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

Bone turnover in a clinical perspective

Paul Lips

Department of Endocrinology

VU University Medical Center

Amsterdam

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

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

Regulation of remodeling and osteon formation

Activation:microcracks,

hormones

Coupling:Cytokines, IGF, BMP

Completion of osteon:sclerostin

Microfractures as a trigger for bone

remodeling

Bone multicellular unit: osteoclasts in cutting cone

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

Osteocytes stained for sclerostin (Poole et al)

Biochemical markers of bone formation and bone resorption

P Szulc et al Osteoporos Int2007; 18: 1451-61

Balance per bone remodeling unit

normal turnoverremodeling (im)balance

decreased bone formation remodeling imbalance(Cushing, menopause)

high turnover(thyrotoxicosis, menopause)

Bone loss in different remodeling situations

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

Pathophysiology of osteoporosis

cytokines,growth factors

hormonescortisol , T4, oestradioltestosterone

nutritioncalcium, vit. D, protein, vit B12, foliumzuur

mechanical stimulation vs.immobilisation

inflammatory diseases, reumatoid arthritis, M. Crohn

geneticpredispositionCol IA1, VDRAPO E4, LRP5/6

Bone resorption > bone formation low bone mass

osteoporosis

“programming”Barker-hypothesiscortisol, IGF-1

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

Increase of bone mass with bisphosphonates

• Decrease of bone resorption filling up of remodeling space

• Change of high turnover bone to low turnover bonehigher degree of mineralization

• Largest increase in first and second year; no further increase after 5 years

Osteoclastogenesis in bone remodeling:RANKL, RANK, Osteoprotegerine

E. Romas et al. Bone 2002;30:340-6.

Bone remodeling in trabecular bone: estrogen effects

Raisz LG et al J Clin Invest 2005

cytokines RANKL, OPG

Human bone marrow cells expressing RANKL before and after oestradiol treatment

Taxel P et al Osteopor Int 2008; 19: 193-9

Osteoprotegerine to improve bone volume and structure in mice

Kearns AE et al Endocr Rev 2008; 29: 155-92

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

Parathyroid hormone: enigma!

Continuous increase

primary or secondary hyperparathyroidism

• increased turnovermore 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 turnovermore BMU’s

• remodeling balance positive• bone gain mainly trabecular• BMD increase in spine and hip

Effect teriparatide on micro-architecture in crista iliaca at 18 months

TPTD 20

Woman, age 65Treatment duration: 637 days

Jiang et al. JBMR 2003

Before treatment After treatment

Parathyroid hormone treatment

Sclerosteosis due to loss-of- function mutation in the SOST geneSOST 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

Regulation of bone mass by Wnt signallingKrishnan et al J Clin Invest 2006; 116: 1202-9

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.

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).