Optimization of glucocorticoid replacement therapy: the long-term effect on bone mineral density.
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Adrenal Insufficiency↗
Biomedical subjects
R Eastell
Publications and source records attributed to R Eastell.
Biochemical markers of bone turnover.
Biochemical markers of bone turnover that are specific to bone allow study of the subtle changes in bone turnover associated with osteoporosis. They have been evaluated in Paget's disease of the bone and chronic renal failure. This review focuses on the use of biochemical markers of bone turnover in osteoporosis. The data in this review period are numerous and varied due to the growing interest in the use of biochemical markers of bone turnover in clinical practice. The data provide support for the use of the newer bone turnover markers for monitoring treatment of osteoporosis, if care is taken to minimize sources of variability.
Alkaline Phosphatase↗
One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density.
BACKGROUND: Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma. However, concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation. This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density (BMD) over one year. METHODS: A one year randomised, prospective, open parallel study comparing inhaled fluticasone propionate (FP), 500 micrograms twice daily in 30 patients, and budesonide (BUD), 800 micrograms twice daily in 29 patients, delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma. Biochemical markers of bone turnover (osteocalcin, procollagen type 1 C-terminal propeptide (PICP), immunoreactive free deoxypyridinoline (iFDpd), N-terminal crosslinked telopeptides of type I collagen (NTx)), BMD at the spine and femoral neck, and serum cortisol concentrations were measured at baseline and 12 months later. RESULTS: There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density. Bone mineral density of the spine increased slightly in both groups over the 12 month period. Serum osteocalcin levels increased from baseline in both treatment groups (FP 16.9%, p = 0.02; BUD 14.3%, p = 0.04). PICP did not differ significantly from baseline. Both markers of bone resorption (iFDpd, NTx) varied considerably with no significant changes after one year. There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months (r = 0.4, p = 0.017). Mean serum cortisol levels remained within the normal range in both groups following treatment. CONCLUSION: There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD. The change in spine BMD correlated with the increase in osteocalcin. Studies extending over several years are needed to establish whether these findings persist.
Administration, Inhalation↗
Bone turnover in preterm infants.
Total parenteral nutrition is associated with osteopenia in preterm infants. Insufficient calcium and phosphate are likely causes: aluminum contamination is another possible contributing factor as this adversely affects bone formation and mineralization. The study was designed to evaluate changes in biochemical markers of bone turnover in 22 preterm infants receiving total parenteral nutrition in comparison with 19 term infants. We collected urine and serum samples from 22 preterm infants, mean gestational age 29 wk, within 48 h and again at 3 wk of life. We also collected urine samples from 19 term infants, mean gestational age 39 wk, during the first day of life. Bone resorption was assessed by the measurement of urinary pyridinium cross-links by HPLC and ELISA and the N-telopeptide of type I collagen by ELISA. Bone formation was assessed in premature infants by the measurement of serum osteocalcin. The N-telopeptide of type I collagen was higher in the preterm infants compared with term at baseline (p < 0.01). There was no difference between the pyridinium cross-links in the preterm and term infants. All the biochemical markers of bone turnover increased significantly in the preterm infants during the first 3 wk of life, e.g. N-telopeptide was a 153% change from baseline (p < 0.001). Aluminum in the total parenteral nutrition solutions did not cause a decrease in bone formation at the level administered (3-6 microg, 0.1-0.2 micromol x kg(-1) x d(-1)).
Bone Diseases, Metabolic↗
Rate of Loss Recalculated.
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Journal Article↗
Variability and response of urinary resorption markers to hormone replacement therapy
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Journal Article↗
Monitoring alendronate therapy for osteoporosis.
Alendronate is an antiresorptive therapy for osteoporosis and results in a decrease in bone turnover. To choose the optimal measurement for monitoring this therapy, the size of the change needs to be compared with the variability of the measurement. We studied 26 women with postmenopausal osteoporosis (bone mineral density [BMD] T score < -2.5), who were randomized in a 2:1 ratio to receive alendronate (10 mg/day) and calcium carbonate (500 mg/day) or calcium carbonate alone for 6 months. We measured serum markers of bone formation (osteocalcin [OC], bone isoform of alkaline phosphatase [BAP], and collagen type I C-terminal propeptide [CICP]) and urinary markers of bone resorption (cross-linked N-telopeptide [NTx], free deoxypyridinoline [iFDpd], and free pyridinolines). All subjects had two measurements 1 week apart at baseline to calculate the short-term variability. Biochemical measurements were then made at 4, 8, 12, 24, and 25 weeks. Measurements of bone mass were made by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and proximal femur twice at baseline and then at 24 and 25 weeks. The mean difference in change in BMD and markers between both groups at the end of the study that were significant were (short-term variability in brackets): DXA total hip 4.3% (2.5%), NTX 49% (10%), iFDpd 22% (12%), OC 28% (13%), BAP 31% (13%), and CICP 31% (11%). Five of the six markers showed significant responses to alendronate therapy, but they differed in the relationship between size of response and variability. These biochemical markers performed better than DXA for monitoring alendronate therapy over 6 months.
Aged↗
Age-related changes in bone turnover in men.
Biochemical markers of bone turnover can be used to study the pathophysiology of osteoporosis. So far there have been few such studies in men. The aims of this study were to determine the effect of aging on bone turnover and to identify which hormones might regulate bone turnover in men. We studied 178 healthy Caucasian men, ages 20-79 years (30 per decade). The data for the effect of age on bone turnover was best fit by a quadratic function (nadirs at age 56, 57, 53, 39, and 58 years for intact propeptide of type I procollagen, osteocalcin, bone alkaline phosphatase, free deoxypyridinoline, and cross-linked N-telopeptides of type I collagen, respectively). For most markers, bone turnover tended to be highest in the third decade, lowest in the fifth and sixth decade, with a small increase in some markers in the eighth decade. Insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3, dehydroepiandrosterone sulfate, testosterone, estradiol, and free androgen index all decreased significantly with age (54, 17, 76, 26, 33, and 57%, respectively), while sex hormone binding globulin and parathyroid hormone increased significantly with age (62% and 43%). IGF-I and sex hormones were positively correlated with bone turnover, and this association was stronger in young men than older men. In conclusion, increased IGF-I and sex hormones may be associated with increased bone turnover in young men, with less influence on bone turnover in older men.
Adult↗
Serum galactosyl hydroxylysine as a biochemical marker of bone resorption.
BACKGROUND: Serum-based biochemical markers of bone resorption may provide better clinical information than urinary markers because direct comparison with serum markers of bone formation is possible and because the within-subject variability of serum markers may be lower. We describe a method for the measurement of free beta-1-galactosyl-O-hydroxylysine (Gal-Hyl) in serum. METHODS: The assay used preliminary ultrafiltration of serum, dansylation, and separation by reversed-phase HPLC with fluorescence detection. Healthy subjects were recruited from population-based studies of bone turnover. RESULTS: The within-run (n = 15) and between-run (n = 15) CVs were 7% and 14%, respectively, at a mean value of 48 nmol/L. In women and pubertal girls, serum free Gal-Hyl correlated with urine free Gal-Hyl (r = 0.84; P <0.001). Serum Gal-Hyl was higher during puberty and increased after menopause. The fractional renal clearance of free Gal-Hyl relative to that of creatinine was 0.90 (95% confidence interval, 0.82-0.98). Serum free Gal-Hyl decreased by 36% (SE = 4%) in 14 patients with mild Paget disease treated with an oral bisphosphonate, and this decrease was significantly (P <0. 001) greater than that seen for either serum tartrate-resistant acid phosphatase (9%; SE = 4%) or serum C-terminal telopeptide of collagen I (19%; SE = 8%). CONCLUSION: Serum free Gal-Hyl may be useful as a serum marker of bone resorption.
Adolescent↗
A randomized, double-blind study comparing the effects of beclomethasone and fluticasone on bone density over two years.
Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids have reduced bone mass. This prospective 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids. Patients (n = 33) (males aged 18-50 yrs, females aged 18-40 yrs) on inhaled corticosteroids 1,000-2,000 microg x day(-1), were randomized in a double-blind fashion to either fluticasone propionate (FP) 1,000 microg x day(-1) or beclomethasone dipropionate (BDP) 2,000 microg x day(-1). In parallel, three open control groups of the same age range were studied: asthmatics (n = 8) receiving low dose inhaled corticosteroids (< or =400 microg x day(-1)) (group A); chronic, severe asthmatics (n = 8) receiving oral corticosteroids (> or =10 mg x day(-1) (group B); and healthy untreated volunteers (n = 7) (group C). Bone densitometry scans (quantitative computed tomography (QCT) of spine; dual X-ray absorptiometry of spine, femoral neck, and single photon absorptiometry of forearm) were performed at baseline and after 6, 12 and 24 months of treatment. Biochemical bone marker measurements (serum osteocalcin, bone alkaline phosphatase, pro-collagen type 1 carboxy terminal propeptide, deoxypyridinoline and C-telopeptide of type 1 collagen) were collected every 3 months. Fifteen FP (mean age 36 yrs, six male) and 9 BDP patients (mean age 33 yrs, five male); completed the study. At 0 months, mean bone mineral density (BMD) was lower in patients receiving inhaled corticosteroids (both low dose and high dose) than in normal volunteers. In the FP-treated group, mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline, whereas there was some decline in the BDP-treated group. The treatment difference between FP and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months (p = 0.006) and 24 months (p = 0.004). This study suggests that over 24 months, changes in bone density are minimal in patients on high-dose inhaled corticosteroids.
Absorptiometry, Photon↗
The engineered human anti-tumor necrosis factor-alpha antibody CDP571 inhibits inflammatory pathways but not T cell activation in patients with rheumatoid arthritis.
OBJECTIVE: We investigated the effect of an engineered human anti-tumor necrosis factor-alpha antibody, CDP571, on immune functions as well as bone and cartilage turnover in patients with rheumatoid arthritis (RA) in a placebo controlled trial. We also assessed the effects of repeated treatment with CDP571 in an open label continuation study. METHOD: Thirty-six patients were treated with either placebo or 0.1, 1, or 10 mg/kg of CDP571 given as an intravenous infusion. The followup period was 8 weeks. Lymphocyte phenotype, soluble CD4 (sCD4), soluble interleukin 2 receptor (sIL-2R), IL-6, and stromelysin levels in the blood were measured before and after treatment; bone and cartilage markers (pyridinoline, deoxypyridinoline, N-terminal telopeptide) were similarly assessed in the urine. Patients who completed a placebo controlled trial of CDP571 were offered further treatment with CDP571. They received a maximum of 2 further doses of 1 mg/kg (7 patients) or 10 mg/kg (9 patients) in an open study. RESULTS: Plasma IL-6 level was statistically significantly reduced in the 1 and 10 mg/kg groups. In the 10 mg/kg group, there were also reductions in plasma stromelysin and urine bone markers, although there was no change in sCD4 and sIL-2R levels. Repeat doses of CDP571 were well tolerated and continued to suppress the acute phase response and disease activity. CONCLUSION: Treatment with 10 mg/kg of CDP571 reduced IL-6 and surrogate markers of bone turnover in RA, suggesting that CDP571 might prevent joint damage in RA. Since there was no effect on lymphocyte markers despite the marked reduction in inflammation, CDP571 appears to have no effect on ongoing CD4 T cell activation.
Antibodies↗
Treatment of postmenopausal osteoporosis.
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Calcitonin↗
Bone loss around 2 different types of hip prostheses.
Dual energy x-ray absorptiometry (DXA) allows the measurement of bone mineral density (BMD) around an uncemented hip prosthesis. The aims of this study were: 1) to determine the reproducibility of periprosthetic BMD measurements; 2) to delineate the time course of bone loss that occurs after insertion of a hip prosthesis; and 3) to compare the bone loss around two different types of hip prosthesis. We studied 20 patients: 11 had Bateman and 9 had porous-coated anatomic prostheses inserted. The mean bone loss in 20 patients between 6 and 52 weeks after surgery was 6%. The greatest loss during this period was 18% and occurred from the proximal medial cortex. We conclude that measurement of periprosthetic bone mass by DXA is a precise technique. Bone loss was rapid in the first 6 months following total hip replacement. There was no difference in the bone loss occurring around the two prostheses studied.
Absorptiometry, Photon↗
Mechanisms of bone loss after cardiac transplantation.
To determine the mechanism of bone loss after cardiac transplantation (CTX), we studied 50 men 0.5-47 months after CTX (ages 18-64 years) who received prednisolone and cyclosporin to prevent rejection, and 40 healthy men as controls (ages 20-70 years). We measured bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), bone resorption using urinary cross-linked N-terminal telopepides of type I collagen (NTx), and bone formation using osteocalcin (BGP) and bone alkaline phosphatase (BAP). The results from the controls were used to calculate z scores. BMD was significantly decreased at the lumbar spine, femoral neck, and total body, and bone turnover was significantly increased as assessed by NTx/creatinine, BGP, and BAP as compared with controls (p < 0.01 for all measurements). To evaluate the cause of the increased bone turnover we measured serum parathyroid hormone (PTH) by IRMA, and this was also elevated (p < 0.001). There was a significant correlation between serum PTH and BGP (r = 0.58, p < 0.01). To evaluate the cause of the increase in PTH, we measured serum calcium and it was decreased (p < 0.001), serum phosphorus was increased (p < 0.001), serum creatinine was increased (p < 0.001), and serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D, RIA] was decreased (p = 0.03). Serum PTH correlated weakly with serum calcium (r = -0.41, p < 0.003) and with serum creatinine (r = 0.35, p = 0.01). There was a weak, but significant, correlation between serum creatinine and 1,25(OH)2D3 (r = 0.33, p = 0.03). Serum levels of testosterone and dehydroapiandrosterone sulfate were decreased after CTX but did not correlate with any other parameters. There was a weak negative correlation between prednisolone daily dose and serum BGP level (r = 0.29, p = 0.06) in those patients whose prednisolone current dose was >7.5 mg/day. We conclude that: (1) the low BMD found after CTX is associated with increased bone turnover which results, in turn, from renal impairment; (2) prednisolone is involved in rapid bone loss, whereas mild secondary hyperparathyroidism may be a major contributor to disorder of bone remodeling after this rapid loss; and (3) decreased androgen levels may not be a major factor resulting in bone loss in men after CTX.
Adolescent↗
Phosphate supplementation in young men: lack of effect on calcium homeostasis and bone turnover.
OBJECTIVE: To examine the effect of phosphate supplements on calcium homeostasis and bone turnover in young men. DESIGN: Study 1 was a randomised, controlled, cross-over trial of 1000 mg elemental phosphate given for one week, with a standard diet of 800 mg/d each of calcium and phosphorus. Study 2 was an escalating dose study of 0, 1000, 1500 and 2000 mg/d elemental phosphate, each given for one week, with a standard diet of 1000 mg/d each of calcium and phosphate. SETTING: Northern General Hospital, Sheffield. SUBJECTS: Study 1, 10 healthy men ages 19-32 y. Study 2, 12 healthy men ages 19-38 y. INTERVENTIONS: Sodium acid phosphate tablets each containing 500 mg elemental phosphorus (16.1 mmol/d), given with meals. RESULTS: Study 1, administration of 32.2 mmol/d phosphorus resulted in a mean increase of 13.2 mmol/d urinary phosphorus, a mean decrease of 1.1 mmol/d urinary calcium, and a mean increase of 7 ng/mL in serum intact PTH. There were no changes in serum phosphate, osteocalcin or urinary N-telopeptide excretion. Study 2, administration of 64.4 mmol/d phosphorus resulted in a mean increase of 27.2 mmol/d urinary phosphorus, a mean decrease of 2.4 mmol/d urinary calcium, with no change in serum phosphate, PTH or urinary deoxypyridinoline. CONCLUSIONS: Phosphate supplementation of the diet does not affect bone turnover in young men.
Adult↗
A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update.
In the UK, over 250 000 patients take continuous oral glucocorticoids (GCs), yet no more than 14% receive any therapy to prevent bone loss, a major complication of GC treatment. Bone loss is rapid, particularly in the first year, and fracture risk may double. This review, based wherever possible on clinical evidence, aims to provide easy-to-use guidance with wide applicability. A treatment algorithm is presented for adults receiving GC doses of 7.5 mg day(-1) or more for 6 months or more. General measures, e.g. alternative GCs and routes of administration, and therapeutic interventions, e.g. cyclical etidronate and hormone replacement, are recommended.
Bone Resorption↗
Management of male osteoporosis: report of the UK Consensus Group.
Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation. Age-related bone loss may be a result of declining renal function, vitamin D deficiency, increased parathyroid hormone levels, low serum testosterone levels, low calcium intake and absorption. Osteoporosis can be diagnosed on the basis of radiological assessments of bone mass, or clinically when it becomes symptomatic. Various biochemical markers have been related to bone loss in healthy and osteoporotic men. Their use as diagnostic tools, however, needs further investigation. A practical approach would be to consider a bone density more than one SD below the age-matched mean value (Z < -1) as an indication for therapy. The treatment options for men with osteoporosis include agents to influence bone resorption or formation and specific therapy for any underlying pathological condition. Testosterone treatment increases BMD in hypogonadal men, and is most effective in those whose epiphyses have not closed completely. Bisphosphonates are the treatment of choice in idiopathic osteoporosis, with sodium fluoride and anabolic steroids to be used as alternatives.
Adult↗
Effects of estrogen therapy of postmenopausal women on cytokines measured in peripheral blood.
Estrogen replacement therapy (ERT) is known to prevent bone loss following the menopause, but the mechanism for this is unclear. Estrogen may suppress the secretion of certain bone-resorbing cytokines. The aim of this study was to assess the effect of ERT on the levels of cytokines measured in peripheral blood. We measured cytokines in 10 postmenopausal women (ages 56-59, 3-9 years since menopause) treated with ERT and 10 age-matched (54-59 years, 4-10 years since menopause) untreated women as controls. Samples of blood were taken and used for mononuclear cell cultures, whole blood (WB) cultures, and the separation of serum. The cultures were treated with lipopolysaccharide (LPS; 500 ng/ml) and hydrocortisone (10(-6) M). The conditioned medium from cultures and the serum were then assayed for interleukin-6 (IL-6), IL-1alpha IL-1beta, IL-1 IL-1ra, tumor necrosis factor alpha (TNF-alpha), and granulocyte macrophage colony stimulating factor (GM-CSF) by enzyme-linked immunosorbent assay. M-CSF and the soluble cytokine receptors soluble IL-6 receptor (sIL-6r) and soluble TNF receptor type 1 (sTNFr1) were also measured in serum and M-CSF in stimulated WB cultures. Measurements were corrected for mononuclear cell count. We also measured serum bone-specific alkaline phosphatase (ibAP) in all subjects. We found that LPS stimulated secretion of all cytokines both in WB and isolated cell cultures, and that this was attenuated by hydrocortisone. A significantly higher ratio of IL-1beta/IL-1ra (p = 0.02) in LPS stimulated WB cultures was seen in the untreated women. Levels of IL-1beta and IL-1alpha measured in WB cultures were lower and IL-1ra was higher in the ERT-treated group but these results were not significant. BAP was higher in the untreated group (p = 0.005) and correlated with IL-alpha/IL-1ra in the whole group (r = 0.49, p = 0.03). Results of other measurements showed no significant differences between groups. We conclude that estrogen may prevent bone loss following the menopause by altering the balance between IL-1beta and IL-1ra.
Administration, Cutaneous↗