Long-term bone loss in insulin-dependent diabetic patients with microvascular complications.

Insulin-dependent diabetic patients have an approximately 10% decreased bone mineral content (BMC) when they are studied a few years after clinical onset of diabetes. After that time, patients without diabetic microvascular complications have no, or only very little, further bone loss. The aim of the present study was to investigate if any substantial long-term bone loss occurs in diabetic patients with microvascular complications. We studied 19 insulin-dependent diabetic patients with neither physiologic nor pathologic conditions known to interfere with bone metabolism, other than diabetes. BMC was determined twice, with an interval of 11 years. At initial examination, no patient had diabetic microangiopathy, but at final examination 7 patients had developed diabetic microvascular complications while 12 patients had not. As compared with gender- and age-matched controls, both subgroups had significantly decreased BMC at the initial examination. During the study period, the patients with complications showed further bone loss, whereas the subgroup without complications had unchanged decreased BMC. At final examination, BMC was significantly lower in patients with microvascular complications than in patients without them. The biochemistry of bone metabolism showed a significantly increased fasting urinary excretion of calcium and hydroxyproline in patients with complications, but not in the group without complications, and there was a negative correlation between plasma BGP (osteocalcin) and hemoglobin A1C for all patients. These findings indicate that, in addition to a decreased BMC (before or shortly after clinical onset of diabetes), patients who develop microvascular complications also develop ongoing bone loss. This loss may be caused by an increased bone resorption, but decreased bone formation during periods of poor diabetic control may be involved as well.

Screening procedure for women at risk of developing postmenopausal osteoporosis.

The present study includes 70 healthy, immediately postmenopausal women stratified according to future rate of bone loss. The stratification was performed by means of four parameters of bone turnover: serum alkaline phosphatase, fasting urinary calcium and hydroxyproline, and body weight, used in an equation developed in a previous study. After the stratification the women were followed without intervention for the next 24 months, with bone mass measurements every 3 months. The bone loss estimated at baseline by means of the equation correlated with the bone loss measured in the forearm (y = 0.72x - 1.52; r = 0.61; P less than 0.001). Plasma bone gla protein (BGP, osteocalcin), which is a new specific marker of bone formation, was now added to the model (replacing body weight). This increased the diagnostic validity (y = x; r = 0.76; P less than 0.001). From the present study we conclude that the postmenopausal bone loss can be predicted by means of four biochemical parameters determined in plasma and urine in women just after the menopause.

Does a single local absorptiometric bone measurement indicate the overall skeletal status? Implications for osteoporosis and osteoarthritis of the hip.

Regional bone mineral content (BMC) and density (BMD) (head, arms, chest, spine, pelvis, legs) of a total body dual photon 153Gd absorptiometry (DPA) scan were measured in 20 healthy postmenopausal women, 27 postmenopausal women with hip fracture, and 17 postmenopausal women with osteoarthritis of the hip. In addition, local BMC and BMD were measured in the proximal and distal regions of the distal forearm (BMCprox, BMDprox, BMCdist, BMDdist) by single photon absorptiometry (SPA); and in the lumbar spine (BMCL2-L4 and BMDL2-L4) by 153Gd DPA. The overall impression was a reduction of bone mass in hip fracture patients compared with healthy controls and an increase in the bone mass of osteoarthritic patients. These results were valid using both regional values of the total body scan, and local forearm and lumbar spine measurements, and statistically significant using one-way analysis of variance. There were, however, also significant within-group between-region differences (one-way analysis of variance), showing that the bone mass of the pelvis and legs in hip fracture patients was more reduced than in the remaining skeleton; in osteoarthritic patients it was not increased but rather unchanged or slightly reduced. The differences between the level of the three local measurements (BMDprox BMDdist BMDL2-L4), on the one hand, and the level of the six regional BMD values, on the other hand, were investigated by the two-way analysis of variance: local measurements = rows; regional values = columns. This analysis showed that none of the three local measurements was statistically better than the other two in predicting the overall level of skeletal bone mass as judged by the six regional values. We conclude that serious osteoporotic bone loss has a generalized nature, however, with a tendency towards lower values in the regions affected by fracture (viz: low bone mass in the legs of femoral neck fracture patients). Osteoarthritis may be associated with a high bone mass in most areas, but low values in the affected regions. Local lumbar spine measurement of bone mass by DPA is not superior to local forearm measurement of bone mass by SPA in predicting the nature of overall osteoporotic or osteoarthritic bone change.

Long-term bone loss in insulin-dependent diabetes mellitus.

The bone mineral content (BMC) in patients with insulin-dependent diabetes is reduced by 10% early in the disease, but due to a lack of long-term longitudinal studies it is unknown whether this diabetic osteopenia develops further through life. Over a time period of 11 years we examined the BMC in a group of seven adult insulin-dependent diabetics, in whom physiological and pathological factors affecting bone metabolism had been excluded; the patients were well regulated without diabetic complications. The BMC was not significantly decreased at the initial examination. The longitudinal study revealed a small but statistically significant fall in BMC, mainly in trabecular bone. The narrow (95%) confidence interval of median end value (93.3-99.0% of initial BMC) indicates that the annual decrease in BMC in such patients is of the order of 0.5%, a reduction that is probably clinically insignificant.

Vitamin D metabolites--relation to age, menopause and endometriosis.

We investigated the influence of menopause, age and sex on vitamin D metabolism in a large group of healthy women (n = 113) and men (n = 108) and in a group of early postmenopausal women (n = 124). Furthermore, we studied the vitamin D metabolism in 42 women with endometriosis. The vitamin D metabolites did not show dependence on age or on duration of menopause. The serum concentrations of vitamin D metabolites did not differ in normal men and women. There were highly significant seasonal oscillations for 25(OH)D and 24,25(OH)2D3 but not for 1,25(OH)2D. Women with endometriosis had significantly elevated serum 1,25(OH)2D compared to the normal women. Our study indicates that ageing is not associated with a significant depletion of 25(OH)D, 24,25(OH)2D or 1,25(OH)2D in normal men and women up to the age of 75 years. Furthermore, changes in vitamin D metabolism seem not to be an important factor in early postmenopausal bone loss. Our results on patients with endometriosis indicate that these patients may have some calcium-metabolic disturbances.

Metabolism of vitamin D2 and vitamin D3 in patients on anticonvulsant therapy.

We examined the effect of short-term treatment with pharmacological doses of vitamin D2 or vitamin D3 on the serum concentration of 1,25(OH)2D metabolites in epileptic patients on chronic anticonvulsant drug therapy. Nine patients were studied before and after treatment with vitamin D2 4000 IU daily for 24 weeks and 10 before and after treatment with vitamin D3 in the same dose. Before treatment the serum concentrations of 1,25(OH)2D and 25(OH)D were significantly lower in epileptics than in normal subjects (P less than 0.01). Vitamin D2 treatment increased the serum concentration of 1,25(OH)2D2, but a corresponding decrease in 1,25(OH)2D3 resulted in an unchanged serum concentration of total 1,25(OH)2D. The serum concentration of 25(OH)D2 and 25(OH)D increased significantly, whereas there was a small decrease in 25(OH)D3. Vitamin D3 treatment did not change the serum concentration of 1,25(OH)2D3 whereas serum 25(OH)D3 increased significantly. The correlation between the serum ratio of 1,25(OH)2D2/1,25(OH)2D3 and 25(OH)D2/25(OH)D3 estimated on vitamin D2-treated epileptic patients and normal subjects was highly significant (P less than 0.01). The data indicate that the serum concentration of 1,25(OH)2D2 and 1,25(OH)2D3 are directly proportional to the amount of their precursors 25(OH)D2 and 25(OH)D3 and that the concentration of total 1,25(OH)2D is tightly regulated.

Validity of rapid estimation of erythrocyte volume in the diagnosis of polycytemia vera.

In the diagnosis of polycytemia vera, estimation of erythrocyte volume (EV) from plasma volume (PV) and venous hematocrit (Hctv) is usually thought unadvisable, because the ratio of whole body hematocrit to venous hematocrit (f ratio) is higher in patients with splenomegaly than in normal subjects, and varies considerably between individuals. We determined the mean f ratio in 232 consecutive patients suspected of polycytemia vera (f = 0.967; SD 0.048) and used it with each patient's PV and Hctv to calculate an estimated normalised EVn. With measured EV as a reference value, EVn was investigated as a diagnostic test. By means of two cut off levels the EVn values could be divided into EVn elevated, EVn not elevated (both with high predictive values), and an EVn borderline group. The size of the borderline EVn group ranged from 5% to 46% depending on position of the cut off levels, i.e. with the efficiency demanded from the diagnostic test. EV can safely and rapidly be estimated from PV and Hctv, if f is determined from the relevant population, and if the results in an easily defineable borderline range of EVn values are supplemented by direct EV determination.

Evaluation of the applicability of the SeHCAT test in the investigation of patients with diarrhoea.

For the assessment of ileal bile acid conservation the retention of orally administered 75Se-23-selena-25-homotaurocholic acid (SeHCAT), a gamma-ray-emitting radioisotope-labelled synthetic bile acid, was measured by an uncollimated abdominal gamma camera in 89 patients with various gastrointestinal disorders and in 20 persons without gastrointestinal complaints. A significant differences in retention was observed between patients with and without previously detected ileal disease. However, it was not possible by use of the test to differentiate between the various types of diarrhoea. Hence the test is not recommended in the routine investigation of patients with diarrhoea.

Climacteric symptoms after oral and percutaneous hormone replacement therapy.

One hundred and ten (110) healthy early post-menopausal women with mild subjective vasomotor symptoms (mean Kupperman index score 11) participated in a long-term, double-blind, placebo-controlled therapeutic trial. The effects of 2 hormone regimens were evaluated. Group I received percutaneous oestrogen therapy for 2 yr, opposed by oral micronized progesterone (200 mg) during the second year, while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate (CPA). The serum oestrogen concentrations differed markedly in the 2 treatment groups. In Group I the serum/oestrone/oestradiol ratio was 1 (comparable to the pre-menopausal value), but in group II the ratio was greater than 5. Despite the difference in the serum oestradiol and oestrone concentrations, the mean symptom scores were rapidly and similarly reduced in both treatment groups (P less than 0.001). They remained low throughout the study and were not significantly different from pre-menopausal values.

Familial hypocalciuric hypercalcaemia. III: Bone mineral metabolism.

Bone mineral metabolism was studied in 10 subjects with familial hypocalciuric hypercalcaemia (FHH) and 10 age-, sex- and surface area matched healthy controls. Bone turnover was estimated by urinary calcium and hydroxyproline excretions relative to creatinine (Ca/Creat and OHPr/Creat, respectively), serum bone Gla-protein (S-BGP) and serum alkaline phosphatase (S-ALP). Bone status was evaluated by measurement of bone mineral content (BMC) on both forearms and X-ray examinations of the hands. Ca/Creat and OHPr/Creat (indices of bone resorption) were both significantly higher in the FHH group than in the controls. S-BGP and S-ALP (indices of bone formation) tended towards a higher level in the FHH subjects, but the differences were not significant. The BMC values were similar in the two study groups and did not change with time. We conclude that these patients with FHH might have a bone turnover higher than normal, and that the increased bone resorption must be paralleled by an increased bone formation.

Bone turnover in postmenopausal women after withdrawal of estrogen/gestagen replacement therapy.

Bone turnover before and after withdrawal of estrogen/gestagen treatment was studied in a randomized trial with 110 healthy female volunteers, who had passed a natural menopause 6 months to 3 years before the start of the study. Urinary excretion of intravenously injected 99m-technetium diphosphonate was measured as an index of bone turnover; plasma bone Gla protein and serum alkaline phosphatase were measured as indices of bone formation; and fasting urinary excretion of hydroxyproline and calcium were measured as estimates of bone resorption. During 2 years of hormone treatment, all variables decreased highly significantly (p less than 0.001) to a constant low level. Three months after withdrawal all variables increased highly significantly (p less than 0.001) towards, but not above, pretreatment and placebo levels. We conclude that withdrawal of estrogen/gestagen replacement therapy in postmenopausal women increases bone turnover, but not in excess of pretreatment values. This indicates that bone loss (after withdrawal) is similar to that seen in the placebo group and that a rebound phenomenon is unlikely.

Prediction of rapid bone loss in postmenopausal women.

Bone loss was determined in 178 women in the early postmenopausal period by photon absorptiometry measurement of forearm bone mineral content (BMC) every 3 months for 2 years. With a sequential cut-off technique, the results of a single determination of body fat mass, urinary calcium and hydroxyproline, and serum alkaline phosphatase, carried out at the first examination, correctly identified 79% of "fast bone losers" (bone loss greater than 3% annually) and 78% of "slow bone losers". With this simple approach the majority of women at highest risk of osteoporotic fractures in later life can be identified in the early postmenopausal period and started on prophylactic hormone replacement therapy.

Bone turnover determined by urinary excretion of [99mTc]diphosphonate in the prediction of postmenopausal bone loss.

Bone mineral content (BMC) of the forearms was measured in 62 healthy early postmenopausal women every 3 months for 2 years to calculate the rate of bone loss. Furthermore, bone turnover was determined at one year using the urinary excretion (UE) of [99mTc]diphosphonate. UE was assessed as a diagnostic test using BMC changes as the gold standard for bone loss. The predictive value for 'accelerated bone loss' (positive test) was 0.58 and for 'non-accelerated bone loss' (negative test) 0.76. The data do not warrant the use of UE as a screening method for bone loss.

Bone metabolism and bone status in osteoporotic patients.

We have studied bone turnover and bone status in 29 patients with hip fractures and compared them with normal subjects and patients with arthritis of the hip. Markers for bone formation, bone Gla protein, alkaline phosphatase and whole body retention of 99mTc-diphosphonate, and fasting urinary hydroxyproline, a marker for bone resorption, were all significantly higher in the hip fracture group than in the control group. The serum concentrations of 1,25-dihydroxyvitamin D were similar in the three groups, whereas the serum 25-hydroxyvitamin D concentration in the control group was higher than in the patient groups. The bone mineral content (BMC) measured in the distal forearm and the spine was lower than normal in the hip fracture group. We conclude that patients with hip fractures have an increased bone turnover with no signs of bimodality and low BMC values at all locations.

Serum concentration of vitamin D metabolites during treatment with vitamin D2 and D3 in normal premenopausal women.

Serum concentrations of vitamin D metabolites were measured in 19 healthy premenopausal women before and during treatment with 4000 IU per day of either vitamin D2 or vitamin D3 for 8 weeks. Vitamin D2 treatment increased the serum concentration of 25(OH)D2, but a corresponding decrease in 25(OH)D3 resulted in an unchanged value for total 25(OH)D. The serum concentration of the D3 dihydroxy metabolites was also significantly decreased. Vitamin D3 treatment increased the serum concentrations of 25(OH)D3 and D3 dihydroxy metabolites. The serum concentration of 1,25(OH)2D did not change in either of the treatment groups. We conclude that vitamin D2 and vitamin D3 given in the same doses in international units have a different effect on the serum concentration of vitamin D metabolites and biochemical indices of calcium metabolism.