Abstract
The net amount of bone lost during aging is determined by the difference between the amount of bone removed from the endocortical, trabecular and intracortical components of its endosteal (inner) envelope and formed beneath its periosteal (outer) envelope. Endosteal bone loss is determined by the remodeling rate (number of basic multicellular units, BMUs) and the negative balance (the difference between the volumes of bone resorbed and formed in each BMU). Bone loss already occurs in young adult women and men and is probably due to a decline in the volume of bone formed in each BMU. The rate of loss is slow because the remodeling rate is low in young adulthood. Bone loss accelerates in women at menopause because remodeling intensity increases and BMU balance becomes more negative as estrogen deficiency reduces osteoblast lifespan and increases osteoclast lifespan. The high remodeling rate also reduces the mineral content of bone tissue. The negative BMU balance results in trabecular thinning, disappearance and loss of connectivity, cortical thinning and increased intracortical porosity. These changes compromise the material and structural properties of bone while concurrent age-related subperiosteal bone formation increases the cross-sectional area (CSA) of bone partly offsetting endosteal bone loss and the loss of structural and material strength. Thus, treatments aimed at reducing the progression of bone fragility, and reversing it, should reduce activation frequency and so reduce the number of remodeling sites, reduce osteoclastic resorption in the BMU, and so reduce the volume of bone resorbed on each of the three components of the endosteal surface thereby reducing the progression of trabecular thinning, loss of connectivity, cortical thinning and porosity. If treatment also increases periosteal bone formation, the CSA of the whole bone and its cortical area will increase. If treatment also increases endosteal bone formation in the BMU, bone balance will be less negative, especially if resorption depth is reduced. This may produce thickening of trabeculae provided activation frequency is not too low. If treatment can increase de novo bone formation at quiescent endosteal surfaces, this will increase cortical and trabecular thickness, and reduce intracortical porosity. In this way, drugs directed at both the resorptive and formative aspects of remodeling, and bone modeling may (i) increase compressive and bending strength of cortical bone by increasing the diameter of the whole bone, its CSA and the distance the cortical mass is placed from the neutral long bone axis; (ii) maintain or increase peak compressive stress and peak strain in trabecular bone, preventing microcracks and buckling; and (iii) increase the material density of bone tissue, an effect that probably should not be permitted to reach a level which reduces resistance to microdamage accumulation and progression (toughness).
Similar content being viewed by others
References
Parfitt AM. Skeletal heterogeneity and the purposes of bone remodelling; implications for the understanding of osteoporosis. In: Marcus R, Zfeldman D, Kelsey J, editors. San Diego: Academic Press, 2001:433–444.
Ruff CB, Hayes WC. Sex differences in age-related remodeling of the femur and tibia. J Orthop Res 1988;6:886–96.
Jordan GR, Loveridge N, Bell KL, Power J, Rushton JN, Reeve J. Spatial clustering of remodeling osteons in the femoral neck cortex: a cause of weakness in hip fracture? Bone 2000;26:305–13.
Fyhrie DP, Schaffler MB. Failure mechanisms in human vertebral cancellous bone. Bone 1994;15:105–9.
Duan Y, Parfitt M, Seeman E. Vertebral bone mass, size and volumetric bone mineral density in premenopausal women, and postmenopausal women with and without spine fractures. J Bone Miner Res 1999;14:1796–802.
Seeman E, Duan Y, Fong C, Edmonds J. Fracture site-specific deficits in bone size and volumetric density in men with spine or hip fractures. J Bone Miner Res 2001;16:120–7.
Vega E, Ghiringhelli G, Mautalen C, Valzacchi GR, Scaglia H, Zylberstein C. Bone mineral density and bone size in men with primary osteoporosis and vertebral fractures. Calcif Tissue Int 1988;62:465–9.
Keaveny TM, Morgan EF, Niebur GL, Yeh OC. Biomechanics of trabecular bone. Annu Rev Biomed Eng 2001;3:307–33.
Meunier PJ, Sellami S, Briancon D, Edouard C. Histological heterogeneity of apparently idiopathic osteoporosis. In: Deluca HF, Frost HM, Jee WSS, Johnston CC, Parfitt AM, editors. Osteoporosis: recent advances in pathogenesis and treatment. Baltimore: University Park Press, 1990:293–301.
Beck TJ, Ruff CB, Scott WW Jr, Plato CC, Tobin JD, Quan CA. Sex differences in geometry of the femoral neck with aging: a structural analysis of bone mineral data. Calcif Tissue Int 1992;50:24–9.
Boonen S, Koutri R, Dequeker J, Aerssens J, Lowet G, Nijs J, et al. Measurement of femoral geometry in type I and type II osteoporosis: differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures. J Bone Miner Res 1995;10:1908–12.
Cheng XG, Lowet G, Boonen S, Nicholson PHF, Brys P, Nijs J, et al. Assessment of the strength of proximal femur in vitro: relationship to femoral bone mineral density and femoral geometry. Bone 1997;20:213–8.
Karlsson KM, Sernbo I, Obrant KJ, Redlund-Johnell I, Johnell O. Femoral neck geometry and radiographic signs of osteoporosis as predictors of hip fracture. Bone 1996;18:327–30.
Duan Y, Seeman E. Proximal femoral dimensions in women and men with hip fractures. Unpublished data.
Beck TJ, Oreskovic TL, Stone KL, Ruff CB, Ensrud K, Nevitt MC, et al. Structural adaptation to changing skeletal load in the progression toward hip fragility: the study of osteoporotic fractures. J Bone Miner Res 2000;16:1106–19.
Kalender WA, Felsenberg D, Louis O, Lopez P, Klotz E, Osteaux M, et al. Reference values for trabecular and cortical vertebral bone density in single and dual-energy quantitative computed tomography. Eur J Radiol 1989;9:75–80.
Riggs BL, Wahner HW, Melton LJ III, Richelson LS, Judd HL, Offord KP. Rate of bone loss in the axial and appendicular skeleton of women: evidence of substantial vertebral bone loss prior to menopause. J Clin Invest 1986;77:1847–91.
Gilsanz V, Gibbens DT, Carlson M, Boechat I, Cann CE, Schulz ES. Peak trabecular bone density: a comparison of adolescent and adult. Calcif Tissue Int 1987;43:260–2.
Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, Wright JK, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994;93:799–808.
Lips P, Courpron P. Meunier PJ. Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 1978;10:13–7.
Parfitt AM. Morphological basis of bone mineral measurements: transient and steady state effects of treatment in osteoporosis. Miner Electrolyte Metab 1980;4:273–87.
Heaney RP. The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change. J Bone Miner Res 1994;9:1515-23.
Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000;21:115–37.
Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 1996;2:1132–6.
Aaron JE, Makins NB, Sagreiy K. The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop 1987;215:260–71.
Bousson V, Meunier A, Bergot C, Vicant E, Rocha MA, Morais MH, et al. Distribution of intracortical porosity in human midfemoral cortex by age and gender. J Bone Miner Res 2001;16:1308–17.
Duan Y, Turner CH, Kim BT, Seeman E. Sexual dimorphism in vertebral fragility is more the result of gender differences in age-related bone gain than bone loss. J Bone Miner Res 2001;16:2267–75.
Oleksik A, Ott SM, Vedi S, Bravenboer N, Compston J, Lips P. Bone structure in patients with low bone mineral density with or without vertebral fracture. J Bone Miner Res 2000;15:1368–75.
Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O'Fallon WM, Riggs BL. Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res 1990;5:311–9.
Hordon LD, Raisi M, Aaron JE, Paxton SK, Beneton M, Kanis JA. Trabecular architecture in women and men of similar bone mass with and without vertebral fracture. I. Two-dimensional histology. Bone 2001;27:271–6.
Kimmel DB, Recker RR, Gallagher JC, Vaswani AS, Aloia JF. A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner 1990;11:217–35.
Foldes J, Parfitt AM, Shih M-S, Rao DS, Kleerekoper M. Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis. J Bone Miner Res 1991;6:759–66.
Legrand E, Chappard D, Pascaretti C, Duquenne M, Krebs S, Rohmer V, et al. Trabecular bone microarchitecture, bone mineral density and vertebral fractures in male osteoporosis. J Bone Miner Res 2000;15:13–19.
Brown JP, Delmas PD, Malavel L, Edouard C, Chapuy MC, Meunier PJ. Serum bone Gla-protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet 1984;I:1091–3.
Eastell R, Delmas PD, Hodgson SF, Eriksen EF, Mann KG, Riggs BL. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab 1988;67:741–8.
Mashiba T, Hirano T, Turner CH, Forward MR, Johnson CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000;15:613–20.
Currey JD. The mechanical consequences of variation in the mineral content of bone. J Biomech 1969;2:1–11.
Boyce RW, Paddock CL, Gleason JR, et al. The effect of risedronate on canine cancellous bone remodeling: three dimensional kinetic reconstruction of the remodeling site. J Bone Miner Res 1995;10:211–21.
Roschger P, Rinnerthaler P, Yates J, Rodan GA, Fratzl P, Klaushofer K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 2001;29:185–91.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–41.
Seeman E, Delmas PD. Reconstructing the skeleton with intermittent parathyroid hormone. Trends Endocrinol Metab 2001;12:281–3.
Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Albanese C, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis: a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002;87:2060–6.
Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int 2001;69:121–9.
Meunier PJ, Roux C, Ortolani S, Badurski J, Kaufman JM, Spector T, et al. Strontium ranelate reduces the vertebral fracture risk in women with postmenopausal osteoporosis. World Congress on Osteoporosis, Lisbon, Portugal. Osteoporos Int 2002;13:520–22 (045).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Seeman, E. Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis. Osteoporos Int 14 (Suppl 3), 2–8 (2003). https://doi.org/10.1007/s00198-002-1340-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-002-1340-9