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Seminar 04-03-2009 - bone turnover in a clinical perspective
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Seminar 04-03-2009 - bone turnover in a clinical perspective


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  • De botbiopten zijn afkomstig van dezelfde patiente. Een biopt in de linkerzijde en een biopt uit de rechterzijde. Voor en na behandeling. In dit geval is dit een botbiopt voor en na 21 maanden behandeling. Het effect na 21 maanden komt overeen met het effect na 18 maanden. Jiang reported improved skeletal architecture by treatment with teriparatide 20  g/day. 3D analysis of iliac crest bone biopsies revealed significant increases in cancellous bone volume and connectivity, increased trabecular bone volume, trabecular connectivity, and cortical thickness and improved trabecular morphology with a shift toward a more plate-like structure. One thousand six hundred thirty-seven postmenopausal women with osteoporosis were enrolled in the teriparatide fracture prevention trial with a median duration of treatment with study drug of 19 months. Patients were randomized to 20  g/day (n=541) or 40 mg/day (n=552) of teriparatide plus calcium and vitamin D compared with patients randomized to calcium and vitamin D alone (n=544). To examine the effects of teriparatide on cancellous and cortical bone, iliac crest bone biopsies were taken from a subset of women at baseline and after 12 to 24 months of treatment. Female, age 65 Duration of therapy: 637 days (approx 21 mos) Baseline BMD: Total spine 0.826 gm/cm**2 (T-score = -2.0, nhanes 98) Fem neck 0.547 gm/cm**2 (T-score = -2.6, nhanes 98) Endpoint BMD: Total spine 0.887 gm/cm**2 (+7.4%) (T-score -1.7) Fem neck 0.621 gm/cm**2 (+13.5%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) __________________ Jiang et al. J. Bone Miner. Res. 2003;18:1932-1941* : niet alle gegevens te vinden in het artikel. Data on file, Eli Lilly and Company
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    • 1. Bone turnover in a clinical perspective Paul Lips Department of Endocrinology VU University Medical Center Amsterdam
    • 2. Bone turnover in a clinical perspective • Bone remodeling: the bone multicellular unit • Remodeling balance and turnover • Hormonal control of balance and turnover • Diseases that affect remodeling balance and /or turnover • Drug design based on the remodeling cycle
    • 3. P.J Meunier: Bone histomorphometry to study bone balance and turnover
    • 4. Regulation of remodeling and osteon formation Activation: microcracks, hormones Coupling: Cytokines, IGF, BMP Completion of osteon: sclerostin
    • 5. Microfractures as a trigger for bone remodeling
    • 6. Bone multicellular unit: osteoclasts in cutting cone
    • 7. Assessment of bone formation: double tetracycline labels schedule: 2 – 10 – 2 days Distance between labels = mineral apposition rate (MAR) Labeled surface = mineralization surface (MS/BS) Bone formation rate = MAR x MS/BS
    • 8. Osteocytes stained for sclerostin (Poole et al)
    • 9. Biochemical markers of bone formation and bone resorption P Szulc et al Osteoporos Int 2007; 18: 1451-61
    • 10. Balance per bone remodeling unit
    • 11. normal turnover remodeling (im)balance decreased bone formation remodeling imbalance↑ (Cushing, menopause) high turnover (thyrotoxicosis, menopause) Bone loss in different remodeling situations
    • 12. Bone turnover in a clinical perspective • Changes in bone volume (mass) depend on: - remodeling balance: bone loss or gain per BMU - turnover (remodeling rate): number of BMU’s active at a certain moment, more or less equivalent to remodeling surface - remodeling space: non-permanent bone loss due to remodeling • Bone formation rate = MAR x MS/BS mineral apposition rate x mineralizing surface
    • 13. Pathophysiology of osteoporosis cytokines, growth factors hormones cortisol , T4, oestradiol testosterone nutrition calcium, vit. D, protein, vit B12, foliumzuur mechanical stimulation vs. immobilisation inflammatory diseases, reumatoid arthritis, M. Crohn genetic predisposition Col IA1, VDR APO E4, LRP5/6 Bone resorption > bone formation low bone mass osteoporosis “programming” Barker-hypothesis cortisol, IGF-1
    • 14. High turnover states causing bone loss • Postmenopause • Hyperthyroidism • Primary hyperparathyroidism • Vitamin D deficiency • Low calcium diet secondary hyperparathyroidism • Hypercortisolism • Renal failure • Severe immobilization • Inflammatory bone disease
    • 15. Increase of bone mass with bisphosphonates • Decrease of bone resorption filling up of remodeling space • Change of high turnover bone to low turnover bone higher degree of mineralization • Largest increase in first and second year; no further increase after 5 years
    • 16. Osteoclastogenesis in bone remodeling: RANKL, RANK, Osteoprotegerine E. Romas et al. Bone 2002;30:340-6.
    • 17. Bone remodeling in trabecular bone: estrogen effects Raisz LG et al J Clin Invest 2005 cytokines RANKL, OPG
    • 18. Human bone marrow cells expressing RANKL before and after oestradiol treatment Taxel P et al Osteopor Int 2008; 19: 193-9
    • 19. Osteoprotegerine to improve bone volume and structure in mice Kearns AE et al Endocr Rev 2008; 29: 155-92
    • 20. Treatment with denosumab (RANKL-antibody) for 12 months in postmenopausal women with low BMD; comparison with alendronate McClung MR et al N Engl J Med 2006; 354: 821-31
    • 21. Parathyroid hormone: enigma! Continuous increase primary or secondary hyperparathyroidism • increased turnover more BMU’s • remodeling balance negative • bone loss mainly cortical • fractures of radius and hip etc Pulsewise stimulation teriparatide (PTH 1-34) as treatment for osteoporosis • increased turnover more BMU’s • remodeling balance positive • bone gain mainly trabecular • BMD increase in spine and hip
    • 22. Effect teriparatide on micro-architecture in crista iliaca at 18 months TPTD 20 Woman, age 65 Treatment duration: 637 days Jiang et al. JBMR 2003 Before treatment After treatment
    • 23. Parathyroid hormone treatment
    • 24. Sclerosteosis due to loss-of- function mutation in the SOST gene SOST encodes for sclerostin • Homozygotes: Increased bone mass BMD Z-score 7 to 14 • Heterozygotes: increased bone mass BMD Z-score 0.5 to 5 • Mainly in South Africa Gardner et al. J Clin Endocrinol Metab 2005; 90: 6392-5
    • 25. Regulation of bone mass by Wnt signalling Krishnan et al J Clin Invest 2006; 116: 1202-9
    • 26. Bone turnover in a clinical perspective • Whether bone is lost or gained depends on remodeling balance in the BMU. • The quantity of bone lost (or gained) depends on the remodeling rate (turnover), i.e. the number of BMU’s or the activation frequency. • Hormones may have an effect on remodeling balance, turnover, trabecular and/or cortical bone.
    • 27. Bone turnover in a clinical perspective • Endocrine and inflammatory diseases usually cause bone loss by inducing a negative remodeling balance associated with high turnover. • Successful treatment of osteoporosis depends upon restoring remodeling balance and/or decreasing bone turnover (remodeling rate).