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L. Cancela, P. J. Marie, N. Le Boulch, and L. Miravet


Mineral, hormonal and skeletal changes were determined in vitamin D-deficient (−D) and vitamin Dreplete (+D) mother rats and in their litters on day 20 of lactation. These results were compared with those obtained in −D mothers and pups, after giving the mothers an oral supplement (10 i.u. vitamin D3/day) during the period of lactation (20 days). Compared to +D animals, both −D lactating mothers and their pups exhibited extremely low plasma levels of 25-hydroxyvitamin D3 (25-OH-D3), diminished 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and increased levels of immunoreactive parathyroid hormone (iPTH). Vitamin D-deficient mothers also had higher levels of calcitonin and lower levels of prolactin than +D mothers. All − D animals (mothers and pups) showed increased osteoclastic bone resorption and severe osteomalacia as shown by decreased bone ash, decreased calcification rate and increased endosteal osteoid surface, volume and thickness. In mothers treated with vitamin D3 during lactation, nearly all the plasma variables measured, as well as bone histomorphometric features, were normal. In contrast, their pups still showed rickets and osteomalacia, despite normal levels of 25-OH-D3 and calcium in the plasma. These pups had raised plasma levels of 1,25(OH)2D3 and iPTH associated with persistent stimulation of bone resorption. This study showed that (1) severe vitamin D deficiency in lactating rats produced marked osteomalacia and secondary hyperparathyroidism in both mothers and pups, and (2) vitamin D treatment of − D mother rats during lactation (10 i.u. vitamin D3/day) reversed the mineral, hormonal and skeletal abnormalities in mothers but not in pups.

J. Endocr. (1985) 105, 303–309

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J H Tobias, A Gallagher, and T J Chambers


Although short-term administration of oestradiol-17β (OE2) stimulates cancellous bone formation in the rat, this is replaced by a tendency to suppression after prolonged treatment. Hence, in rats rendered osteopaenic by ovariectomy, OE2 administration fails either to induce a sustained increase in bone formation or to restore bone volume. A possible explanation for this failure is that OE2 also inhibits bone resorption, secondarily suppressing bone formation through coupling mechanisms. We therefore investigated whether the effects of OE2 treatment might be modified by intermittently stimulating bone resorption with retinoic acid (120mg/kg daily) for 4 out of every 20 days. We found, in a preliminary experiment using intact animals, that intermittent retinoic acid reduced cancellous bone volume, consistent with previously documented stimulation of bone resorption by retinoic acid. Rats were then rendered osteopaenic by ovariectomy, and given vehicle, retinoic acid and/or OE2. We found that animals treated with intermittent retinoic acid and OE2 showed a substantial increase in cancellous bone volume compared with ovariectomized animals treated with vehicle, retinoic acid alone or OE2 alone. Therefore, intermittent retinoic acid appears to cause a net increase in bone formation over resorption when given to ovariectomized animals in conjunction with OE2. We conclude that the effects of OE2 on cancellous bone are modified by intermittent treatment with retinoic acid, resulting in a substantial increase in bone volume.

Journal of Endocrinology (1994) 142, 61–67

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T. J. Allain and A. M. McGregor


There is immense current interest in the effects of thyroid hormones on bone. This is largely due to concern that patients on thyroxine replacement therapy are at increased risk of developing osteoporosis; this concern follows a number of reports describing reduced bone mineral density in this group of patients. The issue is, however, uncertain and the purpose of this review is (i) to summarize what is known about the effects of thyroid hormones on bone at both an experimental and clinical level and (ii) to try to reach a greater understanding of the problem and its implications for patient management.

Bone biology

Bone remodelling requires the tightly coupled actions of osteoclasts and osteoblasts. A normal bone remodelling cycle takes approximately 200 days. Each cycle begins with activation of cells which become osteoclasts and start resorbing bone. This phase lasts for about 50 days and is terminated

Free access

Patricia Forcinito, Anenisia C Andrade, Gabriela P Finkielstain, Jeffrey Baron, Ola Nilsson, and Julian C Lui

The mammalian growth plate undergoes programed senescence during juvenile life, causing skeletal growth to slow with age. We previously found that hypothyroidism in rats slowed both growth plate chondrocyte proliferation and growth plate senescence, suggesting that senescence is not dependent on age per se but rather on chondrocyte proliferation. However, one alternative explanation is that the observed slowing of growth plate senescence is a specific consequence of hypothyroidism. We reasoned that, if delayed senescence is a general consequence of growth inhibition, rather than a specific result of hypothyroidism, then senescence would also be slowed by other growth-inhibiting conditions. In this study, we therefore used tryptophan deficiency to temporarily inhibit growth in newborn rats for 4 weeks. We then allowed the animals to recover and studied the effects on growth plate senescence. We found that structural, functional, and molecular markers of growth plate senescence were delayed by prior tryptophan deficiency, indicating that the developmental program of senescence had occurred more slowly during the period of growth inhibition. Taken together with previous studies in hypothyroid rats, our findings support the hypothesis that delayed senescence is a general consequence of growth inhibition and hence that growth plate senescence is not simply a function of time per se but rather depends on growth.

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Filip Callewaert, Mieke Sinnesael, Evelien Gielen, Steven Boonen, and Dirk Vanderschueren

Structural gender differences in bone mass – characterized by wider but not thicker bones – are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. GH–IGF1 action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-α or -β (ERα or ERβ) following aromatization into estrogens. Both the AR and ERα pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERα-mediated effects in males may – at least partly – depend on interaction with IGF1. In addition, sex hormones and their receptors have an impact on the mechanical sensitivity of the growing skeleton. AR and ERβ signaling may limit the osteogenic response to loading in males and females respectively, while ERα may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between the sexes, but depends on gender differences in GH–IGF1 and mechanical sensitivity to loading as well.

Free access

I Suponitzky and M Weinreb

Prostaglandin E2 (PGE2) has been shown to possess anabolic properties when administered systemically. All the experiments performed so far examined long bones from animals of varying age and bone status. In this study we compared the changes in bone mass of long bones (femur, tibia and humerus) to those in calvariae after a 3-week daily administration of 6 mg/kg PGE2 into 3-week-old rats. This regimen inhibited body weight gain (by 14.1%) as well as longitudinal growth of long bones (by 2.2-3.5%) but increased their mass. Ash weight (measuring both cancellous and compact bone) increased by 10.1-14.1% but tibial cancellous bone area was elevated by 54%. Radial growth was slightly reduced due to transient inhibition of mineral apposition rate at the periosteal envelope but the expansion of the marrow cavity was inhibited to a greater extent, resulting in an 8.1% increase in the relative compact bone area. The increased bone mass was associated with greater mechanical strength of the femoral neck (24.2% increase in fracture load and 19% in stiffness). In contrast, PGE2 administration did not affect calvarial thickness or mineral apposition rate but increased its density, i.e. reduced the area of marrow spaces due to stimulation of endocortical bone formation at this site. The pattern of bone mass changes documented in this study closely correlates with that of the induced expression of early-response genes following a single dose of PGE2 as we recently reported. These data, therefore, support the hypothesis that in vivo administration of an anabolic dose of PGE2 increases bone formation and augments bone mass largely by stimulating the recruitment of new osteoblasts via induction of the proliferation and/or differentiation of bone marrow osteogenic precursors.

Free access

Russell T Turner, Kenneth A Philbrick, Carmen P Wong, Dawn A Olson, Adam J Branscum, and Urszula T Iwaniec

Leptin-deficient ob/ob mice are morbidly obese and exhibit low total bone mass and mild osteopetrosis. In order to disassociate the skeletal effects of leptin deficiency from those associated with morbid obesity, we evaluated bone mass, architecture, gene expression, and indices of bone turnover in WT mice, ob/ob mice allowed to feed ad libitum (ob/ob), and ob/ob mice pair-fed equivalent to WT mice (pair-fed ob/ob). Mice were maintained at 32 °C (thermoneutral) from 6 to 18 weeks of age to minimize differences in resting energy expenditure. ob/ob mice were heavier, had more abdominal white adipose tissue (WAT), and were hyperglycemic compared with WT mice. Femur length, bone mineral content (BMC) and bone mineral density, and midshaft femur cortical thickness were lower in ob/ob mice than in WT mice. Cancellous bone volume (BV) fraction was higher but indices of bone formation and resorption were lower in ob/ob mice compared with WT mice; reduced bone resorption in ob/ob mice resulted in pathological retention of calcified cartilage. Pair-fed ob/ob mice were lighter and had lower WAT, uterine weight, and serum glucose than ob/ob mice. Similarly, femoral length, BMC, and cortical thickness were lower in pair-fed ob/ob mice compared with ob/ob mice, as were indices of cancellous bone formation and resorption. In contrast, bone marrow adiposity, calcified cartilage, and cancellous BV fraction were higher at one or more cancellous sites in pair-fed ob/ob mice compared with ob/ob mice. These findings indicate that the skeletal abnormalities caused by leptin deficiency are markedly attenuated in morbidly obese ob/ob mice.

Open access

J Jeyabalan, M Shah, B Viollet, J P Roux, P Chavassieux, M Korbonits, and C Chenu

AMP-activated protein kinase (AMPK) is a key regulator of cellular and body energy homeostasis. We previously demonstrated that AMPK activation in osteoblasts increases in vitro bone formation while deletion of the Ampk α 1 (Prkaa1) subunit, the dominant catalytic subunit expressed in bone, leads to decreased bone mass in vivo. To investigate the cause of low bone mass in the Ampkα1 −/− mice, we analysed bone formation and resorption in the tibia of these mice by dynamic histomorphometry and determined whether bone turnover can be stimulated in the absence of the Ampkα1 subunit. We subjected 12-week-old Ampkα1 + / + and Ampkα1 −/− mice to ovariectomy (OVX), intermittent PTH (iPTH) administration (80 μg/kg per day, 5 days/week) or both OVX and iPTH hormonal challenges. Tibiae were harvested from these mice and bone micro-architecture was determined by micro-computed tomography. We show for the first time that Ampkα1 −/− mice have a high bone turnover at the basal level in favour of bone resorption. While both Ampkα1 + / + and Ampkα1 −/− mice lost bone mass after OVX, the bone loss in Ampkα1 −/− mice was lower compared with controls. iPTH increased trabecular and cortical bone indexes in both ovariectomised Ampkα1 + / + and Ampkα1 −/− mice. However, ovariectomised Ampkα1 −/− mice showed a smaller increase in bone parameters in response to iPTH compared with Ampkα1 + / + mice. By contrast, non-ovariectomised Ampkα1 −/− mice responded better to iPTH treatment than non-ovariectomised Ampkα1 + / + mice. Overall, these data demonstrate that Ampkα1 −/− mice are less affected by changes in bone turnover induced by OVX but respond better to the anabolic challenge induced by iPTH. These results suggest that AMPKα1 activation may play a role in the hormonal regulation of bone remodelling.

Free access

Julian C Lui

The resting zone houses a group of slowly proliferating ‘reserve’ chondrocytes and has long been speculated to serve as the stem cell niche of the postnatal growth plate. But are these resting chondrocytes bona fide stem cells? Recent technological advances in lineage tracing and next-generation sequencing have finally allowed researchers to answer this question. Several recent studies have also shed light into the signaling pathways and molecular mechanisms involved in the maintenance of resting chondrocytes, thus providing us with important new insights into the role of the resting zone in the paracrine and endocrine regulation of childhood bone growth.

Free access

Michela Rossi, Giulia Battafarano, Viviana De Martino, Alfredo Scillitani, Salvatore Minisola, and Andrea Del Fattore

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati–Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.