Osteoporosis detection and treatment

Osteoporosis : Definition (NIH, 2001)

A skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects integration of bone density and bone quality.

Development of osteoporotic bone

Rizzoli R ed In Atlas of Postmenopausal Osteoporosis (1st edition) Science Press, 2004

Age and Osteoporotic Fractures

4,00 Men Women

Incidence/100,000 person-years

Hip
3,00 0

Hip Vertebrae

Vertebrae

2,00 0

1,00 0 3539

Colles '
>85 Age group, year

Colles '
>85

Cooper C. Epidemiology of Osteoporosis. Chapter 49:IV. Metabolic Bone Diseases. Am Soc for Bone & Min Research 2003.

Osteoporosis Some facts and figures

1 in 2 women and 1 in 5 men aged 50 will suffer a fragility fracture in their remaining lifetime There are 20 million people aged 50 years and over in the UK. By 2020 this will have increased to 25 million. The lifetime risk of fracture in women at age 50 is greater than the risk of breast cancer or cardiovascular disease

Annual Incidence of Osteoporotic fractures in England and Wales

180,000 Symptomatic osteoporotic fractures 70,000 Hip fractures 25,000 Vertebral fractures 41,000 Wrist fractures Estimated total cost of treating osteoporotic fractures in postmenopausal women 1.5 to 1.8 billion in 2000 2.1 billion in 2010

Risk of subsequent fracture after initial vertebral fracture

100 Women Men

Cumulative incidence (%)

80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 Years following vertebral fracture

Melton LJ 3rd, et al. Osteoporos Int. 1999; 10(3): 21421.

Management of Osteoporosis Identifying Risk Factors for Osteoporosis

Previous fragility fracture Corticosteroid use > 3 months Family history, especially maternal hip fracture Medical conditions associated with osteoporosis e.g. RA, coeliac disease, hyperparathyroidism Premature menopause < 45 years old Excess alcohol consumption Low BMI (<19) Smoking

Bone density referral guidelines

REASON FOR REFERRAL: Corticosteroid therapy any dose for more than three months. However, patients of any age who have had a minimal trauma fracture or patients >65 treat without a scan. Minimal trauma fracture eg wrist, vertebra, hip, pelvis. If known vertebral fracture, please state which vertebra. Early menopause before 45 years, or prolonged amenorrhoea > 1 year scan when patient reaches 50 years of age. Other diseases or treatments associated with osteoporosis Please specify .. Family History of osteoporosis in first degree relative, particularly maternal hip fracture. Significant radiological osteopenia Patients with proven osteoporosis who discontinue HRT and who are not on other OP treatment. Scan 12 months after stopping

Osteoporosis and cancer treatments

Prostate cancer Gonadorelin analogues Breast cancer Chemotherapy induced menopause Tamoxifen in pre-menopausal women Aromatase inhibitors

Osteoporosis and aromatase inhibitors

All aromatase inhibitors cause bone loss (anastrazole, letrozole and exemestane) and are associated with increased fracture risk Bone loss is most rapid in the first 6-12 months (approx 3%) after changing from tamoxifen Bone loss then slows eg 4-5% overall at 2 years Consider DXA scan at time of switching from tamoxifen to aromatase inhibitor especially if other risk factors present

Lumbar Spine DXA Results

DXA Results
T Score
> minus 1.0

Classification
Normal

Action
Lifestyle measures.

< minus 1.0 > minus 2.5

Osteopenia

Lifestyle measures. Consider specific treatment where there is ongoing risk, e.g. steroids, and in those who have had a minimal trauma fracture. Lifestyle measures. Prevent falls. Treatment may be indicated.

< minus 2.5

Osteoporosis

Peripheral measurements
Forearm DXA Heel DXA Heel ultrasound

Ten year probability of fracture: age and BMD

Age (yrs) T-score

+1 50 60 70 80 2.4 3.2 4.3 4.6

0 -4 3.8 5.1 7.1 7.7

-1 5.9 8.2 13.0 11.5 12.7 18.3 20.5 9.2

-2 14.1 20.2 28.4 31.8

-3 21.3 30.6 42.3 46.4

Kanis et al. Osteoporosis Int 2001; 12: 98995.

Kanis JA, Johnell O, Oden A et al. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 2001; 12:989995.

Management of Osteoporosis Identifying Risk Factors for Falling Medical conditions e.g. arrhythmias, postural hypotension Failing vision Sedative drugs Physical environment

Osteoporotic vertebral fractures

Investigation of osteoporosis
FBC PV Igs / electrophoresis BJP TT glutaminase Biochemical screen including calcium TFTs Testosterone levels in men ? Vitamin D levels

Age-related changes in bone mass

Attainment of peak bone mass Consolidation

Age-related bone loss

Bone mass

Menopause Men
Fracture threshold

Women
0 50 10 60 20 Age (years) 30 40

Compston JE. Clin Endocrinol 1990; 33: 653682.

Management of Osteoporosis Lifestyle Measures

Treatment Options in Osteoporosis

Antiresorptive drugs HRT Bisphosphonates etidronate alendronate risedronate ibandronate SERMs raloxifene Calcitonin

Dual Action Bone Agents (DABAs) Strontium ranelate

Anabolic drugs PTH (teriparatide)

New Treatment Options in Osteoporosis

Antiresorptive drugs HRT Bisphosphonates etidronate alendronate risedronate ibandronate zoledronate SERMs raloxifene Calcitonin

Dual Action Bone Agents (DABAs) Strontium ranelate

Anabolic drugs PTH analogues Forsteo (teriparatide) Preotact

Bone remodelling cycle

Pre-osteoblasts Osteoclasts Monocytes Osteoblasts Osteocytes

Servier Medical Art

Effect of alendronate on risk of fractures

18 16 RR 0.53 ( 95% Cl 0.41 0.68 ) Alendronate n=1022 Placebo n=1005

Patients with new fractures after 3 years of treatment (%)

14 12 10 8 6 4 2 0 Vertebral fractures
(p=0.001)

RR 0.52 ( 95% Cl 0.31 0.87 )

RR 0.49 ( 95% Cl 0.23 0.99 )

Wrist fractures (p=0.05)

Hip fracture
(p=0.05)

Adapted from: Rizzoli. R: Atlas of Osteoporosis. (Second Edition). Curr Med Group 2005.

Effect of risedronate on incidence of new vertebral and non-vertebral fractures

34 RR 0.51 ( 95% Cl 0.36 0.73 ) Placebo Risedronate 5 mg/day RR 0.67 ( 95% Cl 0.44-1.04) 18

Incidence of new vertebral fractures (%)

32 28 24 20

Incidence of new non-vertebral fractures (%)

16 14 12 10 8 6 4 2 0 Vert-NA Years 0-3 P=0.02 RR 0.61 ( 95% Cl 0.39 0.94 )

RR 0.59 ( 95% Cl 0.43 0.82 )

16 12 8 4 0

VertVert-NA Vert-MN MN Years 0-3 Years 0-3 Years 0P<0.003 NS 3 P<0.00 Vert-MN results adapted from Reginster, J.-Y., Minne, H.W. et al.Osteoporosis International 2000; 11.8391. 1
Vert-NA results adapted from Harris ST, Watts NB, Genant HK et al. JAMA 1999; 282: 13441352.

Effect of ibandronate on incidence of vertebral fractures

12 10
RR 0.50 ( 95% Cl 0.34 0.74) RR 0.38 ( 95% Cl 0.25 * 0.59) *

Fracture incidence (%)

8 6 4 2 0
RR 0.42 ( 95% Cl 0.17 1.02 ) RR 0.44 ( 95% Cl 0.26 0.73 ) RR 0.39 ( 95% Cl 0.23 0.67 ) *

Year 1

Year 2

Year 3 Daily ibandronate (2.5 mg), n=982 Intermittent ibandronate (20 mg), n=982 Placebo, n=982

*p<0.001 versus placbo p<0.0017 versus placbo

Adapted from: Rizzoli. R: Atlas of Osteoporosis. (Second Edition). Curr Med Group 2005. Reproduced with permission from Chestnut CH 3rd, Skag A, Christiansen C; J Bone Miner Res 2004; 19;1241-1249.

Strontium has a dual action

FORMATION
S n m tro tiu

RESORPTION

Pre-OB

REPLICATION

Pre-OC

Strontium
OB OB OB

DIFFERENTIATION

Strontium
BONE RESORBING ACTIVITY

OC

+ BONE FORMING ACTIVITY

Bone
Ref 2: Marie PJ et al. Calcif Tissue Int. 2001;69:121-129.

Strontium increases bone mineral density

Lumbar BMD1 = +14.4 % over 3 years Mean change (%) 16 12 8 4 0 -4 36 Time (mo) 0 * placebo * Protelos * *

Femoral neck BMD1 = +8.3 % over 3 years

Mean change (%) * 8 * 4 * p<0.001 0 * Protelos * *

* p<0.001 placebo

0
1

12

18

24

30

12

18

24

30

36 Time (mo)

mean relative change from baseline versus placebo (p<0.001)

Meunier P J et al. N Engl J Med. 2004; 350:459-468.

Strontium reduces the risk of vertebral fracture (SOTI)

Patients (%) 35 30 25 20 15 10 5 0 First year 0-3 years

- 41%* NNT = 9 - 49%*

Protelos 2 g/day placebo

RR=0.51, 95%CI [0.36 ; 0.74] * p<0.001 RR=0.59, 95%CI [0.48 ; 0.73] * p<0.001
Meunier P J et al. N Engl J Med. 2004; 350:459-468.

Strontium ranelate reduces non-vertebral fracture risk (TROPOS)

% patients with OP-related major non-vertebral fractures over 3 years

12 10 8 6 4 2 0

19 %*
95% Cl 0.66-0.98

* p=0.031

Placeb o n=2537

Strontium ranelate n=2555

1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5): 2816-2822. 2. Reginster JY, Hoszowski K, Roces Varela A et al. Bone 2003; 32(5): S94.

Strontium ranelate reduces hip fracture in patients at higher risk (> 74 yr-old and T-score <-2.4) TROPOS
8 7 6

36%*

n=1977 Strontium ranelate 2 g/day n=982 Placebo n=995

Patients (%)

5 4 3 2 1 0

0-3 years ITT, over 3 years: RR = 0.64 95% CI 0.412; 0.997 ] *p = 0.046

1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5):2816-2822.

NICE guidelines - Teriparatide

Secondary prevention of osteoporotic fragility fractures in women aged 65 year and over who have had an unsatisfactory response to bisphosphonates and Have an extremely low BMD (T score -4) or Have a very low BMD (T score -3) with more than 2 fractures plus 1 or more additional age independent risk factor