Knochenstoffwechsel im Alter

Zusammenfassung

Das Skelettsystem wird unter optimalen Bedingungen lebenslang erneuert, um sich mechanischen Belastungen anpassen sowie Knochenbrüchen Widerstand leisten zu können. Mit dem Alter kann sich das Gleichgewicht zwischen Knochenauf- und -abbau auf die Seite des Abbaus verschieben sowie die Knochenqualität verschlechtern, was zu einem Anstieg des Frakturrisikos führt. Ursächlich hierfür sind u. a. die Abnahme der regenerativen Kapazität mesenchymaler Stammzellen und die dadurch verminderte Knochenformation durch Osteoblasten. Des Weiteren sinkt die Zahl der sich im Knochen befindenden Osteozyten und es kommt zu zellintrinsischen Prozessen wie einer Anhäufung von reaktiven Sauerstoffspezies sowie verminderter lysosomaler Verdauung (Autophagozytose). Der Mangel an Geschlechtshormononen, Wachstumsfaktoren sowie endogener Glukokortikoidüberschuss und fehlende körperliche Bewegung sind weitere Faktoren, die im Alter zu einem katabolen Knochenstoffwechsel und einer Abnahme der Knochenmasse führen können. Patienten nach erfolgter Fraktur und über 60 Jahren sollten daher vor allem bei Vorhandensein von typischen Risikofaktoren osteologisch untersucht werden. Zur osteologischen Basisdiagnostik gehört die Knochendichtemessung in DXA-Technologie (DXA: dual-energy X-ray absorptiometry) und ein ausführliches osteologisches Labor inklusive Bestimmung von Vitamin D (25-Hydroxy-Vitamin-D₃). Die Patienten, deren statistisches Frakturrisiko ein Level von 30% übersteigt, erhalten dann zusätzlich zur Basistherapie in Form von Bewegung und Vitamin-D-Substitution eine spezifische osteologische Therapie (wie z. B. Bisphosphonat, Denosumab, Teriparatid), was mit einer erheblichen Risikoreduktion für weitere Frakturen einhergeht. Zusammenfassend stellt das Lebensalter einen Hauptrisikofaktor für Knochenbrüche und Osteoporose dar, weshalb die entsprechenden Patienten richtig diagnostiziert und behandelt werden müssen. So können die meisten Frakturen verhindert werden.

Abstract

Under optimal conditions, the skeletal system is continuously remodeled throughout life, in order to adapt to mechanical loads and to resist fracture. With aging, the balance between bone formation and resorption may shift and bone quality may decline. This leads to an age-related increase in fracture risk, expressed by a decrease in bone mineral density (BMD). This can be explained by the declining proliferative capacity of mesenchymal stem cells, which leads to decreased osteoblastic bone formation. Furthermore, the number of long-living osteocytes decreases with age. Reactive oxygen species are increasingly produced and lysosomal degradation (autophagy) decreases. Other contributing factors to the decline in bone mass are loss of sex steroids, growth hormones, as well as endogenous glucocorticoid excess and reduced physical activity. Patients suffering from fragility fractures and over the age of 60 years therefore have to be screened for osteoporosis. Osteological basic diagnostic testing includes the bone mineral density scan using dual-energy X-ray absorptiometry (DXA) and comprehensive laboratory tests, including vitamin D (25-hydroxy vitamin D). Aside from vitamin D and physical exercise, patients with a high risk of fracture (> 30% for 10 years) receive specific osteological therapy (bisphosphonates, denosumab, teriparatide), which leads to a substantial reduction in fracture risk. In conclusion, age must be considered as a major risk factor for fractures and osteoporosis, which is why patients at risk have to be diagnosed and treated correctly. In this way, most fractures can be prevented.

• Literatur

• 1 Ensrud KE. Epidemiology of fracture risk with advancing age. J Gerontol A Biol Sci Med Sci 2013; 68: 1236-1242
• 2 Hadji P, Klein S, Gothe H. et al. The epidemiology of osteoporosis – Bone Evaluation Study (BEST): an analysis of routine health insurance data. Dtsch Arztebl Int 2013; 110: 52-57
• 3 Abrahamsen B, van Staa T, Ariely R. et al. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int 2009; 20: 1633-1650
• 4 Hu F, Jiang C, Shen J. et al. Preoperative predictors for mortality following hip fracture surgery: a systematic review and meta-analysis. Injury 2012; 43: 676-685
• 5 Cummings SR, Eastell R. Risk and prevention of fracture in patients with major medical illnesses: a mini-review. J Bone Miner Res 2016; 31: 2069-2072
• 6 Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 1994; 55: 273-286
• 7 Xiong J, Onal M, Jilka RL. et al. Matrix-embedded cells control osteoclast formation. Nat Med 2011; 17: 1235-1241
• 8 Nakashima T, Hayashi M, Fukunaga T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17: 1231-1234
• 9 Bonewald LF. Mechanosensation and transduction in osteocytes. Bonekey Osteovision 2006; 3: 7-15
• 10 Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab 2010; 21: 369-374
• 11 Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci 2007; 1116: 281-290
• 12 Milovanovic P, Zimmermann EA, Hahn M. et al. Osteocytic canalicular networks: morphological implications for altered mechanosensitivity. ACS Nano 2013; 7: 7542-7551
• 13 Ellies DL, Viviano B, McCarthy J. et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res 2006; 21: 1738-1749
• 14 Li J, Bao Q, Chen S. et al. Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt/β-catenin signaling in mice. J Orthop Res 2016; 35: 812-819
• 15 Szulc P, Seeman E, Duboeuf F. et al. Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res 2006; 21: 1856-1863
• 16 Razi H, Birkhold AI, Weinkamer R. et al. Aging leads to a dysregulation in mechanically driven bone formation and resorption. J Bone Miner Res 2015; 30: 1864-1873
• 17 Stenderup K, Justesen J, Clausen C. et al. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 2003; 33: 919-926
• 18 Busse B, Djonic D, Milovanovic P. et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 2010; 9: 1065-1075
• 19 Wijenayaka AR, Kogawa M, Lim HP. et al. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 2011; 6: e25900
• 20 Xiong J, OʼBrien CA. Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 2012; 27: 499-505
• 21 Hay E, Bouaziz W, Funck-Brentano T. et al. Sclerostin and bone aging: a mini-review. Gerontology 2016; 62: 618-623
• 22 Gaudio A, Pennisi P, Bratengeier C. et al. Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 2010; 95: 2248-2253
• 23 Almeida M, OʼBrien CA. Basic biology of skeletal aging: role of stress response pathways. J Gerontol A Biol Sci Med Sci 2013; 68: 1197-1208
• 24 Almeida M, Han L, Martin-Millan M. et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 2007; 282: 27285-27297
• 25 Onal M, Piemontese M, Xiong J. et al. Suppression of autophagy in osteocytes mimics skeletal aging. J Biol Chem 2013; 288: 17432-17440
• 26 Weinstein RS, Wan C, Liu Q. et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010; 9: 147-161
• 27 Mohan S, Baylink DJ. Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 levels in aging and age-associated diseases. Endocrine 1997; 7: 87-91
• 28 Hintzpeter B, Mensink GB, Thierfelder W. et al. Vitamin D status and health correlates among German adults. Eur J Clin Nutr 2008; 62: 1079-1089
• 29 Veldurthy V, Wei R, Oz L. et al. Vitamin D, calcium homeostasis and aging. Bone Res 2016; 4: 16041
• 30 Priemel M, von Domarus C, Klatte TO. et al. Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 2010; 25: 305-312
• 31 Maxmen A. Nutrition advice: the vitamin D-lemma. Nature 2011; 475: 23-25
• 32 Busse B, Bale HA, Zimmermann EA. et al. Vitamin D deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci Transl Med 2013; 5: 193ra88
• 33 Seitz S, Koehne T, Ries C. et al. Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture. Osteoporos Int 2013; 24: 641-649
• 34 Chapuy MC, Arlot ME, Duboeuf F. et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992; 327: 1637-1642
• 35 Sandmann A, Amling M, Barvencik F. et al. Economic evaluation of vitamin D and calcium food fortification for fracture prevention in Germany. Public Health Nutr 2017; 20: 1874-1883
• 36 Schinke T, Schilling AF, Baranowsky A. et al. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med 2009; 15: 674-681
• 37 Aoki K, Kihaile PE, Wenyuan Z. et al. Comparison of prevalence of chronic atrophic gastritis in Japan, China, Tanzania, and the Dominican Republic. Ann Epidemiol 2005; 15: 598-606
• 38 Krause M, Keller J, Beil B. et al. Calcium gluconate supplementation is effective to balance calcium homeostasis in patients with gastrectomy. Osteoporos Int 2015; 26: 987-995
• 39 Amling M, Oheim R, Barvencik F. A holistic hip fracture approach: individualized diagnosis and treatment after surgery. Eur J Trauma Emerg Surg 2014; 40: 265-271
• 40 Eisman JA, Bogoch ER, Dell R. et al. Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention. J Bone Miner Res 2012; 27: 2039-2046
• 41 Schuit SCE, van der Klift M, Weel AEAM. et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2004; 34: 195-202
• 42 Cummings SR, San Martin J, McClung MR. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756-765
• 43 Neer RM, Arnaud CD, Zanchetta JR. 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: 1434-1441