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Erik Fink Eriksen, Kim Brixen and Peder Charles

Bone remodeling constitutes the life-long renewal process of bone whereby the mechanical integrity of the skeleton is preserved. It implies the continuous removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). Moreover, bone remodeling is an integral part of the calcium homeostatic system together with the kidneys and the gut. The ever ongoing removal of old bone by osteoclastic resorption and subsequent coupled osteoblastic formation of new bone leads to liberation of calcium and matrix constituents into the serum. The matrix constituents liberated into the blood during bone resorption can be used as markers of bone resorption in serum or urine and components liberated during osteoblastic matrix synthesis are putative markers of bone formation.

Extensive research over the last 10 years has characterized a wide variety of new markers of cellular activity in bone (Table 1). Serum and urine levels of these

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Jens Bollerslev, Sian Thomas, Ellen Grodum, Kim Brixen and Ole Djøseland

Bollerslev J, Thomas S, Grodum E, Brixen K, Djøseland 0. Collagen metabolism in two types of autosomal dominant osteopetrosis during stimulation with thyroid hormones. Eur J Endocrinol 1995;133:557–63. ISSN 0804–4643

In order to investigate collagen metabolism in two different types of autosomal dominant osteopetrosis (ADO), eight patients with type I (aged 23–61 years, mean 40.4 years) and nine patients with type II ADO (aged 20–49 years, mean 32.8 years) were compared with ten normal controls (aged 22–54 years, mean 35.4 years). The subjects were treated with 100 μg of triiodothyronine (T3) daily for 7 days and followed for a total of 4 weeks. Serum T3 increased in all subjects and a corresponding suppression of thyroid-stimulating hormone (TSH) was observed. Serum carboxy-terminal propeptide of type I collagen (S-PICP) in the control and type I groups showed no difference at baseline, whereas type II was lower than controls (p < 0.01). No significant alterations following stimulation were observed in any of the groups. Serum BGP (osteocalcin) values in the two patient groups were insignificantly lower than controls both at baseline and throughout the study. Following stimulation, a significant response was seen in the three groups (p < 0.001). The increases during the treatment period (delta values) for controls, type I and type II were 47.6% (p < 0.01), 51.7% (p = 0.05) and 34.8% (NS), respectively, with no difference between the groups. Serum bone-specific alkaline phosphatase (S-ALP) was not different between the groups and no alterations were observed in relation to treatment. The serum N-terminal propeptide of type III collagen (S-PIIINP) showed no difference at baseline between type I and controls but was significantly higher (p < 0.003) in type II than in the controls. After stimulation, significant responses were observed in all three groups (p < 0.001). Serum PIIINP increased following 1 week of treatment by 64% (p < 0.01), 41% (p < 0.02) and 18% (NS), respectively. Serum carboxy-terminal telopeptide of type I collagen (SICTP) did not differ between type I and controls at baseline but was increased in type II (p < 0.04), as it was throughout the observation period (p < 0.12 and p < 0.02). A significant response was observed in the three groups following stimulation. The delta values were 69% (p = 0.005), 56% (p < 0.02) and 34% (p < 0.02), respectively. The urinary hydroxyproline (OHP)/creatinine ratio did not differ between the groups either at baseline or following stimulation. A significant response (p < 0.001) was observed, with delta values of 44.2% (p < 0.06), 35.9% (p < 0.04) and 34.3% (p < 0.01), respectively. The two bone resorptive markers (S-ICTP and OHP/creatinine ratio) were correlated significantly at baseline for all three groups. It is concluded that collagen metabolism is disturbed in type II ADO, which might reflect an increased turnover of extra-osseous collagen. Because ICTP levels are increased in disorders with increased extra-osseous collagen turnover, we question the suitability of this parameter as a sensitive marker of bone resorption.

Jens Bollerslev, Department of Medical Endocrinology, National University Hospital, N-0027 Oslo, Norway

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Henning Kaspersen Nielsen, Peter Laurberg, Kim Brixen and Leif Mosekilde

Abstract.

Serum osteocalcin varies in a diurnal rhythm, with peak values during the night and minimum levels before noon, but the factors controlling this rhythm are unknown. In this study, we evaluated the temporal relations between the osteocalcin rhythm and variations in serum concentrations of cortisol, intact parathyroid hormone (PTH(1-84)), and ionized calcium (Ca2+) in 15 normal volunteers, aged 22-46 years. Serum cortisol varied in a typical way preceding inverse changes in serum osteocalcin by about 4 h (r=0.78, p<0.0001). Changes in serum osteocalcin following the early morning increase in serum cortisol were statistically indistinguishable from the changes seen after oral administration of 2.5 or 10 mg of prednisone. Serum PTH (1-84) showed a diurnal rhythm (p<0.01) with peak values (4.06±0.42 pmol/l) at 20.30 h and nadir (2.81±0.10 pmol/l) around 10.30 h, preceding changes in serum osteocalcin in the same direction by 5 h (r=0.55, p<0.02). Prednisone at a dose of 10 mg did not change the time course significantly. Serum Ca2+ varied in an almost bi-phasic pattern (p<0.01) with maximal mean levels around 16.30 and 09.30 h and minimal levels around 05.30 and 14.30 h. Serum Ca2+ correlated inversely with PTH (1-84) (r=0.53, p<0.01), and serum osteocalcin was inversely related to Ca2+ at concurrent time points (r=0.59, p<0.005). Prednisone caused a 2-3 h lasting increase in serum Ca2+ 3-5 h after ingestion (p<0.001). In conclusion, our results suggest that cortisol is strongly associated to the diurnal rhythm in serum osteocalcin. The biological relevance of the reported relation between serum osteocalcin and PTH (1-84) and serum Ca2+ is uncertain.

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Steen B Pedersen, Jens D Børglum, Kim Brixen and Bjørn Richelsen

Pedersen SB, Borglum JD, Brixen K, Richelsen B. Relationship between sex hormones, body composition and metabolic risk parameters in premenopausal women. Eur J Endocrinol 1995;133: 200–6. ISSN 0804–4643

The metabolic complications associated with obesity are dependent upon the degree of obesity and the distribution of adipose tissue. In order to evaluate the associations between sex hormone status, metabolic risk parameters, obesity and distribution of adipose tissue, 25 premenopausal women with a wide range of body mass index (19.3–48.1 kg/m2 were studied. Body composition was determined by dual-energy x-ray absorptiometry scan and anthropometric measurements; in addition, lipid and sex hormone status were determined and an oral glucose tolerance test was performed. We found that sex hormone-binding globulin was correlated negatively with total fat mass (r = –0.77, p < 0.001) and especially with abdominal localization of adipose tissue (r = –0.85, p < 0.001). Free testosterone was correlated positively with total fat mass (r = 0.40, p < 0.05) and with abdominal fat accumulation (r = 0.64, p < 0.001). Free estrogen was correlated negatively with total amount of adipose tissue (r = –0.40, p < 0.05) but not with the distribution of adipose tissue, Finally, total fatness, abdominal localization of adipose tissue and free testosterone were all associated with elevated metabolic risk factors. However, multiple regression analysis revealed that only abdominal localization of adipose tissue was independently associated with a higher risk profile, whereas the effects of sex hormones or total fatness disappeared when abdominal localization of adipose tissue was included in the analysis. In conclusion, these findings in premenopausal women indicate that the connection between sex hormones and metabolic risk factors might be indirect, probably operating through alterations in the amount of adipose tissue in the abdominal region.

SB Pedersen, University Clinic of Endocrinology and Internal Medicine, Aarthus, Amtssygehus, Tage Hansensgade, DK-8000 Aarhus C, Denmark

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Jens Bollerslev, Kim Henriksen, Morten Frost Nielsen, Kim Brixen and Wim Van Hul

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Torben Leo Nielsen, Claus Hagen, Kristian Wraae, Lise Bathum, Rasmus Larsen, Kim Brixen and Marianne Andersen

Background

The number of CAG repeats (CAGn) within the CAG repeat polymorphism of the androgen receptor gene correlates inversely with the transactivation of the receptor.

Objective

To examine the impact of CAGn on muscle, fat distribution, and circulating androgen levels.

Design, settings and participants

Population-based, cross-sectional study of 783 Danish men aged 20–29 years.

Methods

Genotyping was performed in 767 men. Areas of thigh and lower trunk muscle (musclethigh and musclelower trunk), subcutaneous adipose tissues (SATthigh and SATlower trunk), and deep adipose tissues (i.m. and visceral) were measured in 393 men by magnetic resonance imaging (MRI). Lean body mass (LBM) and fat mass (FM) were measured in all men by whole body dual-energy X-ray absorptiometry (DEXA). The absolute areas acquired by MRI were the main outcomes. The absolute DEXA measurements and relative assessments of both modalities were considered as the secondary outcomes.

Results

CAGn (range: 10–32) correlated inversely with absolute musclethigh (r=−0.108), absolute musclelower trunk (r=−0.132), relative musclethigh (r=−0.128), relative musclelower trunk (r=−0.126), relative LBMlower extremity (r=−0.108), and relative LBMtotal (r=−0.082), and positively with relative SATthigh (r=0.137), relative SATlower trunk (r=0.188), relative FMlower extremity (r=0.107), and relative FMtotal (r=0.082). These relationships remained significant, controlling for physical activity, smoking, chronic disease, and age. CAGn did not correlate with any circulating androgen.

Conclusions

The CAG repeat polymorphism affects body composition in young men: absolute musclethigh and absolute musclelower trunk increase as CAGn decreases. Expressed relatively, muscle areas and LBM increase, while SAT and FM decrease as CAGn decreases. The polymorphism does not affect deep adipose tissues or circulating androgen levels in young men.

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Henning K Nielsen, Bente Pedersen, Kim Brixen, Ronald Dahl and Peder Charles

A single dose of 2.5 mg prednisone leads to a significant transient decrease in serum osteocalcin, which is only demonstrated by frequent serum sampling. The aim of the present study was to evaluate whether a single dose of inhaled beclomethasone dipropionate causes transient changes in serum osteocalcin, indicating a systemic effect on bone cells. In a double-blind, placebo controlled, cross-over design we evaluated the effects of single doses of 250 μg and 1000 μg beclomethasone on the circadian rhythm in serum osteocalcin. Fifteen normal subjects aged 2 3-38 years were studied twice with an interval of one week with hourly blood sampling from 16.30 until 1 7.00 the following day; 1000 μg beclomethasone, but not 250 μg, suppressed serum cortisol by 14.4±6.7% (p=0.03). Neither of the beclomethasone doses significantly altered the time pattern of serum osteocalcin. We conclude that a single inhaled dose of beclomethasone in the therapeutical range does not acutely influence osteoblastic activity as judged from serial measurements of serum osteocalcin.

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Kim Brixen, Henning K Nielsen, Roger Bouillon, Allan Flyvbjerg and Leif Mosekilde

We measured changes in serum insulin-like growth factor-1 (IGF-1), calcitriol, parathyroid hormone (PTH), thyroid hormones, insulin, and plasma glucagon in response to seven days of treatment with a pharmacological dosage of recombinant human growth hormone (r-hGH) (0.1 IU/kg sc twice daily) or placebo in 20 normal male volunteers to evaluate whether the effect of r-hGH on biochemical bone markers could be attributed to changes in these hormones. Serum IGF-1 (p<0.001) and vitamin D-binding protein (p<0.001) increased steadily during treatment returning to baseline at day 14. Total calcitriol (p<0.01) and free calcitriol index (p<0.001) increased transiently at day 4. Furthermore, serum insulin (p<0.001) and both total (p<0.001) and free triiodothyronine (p<0.02) increased during treatment, while serum PTH and plasma glucagon remained unchanged. In conclusion, pharmacological doses of r-hGH increased not only IGF-1 but also free-calcitriol index, insulin, and free T3. The increase in these hormones may be co-responsible for some of the observed effects of r-hGH on bone turnover and calcium homeostasis.

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Signe Engkjær Christensen, Peter H Nissen, Peter Vestergaard, Lene Heickendorff, Lars Rejnmark, Kim Brixen and Leif Mosekilde

Introduction

Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign, inherited condition caused by inactivating mutations in the calcium-sensing receptor (CASR) gene. Both FHH and primary hyperparathyroidism (PHPT) are characterized by elevated P-calcium, normal or elevated plasma-parathyroid hormone (P-PTH), and typically normal renal function. In PHPT, vitamin D metabolism is typically characterized by low plasma levels of 25-hydroxyvitamin D (25OHD), and high plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D). In FHH, the vitamin D metabolism is not very well known.

Objective

To compare and evaluate plasma 25OHD, 1,25(OH)2D, and PTH in FHH and PHPT.

Design

Cross-sectional study.

Materials

About 66 FHH patients with mutations in the CASR gene, 147 patients with surgically verified PHPT, and 46 controls matched to FHH patients according to age (±5 years), sex, and season. All patients had a P-creatinine <140 μmol/l.

Methods

We measured P-calcium, P-Ca2 +, P-albumin, P-creatinine, P-phosphate, P-magnesium, and P-PTH by standard laboratory methods. P-25OHD and P-1,25(OH)2D were measured by RIA or enzyme immunoassay. In FHH, all protein-coding exons in the CASR gene were sequenced and aligned to GenBank reference sequence .

Results

PHPT patients had higher body mass index (2p<0.01), together with higher P-PTH (2p<0.01) and P-1,25(OH)2D (2p<0.01) compared with FHH patients. The groups had similar levels of P-Ca2 + and of P-25OHD. The phenotypic expression of the CASR mutations (as determined by the degree of hypercalcemia) did not influence the levels of P-1,25(OH)2D.

Conclusion

Even though P-calcium and P-25OHD were comparable, P-1,25(OH)2D and P-PTH differed between FHH and PHPT.

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Signe Sparre Beck-Nielsen, Bendt Brock-Jacobsen, Jeppe Gram, Kim Brixen and Tina Kold Jensen

Objective

To estimate the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets.

Design

Population-based retrospective cohort study based on a review of medical records.

Methods

Patients aged 0–14.9 years referred to or discharged from hospitals in southern Denmark from 1985 to 2005 with a diagnosis of rickets were identified by register search, and their medical records were retrieved. Patients fulfilling the diagnostic criteria of primary rickets were included.

Results

We identified 112 patients with nutritional rickets of whom 74% were immigrants. From 1995 to 2005, the average incidence of nutritional rickets in children aged 0–14.9 and 0–2.9 years was 2.9 and 5.8 per 100 000 per year respectively. Among immigrant children born in Denmark, the average incidence was 60 (0–14.9 years) per 100 000 per year. Ethnic Danish children were only diagnosed in early childhood and the average incidence in the age group 0–2.9 years declined from 5.0 to 2.0 per 100 000 per year during 1985–1994 to 1995–2005. Sixteen cases of hereditary rickets were diagnosed during the study period giving an average incidence of 4.3 per 100 000 (0–0.9 years) per year. The prevalence of hypophosphatemic rickets and vitamin D-dependent rickets type 1 was 4.8 and 0.4 per 100 000 (0–14.9 years) respectively.

Conclusions

Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high. Hereditary rickets is the most common cause of rickets in ethnic Danish children, but nutritional rickets is most frequent among all young children.