Word count: 1810



Word count: 1810

Bone Density and Inactivity

P. Bergmann1, A. Schoutens2

Cliniques Universitaires de l’Université Libre de Bruxelles

1 Laboratoire de Médecine Expérimentale, Hôpital Brugmann

Recipient of a grant from the Fonds de la Recherche Scientifique Belge (n° 9.4544.92).

2 Service de Médecine Nucléaire, Hôpital Erasme

Brussels, Belgium

Physical activity is necessary for the maintenance of bone integrity (1). Loss of bone has been observed in man in different situations of inactivity.

At one extreme are paraplegic patients, who have completely lost the use of the legs. Bone mineral density is decreased by 30 to 50% after one year in the paralyzed areas (figure 1). The loss is faster in areas of trabecular bone, with a higher turnover rate, than in compact bone. Bone loss is particularly important in the epiphyseal subchondral area on each side of the knee (figure 2). Cortical atrophy, when present, makes its first appearance in the subperiosteal region, which is also the site most responsive to exercise (6). Loss has the same amplitude in patients who develop spasticity and muscle contractures, and have conservation of muscle mass, as in patients who remain flaccid, showing that normal strains, not merely muscle activity is necessary for skeletal integrity.

A decreased bone mass or a negative calcium balance, reflected by an increased calciuria, have also been observed in peripheral palsy and in hemiplegia, during bed rest (2) , in patients immobilized in a cast , and in weightlessness. Eventually, sedentarity could be a risk factor for the development of low bone density and osteoporotic fractures. Conversely, many studies show that physical activity can lead to increased bone density (see review, 4). It seems also that ovariectomized women receiving estrogen therapy who follow a weight training program develop a higher bone mass than those who are on estrogens alone, suggesting a synergistic action of sex hormones and exercise on bone (5). It is less clear if exercise alone could partly prevent bone loss induced by estrogen deficiency.

Several animal models have been used to study the phenomenon of disuse osteoporosis, the most common of which being sciatic neurectomy or tenectomy. Rats have also been rendered paraplegic and submitted to weightlessness or simulated weightlessness by tail suspension (1). All those rat models are characterized by the loss of bone (decreased trabecular volume; decreased cortical surface and thickness; increased cortical porosity). At the opposite, animals submitted to physical training have a higher bone density than their untrained pairs.

Mechanism Of Bone Loss

The skeleton is continuously remodeled by osteoclastic resorption (removal of microscopical bone volumes by large multinucleated cells) followed by osteoblastic formation (matrix and mineral deposition in the previously formed resorption cavity). Bone loss is the result of an imbalance of these two processes, and occurs when the amount of bone deposited by osteoblasts does not exactly replace that removed by osteoclasts; resorption and formation can both be normal, increased or even decreased.

An interesting model to study experimentally the effect of loading and unloading on bone is the functionally isolated externally loadable avian ulna developed by C.T. Rubin and L.E. Lanyon in the turkey (6): with insufficient loading, the authors observed a bone loss of circa 10%, achieved by an increase in the number of active remodeling units which caused cortical thinning by endosteal resorption and increased cortical porosity; the daily application of load cycles greater than 1000 µstrain resulted in new bone being deposited, predominantly on the periosteal surface.

Histomorphometric data in paraplegics show an increase in bone resorption surfaces and a decrease in bone formation (4). This change in bone metabolism is reflected by serum and urine measurements of the biological parameters of bone turn-over: after a spinal cord section, hydroxyprolinuria, a marker of bone resorption, is high; osteocalcin, a parameter of osteoblastic activity, is low when measured soon after the paralysis. The decrease in bone formation is however transient: even in the absence of any gain in motricity, serum osteocalcin increases with time in paraplegic patients, so as calcium accretion rate in paralyzed areas, an index of bone mineralization rate.

An increase in bone resorption with or without decreased bone formation has been confirmed in rat models of disuse. However, in some recent rat studies on the effect of space flight, the increase in resorption is absent, though there is a huge decrease in bone formation (10).

Variable degrees of increased resorption and decreased formation could both result from a functional alteration of osteoblastic cells and osteoblasts precursors: osteoblastic cells from animals submitted to disuse are characterized by less proliferation in vitro (3) and by decreased protein synthesis (9). The increase in resorption could result from an osteoblastic signal, as it is known that osteoblast is the central cell controlling bone turnover in other situations.

Determinants Of Bone Loss

Systemic hormones do not appear to play a major role in the development of disuse osteoporosis. Physical exercise can decrease slightly serum parathyroid hormone concentration while increasing calcitonin. The effect is very small, and its causal relationship with modifications of bone mass or bone turnover has not been proven. After a spinal cord injury resulting in paraplegia, intact parathyroid hormone, the main resorptive stimulator, is low, so as 1,25 dihydroxyvitamin D. Low concentrations of these two hormones could in part account for a decreased bone formation. In some conditions, PTH is an anabolic hormone for bone; the effect of PTH fragments injection on bone loss caused by disuse has not been studied. It has been shown in the tail suspended rat model that 1,25 dihydroxyvitamin D replacement did not alter the evolution of bone mass. Sex hormones (and probably corticosteroids) could modulate the response to unloading, particularly in determining the pattern of bone loss.

However, most probably, the control of bone density by physical strain is mainly local. Indeed, embryonic bone shafts in culture, thus in the absence of systemic hormone regulation, respond with an osteogenic response to mechanical loading. Some hypotheses related to the local control of bone remodeling and bone balance by mechanical strain have been reviewed recently by Rodan (7). Briefly, bone lining cells (osteocytes and resting osteoblasts) could be triggered by bone surface deformation through attachment transmembrane proteins interacting with their cytoskeleton and with stretch sensitive ion channels. This triggering could result in the activation of the osteoblastic proliferation and activity, in the modulation of the secretion by these cells of factors which regulate locally resorption (prostaglandins E2, interleukins) and bone formation (prostaglandins, growth factors) and/or interfere with their response to some of these factors. Systemic hormones, acting on the same target cells, could modulate these events.

Recovery

Only few studies have addressed the question of the recovery of bone mass after activity is resumed in immobilized patients or in subjects submitted to weightlessness. Leblanc et al have shown that during the six months following reambulation, normal subjects recovered from the bone loss observed at different sites of their skeleton (lumbar spine, trochanter, tibia, calcaneum, pelvis) after 17 weeks of bed rest (2). However, this recovery was incomplete at most sites studied; the pelvis and calcaneum were the only sites where bone mineral density was the same at the end of the study as before bed rest. Conversely, no gain at all was observed in the femoral neck six months after reambulation. These authors observed, as others, a large biological variability in the response to immobilization and to the resuming of activity. Though further studies are clearly needed on this important question of bone mass recovery after prolonged immobilization periods, it can be expected that, alike as in bone loss resulting from metabolic disease (i.e. primary hyperparathyroidism), osteopenia due to inactivity will be in part irreversible.

Summary and Conclusions

Complete suppression of loading results in severe bone loss in man and in animal models. An increased physical activity can increase bone mass in some conditions, but the effect is small, and dependent of the presence of systemic factors like estrogens. During inactivity, bone loss results from an imbalance between bone formation and resorption, due to a decreased bone formation, in the presence, at least in some models, of an increased resorption. Physical inactivity exerts its effects both through systemic regulators of calcium metabolism and by modulating locally bone formation and resorption. Systemic and local factors probably interact at the effector level. The respective weight of systemic and local control is not completely understood at this time, but local control is probably most important. Recovery of bone mass occurs when normal activity is resumed but could be still incomplete in the long run.

References

1. Globus, R.K., D.D. Bikle, and E. Morey-Holton The temporal response of bone to unloading. Endocrinology 118: 733-742, 1986.

2. Leblanc, A.D., V.S. Schneider, H.J. Evans, D.A. Engelbreton, and J.M. Krebs. Bone mineral loss and recovery after 17 weeks bed rest. J Bone Miner Res. 5: 843-850, 1990.

3. Machwate, M., E. Zerath, X. Holly, et al. Skeletal unloading in rat decreases proliferation of rat bone and marrow derived osteoblastic cells Am J Physiol 264: E790-E799, 1993.

4. Minaire, P., P. Meunier, C. Edouard, J. Bernard, P. Courpron, J. Bourret. Quantitative histologic data on disuse osteoporosis: Comparison with biological data. Calcif. Tissue Res. 17: 57-73, 1974.

5. Notelowitz, M., D. Martin, R. Tesar, F.Y. Khan, C. Probart, C. Fields, and L. McKenzie. Estrogen therapy and variable-resistance weight training increase bone mineral in surgically menopausal women. J. Bone Miner. Res. 6: 583- 590, 1991.

6. Pead, M.J., Skerry, T.M., and L.E. Lanyon. Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. J. Bone Miner. Res. 3: 647-656, 1988.

7. Rodan, G.A. Mechanical loading, estrogen deficiency, and the coupling of bone formation to resorption J Bone Miner Res 6, 527-530, 1991.

8. Schoutens, A., E. Laurent, and J.R. Poortmans. Effects of inactivity and exercise on bone Sports & Medicine 7: 71-81, 1989.

9. Wakley, G.K. and R.T. Turner. Space flight decreases formation of cancellous bone in rat humeri. J Bone Miner Res 8: S 152, 1993.

10. Wakley, G.K., J.S. Portwood, R.T. Turner. Disuse osteoporosis is accompanied by down regulation of gene expression for bone proteins in growing rats. Am J Physiol 263: E1029-1034, 1992.

11. Wolff, J. The classic. Concerning the interrelationship between form and function of individual parts of the organism. Clin. Orthop. 228: 2-11, 1988.

Legends Of Figures:

Figure 1: Evolution of the bone mineral density (BMD) in the legs of paraplegic patients who do not resume spontaneous activity during one year following spinal injury. Bone loss is linear during the study period and attains 30% of the initial BMD at one year. (Data from Wilmet et al., Centre de Traumatologie et de Revalidation de l’Université Libre de Bruxelles, with permission).

Figure 2: X-ray of the knees of a paraplegic patient, showing severe osteoporosis of the upper tibial metaphysis.

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