1. an underestimated disease
Osteoporosis
an underestimated disease

3. Definition of osteoporosis
…a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.
World Health Organization (WHO). Technical Report Series 843, Geneva 1994 Update TRS 921, 2003

4. normal
osteoporotic

5. Osteoporosis diagnosis
Areal bone mineral density is a important predictor of fracture risk.
Spine/hip dual energy X-ray absorptiometry measurement (DEXA) is the diagnostic standard
WHO. Technical Report Series 921, Geneva 2003

6. Dual Energy X-ray Absorptiometry or DEXA
Measures X-ray absorption
Bone mass per projected area (g/cm2)
BMD correlates with whole bone strength
Bouxsein ML, et al. Bone 1999; 25(1):49-54.

7. BMD T-score = number of SD vs
BMD T-score = number of SD vs. mean BMD of healthy young female population (at peak bone mass)
WHO, – update 2003

8. DEXA as BMD-measurement method
Peak Bone Mass
Osteoporosis
Normal
Osteopenia
0 –1 –2 –2.5
T-score
Diagnosis and assessment
DXA (or DEXA), which is the most commonly-used technique, can measure BMD at the hip and spine and/or peripheral sites. It employs two X-ray beams of different energy levels.
A low-energy beam is attenuated mainly by soft tissue. It produces only a small detectable signal.
A high-energy beam penetrates soft tissue and is attenuated mainly by bone. It produces a stronger detectable signal.
The two-beam method allows the energy absorbed by soft tissues to be subtracted from bone mineral content measurements. The technique delivers high accuracy and precision with modest radiation exposure. It is also widely available and easy to use.
DEXA = Dual-Energy X-ray Absorptiometry

9. WHO criteria for osteoporosis in women
T-Score
Normal
-1 and above
Osteopenia
-1 to -2.5
Osteoporosis
 -2.5
‘Severe’ osteoporosis
 and one or more fragility fractures
Important note:
Although the correct densitometric definition of osteoporosis according to the WHO is a T-score of  -2.5, many documents referring to the WHO mention a T-score of < -2.5.
In this context is important to highlight that the reimbursement of the current biphosphonates on the Belgian market are either based on the presence of a (previous) vertebral fragility fracture (documented on standard X-ray), or based on a T-score of < (and not  -2.5).
‘Established osteoporosis’
World Health Organization (WHO). Technical Report Series 843, Geneva 1994 Update TRS 921, 2003

10. Diagnosis of Osteoporosis
BMD T-score   DEXA
and / or
presence (history)
of osteoporotic fracture  RX
Important note:
Although the correct densitometric definition of osteoporosis according to the WHO is a T-score of  -2.5, many documents referring to the WHO mention a T-score of < -2.5.
In this context is important to highlight that the reimbursement of the current biphosphonates on the Belgian market are either based on the presence of a (previous) vertebral fragility fracture (documented on standard X-ray), or based on a T-score of < (and not  -2.5).

11. Post-menopausal Osteoporosis

12. Progression of vertebral fractures in osteoporosis
Age 40 Age 60 Age 70
Progression of vertebral fractures in osteoporosis
Osteoblast
Osteoclast
imbalance of
bone-remodeling

13. 1959 1989 1996 Inger Lundegaardh, Sweden
IOF: international osteoporosis foundation,

15. Pathophysiology of osteoporosis: bone remodelling
Lining cells cover
resting bone
Osteoclasts resorb bone
Activation resorption phase ~20 days
Bone
Bone
Osteoblasts lay
new osteoid
Reversal formation phase ~160 days
Pathophysiology of osteoporosis
When osteoclast activity exceeds osteoblast activity, bone formation cannot compensate for the amount of bone resorbed. Bone mass inevitably decreases. Mechanisms responsible for bone loss include (American Medical Association, 2000)
that osteoclasts may create an excessively deep cavity that cannot be filled by osteoblasts
the function of the osteoblasts may be diminished, such that even a normal-sized lacuna is not filled
an increased number of bone remodelling units in conjunction with either of the two processes above results in increased bone loss.
Bone
Bone
Newly laid osteoid mineralises over several months

16. Postmenopausal bone loss: role of estrogen deficiency
Indirect
effects
Dietary
calcium (decreased absorption due to Vit. D deficiency) ?
Decreased
bone
formation
Directly increases osteoclast number
and longevity
Secondary
hyperparathyroidism
Increased bone
resorption
Remodelling
imbalance
Bone
Loss
Adapted from Riggs BL, et al. J Bone Miner Res 1998; 13(5):

17. Age-related bone loss occurs in men and women
III
Women II
Bone mass
III
I Peak bone mass
II Rapid bone loss (menopause) III Age-related bone loss
Age (years)

18. Bone Remodelling throughout Life
Bone turnover = a coupled process
always : bone resorption → bone formation
Childhood & adolescence: resorption < formation
As from the age of 40: resorption > formation
always negative balance per bone remodelling cycle
slow bone loss 
Postmenopausal period: accelerated bone loss
estrogens inhibit bone turnover
E-deficiency → higher bone turnover rate

19. Pathogenesis of Osteoporosis
> 40 y negative net balance
per bone remodelling cycle
Low TURNOVER = low BONE LOSS
High TURNOVER = high BONE LOSS

20. Ultimately leading to loss of CONNECTIVITY

21. Bone Turnover Trabecular Bone Cortical Bone % of bone mass 20% 80%
% of bone turnover
mostly present in
Epiphysis of long bones
+ Vertebral Bodies
Diaphysis of long bones

22. Distribution of trabecular and cortical bone throughout the skeletal system
Femoral neck 25% trabecular 75% cortical
Vertebrae 66% trabecular 34% cortical
Forearm (distal radius) 20% trabecular 80% cortical
Trochanteric region 50% trabecular 50% cortical
adapted from

23. Consequences of Postmenopausal Osteoporosis

24. Incidence of osteoporotic fractures in women
Vertebrae
Annual incidence
Hip
Wrist
Age (years)
Adapted from Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72 and Sambrook P et al. Lancet 2006; 367(9527):

25. Lifetime fracture risk of people at 50 years of age
Adapted from Melton LJ, III, et al. J Bone Miner Res 1992; 7(9):

26. All fractures are associated with morbidity
One year after a hip fracture
Unable to carry out at least one independent
activity of daily living
80%
Patients (%)
Unable to walk
independently
Discharged to Nursing Home
40%
Death within
one year
30%
≥20%
Adapted from Cooper C. Am J Med 1997; 103(2A):12S-17S.

27. Morbidity after vertebral fractures
Back pain
Loss of height
Deformity (kyphosis, protuberant abdomen)
Reduced pulmonary function
Diminished quality of life: loss of self-esteem, distorted body image, dependence on narcotic analgesics, sleep disorder, depression, loss of autonomy, social dependence
Increased mortality

28. Mortality after major types of osteoporotic fracture in men and women
5 - Year Prospective Cohort Study
Age-Standardized Mortality Ratio
Fracture Women Men
Proximal femur
Vertebral
Other major
Minor
Adapted from Center JR, et al. Lancet 1999; 353(9156):

29. Economic Impact
Number of bed days (men and women) in Switzerland in 1992:
701,000 for osteoporosis
889,000 for chronic obstructive pulmonary disease
533,000 for stroke
328,000 for myocardial infarction
201,000 for breast cancer
Osteoporosis # 1 when looking at women only
Adapted from Lippuner K, et al. Osteoporos Int 1997; 7(5):

30. Risk factors for Osteoporosis ‘Case-finding’

31. Risk factors that provide indications for the diagnostic use of bone densitometry
Presence of strong risk factors
Previous fragility fracture
Radiographic evidence of osteopenia or vertebral deformity or both
Loss of height, thoracic kyphosis (after radiographic confirmation of vertebral deformities)
Kanis JA. Lancet 2002; 359(9321):

32. Risk Factors that identify people who should be assessed
Risk Factors that identify people who should be assessed* for Osteoporosis
Major Risk Factors
Minor Risk Factor
Age  65 years
Vertebral compression fracture
Fragility fracture after age 40
Family history of osteoporotic fracture (esp. maternal hip fract.)
Systemic glucocorticoids (> 3 m)
Early menopause (before 45)
Malabsorption syndrome
Primary hyperparathyroidism
Propensity to fall
Osteopenia apparent on x-ray film
Hypogonadism
High Bone Turnover
Major immobility
Rheumatoid Arthritis
Hyperthyroidism
Anticonvulsant therapy
Chronic heparin therapy (UFH)
Calcium Intake < 500 mg/d
Smoking
Excessive alcohol intake
BMI < 19
* BMD measurement is recommended for those with at least 1 major or 2 minor risk factors .
Adapted from Brown JP, et al. CMAJ 2002; 167(10 Suppl):S1-34.

33. Who to test (BMD-measurement) for Postmenopausal Osteoporosis ?
post-menopausal,  65 y
post-menopausal, < 65 y
with additional risk factors, or
with fragility fracture, or
with loss of height or deformity of the spine (kyphosis)
pre- or post-menopausal
with disease or receiving a treatment, known that they can cause a ‘secondary’ form of osteoporosis
Adapted from Raisz LG. N Engl J Med 2005; 353(2):

34. Preventing osteoporosisC
alcium D
Vitamin E
xercise F
Prevent
alls G
ain weight
Treatment and prevention
One of the most important preventive strategies is to encourage the achievement of optimal peak bone mass in the young, since this has a major impact on bone mass and the risk of osteoporosis after the menopause. Although peak bone mass is largely determined by genetics and diet (calcium and vitamin D intake), it can also be influenced by physical activity, smoking and alcohol consumption. It is, therefore, important to encourage both children and adolescents to adopt a healthy lifestyle. S
Stop
moking

35. TREATMENT of OSTEOPOROSIS in order to prevent (new) fractures

36. Drugs used in osteoporosis treatment
HRT
SERM/Raloxifene
Calcitonin
Bisphosphonates - Alendronate - Risedronate - Ibandronate
Parathyroid hormone
Strontium ranelate
The cellular actions of strontium are not fully identified.
Uncoupling of normal bone remodeling process → osteclast /~ osteoblast
Overestimation of BMD measurement : Sr is bone seeking agent being incorporated into the bone
→ BMD measurements : adjustment for bone strontium content ?
Marie PJ. Curr Opin Pharmacol 2005; 5(6):
Biskobing DM. Expert Opin Investig Drugs 2003; 12(4):
Nielsen SP, et al. J Clin Densitom 1999; 2(4):
Mosekilde L, et al. Ugeskr Laeger 2005; 167(37):
Ortolani S, et al. Bone 2006; 38(2 Suppl 1):19-22.
Inhibition of resorption
Stimulation of formation
Strontium ranelate