Peder Charles

A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis.

Thirty-seven patients with postmenopausal crush fracture osteoporosis were randomized to oral cyclic estrogen/gestagen (n = 20) or oral calcium (2000 mg elemental calcium per day) (n = 17). Fourteen in each group completed 1 year of treatment. Iliac crest bone biopsies were obtained after intravital double labeling with tetracycline before and after treatment in 10 patients on estrogen/gestagen and 11 patients on calcium. In the estrogen/gestagen group the activation frequency in trabecular bone decreased from 0.52 + 0.11 (SEM) year−1 to 0.27 + 0.08 year−1 (p < 0.01). No significant changes were found in resorption or formation periods. The osteoid surfaces and the mineralizing surfaces decreased (p < 0.05), whereas the decrease in eroded surfaces was insignificant. Furthermore, no significant changes were observed in final resorption depth, wall thickness or bone balance per remodeling cycle. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p < 0.002), whereas the lumbar bone mineral content (BMC) increased {ifp < 0.01}. In the calcium group the extent and thickness of osteoid surfaces decreased (p < 0.05) without significant changes in activation frequency. Serum alkaline phosphatase and renal hydroxyproline excretion decreased during treatment (p < 0.02). No significant changes were observed in lumbar BMC or the other histomorphometric parameters. The study supports that the positive effect of estrogen/gestagen on BMC can be explained by a reduction in the activation frequency of new remodeling cycles leading to a decreased remodeling space and an increase in mean bone age. There is no evidence of a positive balance per remodeling cycle. High dose calcium may improve osteoid mineralization, but there is no histomorphometric evidence of a significant reduction in activation frequency or a more positive balance per remodeling cycle.

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women — results of the Danish Osteoporosis Prevention Study

OBJECTIVES To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. METHODS Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. RESULTS After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years. CONCLUSIONS It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.

Efficacy of wheat germ lectin-precipitated alkaline phosphatase in serum as an estimator of bone mineralization rate: Comparison to serum total alkaline phosphatase and serum bone Gla-protein

SummarySerum levels of total alkaline phosphatase activity (S-T-AP), wheat germ lectin-precipitated alkaline phosphatase activity (S-L-AP), and bone Gla-protein immunoreactivity (S-BGP) were measured in 26 patients (23 females and 3 males) aged 35–73 years (mean 59 years) with primary hyperparathyroidism (n=7), hyperthyroidism (n=9), and hypothyroidism (n=10) in whom the bone mineralization rate (m) was determined by47Ca-kinetics (continuously expanding calcium pool model). A weak positive correlation (r=0.42,P<0.05) was found between S-T-AP and m, which in the range from 0–18 mmol Ca/day could be estimated with a standard error of 4.6 mmol/day. A closer correlation (r=0.65,P<0.001) was found between S-L-AP and m which was estimated with an error of 3.9 mmol Ca/day. The AP activity in the supernatant showed no significant correlation to m (r=0.11,P>0.50). The highest correlation coefficient (r=0.81,P<0.001) was found between S-BGP and m which could be predicted with an error of 3.4 mmol Ca/day. S-BGP showed a closer correlation to S-L-AP (r=0.71,P<0.001) than to S-T-AP (r=0.58,P<0.01). We concluded that S-L-AP predicts bone mineralization at organ level better than S-T-AP in selected metabolic bone disorders and that the supernatant activity shows no relation to bone turnover. We find the assay easy to handle and suitable for large-scale use in the diagnosis and monitoring of metabolic bone disease.

Assessment of bone remodeling using biochemical indicators of type I collagen synthesis and degradation: relation to calcium kinetics

In this study, we investigated the relation between calcium kinetic indices of bone remodeling (resorption rate, r; and formation rate, m, respectively) and two serum markers of type I collagen turnover: the pyridinoline cross-linked carboxyterminal telopeptide domains of type I collagen (S-ICTP a marker of bone matrix degradation) and the carboxyterminal propeptide of human type I procollagen (S-PICP, a marker of bone matrix formation). We studied three groups: (i) healthy controls (n = 19), (ii) a mixed group of high and low-turnover bone diseases without mineralization defects (myxedema, thyrotoxicosis and primary hyperparathyroidism n = 38), and (iii) osteoporosis (n = 52). In healthy controls, a significant regression of S-PICP on m was obtained (R = 0.53, SEE/Y = 0.44, P < 0.02). Significant regressions were also demonstrable in high- and low-turnover bone disease (R = 0.50, P < 0.001), SEE/Y = 61%) and osteoporosis (R = 0.49, P < 0.001, SEE/Y = 50%). In controls the regression coefficient for the regression of S-ICTP on r was 0.19 (NS), in high and low turnover bone disease 0.66, (SEE/Y = 59%, P < 0.001) and in the osteoporotic group 0.40 (SEE/Y = 61%, P < 0.01). We conclude that S-PICP and S-ICTP reflect whole skeletal bone formation and resorption rates in a variety of metabolic bone diseases including osteoporosis.

Primary hyperparathyroidism: Biochemical markers and bone mineral density at multiple skeletal sites in Danish patients

Biochemical bone markers and bone mineral density (BMD) in spine, hip, and forearm were measured, before surgery, in 30 patients with mild to moderate primary hyperparathyroidism (PHP) (25 women and 5 men; mean age 54 +/- 12 years, range 26-73 years) and compared with normal controls. A group of 291 healthy adults (181 women and 110 men) served as controls for BMD. A smaller group of 30 normal individuals (25 women and 5 men; mean age 54 +/- 12 years; range 26-74 years) were used as matched normal controls. Parameters of bone formation (s-osteocalcin, s-alkaline phosphatase activity, and s-bone isoenzyme alkaline phosphatase activity) and bone resorption (s-type-1 collagen telopeptide) were considerably increased in patients with PHP compared with normal controls (p < 0.01 for all parameters). BMD was found to be reduced in the hip (trochanteric: 95.1 +/- 14.7% of expected, p < 0.05; intertrochanteric: 95.2 +/- 13.8% of expected, p < 0.05), and the forearm (proximal: 93.3 +/- 12.2% of expected, p < 0.05; mid: 91.8 +/- 11.6% of expected, p < 0.001; distal: 90.7 +/- 13.1% of expected, p < 0.001). Spine BMD was found significantly reduced in premenopausal (87.8 +/- 7.6% of expected, p < 0.05) but not in postmenopausal patients, and although normal women showed a decrease in spinal BMD with increasing age this was not found in the PHP women. Forearm BMD was reduced in both pre- and postmenopausal patients (distal forearm: 86.7 +/- 12.2% of expected, p < 0.05; 87.6 +/- 12.1% of expected, p < 0.01, respectively). It was concluded that Danish patients with mild or moderate PHP have only small reductions in BMD. The bone loss is mainly found in the appendicular skeleton.

Bone histomorphometry in hypoparathyroid patients treated with vitamin D

Parathyroid hormone (PTH) and vitamin D are both active regulators of bone remodeling. Several studies, mostly in animals and in vitro, have suggested that the two hormones act synergistically or interdependently. The aim of the present study was therefore to describe the actions of vitamin D alone on bone remodeling in the absence of circulating PTH. Bone biopsies were obtained from 12 patients with vitamin D-treated hypoparathyroidism and from 13 age- and gender-matched normal controls. Mean total resorption rate was reduced (0.9 vs. 3.8 mu m/day,p < 0.001), the resorption period was prolonged (80.8 vs. 25.7 days, p < 0.001), and the resorption depth was reduced (41.7 vs. 55.3 mu m, p < 0.001). The fractional active and the total eroded surface were not significantly reduced. The fractional formation surface was reduced (5.2 vs. 12.5 mu m, p < 0.001). Trends toward prolongation of the formation period and reduction of the final wall thickness were found. The balance between resorption depth and final wall thickness was not significantly different from normal (0.96 vs. -4.4 mu m). The quiescent period was prolonged (7.6 vs. 1.7 years, p < 0.001) and the activation frequency was reduced (0.13 vs. 0.6 year(-1), p < 0.001). The structural parameters, trabecular bone volume, trabecular thickness, marrow space star volume, and trabecular star volume, remained unchanged. In the absence of PTH, Vitamin D alone is not able to normalize bone resorption and bone turnover in hypoparathyroid patients.

Skeletal size and bone mineral content in Turner's syndrome: Relation to karyotype, estrogen treatment, physical fitness, and bone turnover

SummaryBone mineral content (BMC), bone mineral density, and metacarpal dimensions were studied in 50 women with Turners syndrome aged 21–45 years in relation to karyotype, estrogen treatment, physical fitness, and biochemical markers of bone turnover. No differences were found between the 25 women with karyotype 45,X and women with other karyotypes. Forty-six women had received estrogen. Significant partial correlations were found between bone mineral density of the forearm and duration of estrogen treatment and physical fitness. BMC of the lumbar spine corrected for vertebral height (BMC(C)spine) was directly correlated with duration of estrogen treatment and height, marginally correlated with physical fitness, and inversely correlated with age. Outer metacarpal width was positively correlated with duration of estrogen treatment, age at initiation of therapy, and body weight. The diameter of medullary space showed negative correlation with physical fitness and height, and positive correlation with age at initiation of estrogen treatment. Cortical thickness was positively correlated with duration of estrogen treatment, physical fitness, and height. No convincing effects of estrogen could be demonstrated in women below the age of 30. Above the age of 30, all bone mineral measurements were markedly elevated in women treated for longer than the average of this age group. BMC(C)spine was inversely correlated with biochemical markers of bone formation. Our results demonstrate that estrogen treatment and physical fitness are important determinants of bone mineral status in Turners syndrome and add to the evidence that estrogen treatment increases BMC in Turners syndrome.

Alcohol decreases serum osteocalcin in a dose-dependent way in normal subjects

SummaryThe acute effect of 25 and 50 g of alcohol on the variation in serum osteocalcin, a specific and sensitive marker of bone formation, and on serum cortisol and serum parathyroid hormone (PTH)(1–84) was calculated in 6 normal young adults. They were studied during three periods, each lasting from 4 p.m.–7:30 a.m. Alcohol was ingested between 4:15 and 5 p.m. during period two and three. Blood was taken at 4 p.m. and every 15 minutes from 4:30 til 6 p.m., followed by hourly sampling until 12 p.m. The last blood sample was taken after an overnight fast at 7:30 a.m. Initial and end values before and after alcohol ingestion did not differ significantly from control values. Repeated measures analysis of variance showed that 50 g of ethanol decreased serum osteocalcin significantly (P<0.02) and increased serum cortisol (P<0.05) during the 4–12 p.m. interval. The interaction of 50 g of ethanol on the variation in serum osteocalcin was already significant during the first 2 hours (P<0.02), where no significant effect on serum cortisol could be detected. Although insignificant, the same pattern was observed after 25 g of alcohol. There was no significant change in the variation of serum iPTH(1–84) during the 4–6 p.m. after alcohol intake. We conclude that 3–4 drinks of alcohol taken over 45 minutes decreases serum osteocalcin in a dose-dependent way. The time lag between changes in serum osteocalcin and cortisol indicates that the decrease in serum osteocalcin is not related to the increase in serum cortisol.

Assessment of Bone Formation by Biochemical Markers in Metabolic Bone Disease: Separation Between Osteoblastic Activity at the Cell and Tissue Level

SummaryIn this study, serum levels of classical serum markers of bone formation [carboxyterminal propeptide of procollagen type I (S-PICP), bone Gla protein (S-BGP)], and total alkaline phosphatase (S-AP)) were related to the calcium kinetic index of whole skeletal mineralization rate (m) by regression analysis in a variety of metabolic bone diseases. For each disease, the regression coefficient (r) as well as the fraction: standard error of estimate/mean dependent variable (SEE/Y) were determined. In a group of 19 normals, only the regression of S-PICP on m reached significance (r=0,53, P<0.02, SEE/Y=0.44), whereas regressions of S-AP and S-BGP on m were nonsignificant. In a pooled material of high-and low-turnover bone diseases without mineralization defects or spinal fracture [myxedema, thyrotoxicosis, and primary hyperparathyroidism (n=48)], a highly significant positive regression of S-PICP on m was demonstrable (r=0.50, SEE/Y=0.63, P<0.001). The regression coefficients obtained for S-BGP and S-AP were 0.74 (P<0.001, SEE/Y=0.41) and 0.42 (P<0.01, SEE/Y=0.55), respectively. When analyzing individual diseases in this group, significant differences among the three markers were detectable. In a group of 52 osteoporotics, S-PICP correlated significantly to m (r=0.49, P<0.001, SEE/Y=0.50). Corresponding r-values for S-BGP and S-AP were 0.21 (NS) and 0.48 (P<0.001, SEE/Y=0.61), respectively.Patients with histologically proven osteomalacia revealed no correlation between S-PICP and m. S-BGP and S-AP were, however. significantly correlated to m [r=0.92 (SEE/Y=0.46) and r=0.82 (SEE/Y=0.57), respectively], indicating that S-BGP and S-AP reflect mineralization activity, whereas S-PICP reflects matrix formation only. In order to study cellular production of the three formative markers, organ level production rate was normalized for bone turnover by division with m. For each marker, the fraction (bone marker concentration/m) was calculated and the means compared with normal controls. S-PICP/m was found to be lower than normal in primary hyperparathyroidism (P<0.01) and thyrotoxicosis (P<0.001). S-AP/m was elevated in myxedema (P<0.05), osteoporosis (P<0.001), and osteomalacia (P<0.01). S-BGP/m only deviated significantly from normal in osteomalacia (P<0.001).In conclusion, we found S-BGP to be a reliable marker of organ level mineralization rate in all diseases studied, whereas the regressions of S-AP and S-PICP revealed disease-specific discrepancies. This study also revealed significant alterations in the osteoblastic production rate of the three formative markers at the level of individual osteoblasts that have to be taken into account when comparing bone marker concentrations with other indices reflecting bone formation (e.g., calcium kinetics and histomorphometry).

The effects of etidronate on trabecular bone remodeling in postmenopausal spinal osteoporosis: A randomized study comparing intermittent treatment and an ADFR regime

Abstract Thirty-seven patients were randomized to receive intermittent cyclic etidronate (400 mg/day oral for 2 weeks, followed by 13 weeks off treatment) or an ADFR treatment (100 μg/day oral triiodothyronine for 7 days, followed by 400 mg/day etidronate for 2 weeks and 12 weeks off treatment). Supplemental calcium (120 mg/day) and vitamin D 3 (400 IU/day) were given throughout the study period to all patients. Biochemical analyses, iliac-crest bone biopsies, and lumbar bone mineral content (BMC) measurements were performed before and during 60 weeks of treatment. Sixteen patients in the intermittent cyclic etidronate group and 15 in the ADFR group completed 60 weeks of treatment. Serum alkaline phosphatase decreased from 185 (43) (mean, ( SD )) to 144 (35) ( p p 48.4 60.0 ) μ m ( median ( 25% 75% quartiles )) to 44.0 ( 39.6 46.2 ) μ m (p from 0.30 ( 0.17 0.62 ) year −1 to 0.10 ( 0.02 0.19 ) year −1 (p and from 0.035 ( 0.020 0.081 ) μm 3 /μm 2 / day to 0.015 ( 0.002 0.025 ) μ m 3 /μm 2 / day , p respectively, during intermittent cyclic etidronate treatment, but were unchanged during ADFR treatment. No significant changes in trabecular bone volume, bone balance per remodeling cycle, or BMC were noted in either treatment group; no evidence of osteomalacia was found. Intermittent cyclic etidronate treatment may be effective in preventing bone loss and in decreasing the risk of trabecular plate perforation, and thereby maintaining the integrity of bone architecture, in postmenopausal osteoporosis. The absence of positive results after 60 weeks of ADFR treatment with triiodothyronine and etidronate suggest that a change in the choice of activator and/or depressor is necessary.