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

4. P.J Meunier: Bone
histomorphometry to
study bone balance
and turnover

5. Regulation of remodeling and osteon
formation
Activation:
microcracks,
hormones
Coupling:
Cytokines, IGF, BMP
Completion of osteon:
sclerostin

6. Microfractures as a
trigger for bone
remodeling

7. Bone multicellular unit: osteoclasts
in cutting cone

8. 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

9. Osteocytes stained for sclerostin (Poole et al)

10. Biochemical markers
of bone formation and
bone resorption
P Szulc et al Osteoporos Int
2007; 18: 1451-61

11. Balance per bone remodeling unit

12. normal turnover
remodeling (im)balance
decreased bone
formation
remodeling imbalance↑
(Cushing, menopause)
high turnover
(thyrotoxicosis,
menopause)
Bone loss in different remodeling situations

13. 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

14. 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

15. 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

16. 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

17. Osteoclastogenesis in bone remodeling:
RANKL, RANK, Osteoprotegerine
E. Romas et al. Bone 2002;30:340-6.

18. Bone remodeling in trabecular bone:
estrogen effects
Raisz LG et al J Clin Invest 2005
cytokines RANKL, OPG

19. Human bone marrow cells expressing RANKL before
and after oestradiol treatment
Taxel P et al Osteopor Int 2008; 19: 193-9

20. Osteoprotegerine to improve bone volume and
structure in mice
Kearns AE et al Endocr Rev 2008; 29: 155-92

21. 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

22. 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

23. 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

24. Parathyroid hormone treatment

25. 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

26. Regulation of bone mass by Wnt signalling
Krishnan et al J Clin Invest 2006; 116: 1202-9

27. 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.

28. 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).