Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats

doi:10.1016/S0169-6009(08)80057-8

Bone and Mineral

Volume 26, Issue 2, 1994, Pages 123-131

Bone and Mineral

https://doi.org/10.1016/S0169-6009(08)80057-8 Get rights and content

Abstract

Bone loss during androgen deficiency has been associated with accelerated bone turnover and imbalance between bone formation and resorption but the relative increase of both phenomena is not well described. Serum osteocalcin as marker of bone formation and urinary excretion of pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone resorption were measured in both orchidectomized (ORCH, n = 8) and sham-operated (SHAM, n = 8) aged (12-month-old) male rats from 2 days before until 66 days after surgery. PYD and DPD were significantly higher in the ORCH group compared to the SHAM group starting from 21 days after surgery until the end of the experiment. Serum osteocalcin was only significantly increased in the ORCH group at 30 and 40 days. The maximal increase of serum osteocalcin was also smaller than the increase in PYD and DPD (30% versus 74% and 112%, respectively). The two markers of bone resorption were correlated with osteocalcin (r = 0.63 for PYD and r = 0.71 for DPD). Based on these results, we conclude that (1) bone resorption, as measured by PYD and DPD, increased during androgen deficiency; (2) moreover, the increase of bone resorption, as measured by DPD and PYD, was followed by a more moderate increase in bone formation as measured by serum osteocalcin, supporting the hypothesis that androgen deficiency causes accelerated bone turnover and imbalance between bone resorption and bone formation.

References (24)

SP Robins et al.
Pyridinium crosslinks of bone collagen and their location in peptides isolated from rat femur
Biochem Biophys Acta
(1987)
D Uebelhart et al.
Urinary excretion of Pyridinium crosslinks: A new marker of bone resorption in metabolic bone disease
Bone Miner
(1990)
JP Brown et al.
Serum bone Gla-protein: a specific marker for bone formation in postmenopausal osteoporosis
Lancet
(1984)
D Fujimoto et al.
The structure of pyridinoline, a collagen crosslink
Biochem Biophys Res Commun
(1978)
SM Seyedin et al.
Immunoassay for urinary pyridinoline: the new marker of bone resorption
J Bone Miner Res
(1993)
MJ Seibel et al.
Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis
J Bone Miner Res
(1993)
D Black et al.
Excretion of pyridinium cross-links of collagen in ovariec-tomized rats as urinary markers for increased bone resorption
Calcif Tissue Int
(1989)
JJ Stefan et al.
Castrated men exhibit bone loss: Effect on calcitonin treatment on biochemical indices of bone remodeling
J Clin Endocrinol Metab
(1989)
D Goldray et al.
Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist Decapeptyl
J Clin Endocrinol
(1993)
D Vanderschueren et al.
Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency
Endocrinology
(1992)

GK Wakley et al.

Androgen treatment prevents cancellous ostepenia in the orchidectomized rat

J Bone Miner Res

(1991)

F Ismail et al.

Serum bone Gla protein and the vitamin D endocrine system in the oophorectomized rat

Endocrinology

(1988)

Cited by (52)

Androgens and Skeletal Biology: Basic Mechanisms
2013, Osteoporosis: Fourth Edition
The obvious impact of the menopause on skeletal health has focused much of the research describing the general action of gonadal steroids on the specific effects of estrogen in bone. However, androgens clearly have important beneficial effects, in both men and women, on skeletal development and on the maintenance of bone mass. Thus it has been demonstrated that androgens (a) influence growth plate maturation and closure helping to determine longitudinal bone growth during development, (b) mediate regulation of trabecular (cancellous) and cortical bone mass in a fashion distinct from estrogen, leading to a sexually dimorphic skeleton, (c) modulate peak bone mass acquisition, and (d) inhibit bone loss. In castrated animals, replacement with nonaromatizable androgens (e.g., 5α-dihydrotestosterone (DHT)) yields beneficial effects that are clearly distinct from those observed with estrogen replacement. In intact females, blockade of the androgen receptor (AR) with the specific AR antagonist hydroxyflutamide results in osteopenia. Furthermore, treatment with nonaromatizable androgen alone in females results in improvements in bone mineral density (BMD). Finally, combination therapy with estrogen and androgen in postmenopausal women is more beneficial than either steroid alone, indicating complementary but nonparallel and distinct pathways of action. Combined, these reports illustrate the distinct actions of androgens and estrogens on the skeleton. Thus, in both men and women it is probable that androgens and estrogens each have important yet distinct functions during bone development, and in the subsequent maintenance of skeletal homeostasis. As is clear from the osteopenia that develops after androgen deprivation therapy (ADT) used for the treatment of prostate cancer and with the loss of sex steroids in older men, androgen signaling is important for bone health in the adult and during aging. With the awareness of the importance of the effects of androgen on skeletal homeostasis, and the potential to make use of this information for the treatment of bone disorders, much remains to be learned.
Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes
2012, Bone
Citation Excerpt :
High turnover is also observed in humans immediately after menopause or gonadectomy [25]. In both humans and rodents, turnover rates decline with time [21–23,26]. In the therapeutic-LT arm, the response to therapy is evaluated after turnover has declined.
Androgen receptor (AR) is expressed throughout the osteoblast lineage. Two different AR transgenic families (AR2.3-tg and AR3.6-tg mice) demonstrating overlapping and distinct expression profiles were employed to assess the effects of enhanced androgen sensitivity to ameliorate hypogonadal loss. Two different paradigms of steroid replacement following orchidectomy (ORX) were used as either preventative or therapeutic therapy. ORX was performed in male wild-type (WT), AR2.3-tg and AR3.6-tg mice at 5 months with immediate DHT replacement (prevention, higher turnover) or at 3 months with DHT treatment delayed for 2 months (therapeutic, lower turnover), both with treatment for the last 6 weeks. Dual energy X-ray absorptiometry (DXA), micro-computed tomography (μCT), and histomorphometry were performed. In the prevention model, ORX significantly reduced BMD and BMC in all genotypes compared to sham and DHT was effective at prevention of osteopenia. In the therapeutic model, all genotypes became osteopenic compared to sham, but after a prolonged hypogonadal period, delayed DHT treatment provided little benefit. μCT analysis of mid-shaft total bone in all genotypes generally showed reductions after ORX. Delayed DHT was ineffective at restoring bone volume in any genotype whereas immediate treatment prevented loss only in AR transgenic mice. Cortical thickness also decreased with ORX but immediate DHT treatment was effective to increase thickness only in WT mice, likely due to expansion of marrow volume in both AR-tg lines. In metabolically highly active cancellous bone, ORX resulted in lower bone volume/tissue volume (BV/TV) in all genotypes, consistent among 3 sites measured. Again with delayed treatment, there was little effect of DHT to restore BV/TV, but when administered at the time of ORX, DHT completely prevented the decrease in cancellous bone in all genotypes. Improvement in cancellous bone architecture was seen with immediate DHT replacement that was enhanced in AR transgenic lines compared to WT. In contrast, there were only modest changes in all genotypes using the delayed treatment paradigm. With ORX in both paradigms, trabecular number was decreased while spacing increased. Thus, androgen therapy is effective for the prevention of endosteal and cancellous osteopenia primarily through its anti-resorptive properties, but shows little anabolic action as a therapeutic strategy to restore bone. Given the similarity in response to androgen treatment in both AR transgenic lines, overlapping expression profiles suggest that the target cells mediating androgen action in vivo are mature osteoblast/osteocytes. Combined, these results demonstrate that in the adult mouse, androgen treatment can reduce bone resorption but has little overall anabolic activity.
Androgens and Bone: Basic Aspects
2010, Osteoporosis in Men
The specific mechanisms by which androgens affect skeletal homeostasis, and whether these effects are directly mediated in bone, are areas of intensified research. As a classic steroid hormone, the biological cellular signaling responses to androgen are mediated through the androgen receptor (AR), a ligand-inducible transcription factor. ARs have been identified in a variety of cells found in bone and the characterization of AR expression in these cells thus clearly identifies bone as a target tissue for androgen action. The direct effects of androgen that influence the complex processes of proliferation, differentiation, mineralization and gene expression in the osteoblast are being characterized, but much remains to be established. Androgen effects on bone may also be indirectly modulated and/or mediated by other autocrine and paracrine factors in the bone microenvironment. This chapter reviews recent progress on the characterization of androgen action in bone.
Androgens and Bone: Basic Aspects. Basic Aspects.
2009, Osteoporosis in Men: The Effects of Gender on Skeletal Health
The specific mechanisms by which androgens affect skeletal homeostasis, and whether these effects are directly mediated in bone, are areas of intensified research. As a classic steroid hormone, the biological cellular signaling responses to androgen are mediated through the androgen receptor (AR), a ligand-inducible transcription factor. ARs have been identified in a variety of cells found in bone and the characterization of AR expression in these cells thus clearly identifies bone as a target tissue for androgen action. The direct effects of androgen that influence the complex processes of proliferation, differentiation, mineralization and gene expression in the osteoblast are being characterized, but much remains to be established. Androgen effects on bone may also be indirectly modulated and/or mediated by other autocrine and paracrine factors in the bone microenvironment. This chapter reviews recent progress on the characterization of androgen action in bone.
Physical activity in the androgen receptor knockout mouse: Evidence for reversal of androgen deficiency on cancellous bone
2009, Biochemical and Biophysical Research Communications
Citation Excerpt :
Serum osteocalcin was measured by an in-house radioimmunoassay (RIA) [20]. Urinary collagen cross-links (deoxypyridinoline [DPD]) were measured by high-performance liquid chromatography (HPLC) with fluorescence detection after acid hydrolysis [21]. The concentration of DPD was corrected for creatinine excretion, which was measured colorimetrically.
Disruption of the androgen receptor (AR) in male mice reduces cortical bone expansion and muscle mass during puberty and results in high bone turnover-related cancellous osteopenia. We hypothesized that voluntary wheel running during growth is able to rescue the effects of AR disruption on bone. To this end, 5-week-old AR knockout (ARKO) mice were randomized to a running group (cage with running wheel) and a sedentary group (cage without wheel) and followed-up until 16 weeks of age. Voluntary wheel running in ARKO mice did not influence body weight, muscle mass or periosteal bone expansion. Interestingly, voluntary running significantly reduced bone turnover in ARKO mice and prevented cancellous bone loss due to a preservation of trabecular number. Thus, voluntary running in ARKO mice was able to reduce cancellous bone resorption, suggesting that sustained exercise may potentially compensate the effects of androgen disruption on cancellous bone.
Androgens and Skeletal Biology: Basic Mechanisms
2008, Osteoporosis, Two-Volume Set

View all citing articles on Scopus

View full text

Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats

Abstract

Biochem Biophys Acta

Bone Miner

Lancet

The structure of pyridinoline, a collagen crosslink

Biochem Biophys Res Commun

Immunoassay for urinary pyridinoline: the new marker of bone resorption

J Bone Miner Res

Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis

J Bone Miner Res

Excretion of pyridinium cross-links of collagen in ovariec-tomized rats as urinary markers for increased bone resorption

Calcif Tissue Int

Castrated men exhibit bone loss: Effect on calcitonin treatment on biochemical indices of bone remodeling

J Clin Endocrinol Metab

Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist Decapeptyl

J Clin Endocrinol

Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency

Endocrinology

Androgen treatment prevents cancellous ostepenia in the orchidectomized rat

J Bone Miner Res

Serum bone Gla protein and the vitamin D endocrine system in the oophorectomized rat

Endocrinology