1. OSTEOPOROSIS: A HOT TOPIC!
Dr Felicity Kaplan

2. Osteoporosis
Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture
Osteoporosis is present when the bone mineral density
or bone mineral content is over 2.5 standard deviations
below the young adult mean (–2.5 T-score)
Osteoporosis is a skeletal disorder characterised by compromised bone strength, predisposing a person to an increased risk of fracture1
This risk increases as bone mineral density (BMD) decreases but factors other than the amount of bone contribute to fracture risk
Although bone mineral measurements may provide an index of the risk of fracture, they do not reflect all elements of the risk, which vary with the techniques used, age, cause of bone loss (e.g. postmenopausal osteoporosis or glucocorticoid-induced osteoporosis) and site of interest
However, there are four general diagnostic categories2:
Normal: BMD within 1 SD of the young adult reference mean
Low bone mass (osteopenia): BMD >1 SD below the young adult mean but <2.5 SD below this value
Osteoporosis: BMD 2.5 SD below the young adult mean
Severe osteoporosis: BMD 2.5 SD below the young adult mean in the presence of one or more fragility fracture
__________
1. Consensus Development Conference, JAMA 2001; 285:785–795.
2. WHO Study Group, WHO Technical Report Series, 843, 1994.

3. Age Related Changes in Bone Mass
Attainment of Peak
Bone Mass
Consolidation
Age-related Bone Loss
Menopause
Bone Mass
Men
This figure illustrates the changes in bone mass throughout life and shows the rapid bone loss that occurs in women at the menopause
Bone mass in both men and women increases until a peak is attained at around age 30 years. In both sexes, a slow rate of bone loss starts at around age 40 years
However, in women, the accelerated postmenopausal phase of bone loss is superimposed on top of this slow loss phase. Rates of bone loss in postmenopausal women can be as great as 6% per year
In women, oestrogen deficiency is the major determinant of bone loss after the menopause
__________
Compston JE. Clin Endocrinol 1990; 33:653–682.
Fracture
Threshold
Women
Age (years)
Compston JE. Clin Endocrinol 1990; 33:653–682.

5. Clinical Impact of Osteoporosis Over Time
Symptoms
Neck becomes weak
Pain in back
Breathing difficulties
Indigestion & GOR
Stress incontinence
Difficulty with mobility following a fracture
Signs
Kyphosis
Loss of height
Abdo bulges
Clinically diagnosed fracture
Fractures are an important consequence of osteoporosis and this slide shows some of the effects it can have on a patient
Osteoporosis can initially exist without many signs or symptoms. However, over time, more symptoms due to deformity will present and may result in decreased quality of life for the patient
The clinical signs are deformity such as kyphosis and loss of height. In addition, the patient may complain of a number of symptoms
Pain can be present in the whole or part of the back, and the vertebral deformity can lead to other complications such as breathing difficulties and digestive problems
Moreover, fractures can impair mobility. Overall, these factors can combine to lead to a loss of independence and dignity

6. Risk Factors For Osteoporosis
For women – a lack of oestrogen caused by:
Early menopause (before the age of 45 years)
Early surgical menopause (before the age of 45 years), especially if both ovaries are removed (oophorectomy)
Missing periods for 6/12 or more (excluding pregnancy) as a result of over-exercising or over-dieting
For men
Low levels of testosterone (hypogonadism)
The following two slides show many of the risk factors for osteoporosis
Hormones play a key role in osteoporosis in both men and women, though women are at greater risk than men
The deficiency of oestrogen after menopause is known to be the primary cause of postmenopausal osteoporosis in women and, therefore, any early menopause (surgically or otherwise) is a strong risk factor
Missing periods for 6 months or more can also upset the normal hormone balance in younger women, lowering oestrogen levels and thus increasing the risk of osteoporosis
Similarly, an increased risk of osteoporosis in men can result from low levels of testosterone (either from a problem with the testes themselves or the pituitary gland, which controls testosterone production)
__________
National Osteoporosis Society
National Osteoporosis Society

7. Risk Factors For Osteoporosis
For men and women
Low body weight
Maternal history of a hip fracture
Malabsorption, inflammatory bowel disease and gastric surgery
Use of oral glucocorticoids and other Rx’s…
Long-term immobility
Heavy drinking
Smoking
There are additional risk factors for osteoporosis for both men and women, some of which cannot be modified (such as a maternal history of hip fracture), but there are other modifiable factors that relate to lifestyle
Both medical disorders and some of the medicines used to treat them can also contribute to osteoporosis. Glucocorticoids are certainly a class of drugs commonly associated with osteoporosis
Finally, a patient considered to be at risk should also be offered lifestyle and nutritional advice. Poor diet, smoking and excessive drinking are all associated with the development of osteoporosis
__________
National Osteoporosis Society
National Osteoporosis Society

8. Bone-unfriendly drugs
TZDs
PPIs (studies suggest increased fracture risk)
Aromatase inhibitors eg anastrozole
Ovarian suppressing agents (depot-medroxyprogesterone acetate)
Risk assess after 2 years
Androgen deprivation therapy (PCa)
Anticonvulsants esp Phenytoin/CMZ
Heparin

9. Current treatments in OP
Antiresorptive
Estrogens and SERMs
Bisphosphonates
Calcitonin
Denosumab
Anabolic (stimulate bone formation)
Parathyroid hormone
Dual action agents
Strontium ranelate

12. Vitamin D levels 25-OHD Vit D status Manifestation Management
<25 nmol/l Deficient Rickets/ Osteomalacia High-dose calciferol
25-50 nmol/l Disease risk Vit D supps
50-75 nmol/l Adequate Healthy Lifestyle advice
>75 nmol/l Optimal Healthy None
Divide by 2.5 for ug/L

13. Treatment of vitamin D deficiency
Deficiency (25-OHD <25 nmol/l)
IU calciferol daily or IU calciferol weekly for 8-12 weeks* or
Calciferol or IU orally or by intramuscular injection once or twice

14. Treatment of vitamin D insufficiency
Insufficiency (25-OHD nmol/l) or maintenance therapy following deficiency
IU calciferol daily or
IU calciferol weekly
*To convert IU to μg of calciferol, divide by 40.
†One off high dose treatments are effective, but should be followed by a maintenance therapy dose of calciferol.

15. Hormone replacement therapy

16. HRT: A CONSENSUS Prime role of HRT is relief of menopausal Sx
Risks/benefits need to be explained to each woman (breast Ca extra 2-6 cases per 1000 women treated with HRT for 5 years)
Use lowest effective estrogen dose, assess CV risk
Review need annually (esp aged>60)

17. HRT: A CONSENSUS Can give up to age 50 if prem menopause
Do not use as primary or secondary prev. of CAD/CVA, or Alzheimers
Transdermal estrogen has lower DVT risk

18. RALOXIFENE SERM licensed for OP
Reduces vertebral (not non-vertebral) fracture risk
Reduces development of new breast Ca.
No increased risk of CVD (reduces CV events!)
Increased risk of thromboembolism
May worsen flushes
Well tolerated, easy dosing

19. NICE TA 2005: SERMs (secondary prevention)
Raloxifene - alternative in women for whom bisphosphonates are contraindicated or not tolerated
Patients not responding to bisphosphonates
Patients physically unable to comply with the recommendations for use of bisphosphonates
This slide summarises the NICE guidance on when SERMs should be prescribed:
Raloxifene - recommended as an alternative treatment option in women for whom bisphosphonates are contraindicated or not tolerated
Patients not responded to bisphosphonates
Patients physically unable to comply with the recommendations for use of bisphosphonates
______________________
Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

20. BISPHOSPHONATES
Etidronate, risedronate, alendronate, ibandronate, zoledronate
Interfere with action of osteoclasts
Alendronate and risedronate firstline option in postmenopausal osteoporosis
Strict dosing instructions
Consider renal function!

21. PARATHYROID HORMONE PEPTIDE (Teriparatide / Forsteo)

22. NICE 2005: (secondary prevention)
Teriparatide – use in women >65 years unresponsive to / intolerance of bisphosphonates, and:
with extremely low BMD (<-4)
with very low BMD (<-3), multiple fractures PLUS an additional risk factor
This slide summarises the NICE guidance on the use of parathyroid hormones (currently teriparatide only)
Patients with extremely low BMD
Patients with extremely low BMD, multiple fractures PLUS an additional risk factor
______________________
Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005
National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

23. Strontium ranelate Protelos

24. Clinical use of strontium ranelate
In women with postmenopausal osteoporosis:
alternative to bisphosphonates, particularly in the elderly
if potential for upper gastrointestinal complications
failed (intolerance or inadequate response) to treatment with other osteoporosis therapies
Beware rash (DRESS) and VTE (RR 1.4)
Protelos is indicated for patients with postmenopausal osteoporosis:
As a first line alternative to bisphosphonate therapy, particuarly in the elderly
In those with a history or potential for upper gastrointestinal complications
In women who have tried/failed (intolerance or inadequate response) treatment with other osteoporosis therapies.

25. DENOSUMAB: A NEW TREATMENT

26. Emerging Rx’s in osteoporosis Prof Compston 2010
Denosumab
Monoclonal Ab to RANKL which drives osteoclasts
Subcut every 6/12! 60mg
Dramatic and quick effect
Fracture reduction similar to Zoledronate
Cost similar to risedronate (in 2010)!
NICE appraised

27. Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival
OPG Denosumab
CFU-GM
Prefusion Osteoclast
Hormones Growth Factors
Cytokines
Osteoclast Formation, Function, and Survival Inhibited
Denosumab is the first fully human monoclonal antibody in clinical development that specifically targets RANK ligand, an essential mediator of osteoclast formation, function, and survival. 1,2
References
Lewiecki EM. RANK ligand inhibition with denosumab for the management of osteoporosis. Exper Opin Biol Ther. 2006;6:
McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:
Osteoblasts
Bone Resorption Inhibited
Bone Formation
Adapted from: Boyle WJ, et al. Nature. 2003;423: 27

28. The Effect of Denosumab on Fracture Risks at 36 Months Phase 3: The FREEDOM Trial
ARR = 1.5%
RRR = 20% P = 0.01
Placebo
Denosumab
ARR = 4.8%
RRR = 68% P < 0.001
In the analysis of the primary endpoint, the relative risk of new vertebral fractures was (95% confidence interval [CI]: 0.26–0.41) for denosumab vs placebo, representing a 68% reduction (P < 0.001).1
The percentages of new and multiple new vertebral fractures are calculated for 3,702 subjects in the denosumab group and 3,691 in the placebo group who underwent spinal radiography at baseline and during ≥ 1 visit after baseline.
The percentage of nonvertebral, hip, and new clinical vertebral fractures are cumulative Kaplan-Meier estimates for 3,902 subjects in the denosumab group and 3,906 in placebo group.
The hazard ratio of denosumab vs placebo was1:
0.80 (95% CI: 0.67–0.95) for nonvertebral fractures, representing a 20% reduction (P = 0.01)
0.60 (95% CI: 0.37–0.97) for hip fractures, representing a 40% reduction (P = 0.04)
[Not shown] 0.31 (95% CI: 0.20–0.47) for new clinical vertebral fractures, representing a 69% reduction (P < 0.001) [Note: clinical vertebral fracture is different from the primary endpoint of vertebral fracture]
[Not shown] 0.39 (95% CI: 0.24–0.63) for multiple new clinical vertebral fractures, representing a 61% reduction (P < 0.001)
Analysis of efficacy was based on intent-to-treat principle.1
The study was designed to maintain an overall significance level at 0.05 despite the multiple comparisons.1
Statistical significance of the primary endpoint was required before the secondary and other fracture endpoints would be analyzed.
The absolute risk reduction was calculated based on the difference in incidence at month 36 for the primary endpoint.
The difference in the Kaplan-Meier estimates at month 36 was used to calculate the absolute risk reduction for the secondary endpoints.
References
Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:
ARR = 0.5%
RRR = 40% P = 0.04
Primary Endpoint
ARR = absolute risk reduction; RRR = relative risk reduction
Cummings SR, et al. N Engl J Med. 2009;361: 28

29. Proven osteoporotic fracture reduction throughout the skeleton
PROLIA®: PROTECTION AGAINST FRACTURE
Proven osteoporotic fracture reduction throughout the skeleton 6 P
PROLIA®: PROTECTION AGAINST FRACTURE
Prolia®: proven osteoporotic fracture reduction throughout the skeleton1
• FREEDOM was an international, randomised, placebo-controlled trial
• Patients received subcutaneous injections of either 60 mg Prolia® or placebo every 6 months for 36 months
• The study included 7,868 women aged 60–90 years old with a bone mineral density (BMD) T-score of less than –2.5, but not less than –4.0, at the lumbar spine or total hip.
• Approximately 24% of the study population had a vertebral fracture at baseline, and about 32% of patients were aged ≥ 75 years. The primary endpoint was the incidence of new vertebral fractures1
In FREEDOM - one of the largest registrational studies ever conducted in postmenopausal osteoporosis (7,868 patients enrolled) - Prolia® significantly reduced the risk of osteoporotic fractures at vertebral, hip and non-vertebral sites1
Presenters Notes Reference:
1. Cummings SR et al. N Engl J Med 2009; 361: 756–765.
The absolute risk reductions demonstrated for Prolia® versus placebo were 4.8%, 1.5% and 0.5% for vertebral, non-vertebral and hip fractures respectively. 1
In the pivotal FREEDOM study (published in the New England Journal of Medicine), Denosumab reduced the risk of fracture at key osteoporotic fracture sites versus placebo 29

30. Percent Change From Baseline (Least Squares Mean ± 95% CI)
Effects of Treatment on Femoral Neck BMD Over 12 Months Phase 3: The STAND Trial
2.0
Alendronate 70 mg QW (n = 241)
Denosumab 60 mg Q6M (n = 246) *
1.6 *
1.2
Percent Change From Baseline (Least Squares Mean ± 95% CI)
0.8
Significantly greater gains in BMD were observed at month 12 at the femoral neck with denosumab therapy than with alendronate therapy (P ≤ ).1
BMD was significantly improved at all measured femoral sites as early as month 6 with denosumab as compared with alendronate (P < 0.05).1
NB: The following figure presents the least-squares mean and the associated 95% confidence interval around the least-squares change from baseline for each group. Even though the CIs overlap, statistical significance is demonstrated at months 6 and 12 based on the differences in the least-square mean between the denosumab and alendronate groups (data not presented). For a significant result to be demonstrated in clinical trials, the CI range must not cross 0. In this study it is the difference in least-square mean between the denosumab and alendronate groups and its associated CI that is measured for statistical significance. In this case the CI does not cross 0 for both the time points measured. Therefore, there is a significant difference in the percent change in LS means between denosumab and alendronate groups. Further details on this explanation can be seen on slide 52.
References
Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy J Bone Miner Res. 2010;25:72-81
0.4
0.0 6 12
Study Month
n = number of patients who have a baseline and ≥ 1 postbaseline evaluation.
*P < 0.01.
Adapted from: Kendler DL, et al. J Bone Miner Res. 2010;25:72-81 30

31. Adverse Events Over 36/12 Adverse events, n (%) Placebo (n = 3,876)
Denosumab 60 mg Q6M
(n = 3,886)
P value
Serious adverse events
Malignancy
125 (3.2)
144 (3.7)
0.28
Infection
133 (3.4)
159 (4.1)
0.14
Cardiovascular events
178 (4.6)
186 (4.8)
0.74
Stroke
54 (1.4)
56 (1.4)
0.89
Coronary heart disease
39 (1.0)
47 (1.2)
0.41
Peripheral vascular disease
30 (0.8)
31 (0.8)
0.93
Atrial fibrillation
29 (0.7)
0.98
Serious adverse events occurring with  0.1% incidence and P  0.01
Cellulitis (includes erysipelas)
1 (< 0.1)
12 (0.3)
0.002
Concussion
11 (0.3)
0.004
Serious adverse events of cellulitis were reported in 12 patients (0.3%) in the denosumab group and one subject (< 0.1%) in the placebo group (p = 0.002).1
In order to adjust to multiple comparisons of many adverse events, the following prespecified criteria were used1:
Serious adverse events reported for at least 0.1% of patients and for which P ≤ 0.01
The data shown above does not include all1:
152 MedDRA preferred terms of serious adverse events occurring at an incidence of at least 0.1% in either treatment arm
References
Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:
Adapted from: Cummings SR, et al. N Engl J Med. 2009;361: 31

32. Factors influencing treatment
PROLIA®: REAL WORLD
Factors influencing treatment
Efficacy
Adherence
Cost
Convenience/ patient choice
Safety/ tolerability

33. Approximate annual costs 2012 (£)
Denosumab 366
Alendronate 12
Risedronate 22
Zoledronate IV 267
Raloxifene 259
Strontium 353
Teriparatide sc 3308

34. In a head-to-head, double-dummy study, 77%
In a head-to-head, double-dummy study, 77%* of patients preferred a 6-monthly injection to a weekly oral tablet
* Among patients who reported a preference (n = 1322, p < )

35. NICE: Denosumab recommended by NICE for the primary and secondary prevention of osteoporotic fractures in postmenopausal women 18
Denosumab is a cost effective use of NHS resources in the primary and secondary prevention of fractures in postmenopausal women for whom oral bisphosphonates* are unsuitable
There is good quality evidence to support the clinical effectiveness of denosumab compared with placebo.
Denosumab may improve adherence to therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates.
Secondary and primary care have a role to play in the delivery of denosumab. *

36. NICE: Denosumab for the secondary prevention of fractures
a treatment option for secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:
who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments.
NICE: Denosumab (Prolia®) for the secondary prevention of fractures
For secondary prevention of fractures, the NICE Appraisal Committee noted that denosumab had an incremental
cost effectiveness ratio (ICER) of £2,046/QALY gained compared to raloxifene (age 70, T-score < -2.5) in the base-case
presented by the manufacturer. Denosumab dominated strontium ranelate and compared with no treatment the ICER
was £12,381/QALY gained.
The NICE Appraisal Committee therefore concluded that treatment with denosumab was considered to be a cost
effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral
bisphosphonates are unsuitable. Denosumab may also provide an alternative treatment option that would be costeffective
use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology
appraisal guidance 161. Therefore the NICE Appraisal Committee concluded that denosumab may provide an alternative
treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with
teriparatide as defi ned in NICE technology appraisal guidance 161. 36

37. NICE: Denosumab for the primary prevention of fractures
a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at
increased risk of fractures:
who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and
who also have a combination of T-score, age and number of independent clinical risk factors for fracture as indicated in the following table:
NICE: Denosumab (Prolia®) for the primary prevention of fractures
For primary prevention of fractures, the NICE Appraisal Committee noted that denosumab dominated strontium
ranelate. For denosumab vs no treatment the ICER was £29,223. The NICE Appraisal Committee concluded that
treatment with denosumab was considered to be a cost effective use of NHS resources as a treatment option only for
postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have
the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium
ranelate. 37

38. Number of independent clinical risk factors for fracture
Age (years) 1 2
65–69 –a
-4.5
-4.0
70–74
-3.5
75 or older
-3.0

39. QOF
Osteoporosis indicators approved for inclusion on QOF menu from 4/2012
Payment for
prospective register of patients with fragility fractures
Treating those with fragility fracture with appropriate Rx

40. The Domino Fracture Effect
This ‘domino fracture effect’ can lead to impaired mobility and have devastating consequences on a patient’s quality of life through a decline of independence and dignity