P. Hulme

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.

The relationship between changes in femoral bone density and calcium balance in patients with involutional osteoporosis treated with human parathyroid hormone fragment (hPTH 1–34)

Abstract The effect of treatment of crush fracture osteoporosis with human parathyroid hormone fragment (hPTH 1–34) in low (normocalcaemic) dosage was monitored by calcium balances and serial measurements of cortical bone density in the distal femur. There was a significant correlation between the results using the two techniques, so that serial densitometry may be used in the estimation of calcium balance although with somewhat less precision than is obtainable with the best balance technique. Further analysis of the data suggested that hPTH therapy was associated with a significant redistribution of bone mineral away from this cortical bone site, presumably towards trabecular bone volume (Reeve et al., 1980).

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.

Treatment with parathyroid peptides and estrogen replacement for severe postmenopausal vertebral osteoporosis: prediction of long-term responses in spine and femur

Abstract Fifteen women with severe vertebral osteoporosis were treated with daily parathyroid peptide (hPTH) plus hormone-replacement co-therapy (HRT) for 1 year. Eight other patients were randomized to HRT alone. Co-therapy with hPTH and HRT resulted in an impressive mean treatment response at the spine (dual-energy X-ray absorptiometry DXA) 15% above baseline; P < 0.015 compared with the HRT group) at 2 years, while at the proximal femur and radius there were smaller increases. hPTH co-therapy led to a significantly positive metabolic calcium balance at 1 year (by 2.13 mmol Ca/day, equivalent to a 5% annual increment in total body calcium; P = 0.015). The magnitude of the lumbar spine DXA response at 2 years depended statistically on the increase in bone formation rate, measured with 85Sr (r2 adjusted 0.48; P < 0.005) and patients with a large spine DXA response had larger calcium balance improvements (P < 0.03). Plasma osteocalcin changes tracked closely with increases in bone formation rate (r2 = 0.87). In seven patients treated throughout with HRT alone, and in eight hPTH-treated patients (three of whom switched to bisphosphonate therapy at year 4), DXA spine changes seen in years 3–5 were minimal, with no evidence of a statistically significant difference between groups. It is concluded that hPTH or comparable PTH receptor activators remain the most promising anabolic treatment for osteoporosis currently under clinical evaluation and a 6- or 12-month measurement of bone formation or a marker predicts the 2–5 year bone density outcome. Post-hPTH treatment, loss of bone appeared preventable with anti-resorptive therapy.

The clinical measurement of urinary total hydroxyproline excretion

The effect of dietary control on the day-to-day variation in total hydroxyproline excretion has been examined in two studies. In the first, a normal volunteer ate a controlled diet containing varying gelatin supplements for several weeks. In the second, the effect of removing hydroxyproline-containing foods from the diets of 8 volunteers was examined. Both studies confirm that the day-to-day variation in total hydroxyproline excretion falls when the gelatin content of the diet is decreased, whether the results are expressed as total hydroxyproline excretion rate or as the total hydroxyproline: creatinine ratio. This fall in variation takes place within 24 h of dietary control beginning and therefore longer periods of dietary restrictions to achieve optimum precision in the measurement of total hydroxyproline are unnecessary. For some analytical methods, results are better expressed as the ratio total hydroxyproline:creatinine than as the total hydroxyproline excretion rate.

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.