Recommendations for the registration of agents used in the prevention and treatment of glucocorticoid-induced osteoporosis.
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Animals↗
Biomedical subjects
R Eastell
Publications and source records attributed to R Eastell.
Forearm fracture.
Bone mineral density of the distal forearm decreases with age in women, and this results in an increased risk of forearm fractures. Men have no increase in risk of forearm fractures with age because they have a higher peak bone mass at this site and less of a decrease in bone mineral density with ageing. Bone loss from the forearm slows in women after the age of 65 years in women and this may account for the plateau in forearm fracture rate after this age. Women with forearm fractures have twice the expected risk of vertebral and hip fractures. Forearm fractures before the age of 60 years are associated with an increase in the risk of vertebral fractures. Forearm fractures after the age of 70 years are associated with an increased risk of hip fractures. Thus, women presenting with forearm fractures are a good target population for the prevention of osteoporosis.
Aged↗
Measurement of bone specific alkaline phosphatase in the horse: a comparison of two techniques.
For many years total alkaline phosphatase (AP) activity in serum has been used to monitor bone metabolism in different species. However, total AP lacks bone specificity because the total activity in serum is made up of several isoenzymes, of which the liver and bone isoforms predominate. The aim of the present study was to evaluate an immunoradiometric assay for measuring bone specific alkaline phosphatase (BAP) in horses. BAP, a specific marker of bone formation, was measured in sera from thoroughbred horses by using a previously characterised wheat germ lectin (WGL) precipitation assay and an immunoradiometric assay. The levels of immunoreactive BAP (iBAP) and WGL precipitated BAP (wBAP) were related to the serum levels of total AP and another marker of bone formation, the carboxy-terminal propeptide of type 1 collagen (PICP). In horses over one year old, iBAP correlated at least as strongly with total AP as with wBAP, which suggests that the immunoradiometric assay may partially cross-react with liver alkaline phosphatase in horse serum. This possibility was supported by the observation that there was a weaker correlation between iBAP and PICP than between wBAP and PICP. These data indicate that WGL precipitation is currently the most specific method for measuring bone specific alkaline phosphatase in horses.
Aging↗
Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment.
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Alkaline Phosphatase↗
Metabolic effects of pamidronate in patients with metastatic bone disease.
We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates.
Aged↗
Bone turnover and bone mineral density in patients with congenital adrenal hyperplasia.
BACKGROUND AND OBJECTIVE: Glucocorticoid replacement is the most effective therapy for patients with congenital adrenal hyperplasia (CAH). It has been reported that excessive steroid therapy leads to bone loss and osteoporosis, but it is uncertain whether steroid replacement therapy affects bone turnover and bone mineral density (BMD) in adult patients with CAH. DESIGN: Case-control study: patients with CAH were compared to normal subjects, individually matched for age and body weight. PATIENTS: Eleven patients, aged 19-65 years, were evaluated in this study. The age at diagnosis of CAH was 0-26 years. Nine patients (6 females and 3 males) were diagnosed with 21-hydroxylase deficiency and 2 male patients with 11-hydroxylase deficiency. 17-Hydroxyprogesterone levels in patients had never been below the reference range in the previous 2 years. These patients were individually matched for sex, age and weight to 11 healthy controls. MEASUREMENTS: Total body, lumbar spine and femoral neck BMD was measured by dual-energy X-ray absorptiometry. Serum bone Gla-protein (BGP, osteocalcin) and bone alkaline phosphatase (BAP) were measured to assess bone formation whereas serum tartrate-resistant acid phosphatase (TRAP) and urinary cross-linked N-telopeptides of type I collagen (NTx) were measured to assess bone resorption. NTx was expressed as a fraction of urinary creatinine excretion (NTx/Cr). Serum dehydro-epiandrosterone sulphate (DHEA-S) and androstenedione levels were measured to assess adrenal androgen status. RESULTS: Serum DHEA-S, androstenedione, BGP and BAP and urinary NTx/Cr were decreased in patients when compared with controls (paired t-test, P = 0.005, 0.0003, 0.002, 0.03 and 0.03, respectively). BMD was not significantly decreased in patients. The difference of total body BMD between patients and controls (i.e. BMD in patients minus BMD in controls) was negatively correlated with age. There was no correlation between androgen levels and either BMD or bone turnover. The total dose of steroid taken in the previous 2 years was not correlated with BMD, bone turnover or androgen levels. The was no correlation between BMD adjusted by age and bone turnover or initial age at diagnosis. CONCLUSIONS: We conclude that (1) bone turnover is decreased in congenital adrenal hyperplasia, (2) bone mineral density is not decreased in congenital adrenal hyperplasia and (3) patients initially have higher bone mineral density but later have lower bone mineral density than controls, especially in women.
Adrenal Hyperplasia, Congenital↗
To determine the effects of ultraviolet light, natural light and ionizing radiation on pyridinium cross-links in bone and urine using high-performance liquid chromatography.
The aims of the study were to characterize the denaturation of urinary free and conjugated pyridinoline (Pyr) and deoxypyridinoline (Dpyr) on exposure to ultraviolet (UV) and natural light at different pH levels and to study the effects of X- and gamma-irradiation on Pyr and Dpyr in urine and in the mineralized and non-mineralized compartments of human bone. Urine samples from six normal subjects, adjusted to pH 3.0, 7.0 and 9.0 were exposed to UV light for up to 3 days. Urine collections (2 mL and 24 h) from three subjects, pH adjusted to 1.0, 2.0, 3.0, 4.0 and 5.0, were exposed to natural light for up to 1 day. Urine samples and bone slices from seven human cadaveric femurs were irradiated with increasing doses of X-rays (0-100 Gy) and high-dose gamma-radiation (28 kGy). Mineralized and non-mineralized bone were separated using a modification of a published method employing heat denaturation followed by trypsin hydrolysis and analysed for Pyr, Dpyr and hydroxyproline (Hypro). The rate of UV photolysis of urinary Pyr and Dpyr increased with pH and was faster in the free fraction (after 3 days' exposure: free Pyr and Dpyr at pH 7.0 vs. 9.0, P < 0.05, conjugated pH 3.0 vs. 9.0, P < 0.05). Exposure to natural light for 3 h did not significantly decrease urinary Pyr and Dpyr in either sample collections, but levels were reduced in the 2-mL aliquots after exposure for 1 day (P < 0.05). X-irradiation of urine and bone did not affect Pyr and Dpyr. Pyr content was similar in both bone compartments (Pyr/ Hypro = 0.12 +/- 0.004), but Dpyr was higher in the non-mineralized compartment (Dpyr/Hypro = 0.047 +/- 0.002 vs. 0.038 +/- 0.002, P < 0.001). UV light and gamma-irradiation result in denaturation of pyridinium cross-links in urine. These cross-links are present in both the mineralized and non-mineralized bone compartments but are not affected by the doses of gamma-irradiation that denature these cross-links in urine.
Amino Acids↗
Paget's disease in a patient with ankylosing spondylitis--a diagnostic dilemma.
A patient is described in whom the diagnosis of Paget's disease was complicated by the presence of ankylosing spondylitis. The mechanism for the unusual distribution of pagetic bone is discussed.
Aged↗
Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism.
The aims of this study were to determine 1) whether primary hyperparathyroidism (PHPT) is associated with accelerated bone loss in postmenopausal women, 2) whether bone mineral density (BMD) and bone turnover change to a similar extent with surgery and hormone replacement therapy (HRT) in these patients, and 3) whether biochemical markers of bone turnover measured at baseline can be used to predict the change in BMD in these patients after different therapies. We studied 33 postmenopausal women with PHPT; their ages at the time of study ranged from 48-80 yr (mean +/- SD, 63 +/- 10). Total body (TB), lumbar spine (LS), and femoral neck (FN) BMD and biochemical markers of bone turnover were measured at baseline and 10-30 months (19 +/- 5) after parathyroid surgery, HRT, or no treatment. BMD was measured in 33 age-matched healthy controls at baseline and at a mean of 24 months. Baseline biochemical markers of bone turnover were measured in controls. In PHPT at baseline, the mean z-score of BMD was -1.25 at TB (95% confidence interval, -1.64 to -0.86), -0.95 at LS (-1.37 to -0.53), and -1.30 at FN (-1.65 to -0.95), whereas the mean z score was 0.45 for serum carboxy-terminal propeptide of human type I procollagen (0.02-0.89), 1.05 for bone alkaline phosphatase (0.38-1.71), 2.38 for 24-h urinary excretion of cross-linked N-terminal telopeptide of type I collagen (NTx; 1.63-3.13), and 2.36 for 24-h urinary excretion of galactosyl hydroxylysine (1.97-2.74). After surgery and HRT, BMD increased and bone turnover decreased during the follow-up. In the untreated group, BMD decreased at TB and FN, and levels of bone alkaline phosphatase, NTx/creatinine, and galactosyl hydroxylysine/creatinine increased. When the rate of change in BMD (percentage per yr) was compared with that in the control group, bone gain was significant at all three skeletal sites after surgery and HRT, and bone loss was significant at TB and FN, but not at LS, in the untreated group. There was a weak, but significant, correlation between baseline urinary NTx and the change in femoral neck BMD in the untreated group (r = -0.36; P = 0.05). We conclude that untreated postmenopausal women with PHPT have low BMD resulting from accelerated bone loss at the TB and FN. Surgery and HRT both restore BMD and bone turnover toward normal in postmenopausal women with PHPT. A single measurement of bone turnover is insufficient to predict BMD changes in individual patients with PHPT.
Aged↗
ABC of rheumatology. Osteoporosis.
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Bone Density↗
Comparison of rates of bone loss from the spine measured using two manufacturers' densitometers.
Measurements of bone mineral density of the lumbar spine (LS-BMD) by dual-energy X-ray absorptiometry (DXA), made using different manufacturers' densitometers, differ by approximately 15%. The aim of this study was to compare the rate of bone loss from the lumbar spine measured using two manufacturers' densitometers. LS-BMD (vertebrae L2-L4) was measured using both a Lunar DPX and a Hologic QDR 1000/W in 17 postmenopausal women at baseline and 2 years. The mean rate of change of LS-BMD made using the two densitometers did not differ (DPX -0.54% per year; QDR -0.17% per year). although rates of change of LS-BMD measured using the two densitometers correlated (r = 0.47, p = 0.05), the variance of the rates of loss differed such that, in individual subjects, the difference between the rates of loss of LS-BMD, measured using the two densitometers, was related to the average rate of loss (r = 0.61, p = 0.009). For both densitometers, as bone mineral content (BMC) increased, the measured area also increased, leading to an underestimate of change in bone mineral density (BMD). This relation differed between the two densitometers such that the change in BMD was underestimated to a greater extent by QDR. We conclude that in the context of multicenter studies it may not be possible to directly combine data on the rate of bone loss acquired using different manufacturers' densitometers.
Absorptiometry, Photon↗
The response of the skeleton to physical training: a biochemical study in horses.
In this study we tested the hypothesis that exercise induces an adaptive response in the developing skeleton which may be monitored in vivo by measuring biochemical markers of bone metabolism. The effects of exercise on two biochemical markers of bone formation were determined; the carboxy-terminal propeptide of type I procollagen (PICP), and the bone-specific isoenzyme of alkaline phosphatase (BAP), and one putative marker of resorption, the pyridinoline crosslinked telopeptide domain of type I collagen (ICTP). All three markers were measured for a year in 2-year-old thoroughbred horses exercised three times a week on a treadmill, and values compared to a control group of age-matched animals. Levels of all three markers fell in both exercised and control groups over the 12-month period reflecting normal age changes. However, there were differences between groups in the pattern of this decrease. When expressed as a percentage of baseline values, BAP was higher (p < 0.05) at 2 months and both BAP and the PICP were higher at 4 months (p < 0.01 and p < 0.05, respectively) in the exercised group, reflecting an increase in bone turnover in this group in the early stages of training. PICP levels were also elevated in the exercised group at 10 months and this result indicates an increase in bone turnover at this time. The changes in ICTP were different; at 2 months, levels were higher in exercised animals than in controls, but there was no significant difference between the two groups at 4 and 6 months. After 8 months, ICTP levels in the exercised group increased returning to near baseline values at 10 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkaline Phosphatase↗
Histomorphometric and biochemical characterization of bone following acute severe burns in children.
Severe burns in adults is associated with an uncoupling of normal remodeling, low bone formation without reduced resorption. The risk of osteopenia that may occur under such circumstances is heightened by our detection in a cross-sectional study of low bone mass in severely burned children. We report here the acute histomorphometric and biochemical response of bone to severe burn injury, as well as bone mass in severely burned children. We enrolled 24 patients ages 5.8 to 17.5 years following burns of 63 +/- 16% (SD) body surface area. Serum and urine were collected weekly until iliac crest bone biopsy was obtained 26 +/- 10 days postburn. Seventeen of 18 patients, including 5 patients receiving growth hormone treatment to accelerate wound healing, failed to take up doxycycline in trabecular bone, and had no detectable osteoblasts at the osteoid seam, while eroded surface was normal and osteoblasts were documented by staining. Thus, bone formation was virtually absent. There was an eightfold elevation in urinary free cortisol excretion and high serum levels of acute phase reactants and interleukin-1 beta and -6. Biochemical markers of bone formation, osteocalcin, and type I procollagen propeptide were low, as were resorptive markers urinary pyridinoline and deoxypyridinoline. However, there was no correlation with resorptive surface. Mean age-related z-score for bone mass was -1.06 +/- 1.05, 40 days postburn. Immobilization and endogenous corticosteroid production may be the main factors responsible for acutely reduced bone formation while inflammatory cytokines may mediate resorption.
Absorptiometry, Photon↗
Management of corticosteroid-induced osteoporosis. UK Consensus Group Meeting on Osteoporosis.
Corticosteroid therapy results in osteoporosis. There is a doubling in the risk of fracture in patients taking more than the equivalent of 7.5 mg day-1. The bone loss is most rapid from the axial skeleton, particularly during the 1st year of therapy. The most important mechanism for the bone loss is a decrease in osteoblastic activity. Preventative strategies should be targeted to patients with low bone-mineral density, especially if the dose of corticosteroids is likely to be high. Treatment strategies agreed on by the Consensus Panel included hormone replacement therapy and bisphosphonates, with monitoring of efficacy by bone densitometry.
Adrenal Cortex Hormones↗
Age related changes in biochemical markers of bone metabolism in horses.
Biochemical markers of bone metabolism were analysed in serum samples obtained from 60 horses with no history of orthopaedic disease (age 3 months-20 years). Serum levels of the carboxyterminal propeptide of type I procollagen (PICP), a marker of bone formation and the pyridinoline cross linked telopeptide domain of type I collagen (ICTP), a putative marker of bone resorption, were measured by radioimmunoassay (RIA). Serum levels of the bone specific isoenzyme of alkaline phosphatase (BALP), another marker of bone formation, were measured by a wheatgerm agglutinin affinity (WGA) method. Total alkaline phosphatase levels were also determined. Serum levels of PICP were significantly correlated with bone ALP (r = 0.78, P < 0.0001) and ICTP (r = 0.87, P < 0.0001). ICTP levels also correlated significantly with bone ALP (r = 0.81, P < 0.0001). However, total alkaline phosphatase did not correlate significantly with PICP, ICTP and BALP in horses over 1 year of age. There was an inverse correlation between serum levels of all biochemical markers and age of animals, with the most significant changes seen over the first 2 years. In animals less than 1 year of age, the reference ranges (mean +/- s.d. 1.96) were as follows: PICP 1216-2666 micrograms/l, ICTP 13.8-26.7 micrograms/l, bone ALP 134-288 u/l and total ALP 223-498 u/l. In 2-year-olds, the equivalent reference ranges were: PICP 550-1472 micrograms/l, ICTP 7.96-22.8 micrograms/l, bone ALP 32.7-125 u/l and total ALP 134-238 u/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis.
OBJECTIVES: To determine the prevalence of vertebral fracture in postmenopausal women with steroid treated rheumatoid arthritis (RA), and whether the risk of vertebral fracture could be predicted from measurements of bone mineral density (BMD). METHODS: Vertebral deformities were defined from spine radiographs in 76 postmenopausal women with steroid treated RA (aged 50-79 years) and 347 age matched women from a population based group, using a morphometric technique. Lumbar spine (LS) BMD was measured by dual energy x ray absorptiometry. RESULTS: The odds ratio for vertebral fracture in the women with RA was 6.2 (95% confidence interval 3.2 to 12.3). The decrease in LS-BMD was less than expected for the observed prevalence of vertebral fracture and, among the women with RA, LS-BMD was not lower in those with vertebral fractures. CONCLUSIONS: We conclude that patients with steroid treated RA may have abnormal bone quality, and that LS-BMD cannot be used to predict the risk of vertebral fracture in these patients.
Aged↗
Bone mineral density and bone turnover in spinal osteoarthrosis.
OBJECTIVES: To determine whether there was a generalised increase in bone mineral density (BMD) in spinal osteoarthrosis (OA), and to determine the mechanism of this possible protection against osteoporosis as assessed by biochemical markers of bone turnover. METHODS: We studied 375 women (ages 50 to 85) from a population based group. Spinal OA was defined from radiographs as the presence of degenerative changes affecting intervertebral or facet joints. BMD of the lumbar spine (LS), femoral neck (FN) and total body (TB) was measured by dual energy x ray absorptiometry (Lunar DPX). Bone turnover rates were estimated from measurement of biochemical markers of bone formation and resorption (urine deoxypyridinoline (Dpyr) and serum bone specific alkaline phosphatase (BAP)). RESULTS: BMD at each site was greater in the women with spinal OA (mean increase in LS-BMD 7.9%, 95% confidence interval (CI) 1.0 to 15.1; TB-BMD 8.4%, 95% CI 1.9 to 9.7; FN-BMD 6.4%, 95% CI 0.3 to 12.6). Twenty four hour urinary excretion of Dpyr, corrected for TB bone mineral content, and serum BAP were 19% lower in the women with spinal OA (95% CI for Dpyr 4.3 to 31.9%; for BAP 6.3 to 32.0%). CONCLUSIONS: Spinal OA is associated with a generalised increase in BMD and a decreased rate of bone turnover. This suggests that the protective effect of spinal OA against osteoporosis may be mediated by decreased bone turnover.
Absorptiometry, Photon↗
Circadian rhythm of in vitro bone-resorbing activity in human serum.
Calciotropic hormones as well as biochemical parameters of bone formation and resorption show circadian rhythms. In a previous study in the rat, we observed a circadian rhythm in serum bone-resorbing activity (SBRA). In the present study, we investigated whether there was a circadian rhythm of SBRA in human serum. For this purpose, we studied 10 healthy premenopausal women and 5 healthy men. Blood was collected every 2 h, and urine samples were collected during 4-h periods for 24 h. For the determination of SBRA, media were prepared by reconstituting serum samples with Dulbecco's Modified Eagle's Medium at a ratio of 20% serum and 80% Dulbecco's Modified Eagle's Medium. Limb bones were dissected from 19-day old fetal rats prelabelled with 45Ca and were cultured for 72 h in the presence of the sera. Bone resorption was assessed from the 45Ca released into the culture medium and from that retained in the bone and was expressed as percentage 45Ca release. Serum calcium, phosphorus, PTH, cortisol, and urinary pyridinium cross-links were also determined. SBRA in human serum followed a circadian rhythm with a peak at about 0300 h and a nadir at 0700 h. There was no significant difference between the rhythm of SBRA of women and men. At concurrent time points, SBRA and serum PTH were positively correlated (r = 0.629; P < 0.01), and SBRA and serum cortisol were negatively correlated (r = 0.797; P < 0.01). To further investigate the possible contribution of these hormones to SBRA, either neutralizing anti-PTH antibody or RU-486 (mifepristone), a glucocorticoid receptor antagonist, was added to the serum samples of 6 subjects. Neutralizing the effect of PTH did not change the pattern of SBRA rhythm. The addition of RU-486 had a significant effect on the rhythm of SBRA, reducing the peak and nadir amplitudes. Thus we conclude that cortisol plays a major role in the rhythm of SBRA present in human serum; however, the influence of other factors cannot be excluded. Cortisol may be an important determinant of the circadian rhythm of bone resorption in vivo.
Adult↗