OSTEOPOROSIS: A HOT TOPIC! Dr Felicity Kaplan

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.

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 0 10 20 30 40 50 60 Age (years) Compston JE. Clin Endocrinol 1990; 33:653–682.

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

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 http://www.nos.org.uk/PDF/AreYouAtRisk.pdf. National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf

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 http://www.nos.org.uk/PDF/AreYouAtRisk.pdf. National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf

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

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

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

Treatment of vitamin D deficiency Deficiency (25-OHD <25 nmol/l) 10 000 IU calciferol daily or 60 000 IU calciferol weekly for 8-12 weeks* or Calciferol 300 000 or 600 000 IU orally or by intramuscular injection once or twice

Treatment of vitamin D insufficiency Insufficiency (25-OHD 25-50 nmol/l) or maintenance therapy following deficiency 1000-2000 IU calciferol daily or 10 000 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.

Hormone replacement therapy

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)

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

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

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

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!

PARATHYROID HORMONE PEPTIDE (Teriparatide / Forsteo)

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

Strontium ranelate Protelos

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.

DENOSUMAB: A NEW TREATMENT

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

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;6:1041-1050. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831. Osteoblasts Bone Resorption Inhibited Bone Formation Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342. 27

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 0.32 (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;361:756-765. 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;361:756-765. 28

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

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 ≤ 0.0121).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

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;361:756-765. Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:756-765. 31

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

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

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 < 0.0001)

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. *

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

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

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

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

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