J. R. Green

hPTH 1–34 treatment of osteoporosis with added hormone replacement therapy: Biochemical, kinetic and histological responses

Twelve patients with vertebral fracture osteoporosis were recruited into a trial of treatment with hPTH 1–34 by daily injection for 1 year combined (from the 5th month) with an anti-resorptive agent (oestrogen, n=9; nandrolone, n=3). Treatment outcomes were monitored by biochemical and radiotracer measurements together with histomorphometry of transiliac biopsies before and at the end of treatment following double in vivo pre-labelling with demethylchlortetracyc-line. Indices of whole body bone formation, obtained from the analysis of85Sr data, showed substantial increases (P<0.005) for all three indices measured) while biochemical (hydroxyproline) and kinetic measurements of bone resorption showed modest and equivocal changes only. As a result calcium balance improved. Gastrointestinal calcium absorption showed a tendency to improve, while urine calcium decreased; but these changes were statistically not significant except for radiocalcium absorption in the oestrogen treated subgroup. Histomorphometry revealed substantial increases in cancellous bone volume as reported previously with hPTH 1–34 given alone. However, iliac (as distinct from whole body) indices related to bone formation and resorption appeared to have returned towards pre-treatment values by the time of the second biopsy under the influence of the anti-resorptive agent given with the hPTH 1–34. It is confirmed that hPTH 1–34 therapy can increase iliac cancellous bone mass (as well as spinal cancellous bone mass as reported earlier) without a long-term increment in whole body bone resorption, providing the hPTH is combined with an anti-resorptive agent.

Estimation of whole body bone resorption rate: a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis

Abstract In 37 female patients with primary osteoporosis, urinary hydroxyproline excretion, determined in 18 24-h consecutive complete urine collections was compared with two radioisotopic measurements of bone resorption rate measured simultaneously using 85Sr. A somewhat better fit was obtained when the kinetically determined bone resorption rate was corrected for long-term exchange processes within bone. Regression analysis showed that the intercept of the regression of hydroxyproline excretion on resorption rate, corrected or uncorrected for exchange, was significantly higher than zero at about 100 μmol/day. This is consistent with a substantial fraction of urinary hydroxyproline arising from non-bony sources. Fifteen paired studies were analysed and the results suggested that intra-individual variability in these relationships (when studies were separated by a year or more) were similar to inter-individual variability. We calculated the precision with which an estimate of bone resorption could be determined based on the calculated regressions. As a means of non-invasive quantitation of whole body bone resorption rate, the excretion rate of hydroxyproline, measured over 5 days, for example, appeared competitive with isotopic methods making no correction for exchange and relatively little worse than our exchange corrected method.

EVOLUTION OF SPINAL BONE LOSS AND BIOCHEMICAL MARKERS OF BONE REMODELING AFTER MENOPAUSE IN NORMAL WOMEN

The main objective of this study was to describe longitudinal patterns of spinal bone loss in normal women who undergo a natural menopause. The second objective was to determine if a proportion of women suffer excessively rapid postmenopausal bone loss from the spine. If this was the case it was the aim to devise a means of predicting the women at excess risk; but if all women lost bone at similar rates, the aim was to document changing loss rates over the first 5–8 postmenopausal years. Responding women in six suburban general practices recalled for cervical smears who had their last menstrual period 9–36 months previously were invited to participate in a longitudinal study of bone loss and the biochemical markers plasma osteocalcin and urinary hydroxyproline. Sixty-four subjects agreed to participate, a response rate of 80%. In the ensuing 5 years, six received hormone replacement therapy and are not reported on. The main outcome measures were rates of spinal bone loss over 5 years, measured by dual photon absorptiometry, and radial bone loss over the first 2 years measured to quantitative computed tomography. Spinal bone loss was similar between individuals, with 94% of the variability in the data being accounted for by a statistical model that assumed parallel rates of bone loss. A less restrictive model allowing women to have different rates of spinal bone loss accounted for 12% more of the remaining variance in the data than the previous model. However, rates of radial bone loss were more dissimilar between women than rates of spinal loss. The results of the biochemical data collected serially showed that the plasma osteocalcin rose slowly to a plateau at 5 years postmenopause; in contrast, the hydroxyproline fell progressively with time over the whole period of study. These results were interpreted as being consistent with diminishing rates of bone destruction which gradually reequilibrated with bone formation as time passed after menopause.

Dietary determinants of post-menopausal bone loss at the lumbar spine: a possible beneficial effect of iron

IntroductionPrevious studies suggesting different effects of diet on post-menopausal bone loss may have given conflicting results because they sometimes failed to exclude confounding conditions or used imprecise methodology.DesignTo identify dietary determinants of bone loss from the lumbar spine after menopause in women not taking hormone replacement who developed no evidence of spondylotic or sclerotic degenerative disease, forty-three women were followed with repeated (mean = 12) measurements of bone mineral density (BMD) at L2–4 for 11–14 years. Eleven developed evidence suggestive of degenerative disease and were excluded. Diet was assessed at the beginning of the study and 2.5 years later using 3-day and 7-day periods of weighed intakes. Nutrients estimated were: carbohydrate, fat, protein, fibre, calcium, magnesium, iron, phosphorus, copper, zinc and six vitamins. We tested the ability of diet to predict post-menopausal bone loss using stepwise regression.ResultsEach woman’s BMD change was described by a single coefficient after log transformation of the BMD data. The best model for BMD loss including dietary factors alone had two significant determinants: daily energy or protein (p=0.0003) intake was adverse, while dietary iron (p=0.002) was predictive of bone maintenance, an effect that persisted if iron was expressed as a ratio to energy intake. Adding body mass index to the model increased the goodness of fit (R2adj rose from 0.33 to 0.42) without affecting the statistical significance of the dietary determinants.ConclusionsDiet may influence bone loss after menopause, with dietary iron (or an associated factor) possibly having a protective effect on bone at the spine.

Bone remodelling does not decline after menopause in vertebral fracture osteoporosis.

There is considerable current interest in whether activators of bone remodelling, such as IL-1 and other cytokines, are involved in the pathogenesis of osteoporosis. We have therefore studied indices relating to remodelling activation in 50 patients with postmenopausal vertebral osteoporosis and 12 with hip fracture osteoporosis in comparison with 25 age- and sex-matched controls. Because of uncertainty regarding the accuracy of current biochemical markers of bone formation with respect to the estimation of whole body rates of bone formation, a 85Sr-based radioisotopic method was used. This method was previously validated by comparison with data obtained after double in vivo labelling of transiliac biopsies taken nearly simultaneously. Bone resorption was estimated from urinary hydroxyproline data. Controls selected for their continued good health showed a progressive and statistically highly significant decline in indices of bone formation with time after menopause. No such decline was seen in the vertebral fracture patients (P less than 0.005). There were no hip fracture patients within 10 years of menopause so this statistical test could not be applied appropriately to them. The hydroxyproline data were consistent with the suggestion arising from the bone formation data that remodelling declines progressively after menopause in the controls but not in the vertebral fracture patients. The data also suggested that these two fracture groups were in more negative calcium balance than the controls, this being particularly marked in the hip fracture cases. Plasma osteocalcin data correlated moderately well with the kinetic measurements of bone formation. It is concluded that vertebral fracture osteoporosis is associated with prolongation of menopausal levels of bone remodelling which is inappropriate by comparison with healthy controls.

Gastrointestinal calcium absorption and dietary calcium load: relationships with bone remodelling in vertebral osteoporosis.

Patients with vertebral osteoporosis have a wide range of bone loss rates, bone remodelling rates and capacities for gastrointestinal (GI) calcium absorption. To test the hypothesis that variations in GI absorptive capacity determine rates of bone loss or remodelling, we have sought relationships betwen calcium absorption or vitamin D metabolite levels on the one hand and rates of cancellous and cortical bone loss (measured by serial quantiative computed tomography in the radius;n=25) or indices of bone remodelling in tetracycline-prelabelled transiliac biopsies (n=41) on the other, in a sequential untreated group. Calcium absorption (net and true) was measured in 18-day balances and by a two-isotope deconvolution method (fractional absorption and maximum absorption rate, MAR). There was no significant seasonal effect on any of these four measures of calcium absorption (variance ratio,F=0.52–1.61,p>0.1) or on 1,25-dihydroxyvitamin D levels (F=0.13,p>0.1; range 11–69 pg/ml), notwithstanding the expected seasonal effect on 25-hydroxyvitamin D levels (mean 18.7 ng/ml, zenith mid July, semi-amplitude 7.5 ng/ml;F=6.82,p<0.01). Neither this metabolite nor 1,25-dihydroxyvitamin D correlated with any index of calcium absorption (p>0.1). No measure of calcium absorption (or intake) had a significant relationship with radial cortical or cancellous bone loss (p all >0.1) but cancellous bone loss was associated with the rate of endogenous calcium excretion (r=0.50,p<0.05). A positive relationship between 25-hydroxyvitamin D and unlabelled osteoid surface (a marker of reduced blast vigour) persisted after adjustment for season (Studentst=2.70,p<0.01) but did not reflect 1,25-dihydroxyvitamin D levels. This study did not address the question of whether reduced GI calcium absorption has a uniform effect on bone remodelling in osteoporosis. However, variations in capacity for calcium absorption are unlikely to be responsible for the heterogeneity in bone loss and remodelling rates seen in vertebral osteoporosis.

Temporal variations in iliac trabecular bone formation in vertebral osteoporosis.

SummaryThe histologic heterogeneity of osteoporosis relative to normal controls has attracted great interest. There has been controversy as to whether patients with high turnover osteoporosis may convert to a normal or low turnover form, and vice versa. We have studied 44 patients over 12 years by dynamic histomorphometry and85Sr kinetics + calcium balance performed within 60 days in 20 patients (Group 1) and 75–808 days apart in the remainder (Group 2). In the first group, the histologic tissue level bone formation rate (BFR/BV or BFR/BS) was predictive of the85Sr measurements of bone formation (r=0.66P<0.01). There was no statistically significant correlation in Group 2 and the regression coefficients were significantly different (P=0.01). Periodic regression was used to determine if seasonal changes were responsible for this loss of correlation; none was found that was of statistical significance. No systematic changes with time in bone formation were found in Group 2 during the period of observation; nor were consistent secular changes detected when the data for both groups were examined according to procedure data. In conclusion, bone formation may change with time in postmenopausal osteoporosis. Evidence that these changes are systematic was not found and this has implications for the design of treatment studies.

The relationship between serum vitamin D concentrations andin vivo tetracycline labeling of osteoid in crush fracture osteoporosis

SummaryTwenty of 22 consecutive British patients with crush fracture osteoporosis had transiliac bone biopsies following doublein vivo tetracycline labeling synchronized with the collection of serum for the measurement of vitamin D metabolites. A significant but direct (rather than inverse) relationship was found between 25-hydroxyvitamin D (calcidiol) levels and the fraction of cancellous surfaces covered with osteoid not taking either tetracycline label (r=0.53,P<0.02). There was no correlation with 1,25-dihydroxyvitamin D levels. No patient had frankly thickneded osteoid seams although 3 had reduced but measurable calcidiol levels. These results make it unlikely that the majority of patients with osteoporosis who have osteoid of normal thickness but reduced uptake of tetracycline have a mineralization defect secondary to vitamin D deficiency. The pathophysiological significance of unlabeled osteoid in osteoporosis requires further investigation.