Biochemical markers--a new approach for identifying those at risk of osteoporosis.
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Adult↗
Biomedical subjects
B J Riis
Publications and source records attributed to B J Riis.
Desogestrel in hormone replacement therapy: long-term effects on bone, calcium and lipid metabolism, climacteric symptoms, and bleeding.
Seventy-three healthy, postmenopausal women, aged 45-54 years, were randomly assigned to one of three groups for 2 years of treatment: 17 beta-oestradiol 1.5 mg on days 1-12 and 17 beta-oestradiol 1.5 mg + desogestrel 150 micrograms on days 13-24 (E2/DG) or oestradiol valerate 2 mg on days 1-11 and oestradiol valerate 2 mg + medroxyprogesterone acetate 10 mg on days 12-21 (E2V/MPA) or placebo. Fifty-seven women (78%) completed the study. Bone mineral content of the distal regions of the forearms (measured by single photon absorptiometry, SPA) and bone mineral density of the spine (measured by dual energy X-ray absorptiometry, DXA) showed increases of 0.5-1% and 4-5%, respectively, in the hormone groups over 2 years. The placebo group exhibited a decrease in spinal bone density of 2% per year, and in the forearm of 2.5-3.5% per year. Biochemical estimates of bone turnover (serum alkaline phosphatase and fasting urinary calcium) decreased significantly to premenopausal levels in the hormone groups but remained unchanged in the placebo group. In both hormone groups total cholesterol decreased by about 9% (P less than 0.001), whereas low density lipoprotein cholesterol decreased by 16% in the E2/DG group and 20% in the E2V/MPA group (P less than 0.001). High density lipoprotein cholesterol showed only minor, insignificant changes in the hormone groups. The placebo group had virtually unchanged values. Climacteric symptoms, including hot flushes, were significantly reduced in both hormone groups. Bleeding occurred regularly in about 80% of the women.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
Serum lipids, lipoproteins, and apolipoproteins during postmenopausal estrogen replacement therapy combined with either 19-nortestosterone derivatives or 17-hydroxyprogesterone derivatives.
PURPOSE: To study the influence of combined hormone replacement therapy on levels of serum lipids, lipoproteins, and apolipoproteins. PATIENTS AND METHODS: One hundred thirty-nine healthy early postmenopausal women selected by means of a questionnaire, a medical examination, and a laboratory screening procedure to be a representative sample of postmenopausal Danish women aged 45 to 55 years old were randomized to four treatment and two placebo groups. The four groups receiving hormone replacement therapy were given 2 mg estradiol valerate equivalents (E), either sequentially combined with 75 micrograms levonorgestrel (E/LNG), 10 mg medroxyprogesterone acetate (E/MPA), or 150 micrograms desogestrel (E/DG), or continuously combined with 1 mg cyproterone acetate (E/CPA). Serum lipids, lipoproteins, and apolipoproteins were measured before institution of hormone replacement therapy and at nine well-defined times during the following 84 days. Total response and cyclical variations were calculated. RESULTS: All active treatment regimens reduced serum low-density lipoprotein cholesterol (LDL-C) significantly: E/CPA, 6% (95% confidence limits 0.3% to 11.3%); E/LNG, 10.9% (4.9% to 16.6%); E/MPA, 14.4% (7.4% to 20.9%); E/DG, 10.7% (3.3% to 17.6%). The changes in serum total cholesterol and apolipoprotein B were similar but smaller than those in LDL-C. None of these treatment regimens induced significant overall changes in serum high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A1 (Apo A1). The sequentially combined hormone treatments induced significant cyclical variations in HDL-C, with an increase during estrogen therapy and a decrease during combined therapy: E/LNG, 13.3% (7.4% to 19.4%); E/MPA, 6.9% (1.6% to 12.6%); E/DG, 10.3% (5.8% to 14.9%). No cyclical changes in HDL-C were found in the group receiving continuously combined hormone replacement therapy (E/CPA). The changes in Apo A1 parallel those in HDL-C. CONCLUSION: All the treatment regimens produced changes in levels of serum lipids, lipoproteins, and apolipoproteins that may be considered favorable in terms of cardiovascular disease.
Androgen Antagonists↗
[Evaluation of risk factors in development of osteoporosis].
Bone mass may be measured by several techniques. The most recently developed equipment has sufficient accuracy to diagnose the low peak bone mass or a low bone mass later in life and sufficient precision to be able to follow the effects of a given treatment. Future bone loss can be estimated around the menopause by a combination of biochemical estimates and bone turnover. Together with measurement of bone mass at the menopause this method is helpful in deciding who should receive preventive treatment.
Absorptiometry, Photon↗
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.
Biomarkers↗
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.
Absorptiometry, Photon↗
Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women.
We studied 20 healthy premenopausal women aged 36.5 +/- 4.0 years (mean +/- 1 SD), 123 healthy postmenopausal women aged 50.0 +/- 2.4 years, and 103 postmenopausal women aged 65.1 +/- 5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)2D3, and 1,25-(OH)2D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protein), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)2D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women serum 1,25(OH)D was related to forearm bone mass (r = -0.20; P less than 0.05), intestinal calcium absorption (r = 0.18; P less than 0.05), and 24-hour urinary calcium (r = 0.21; P less than 0.05); serum 25(OH)D was related to spinal bone mass (r = 0.23; P less than 0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)2D was related to bone Gla protein (r = 0.33; P less than 0.001), serum phosphate (r = -0.27; P less than 0.01), and 24-hour urinary calcium (r = 0.43; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
24,25-Dihydroxyvitamin D 3↗
Discontinuous calcitonin treatment of established osteoporosis--effects of withdrawal of treatment.
PURPOSE: The purpose of this study was to examine the effects of discontinuous treatments with intranasal salmon calcitonin on bone and calcium metabolism in postmenopausal women and to establish the effects of withdrawing treatment. PATIENTS AND METHODS: This report presents data from 26 postmenopausal women with established osteoporosis (forearm fracture) 12 months after withdrawal of a 1-year double-blind, placebo-controlled therapy with intranasal calcitonin. The women then resumed treatment with calcitonin 200 IU plus calcium 500 mg daily in an open design for an additional 1-year period. A control group of 19 age-matched women (no forearm fracture) did not receive any treatment. RESULTS: At the end of the 3 years, the control group had lost significantly more bone in the forearm (single photon absorptiometry) and spine (dual photon absorptiometry) than had the group treated with intranasal calcitonin for 2 years, whereas the group receiving calcitonin for 1 year had intermediate values. During the year of withdrawal, the rate of bone loss was similar in the women who had received calcitonin and those who had received placebo. Calcitonin was especially effective in women with initially high bone turnover and low bone mass. The bone response in the spine could, furthermore, be estimated by the changes in bone turnover. CONCLUSION: Discontinuous treatment with intranasal calcitonin affects bone and calcium metabolism in established osteoporosis. In women with high-turnover osteoporosis, therapy results in a net gain of bone in both the peripheral and axial skeleton. Response to treatment may be monitored by changes in bone turnover.
Absorptiometry, Photon↗
Time-dependent variations in bone turnover parameters during 2 months' cyclic treatment with different doses of combined estrogen and progestogen in postmenopausal women.
We determined the time-dependent variations in biochemical estimates of bone resorption and bone formation in 30 healthy postmenopausal women treated for two consecutive cycles of 28 days with a sequential estrogen/gestagen therapy. The women received either 1, 2, or 4 mg estradiol (E2) for 22 days and 1 mg norethisterone acetate (NETA) from day 13 to 22 of each cycle. Blood samples were drawn twice a week, ie, 16 blood samples in each woman. Biochemical estimates of bone resorption (fasting urinary hydroxyproline/creatinine, fasting urinary calcium/creatinine) decreased significantly during the two treatment cycles. In contrast, there was no overall decrease in bone formation parameters (plasma bone Gla protein [pBGP], serum alkaline phosphatase), and serum alkaline phosphatase decreased significantly during the estrogen-only phase, but increased during the E2 plus NETA phase. The present study supports our previous suggestion that NETA stimulates bone formation in early postmenopausal women.
Animals↗
Collagen synthesis in postmenopausal women during therapy with anabolic steroid or female sex hormones.
The effect of anabolic steroid therapy and estrogen-progestogen substitution therapy on serum concentration of procollagen type III aminoterminal peptide (PIIINP), a measure of collagen synthesis, in postmenopausal women was studied in two double-blind studies: (1) 39 women allocated to treatment with either 50 mg nandrolone decanoate as an intramuscular depot or placebo injections every third week for 1 year, and (2) 40 women allocated to receive either 2 mg 17 beta-estradiol plus 1 mg norethisterone acetate daily or placebo tablets for 1 year. Serum PIIINP was measured every 3 months during the study. Anabolic steroid therapy resulted in a more than 50% increase (P less than .001) in serum PIIINP at 3 months, which thereafter decayed but remained significantly increased throughout the study period. Serum PIIINP showed the same pattern during estrogen-progestogen therapy, but to a lesser degree. We conclude that anabolic steroids stimulate type III collagen synthesis in postmenopausal women, while estrogen-progestogen therapy may have such an effect, but only to a lesser degree.
Aged↗
Hormonal replacement therapy and the skeletal system.
The two most important risk factors for maintaining skeletal health are the bone mass obtained at skeletal maturity (peak bone mass) and the subsequent bone loss. Those women with a low peak bone mass and a rapid bone loss are thus at increased risk of developing osteoporosis in the future, and should be identified. This may be accomplished by determination of the bone mass combined with an estimate of the rate of the postmenopausal bone loss. The bone mass can be accurately assessed in the forearm by single photon absorptiometry. The postmenopausal bone loss can be estimated by three or four biochemical markers of bone turnover. The women at highest risk of developing osteoporosis should be offered preventive therapy, e.g., hormonal replacement therapy (HRT). HRT arrests the bone loss not only in early, but also in elderly postmenopausal women. The effect lasts as long as the therapy is continued. Several epidemiological studies have demonstrated that HRT decreases the number of osteoporotic fractures.
Bone and Bones↗
Serum placental protein 14 in pre-menopausal and post-menopausal women--dependency on oestrogen/progestogen status.
In view of the increasing use of oestrogen-progestogen therapy in post-menopausal women the availability of possible biochemical marker of endometrial response to progestogen would be highly desirable. Placental protein 14 (PP14) has recently been shown to be excreted from the endometrium during the secretory phase of the menstrual cycle. In the present study we examined the concentration of serum PP14 (S-PP14) in 15 pre-menopausal women during the menstrual cycle and in 30 early post-menopausal women receiving three different doses of 17 beta-oestradiol (E2), cyclically combined with norethisterone acetate (NETA). S-PP14 levels peaked on day 1 following the onset of menstrual bleeding and on day 7 during NETA administration. It was possible to estimate the area under the S-PP14 curve reliably from one or two blood samples taken at optimal times. In the post-menopausal women, S-PP14 varied in a highly significant dose-dependent manner, i.e., the higher the E2 dose (in relation to the fixed NETA dose) the higher the S-PP14 response was found to be. We suggest that S-PP14 measurements might reflect the quantitative development of the endometrium in the secretory phase in both pre-menopausal and post-menopausal women.
Adult↗
Smoking induces increased androgen levels in early post-menopausal women.
In order to clarify the effect of smoking on androgen status in the early post-menopause we examined 267 women aged 45-54 years, of whom 146 (55%) were smokers. The cigarette smokers had a significantly higher serum concentration of androstenedione (P less than 0.001) and a raised serum concentration of luteinizing hormone (P = 0.06) in comparison with the non-smokers. The number of cigarettes consumed was apparently immaterial. The concentrations of oestrone, oestradiol and follicle-stimulating hormone were similar in the two groups. This study lends support to the hypothesis that the observed decreased risk of endometrial and breast cancer associated with cigarette smoking may be mediated by androgenic protection.
Androstenedione↗
Bone mass measured by photon absorptiometry: comparison of forearm, heel, and spine.
We assessed bone mass quantification at different skeletal sites by single and dual photon absorptiometric (SPA and DPA) methods. Improved DPA measurement of spinal bone mineral density in young healthy subjects showed a short- and long-term precision of 1.2% and 1.6%. Compared to the conventional DPA method the imprecision was reduced by more than 50%. The appendicular measurements were more precise (0.5-1.2%). We present the intercorrelations and predictive errors between peripheral measurements and improved spinal and total body bone measurements in early postmenopausal women (n = 144) recruited in 1988. To compare the improved system with the conventional methods, we retrieved data on age-matched early postmenopausal women (n = 151) recruited in 1983. In the 1988 population all peripheral methods had similar predictive errors in estimation of spinal bone mineral density (SEE = 11-13%) and total body bone mineral density (SEE = 4-5%). Measurement of trabecular bone in the heel and distal forearm did not improve the validity of predicting spinal bone mass. In a cadaver study (n = 11) the predictive error in estimation of the spinal ash weight from forearm measurements was of the same magnitude (15%) as that in estimation of the spinal BMC from the forearm (16%). We conclude that the predictive error in estimation of spinal bone mass from peripheral bone measurements is more likely to be caused by intra-skeletal variation in bone mass than by precision errors. However, this does not reflect the inability of peripheral bone mass measurements to predict fracture risk.
Absorptiometry, Photon↗
Five years with continuous combined oestrogen/progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern.
OBJECTIVE: To study the effect of long-term continuous combined oestrogen/progestogen therapy on calcium metabolism, lipoproteins, and bleeding pattern in early postmenopausal women. DESIGN: A prospective, open, controlled study. After initial examinations, control examinations were performed every three months for the first two years and every year for the following three (two) years, with determinations of bone mass, serum lipoproteins, and bleeding pattern. SETTING: Out-patient research clinic at The Department of Clinical Chemistry, Glostrup Hospital, Denmark. PARTICIPANTS: Eighteen healthy women between 6 months and 3 years after a natural menopause, entered in a trial of continuous long-term hormone replacement therapy and a comparison group of 19 age-matched untreated women. INTERVENTION: The treated group received 2 mg of 17 beta-oestradiol combined with 1 mg of norethisterone acetate orally each day continuously for 5 years with a 3 month therapy-free interval after the first 2 years. The women were investigated before treatment, then every 3 months for the first 2 years and every year for the next 3 years for determinations of bone mass, serum lipoproteins and bleeding patterns. The comparison group was followed-up in parallel for the first 4 years. Forearm bone mass was measured with single photon absorptiometry. Blood and urine samples were taken in the morning after an overnight fast and tobacco abstinence. MAIN OUTCOME MEASURES: The effects of hormone therapy on bone mineral content in the forearm, on serum and urine indices of calcium metabolism, on serum levels of total, high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, and bleeding pattern. RESULTS: Bone mineral content in the forearm was stable during the 5 years of treatment, whereas it declined significantly averaging 10% after 4 years in the comparison group. The biochemical estimates of bone turnover decreased to premenopausal level in the hormone group, whereas they remained at a high level in the comparison group. In the hormone group total cholesterol and LDL-C decreased by 20% whereas HDL-C was virtually unchanged. The treatment was associated with minor irregular bleeding in nine women during the first 6 months of treatment, after which no bleeding was experienced. CONCLUSION: Continuous combined oestrogen/progestogen therapy can keep early postmenopausal women free of bleeding episodes for a period of 5 years, after the first 6 months in which spotting occurs in 25%. The therapy prevented bone loss completely. The changes in serum lipoproteins were concordant with a lipid profile associated with a decreased risk of coronary heart disease.
Bone Density↗
Effects of growth hormone (GH) on plasma bone Gla protein in GH-deficient adults.
Both deficiency and excess of GH are related to disturbances in calcium metabolism. Bone Gla protein (BGP) is the only specific marker of bone turnover identified in peripheral blood. We, therefore, determined plasma BGP in 21 adult GH-deficient patients treated with biosynthetic human GH in a double blind cross-over study. We also examined 9 patients with acromegaly before and after surgery. The GH-deficient patients had normal initial plasma BGP concentrations, whereas the acromegalic patients had highly significantly increased concentrations (P less than 0.001). During treatment with human GH, plasma BGP (and other nonspecific biochemical markers of bone turnover) increased significantly (P less than 0.001). During placebo treatment plasma BGP showed baseline values. In the acromegalic patients a significant decrease in plasma BGP concentrations was seen 1 week after surgery. The present study suggests that plasma BGP is a useful biochemical marker of the effect of treatment of both GH deficiency and GH excess/disorders.
Acromegaly↗
Is it possible to prevent bone loss in young women treated with luteinizing hormone-releasing hormone agonists?
Recent studies have shown that treatment with the LHRH agonist nafarelin gives symptomatic and objective relief to women with endometriosis. Such a treatment, however, results in increased bone turnover and loss of bone mass. In the present study 17 women with endometriosis were treated with 400 mg nafarelin combined with 1.2 mg norethisterone (NET) for 6 months, followed by 6 months with only 1.2 mg NET. The data were compared to data from a previously published study of 9 women treated for 6 months with 400 mg nafarelin alone, followed by 6 months without treatment. In the group treated with nafarelin plus NET the biochemical parameter of bone resorption (fasting urinary hydroxyproline) remained virtually unchanged, compared to a highly significant increase in the nafarelin-treated group. Estimates of bone formation (serum alkaline phosphatase and plasma bone Gla protein) increased in the nafarelin plus NET group, but to only a minor extent compared to those in the nafarelin group. In addition, bone mineral in the forearm, the spine, and the total skeleton remained virtually unchanged in the group treated with nafarelin plus NET, compared to the bone loss of 2-6%/6 months in the nafarelin group. We conclude that addition of NET to nafarelin treatment of endometriosis seems to have a bone-sparing effect.
Adult↗
Serum bone Gla protein: a potential marker of growth hormone (GH) deficiency and the response to GH therapy.
Serum bone Gla protein (BGP), a sensitive and specific biochemical marker of bone formation, was measured in 66 children deficient in GH before and after 3, 6, 9, and 12 months of treatment with biosynthetic human GH. Initial serum BGP levels were significantly lower than those of normal age-matched children. After 3 months of treatment, the mean serum BGP level had increased to normal. There was no relation between baseline serum BGP and the growth response, but the GH-induced increment in serum BGP levels at 3 months was highly significantly related to growth response after 12 months of therapy. The study shows that serum BGP could be a helpful biochemical marker in prediction of the growth response to long term GH therapy.
Adolescent↗