Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.     

Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers

Urinary excretion of the bone collagen derived pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) was measured in 19 patients (4 M:15 F) with untreated thyrotoxicosis, and 20 pre-, and 20 postmenopausal women taking T4 100-200 micrograms daily for autoimmune hypothyroidism. Both PYD and DPD excretion (nanomoles per mmol creatinine) was elevated in the thyrotoxic patients compared to 287 controls; median 131 vs. 26 and 37.5 vs. 7.2, respectively, P less than 0.0001. In premenopausal women mean urinary pyridinium cross-link excretion and serum osteocalcin levels were similar in both T4-treated and matched control groups, despite suppression of serum TSH concentrations to below 0.1 mU/L in 14 of the 20 taking T4. In postmenopausal women mean (+/- 1 SE) urinary PYD excretion (nanomoles per mmol creatinine) was raised in those taking T4, relative to euthyroid controls; 40.0 +/- 2.7 vs. 32.1 +/- 2.3, P less than 0.05. DPD excretion and serum osteocalcin levels were also higher, but not significantly. When only the T4-treated women with a subnormal serum TSH were considered the difference in PYD excretion was more marked, and mean DPD excretion was also significantly elevated; 13.7 +/- 1.3 vs. 10.1 +/- 0.8, P less than 0.05. Conclusion: bone collagen breakdown is increased in thyrotoxicosis, and in postmenopausal women taking sufficient T4 to suppress serum TSH. Similarly treated premenopausal women appear to be at lower risk.     

Urinary hydroxypyridinium cross-links of collagen in primary hyperparathyroidism.

Urinary concentrations of the collagen cross-links, pyridinoline (PYD) and deoxypyridinoline (DPD), were determined in 87 patients with untreated or surgically treated primary hyperparathyroidism (PHPT). Eighty-four healthy individuals, matched for age and sex, constituted the control group for the excretion of pyridinium cross-links. In addition, a subgroup of 25 patients with PHPT was followed longitudinally for up to 2 yr after successful parathyroidectomy. Mean urinary excretion of PYD (46.8 +/- 2.7 nmol/mmol creatinine) and DPD (17.6 +/- 1.3 nmol/mmol creatinine) was significantly higher in patients with untreated PHPT than in normal subjects (P less than 0.001). In the group undergoing successful parathyroidectomy, mean urinary concentrations of PYD (34 +/- 2.5) and DPD (9.4 +/- 0.8) were similar to those in normal controls and significantly lower than those in the untreated patient population (P less than 0.001). The urinary concentration of both cross-links was significantly correlated with serum levels of both alkaline phosphatase and PTH. Mean urinary concentrations of both cross-link compounds decreased significantly within 6 months in patients followed longitudinally and as early as 2 weeks after surgery in individual patients compared to presurgical baseline values. These changes preceded the reduction in serum alkaline phosphatase and hydroxyproline by approximately 6 months. The results demonstrate that urinary hydroxypyridinium cross-links of collagen are useful indices in the clinical assessment of bone involvement in PHPT.     

Rapid suppression of bone resorption and parathyroid hormone secretion by acute oral administration of calcium in healthy adult men

Acute effects of oral calcium supplementation have been studied mainly in pre- and post-menopausal women, whereas very few data concerning men are available. We investigated the effects of 1.2 g of oral calcium administered for 4 days in 18 healthy young men. The day before the first calcium dosing (day -1) and the day of the last calcium dosing (day 4) total and ionized serum calcium and intact PTH were measured at multiple time-points up to 24 h; calcium, C-terminal telopeptide (CTX), pyridinoline (PYD) and deoxypyridinoline (DPD) were measured in urine collected every six h. On day 4, total and ionized serum calcium increased during the 6 h following oral calcium: the maximum increase over baseline was 5.04 and 7.4% respectively, occurring after 2.9 +/- 1.9 h (mean +/- SD) and 2.6 +/- 0.9 h. The AUC was significantly higher on day 4 than on day -1 for both total serum calcium (+4.6%, p<0.02) and ionized serum calcium (+9.2%, p<0.0001). Twenty-four h urinary excretion of total calcium increased significantly on day 4 (+15.1%, p<0.02), mainly as a consequence of increased excretion during the first 6 h. Serum PTH was suppressed by oral calcium, with a significant reduction of AUC on day 4 (-15.1%, p<0.05). Serum concentrations of intact PTH dropped from 26.4 +/- 9.8 pg/ml at time zero to a minimum mean value of 14.9 +/- 7.6 pg/ml at time +2 h. Bone resorption markers significantly decreased on day 4 (CTX -33.2%, p<0.001; PYD -28.5%, p<0.05; DPD -35.8%, p<0.02). Most of the effect was seen in the first 6 h after oral calcium load. These data support the concept that acute suppression of PTH and bone resorption induced by calcium administration is not gender specific and provide the rationale to further assess also in men the long-term effects of oral calcium in the prevention and treatment of osteoporosis.     

Non-invasive markers of bone turnover and plasma cytokines differ in osteoporotic patients with multiple myeloma and monoclonal gammopathies of undetermined significance

Abstract Aims: To determine whether various markers of bone turnover and/or plasma cytokines differ in patients with multiple myeloma (MM) compared with patients with monoclonal gammopathies of undetermined significance (MGUS). Methods: We studied 22 MM patients and 18 MGUS patients presenting over an 18‐month period and compared their data with those from 20 age‐ and sex‐matched patients presenting with primary osteoporosis. According to the Salmon and Durie classification, there were eight patients with stage I, nine with stage II and five with stage III disease. All patients had densitometric evidence of osteoporosis and were classified according to bone marrow evidence of plasma cell dyscrasia. Measured variables included markers of bone formation and bone resorption, and plasma cytokines. Results: Patients with MM and MGUS did not differ with respect to their mean age, male : female sex ratio, height, weight, serum calcium, 25‐hydroxyvitamin D and parathyroid hormone concentrations. Patients with MM had significantly lower concentrations of haemoglobin (109 vs 135 g/L) and serum transforming growth factor (TGF)‐β (261 vs 348 pg/mL) than patients with MGUS, and higher concentrations of serum paraproteins (31.1 vs 7.4 g/L), β2‐microglobulin (3.5 vs 2.2 g/L), % plasma cell numbers (35.3 vs 2.1%) and urinary deoxypyridinoline excretion rates (u‐DPYD; 7.7 vs 5.9 nmol/mmol creatinine; P < 0.05 for all comparisons). In multivariate analysis, the serum paraprotein (β coefficient = –0.067; 95% confidence intervals (CI), –0.019 to –0.005; P = 0.0012), u‐DPYD excretion rates (β coefficient = –0.012; 95% CI, –0.113 to –0.02; P = 0.0058) and serum TGF‐β concentrations (β coefficient = –0.002; 95% CI, –0.0002 to –0.02; P = 0.02) were the most important variables differentiating between MM and MGUS, after excluding lytic bone lesions, % plasma cell numbers and haemoglobin concentrations. Conclusions: The well‐established criteria for diagnosing MM include the presence of lytic bone lesions, plasmacytosis, haemoglobin and paraprotein concentrations. The u‐DPYD excretion rate, a sensitive non‐invasive marker of bone resorption, may help in differentiating between MM and MGUS, as well as serving as a marker of underlying bone disease activity in these patients. (Intern Med J 2001; 31: 272–278)     

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).     

Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.     

Malignancy-associated hypercalcaemia: resolution of controversies over vitamin D metabolism by a pathophysiological approach to the syndrome

OBJECTIVE Parathyroid hormone-related protein (PTHrP) is recognized as a major pathogenetic factor of humoral hypercalcaemia of malignancy but Its action on vitamin D metabolism is controversial. Our aim was to study the relation between serum 1,25-dihydroxyvitamin D and humoral activity in malignancy-associated hypercalcaemia. DESIGN Prospective, cross-sectional, single-centre study of patients with documented solid malignancles, hypercalcaemia and suppressed plasma PTH concentrations. PATIENTS AND METHODS Vitamin D metabolites, PTH, nephrogenous cyclic AMP (N-CAMP), PTHrP and biochemical parameters of calcium and bone metabolism were measured in 39 patients with solid mallgnancles and hypercalcaemia and bone scans were performed. RESULTS In 27 patients plasma PTHrP levels were elevated (69%) and in 9 patients (23%) serum 1,25-(OH)₂D concentrations were not appropriately suppressed (>92pmol/l). Patients with plasma PTHrP levels below the upper limit of normal (< 1·6 pmol/l) had lower serum 1,25-(OH)₂,D concentrations than those with elevated levels (>1 6 pmol/l) (47±6 vs 70± 7 pmol/l, respectively; P < 0·04). Serum 1,25-(OH)₂D concentrations were higher in patients with negative bone scans than In those with metastatic bone disease (80 ± 9 vs 50 ± 5 pmol/l; P < 0·01) and similar levels of plasma PTHrP. In the patients with negative bone scans there was a significant relation between plasma PTHrP and serum 1,25(OH)₂,D (r= 0·51; P < 0·03) whereas there was no such correlation in those with a positive scan. CONCLUSION Contrary to current belief, serum 1,25-(OH)₂D concentrations are not generally suppressed in humoral hypercalcaemia of malignancy and PTHrP is a determinant of these levels in the absence of demonstrable bone metastases. These findings provide further Insights into the pathophysiology of malignancy-associated hypercalcaemia and may help in the clinical management of these patients.     

Bone mineral density and metabolism in premenopausal women taking l-thyroxine replacement therapy

BACKGROUND AND OBJECTIVE Excess endogenous thyroxine causes bone loss, but the effects of exogenous thyroxine are disputed. We report on bone mass and metabolism in women taking l -thyroxine therapy. DESIGN Cross-sectional and longitudinal studies. PATIENTS Cross-sectional study: 40 healthy premenopausal women with autoimmune thyroiditis taking either physiological (serum TSH usually normal, 0·35–3·3 mU/l) or suppressive (serum TSH usually < 0·35 mu/l) doses of l -thyroxine; patients were also compared with previously acquired age and weight matched premenopausal volunteers with no history of thyroid dysfunction. Longitudinal study: 28 patients were followed-up ≥ 1 year later. MEASUREMENTS In all subjects bone mineral density (BMD) was measured at the anteroposterior lumbar spine and left hip (femoral neck, greater trochanter and Ward's area) using dual-energy X-ray absorptiometry, and physical activity assessed using the Framingham physical activity index. Serum osteocalcin (OC), PTH and vitamin D, and urinary pyridinoline and deoxypyridinoline excretion were measured in patients. RESULTS Cross-sectional study: The patient groups were well matched for disease duration and physical activity although the suppressed group were slightly younger (mean 3·1 (SD 7·5) vs 43·3 (3·9) years, P < 0·05). BMD, serum OC, PTH and vitamin D, and urinary cross-link excretion did not differ significantly between the two groups. Multivariate analysis of the whole group suggested that BMD at the femoral neck and greater trochanter was related positively to weight and physical activity and negatively to thyroxine dose (μg/kg/day) and patient age. At the lumbar spine BMD was reduced non-specifically in the presence of thyroid disease and treatment, but this effect appeared to decline with increasing duration of therapy. A similar analysis of the patient group suggested that urinary cross-link excretion correlated positively with thyroxine dose, and negatively with duration of treatment. Longitudinal study: Annualized changes in BMD were inversely related to thyroxine dose (μg/kg/day) at all sites but achieved statistical significance only at the femoral neck and Ward's area. CONCLUSION We did not find any effect of persistent historical TSH suppression on current bone mass, and this might relate to the relative insensitivity of older TSH assays. However, the cross-sectional and longitudinal data suggest that high daily doses of thyroxine In relation to patient body weight might adversely affect bone mass, particularly at the hip. These findings support the contention that excess exogenous thyroxine might predominantly deplete skeletal sites, such as the femoral neck, rich in cortical bone.     

Urinary markers of bone resorption, pyridinoline and deoxypyridinoline, are increased in sickle cell patients with further increments during painful crisis

The painful crisis is the hallmark of sickle-cell disease (SCD). Bone resorption, as part of physiological bone turnover, results in release into the circulation with subsequent urinary excretion of the collagen cross-links pyridinoline (PYD) and deoxypyridinoline (DPD). Urinary PYD and DPD concentrations could reflect the extent of bone infarction during painful sickle-cell crisis. Urinary concentrations of PYD and DPD, adjusted for urine creatinine, were measured in sickle-cell patients (38 clinically asymptomatics and 27 during painful crisis) and healthy controls (n 5 25) using high-performance liquid chromatography(HPLC). PYD and DPD concentrations were higher in asymptomatic HbSS/HbSb0-thalassemia patients compared to controls (P <0.05) with further increments during painful crisis in both HbSS/HbSb0-thalassemia and HbSC/HbSb1-thalassemia patients (P < 0.05). In the asymptomatic HbSS/HbSb0-thalassemia patients, there was a statistically significant positive correlation between DPD and hemolytic rate.Based on urinary PYD and DPD concentrations, bone degradation is increased in asymptomatic sickle-cell patients, with further increments during painful crisis. Urinary PYD and DPD concentrations are potentially diagnostic and prognostic tools in SCD.     

Discrepant influence of vitamin D status on parathyroid hormone and bone mass after two years of calcium supplementation

Objective To investigate the influence of vitamin D status on parathyroid hormone and bone mass after a 2‐year supplementation of calcium alone. Patients and Methods Randomized, double‐blind, placebo‐controlled clinical trial, in healthy postmenopausal women without osteoporosis: three hundred and thirty‐six subjects aged 60–97 years were studied and randomized to receive elemental calcium 500 mg/day (n = 175) or placebo (n = 161) for 2 years. Measurements Changes in parathyroid hormone (PTH) and bone mineral density (BMD) from baseline and vitamin D status. Values are presented as means ± SD. Results After 2 years, subjects with calcium supplementation had significant decrease in plasma PTH level (4·4 ± 1·7 vs 4·7 ± 1·9 pmol/l, P < 0·01), improved lumbar BMD (1·031 ± 0·12 vs 1·004 ± 0·12 g/cm², P < 0·001) and total hip BMD (0·890 ± 0·10 vs 0·883 ± 0·10 g/cm², P < 0·001) without change in femoral neck BMD. In the placebo group, PTH level significantly increased (4·8 ± 1·6 vs 4·5 ± 1·5 pmol/l, P < 0·001), lumbar BMD slightly increased (1·027 ± 0·14 vs 1·018 ± 0·14 g/cm², P < 0·001), total hip and femoral neck BMD decreased (0·876 ± 0·11 vs 0·887 ± 0·11 g/cm², P < 0·001 and 0·783 ± 0·10 vs 0·798 ± 0·10 g/cm², P < 0·001, respectively). When subjects were classified according to baseline 25‐hydroxyvitamin D [25(OH)D] levels into those with 25(OH)D in the lower tertile (lowVitD) and those in the middle and upper tertiles combined (normVitD). The degree of PTH suppression after calcium supplementation was significantly higher in the normVitD compared to the lowVitD groups (?5·6 ± 26·7%vs 1·3 ± 27·2%, P < 0·05). No effect of vitamin D status on the change in lumbar BMD after calcium supplementation was demonstrated. Despite the higher suppression of PTH, there was a slight decrease in femoral neck BMD after calcium supplementation in the normVitD group while femoral neck BMD was more or less maintained in the lowVitD group (?0·6 ± 3·2%vs 0·5 ± 2·9%, P < 0·05). Conclusion Calcium supplementation appears to affect femoral bone mass less in Thai postmenopausal women with adequate vitamin D status, despite higher suppression of PTH.     

Analysis of the contribution of dydrogesterone to bone turnover changes in postmenopausal women commencing hormone replacement therapy

Although gestagens have been reported to influence bone metabolism, whether these contribute to the beneficial effects of hormone replacement therapy (HRT) on the skeleton of postmenopausal women is currently unclear. To address this question, we compared changes in bone turnover markers after commencing HRT in 26 postmenopausal women randomized to receive 8 weeks of treatment with 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily. Serum and second morning void urine samples were obtained at baseline (twice) and after 1, 2, 4, and 8 weeks. Serum estradiol was measured by RIA, urinary total deoxypyridinoline (DPD) excretion by high pressure liquid chromatography, and serum osteocalcin and C-terminal procollagen peptide by enzyme-linked immunosorbent assay. The increase in serum estradiol after treatment with estradiol alone was slightly, but significantly, greater than that in the combination group (P = 0.04). Although estradiol suppressed urinary DPD excretion to a greater extent when given alone (P = 0.02), osteocalcin levels were significantly higher in this group than in women receiving combination therapy (P = 0.04). To assess the effect of dydrogesterone on the balance between formation and resorption in more detail, we subsequently compared the ratio between formation and resorption markers in the two treatment groups. We found that osteocalcin/DPD and C-terminal procollagen peptide/DPD ratios were significantly higher in women treated with estradiol alone (P < 0.0001 and P = 0.002, respectively), suggesting that dydrogesterone may reduce formation relative to resorption. These results suggest that gestagens may reduce estrogen's beneficial effects on the skeleton of postmenopausal women, as assessed over the first 8 weeks of replacement therapy.     

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism

BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls. SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary. MEASUREMENTS Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol. RESULTS Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1 vs 5.3 ± 0.1 mmol/l, P = 0.0001; 291 ± 46 vs 448 ± 48 μmol/l, P = 0.015; 78 ± 8 vs 136 ± 24 μmol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154 vs 1593 ± 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 ± 8 vs 161 ± 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 ± 5.1 vs 74.6 ± 19.6 mU/l h, P = 0.008). CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.     

Acute effects of etidronate on glucocorticoid-induced bone degradation

OBJECTIVES: To study the acute short-term effects on the biochemical parameters of calcium and bone homeostasis in post-menopausal women treated with a high dose of prednisone alone or with additional etidronate, before and during 5 days of treatment. METHODS: Serum calcium, phosphorus, creatinine, alkaline phosphatase activity, osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), parathyroid hormone (PTH), 25-hydroxyvitamin D and urinary excretion of calcium over 24 h were measured before and during 5 days of treatment in 14 post-menopausal women treated with a high dose of prednisone (60 mg/day) alone (group A) or combined with cyclical etidronate (group B). RESULTS: Significant differences from baseline were found in osteocalcin and urinary excretion of calcium in both groups and for ICTP in group B. Significant differences between groups were calculated at day 5 of the study for osteocalcin, ICTP and 24 h urine calcium excretion (P < 0.01). Urinary excretion of calcium over 24 h increased in group A (+14.7%; P < 0.05) and decreased in group B (-22.1%; P < 0.01). Osteocalcin levels decreased in group A (- 38.1%) and increased in group B (+27.4%; both P < 0.01). ICTP decreased only in group B (-19.4%; P < 0.01). CONCLUSIONS: The results are consistent with the fact that etidronate is acutely able to prevent bone resorption due to corticosteroids. The increase in osteocalcin in the etidronate-treated group is a new feature. A direct or indirect (PTH, 1,25 vitamin D?) stimulatory effect of etidronate on the osteoblast cannot be excluded.     

Bone metabolism in male patients with type 2 diabetes

Few reports are available on bone turnover in type 2 diabetes. Impaired bone turnover in type 2 diabetes appears to result from decreased bone formation. Studies also suggest that poor glycaemic control in type 2 diabetes may contribute to osteopaenia. The aim of this study was to investigate biochemical markers of bone turnover in males with poorly controlled type 2 diabetes and look for correlations with glycaemic control and gonadal and hypophyseal hormonal axis. Consecutive male patients with poorly controlled type 2 diabetes and attending the internal medicine department during a period of 6 months were enrolled. The patients were receiving oral hypoglycaemic agents (metformin or sulphonylureas or both). None of the patients had any evidence of macroangiopathy, nephropathy or neuropathy. Only two patients had proliferative retinopathy. Serum osteocalcin, crosslaps (C-telopeptide, CTx), parathyroid hormone (PTH), testosterone, oestrogen, prolactin, follicle-stimulating hormone (FSH) and luteinising hormone (LH) were measured in 35 patients and 35 controls. The mean age of the study population was 53.7 (10.3) years (range: 50.2–57.3) and the mean disease duration was 8.6 (6.0) years (range: 6.5–10.7). No differences between patients and controls were observed in serum calcium, phosphorus, creatinine, albumin, PTH, CTx, oestrogen, testosterone, LH, FSH, prolactin and urinary calcium. Patients had lower serum levels of osteocalcin than controls with a significant statistical difference [15.3 (4.1) vs 18.3 (5.3), p=0.012]. There was a negative significant statistical correlation between CTx levels and HbA1c (r=–0.41, p< 0.05). Our study suggested that bone formation is altered in type 2 diabetes and that bone turnover is affected by glycaemic control status.     

Erosive disease associated with higher bone resorption and lower bone density in women with rheumatoid arthritis

Objective: To evaluate the bone density and bone metabolism in women with rheumatoid arthritis (RA), focusing on disease activity, joint erosion, and RA‐epitope. Methods: Disease activity was assessed using erythrocyte sedimentation rate, C‐reactive protein, rheumatoid factor, Ritchie articular index (RAI), and disease activity score (DAS). The presence of joint erosion was assessed using wrist‐hand and feet X‐ray, and wrist‐hand magnetc resonance imaging. A fasting metabolic bone study was done including serum calcium, phosphate, 25(OH) vitamin D, parathyroid hormone (PTH), alkaline phosphatase (ALP), osteocalcin, and urine deoxypyridinoline/creatinine (DPD/Cr) ratio. Bone mineral density (BMD) was measured at hip, spine, distal forearm, hand, and total body using dual energy X‐ray absorptiometry (DEXA) machine. HLA‐DRB1 genes were examined using DNA sequencing based typing. Results: Seventy‐six women with RA according to 1987 American College of Rheumatology (ACR) criteria with clinical onset equal to or less than 5 years were examined. Mean (SD) of age was 55.4 (13.7) years, disease duration 34.9 (36.4) months, and 96% with ACR functional criteria class I and II. HLA typing demonstrated that 61.4% of them have the RA shared‐epitope (QRRAA or QKRAA or RRRAA) in their HLA‐DRB1 alleles. Most of them had been receiving disease‐modifying antirheumatic drugs and glucocorticoid. Erosive disease was significantly correlated with intertrochanter BMD (P = 0.044), serum calcium (P = 0.005), and urine DPD/Cr ratio (P < 0.001). Patients with erosive disease had higher DAS (P = 0.017), lower serum calcium (P = 0.006), and higher urine DPD/Cr ratio (P < 0.001). There were no statistically significant differences in serum ALP, osteocalcin, 25(OH) vitamin D, and PTH. Patients with erosive disease had lower BMD at all sites including hip, forearm, hand, lumbar spine, and total body, though only statistically significant at intertrochanter (P = 0.042). Bivariate correlation demonstrated that at all sites BMD, except femoral neck and hand BMD, negatively correlated with urine DPD/Cr ratio. Logistic regression model showed that erosive disease was a significant factor for low bone density (T‐score < ?1) at intertrochanter (OR = 6.0; 95% CI = 1.3–27.3; P = 0.020), total hip (OR = 5.5; 95% CI = 1.1–26.8; P = 0.035), and distal radius‐ulna (OR = 3.9; 95% CI = 1.1–14.0; P = 0.041). Conclusion: Patients with erosive disease demonstrated lower BMD, lower serum calcium level, and higher bone resorption. Erosive disease was a significant factor for osteopenia or osteoporosis.     

Impact of vitamin D-related serum PTH reference values on the diagnosis of mild primary hyperparathyroidism, using bivariate calcium/PTH reference regions

Background, objective An international consensus conference underlined the importance of defining upper parathyroid hormone (PTH) reference values based on 25‐OH‐vitamin D [25(OH)D] to diagnose mild primary hyperparathyroidism. We determined the importance of this factor in a Belgian population. Design, patients, methods Intact PTH and 25(OH)D were measured in 261 healthy controls (18–65 years, winter/summer). They were classified as 25(OH)D replete (50–153 nmol/l; n = 129) or deplete (8–50 nmol/l; n = 132). PTH was determined in 49 patients with surgically proven primary hyperparathyroidism. PTH thresholds for 95% specificities and corresponding sensitivities were computed from both 25(OH)D replete and deplete receiver operating characteristic (ROC) curves. The 95% bivariate reference ellipses, relating PTH to calcium for 25(OH)D replete and deplete controls, were compared to the PTH/calcium pairs of patients with primary hyperparathyroidism. Results Parathyroid hormone correlated with 25(OH)D (r = ?0·3232; P < 0·0001). PTH normative values were 20% lower in 25(OH)D replete than deplete controls (P < 0·0001). PTH thresholds, providing 95% specificities for primary hyperparathyroidism diagnosis, were 7·6 pmol/l and 5·8 pmol/l, using ROC curves derived from 25(OH)D deplete or replete controls, respectively. Corresponding sensitivities were of 56%vs 88%, respectively (P < 0·05). The 95% PTH/calcium bivariate reference ellipses for?deplete and replete 25(OH)D controls differed, but the PTH/calcium pairs of patients with primary hyperparathyroidism did not overlap these ellipses. Conclusion For a given specificity, primary hyperparathyroidism diagnostic parathyroid hormone thresholds were lower and sensitivities higher using ROC curves, derived from 25(OH)D replete vs deplete controls. The 25(OH)D status does not affect the efficiency of primary hyperparathyroidism diagnosis, using bivariate PTH/calcium reference density ellipses.     

Metabolic bone disease of liver cirrhosis: Is it parallel to the clinical severity of cirrhosis?

Metabolic bone disease has long been recognized in chronic liver disease, especially cholestatic or alcoholic liver diseases. The aim of the present study was to investigate the prevalence and severity of osteodystrophy in cirrhotic men and the correlation of its incidence with the clinical severity of cirrhosis in an endemic area of post-necrotic hepatitis. We measured serum levels of osteocalcin, 25-hydroxyvitamin D, parathyroid hormone mid-molecule, calcium and testosterone in 74 cirrhotic men (Child-Pugh's classification grade A n= 30, B n= 21 and C n= 23) and 16 healthy controls. Standard X-rays and bone mineral densities of lumbar spine were performed in 30 patients with post-necrotic cirrhosis and 10 healthy controls. Serum levels of osteocalcin, parathyroid hormone and testosterone were significantly lower in patients with cirrhosis than in controls. Changes paralleling an increased severity of cirrhosis were found in the serum levels of 25–hydroxyvitamin D and testosterone, but not in the serum levels of osteocalcin and parathyroid hormone. The lumbar bone mineral density was significantly lower in patients with post-necrotic cirrhosis than in controls (0.97 ± 0.13 vs 1.07±0.12 g/cm², P<0.05) and was correlated with serum 25–hydroxyvitamin D levels (r = 0.467; P<0.005). There was no correlation between the bone mineral density and serum osteocalcin or the clinical severity of cirrhosis. The prevalence of spinal osteoporosis, as defined by a lumbar bone mineral density greater than two standard deviations below the mean value of the controls, was 20% in cirrhotic patients compared with 10% in controls. Two (6.7%) patients (both grade C) had spinal compression fractures compared with none in the control group. In conclusion, serum osteocalcin and lumbar bone mineral density were significantly lower in cirrhotic men than in controls. However, they were not correlated with each other or the clinical severity of cirrhosis.     

Bone turnover in asthmatic children treated with oral prednisolone or inhaled budesonide

Biochemical markers of bone turnover were studied in prepubertal school children with asthma in two randomized double-blind crossover trials with run-in, treatment, and wash-out periods of 2 weeks. One group (n = 11) was treated with 2.5 and 5.0 mg prednisolone, the other (n = 14) with 200 and 800 μg inhaled budesonide per day. Serum osteocalcin, serum total alkaline phosphatase, fasting urinary excretion of hydroxyproline and calcium, serum 25-hydroxyvitamin D, and 1,25 dihydroxyvitamin D were assessed. A dose-related reduction of serum osteocalcin (Page's test for trend: P = 0.04; z = ?2.3) and of the fasting urinary hydroxypro1ine:creatinine ratio (Page's test for trend: P = 0.05; z = ?2.0) was found in the children who were treated with prednisolone. Inhaled budesonide was not associated with statistically significant effects on any of the biochemical markers. Short-term treatment with low daily doses of prednisolone may cause a suppression of bone turnover in children with asthma. To reduce the risk of adverse effects on bone turnover, doses of inhaled budesonide up to 800 μg daily may be preferable to low doses of prednisolone. Bone turnover remains to be evaluated during long-term treatment. Pediatr Pulmonol. 1993; 16:341–346. © 1993 Wiley-Liss, Inc.