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Recovery from osteoporosis through skeletal growth: early bone mass acquisition has little effect on adult bone density¹

RACHEL I. GAFNI², EDWARD F. MCCARTHY^*, TRACY HATCHER^*, JODI L. MEYERS, NOZOMU INOUE, CHITRA REDDY, MARTINA WEISE, KEVIN M. BARNES, VERONICA ABAD and JEFFREY BARON

Unit on Growth and Development, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA;
^* Bone Histomorphometry Laboratory, Department of Pathology, and
Orthopaedic Biomechanics Laboratory, Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, Maryland, USA

²Correspondence: National Institutes of Health, Bldg. 10, Room 10N262, 10 Center Dr. MSC 1862, Bethesda, MD 20892-1862, USA. E-mail: gafnir{at}mail.nih.gov

SPECIFIC AIMS

It is often assumed that bone mineral accretion should be optimized throughout childhood to maximize peak bone mass. In contrast, we hypothesized that bone mineral acquisition early in life would have little or no effect on adult bone mass because many areas of the juvenile skeleton are replaced in toto through skeletal growth.

PRINCIPAL FINDINGS

1. Glucocorticoid excess induces osteoporosis in cortical and trabecular bone in young rabbits
We administered subcutaneous (s.c.) dexamethasone (0.5 mg·kg^-1·day^-1) to male New Zealand white rabbits beginning at 5 wk of age. This supraphysiologic dose of glucocorticoid induced severe osteoporosis. Tibial dry bone density (dry weight/volume), bone mineral density (ash weight/volume) (Fig. 1 , time=0), and strength (resistance to 3 point bending) were markedly diminished at the end of the 5 wk treatment period compared with untreated controls. In treated animals, histomorphometry demonstrated significantly diminished bone volume in the epiphyseal and metaphyseal trabecular bone and decreased cortical thickness in the metaphyseal and diaphyseal cortex (Fig. 2 A).

View larger version (21K): [in this window] [in a new window]   Figure 1. Tibial dry bone density (dry weight/volume, A) and bone mineral density (ash weight/volume, B) after stopping dexamethasone treatment (mean±SE). Five-wk-old rabbits received dexamethasone (0.5 mg·kg-1·day-1) s.c. for 5 wk, then were allowed to recover for 0–16 wk. Open circles, control animals (n=8 per time point); filled circles, dexamethasone-treated animals (n=7–8 per time point). After dissection, tibial volume was measured by underwater weighing. Tibias were dehydrated and defatted to determine dry weight, then ashed for 24 h in a furnace to ascertain ash weight.

View larger version (57K): [in this window] [in a new window]   Figure 2. Photomicrographs of the distal femur at the end of dexamethasone treatment (A) and 16 wk (B) after stopping dexamethasone. Five-wk-old rabbits received dexamethasone (0.5 mg·kg-1·day-1) s.c. for 5 wk and were allowed to recover. Untreated animals served as controls. Longitudinal coronal sections were stained with Goldner’s Trichrome. Scale bar, 3 mm. C) Photomicrograph of the femoral diaphyseal cortex 16 wk after stopping dexamethasone. During recovery, all animals received weekly injections of oxytetracycline to label newly formed bone. Diaphyseal cross sections were examined by fluorescence microscopy. The periosteal surface is at the upper edge and the endosteal surface at the lower edge of the sections. Arrows indicate oxytetracycline-labeled fluorescent bone formed after stopping dexamethasone. Scale bar, 300 µm. D) Photomicrograph of the distal femoral epiphyseal trabeculae 16 wk after stopping dexamethasone. Unstained sections were examined by fluorescence microscopy. The section from a dexamethasone-treated animal contains only labeled bone, indicating that all bone was formed after the dexamethasone was discontinued. b, bone tissue; m, marrow. Scale bar, 200 µm.

2. Release from glucocorticoid excess results in complete recovery of osteoporosis in young rabbits
After dexamethasone treatment was discontinued, rabbits were allowed to recover for 0–16 wk. Tibial dry bone density (dry weight/volume) and bone mineral density (ash weight/volume) recovered completely as the animals approached near-final size (Fig. 1) . Resistance to 3 point bending was not significantly different among groups after 16 wk of recovery.

3. Recovery from juvenile osteoporosis in the metaphyseal trabecular and cortical bone occurs through endochondral skeletal growth
After dexamethasone treatment was stopped, computer-assisted histomorphometry demonstrated that the metaphyseal trabecular bone density and metaphyseal cortical thickness recovered (Fig. 2B ). Oxytetracycline labeling indicated that the osteoporotic bone formed during dexamethasone treatment was resorbed as the medullary cavity enlarged and was replaced with new bone formed by endochondral ossification at the growth plate. Thus, recovery from osteoporosis was not due to the repair of preexisting bone (remodeling), but rather to replacement through longitudinal bone growth (modeling).

4. Recovery from osteoporosis in the diaphyseal cortex is due to increased periosteal bone formation
At the end of treatment, animals given glucocorticoid had decreased diaphyseal cortical width compared with controls whereas the marrow diameter was unaffected. Thus, glucocorticoid excess did not cause thinning of the cortex by stimulating endosteal bone resorption but by inhibiting periosteal bone formation.

After dexamethasone was stopped, measurement of oxytetracycline-labeled cortex revealed that the diaphyseal cortical width recovered due to an increased rate of periosteal bone formation (Fig. 2C ). Therefore, as in the metaphysis, the diaphyseal osteoporosis recovered through skeletal growth, but the mechanism differed in the two regions. Recovery of metaphyseal osteoporosis involved replacement of osteoporotic bone with qualitatively normal bone whereas recovery of diaphyseal cortex involved a quantitative increase in the rate of bone formation. This increased periosteal growth may be an example of a general phenomenon, termed catch-up growth, in which increased growth follows the release from growth inhibition.

5. Recovery from osteoporosis in the epiphyseal trabecular bone is due to increased mineral apposition rate
After glucocorticoid was discontinued, the osteoporotic epiphyseal trabecular bone was replaced with new bone and recovered (Fig. 2B ). Computer-assisted histomorphometry using oxytetracycline labeling demonstrated that the mineral apposition rate was significantly greater in animals previously treated with dexamethasone, suggesting that a mechanism similar to catch-up growth contributed to recovery in this region also (Fig. 2D ).

CONCLUSIONS

Bone mass increases during childhood, peaks in late adolescence or early adulthood, then may decrease with age, sometimes eventuating in osteoporosis. Individuals who attain a higher peak bone mass may be at decreased risk for the development of osteoporosis later in life. Therefore, it is often assumed that bone mass acquisition should be optimized throughout childhood to maximize peak bone mass. Our results, however, suggest that alterations in bone mass acquisition during early childhood may have little effect on peak bone density.

Our findings appear to contradict many studies showing that altered bone mass acquisition in early life does influence adult bone density. For example, retrospective clinical studies suggest that physical activity, calcium intake, and cranial irradiation during childhood and adolescence affect adult bone mass. Similarly, prospective animal studies indicate that calcium intake throughout growth influences peak bone mass in rats and rabbits. The commonality among these studies is that they involve prolonged and uninterrupted environmental conditions or, in the case of cranial irradiation, may have resulted in a permanent alteration in hormonal milieu. Therefore, these studies do not distinguish between factors present in early childhood and those present in adolescence, the years immediately preceding attainment of peak bone mass. Nevertheless, it has been suggested that any intervention during childhood that either increases or decreases bone mass acquisition, even temporarily, may change the genetically predetermined bone phenotype and result in an altered peak bone mass.

The findings in our study challenge this concept. We have shown that a period of altered bone mass acquisition in early life may not result in an altered peak bone mass. This principle may also apply to humans. In children, significant recovery from osteoporosis occurs after treatment for Grave’s disease, juvenile arthritis, Crohn’s disease, leukemia, and Cushing’s syndrome. In these cases, the patients experienced either complete cure or total remission of their underlying disease before the completion of growth. Conversely, calcium supplementation during childhood can increase bone mineral acquisition but, after the supplementation is discontinued, the juvenile skeleton has the tendency to return to its genetically determined trajectory toward peak bone mass. This reversibility has been attributed to a rebound in the rate of bone remodeling.

The present study demonstrates an additional mechanism underlying this phenomenon. Many areas of the juvenile skeleton are not just remodeled but actually replaced in toto through skeletal growth. As a juvenile bone enlarges and the medullary cavity expands, bone formed early in life, regardless of quality, is gradually resorbed and replaced by new bone through modeling (Fig. 3 ). In addition, the catch-up growth that occurs after transient growth inhibition also contributes to the normalization of bone mass. Therefore, perturbations in bone mass acquisition are not reversed solely by remodeling but by a combination of modeling and remodeling.

View larger version (38K): [in this window] [in a new window]   Figure 3. Schematic diagram representing the replacement of juvenile bone through skeletal growth. As the bone enlarges, new bone (black) is created by endochondral bone formation at the growth plate and periosteal bone formation at the cortex. As the marrow cavity expands, the juvenile bone (gray) is largely resorbed. Areas surrounded by dotted lines represent juvenile bone that has been resorbed.

If these findings generalize to humans, then bone mass acquisition in early childhood may not influence peak bone mass. Public health efforts to prevent osteoporosis emphasize calcium intake, weight-bearing exercise, and limiting anti-bone therapies, such as glucocorticoid use, during the growing years. However, our findings suggest that such interventions during early childhood, although they might have other benefits, may not affect adult bone density.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0640fje; to cite this article, use FASEB J. (March 26, 2002) 10.1096/fj.01-0640fje

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