity like the development of hypercalcemia.

Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee

OBJECTIVE To study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women. METHODS In this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I. RESULTS We found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA. CONCLUSION Our findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.

Hepatic lipase and lipoprotein lipase are not major determinants of the low density lipoprotein subclass pattern in human subjects with coronary heart disease

The influence of hepatic lipase (HL) and lipoprotein lipase (LPL) activity on the low density lipoprotein (LDL) subclass pattern was studied in a population of males with coronary heart disease and without severe hypercholesterolemia. LDL subclass patterns, lipases and plasma lipoproteins were determined in 326 patients. In part of the study population, fasting insulin and glucose levels were also determined. The LDL subclass pattern was determined by gradient gel electrophoresis (GGE) and classified according to Austin et al. (J. Am. Med. Assoc. 260 (1988) 1917 (predominantly large LDL = A-pattern, predominantly small LDL = B-pattern). An LDL subclass A-pattern was exhibited by 199 subjects; 108 exhibited a B-pattern. In 19 subjects no distinctive A- or B-pattern was present (A/B-pattern). Hepatic and lipoprotein activities differed significantly between patients with the A- or B-pattern. The median hepatic lipase activity was lower (384 vs. 417 mU/ml, P = 0.006), and the lipoprotein lipase activity higher (122 vs. 101 mU/ml, P = 0.001) in the A-pattern subjects than in the B-pattern subjects. In subjects with the A/B pattern the lipase activities were intermediate between the values in the A- and B-pattern subjects (HL 408 +/- 87 mU/ml, LPL 115 +/- 55 mU/ml). Plasma triglyceride, very low density lipoprotein (VLDL)-triglyceride, intermediate density lipoprotein (IDL)-triglyceride and LDL-triglyceride were higher in the patients with a B-pattern (+84%, +171%, +10% and +16%, respectively). Total plasma cholesterol was not different between A- and B-pattern subjects. VLDL- and IDL-cholesterol were higher in the B-pattern group (+174% and +66%, respectively), while LDL- and HDL-cholesterol were higher in the A-pattern group (+2 and +24%, respectively). In univariate analysis HL, LPL, plasma (and VLDL) triglyceride, HDL-cholesterol and IDL-cholesterol were each significantly associated with the LDL subclass pattern. In multivariate analysis plasma triglyceride (or VLDL-triglyceride) and HDL-cholesterol appeared to be independently associated with the LDL subclass pattern. No additional discriminative value of HL or LPL was found. Similar results were obtained if the patients with or without beta blocker were evaluated separately. An estimate of insulin resistance (EIR), calculated from plasma insulin and glucose in part of the study population (n = 145), was significantly higher in the subjects with a B-pattern than in those with an A-pattern (3.12 vs. 2.00, P < 0.003). EIR correlated positively with plasma triglyceride (P < 0.0001), but not with HL or LPL.(ABSTRACT TRUNCATED AT 400 WORDS)

Results of operative treatment of 615 patients with primary hyperparathyroidism

This is a report of 615 patients who were operated on for primary hyperparathyroidism during the 20 years from 1950 to 1979. There were twice as many females in the series as males, mainly because of a sharp rise in the incidence in females over the age of 45 years. Identification of all parathyroid glands and confirmation by frozen section was always attempted. Only macroscopically enlarged glands were removed, regardless of histologic findings. Enlargement of 1 gland was found in 433 patients, of 2 glands in 106, and of 3 glands in 43. In 33 patients all glands were enlarged. Bilateral exploration of the neck is mandatory in order to prevent persistent hyperparathyroidism. An abnormal location of parathyroid glands was found in 263 patients; location within the thymus was the most frequent. Most ectopically located parathyroids can be removed through the neck. Sternotomy gave disappointing results; in only 3 of 9 patients was an enlarged parathyroid found. Persistent hyperparathyroidism necessitating reoperation occurred in 25 patients. The results of reoperation were not as favorable as those of primary operations and gave rise to more complications, especially inadvertent removal of all parathyroid tissue. The mean follow-up time was 5.6 years. During this period no patient developed true recurrent hyperparathyroidism arising in a previously identified normal appearing gland. Therefore, we advise removal of only those glands that are macroscopically enlarged.