Optimizing the management of osteoporosis in elderly patientsAmgen symposium at the European Calcified Tissue Society (ECTS) Congress, Salzburg, Austria Sunday 14 May 2017, 12:30–14:00

Approximately 40% of women aged >50 years will experience a fracture in their lifetime,5 and the risk of subsequent fracture significantly increases following the first event.6

In addition, site-specific fracture patterns change with age; in a study of the pattern of sites of osteoporotic fractures, 39% of all fractures in 50–54 year old women were forearm fractures, with hip fractures making up only 4% of the total. By contrast, among 85–89 year olds, the majority of fractures occurred at the hip (36%), with distal forearm making up a smaller proportion (13%).7

Perhaps of most concern is the increased risk of subsequent fracture and death following the first event. In a study of women who had experienced a hip fracture, followed for up to 22 years or until death, 45% of patients experienced another fracture, with an average of 2.3 fractures per patient.8 All-cause and excess mortality was significantly higher than in matched controls.9 It is therefore important to identify elderly patients at increased risk of fracture, in order to prevent these life-changing events during their remaining years.

Strategies to identify patients at increased risk of fracture

Current strategies to identify older patients (≥50 years old) at increased risk of fracture include:10

• Assessment of clinical risk factors (e.g. older age, previous fragility fracture)

• Dual-energy X-ray absorptiometry (DXA) scan and other imaging techniques

• Screening for underlying secondary causes

How can we best identify elderly patients with increased risk of fracture?Kristina Åkesson

The Amgen-sponsored symposium at the ECTS 2017 Congress provided an interactive educational opportunity for delegates, and featured two presentations from international experts in the field of osteoporosis. The symposium was led by Heinrich Resch (Austria) as Meeting Chair, joined by Kristina Åkesson (Sweden) and Socrates Papapoulos (Netherlands), who shared their opinion on optimizing the management of osteoporosis in elderly patients.

Heinrich Resch welcomed delegates to the meeting, and gave an overview of the incidence of hip fracture in elderly patients. He summarized data from an Austrian epidemiological study from 1989–2008, which demonstrate that the age-standardized incidence of both hip and proximal humerus fractures increases with time.1–3 A recent study that examined almost half a million patients who presented with de novo fractures produced similar findings, and indicated those patients suffering a fracture are subsequently at high risk of developing further fractures.4 This highlights that fractures present a significant burden to the health of the elderly population.

How can we best identify elderly patients with increased risk of fracture? - Kristina Åkesson | 2

40% OF WOMEN AGED > 50 YEARS WILL EXPERIENCE A FRACTURE IN THEIR LIFETIME, AND THE RISK OF SUBSEQUENT FRACTURE SIGNIFICANTLY INCREASES FOLLOWING THE FIRST EVENT5,6

Information yielded from these screening procedures can be interpreted to assess the risk of fracture using several tools, including:10

• Fracture Risk Assessment Tool (FRAX)

• Garvan fracture risk calculator

• Q-fracture

Risk factors for fracture

Low BMD is directly correlated with high risk of experiencing a fracture, however, many patients do not have low BMD when they experience their first fracture.11 It is therefore important to consider other factors when screening patients for high fracture risk.

Numerous factors are associated with high risk of fracture, including comorbidities, a history of previous fractures, increasing age and female gender. Furthermore, certain medications are associated with increased fracture incidence, although not necessarily associated with decreases in BMD.12 In addition, gait speed assessment is a simple tool to determine an individual’s physical and cognitive function, and tends to improve the predictive ability of FRAX in women aged 69–79 years.13

Another factor that should be considered when assessing an older patient’s risk of fracture is their degree of frailty. Frailty signifies a high state of vulnerability and risk of adverse health outcomes, such as fractures. In a 10-year study examining frailty in community-dwelling women of 75 years old, frailty increased by 6–7% annually during follow-up. In addition, more of the frailest women at age 75 fell in the previous 12 months, compared with those who were least frail (45% versus 14%, respectively). The incidence of hip fractures was also greater in the most frail patients.14

Secondary fracture prevention

Various initiatives have been implemented within health care systems for the identification, treatment and prevention of secondary fractures, such as Fracture Liaison Services (FLS), which are frameworks set-up to coordinate services to increase identification of patients with osteoporosis.15 Additionally, ‘Capture the Fracture’ provides a best practice framework, and sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery to improve patient care and reduce fracture-related care costs worldwide.16 However, a recent report from the United Kingdom has demonstrated that further initiatives are needed for the identification and management of osteoporosis, indicating that a DXA scan was performed in over 60% of patients aged 50–74 years, but in only 20% of patients aged ≥75 years, and was not generally recommended by physicians.17

How can we best identify elderly patients with increased risk of fracture? - Kristina Åkesson | 3

LOW BMD IS DIRECTLY CORRELATED WITH HIGH RISK OF EXPERIENCING A FRACTURE11

Long-term management of elderly patients with post-menopausal osteoporosis - Socrates Papapoulos | 4

Professor Papapoulos summarized the effects of calcium and vitamin D supplementation as an addition to pharmacological therapies for the treatment of osteoporosis in elderly patients. He also reviewed several therapeutic options for the treatment of post-menopausal osteoporosis, and presented data on alendronate, zoledronic acid and Prolia®.

It is important to correct calcium and vitamin D deficiencies and insufficiencies in patients with a high risk of fracture – it has been shown that calcium and vitamin D supplementation reduces the risk of hip fractures in elderly women with these deficiencies/insufficiencies. However, there is still a very high risk of fracture in these patients,18,19 and more must be done to reduce the incidence of these life-changing events.

A study of elderly women (aged ≥70 years) investigated the effect of risedronate or placebo, in addition to supplementation with calcium and vitamin D if serum 25-hydroxyvitamin D concentration at the time of screening was below 16 ng/ml on hip fracture. In a group of patients with confirmed osteoporosis, risedronate significantly reduced the incidence of hip fractures compared with placebo.20 This shows that the addition of risedronate to appropriate calcium and vitamin D supplementation can further reduce the risk of fracture in elderly women

with osteoporosis.

However, in the same study, in a group of women ≥80 years of age who did not have confirmed osteoporosis, but had one non-skeletal risk factor for hip fracture (such as age, poor gait or a propensity to fall), risedronate did not significantly reduce the incidence of hip fractures compared with placebo. This indicates it is essential to select patients for treatment with risedronate on the basis of osteoporosis, as non-skeletal risk factors alone are not predictive of treatment benefit.20

A study that examined the rate of fractures in women aged ≥75 years, living in the community, who were not selected on the basis of proven osteoporosis or other known risk factors, further confirms this.21 In this study, women were randomized to receive either clodronate or placebo, and were not provided with calcium or vitamin D supplementation. After 3 years, the effect of clodronate on the incidence of hip fractures was not significant. This may be due to a lack of efficacy of clodronate, which is not widely approved for the treatment of osteoporosis, or poor treatment adherence.21

These studies indicate that while maintaining recommended levels of calcium and vitamin D, and accurately assessing a patient’s risk of fracture, more needs to be done to protect against hip fracture in this population.

A meta-analysis assessing the consistency of alendronate treatment in reduction of hip fracture risk has shown that alendronate is associated with significant reductions in the incidence of hip fracture in patients with a T-score of ≤–2.0 or a previous vertebral fracture. In addition, sub-analyses revealed that the overall risk reduction in hip fracture incidence was higher in patients who met the

Long-term management of elderly patients with post-menopausal osteoporosisSocrates Papapoulos

CALCIUM AND VITAMIN D SUPPLEMENTATION HAS BEEN SHOWN TO REDUCE THE RISK OF HIP FRACTURES IN ELDERLY WOMEN18,19

criteria of osteoporosis compared with those with unconfirmed osteoporosis.22

A post-hoc analysis of the Health Outcome and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial, evaluated the effect of zoledronic acid in elderly post-menopausal women (≥75 years old) with osteoporosis. At 3 years, zoledronic acid was associated with a significant reduction in the risk of new vertebral and non-vertebral fractures. Interestingly, the incidence of hip fracture was lower with zoledronic acid; however, did not reach statistical significance.23

The long-term efficacy and safety of Prolia® over 10 years has been established in the FREEDOM trial and its extension. In the three year FREEDOM trial, treatment with Prolia® significantly reduced the risk of new vertebral, non-vertebral and hip fractures in post-menopausal women with osteoporosis.24 Post-hoc analysis in subgroups of women with known risk factors for fracture revealed that Prolia® significantly reduced the risk of hip fractures in women aged ≥75 years or with a baseline femoral neck BMD T-score of ≤–2.5, compared with placebo.25 The FREEDOM trial extension went on to show that treatment with Prolia® continually increased BMD over 10 years without therapeutic plateau, and sustained low incidence of vertebral and non-vertebral fractures.26,27 In addition, in a large real-life effectiveness study examining the reduction in fracture incidence among

female patients with osteoporosis treated in routine clinical practice with Prolia®, raloxifene, intravenous zoledronic acid, oral bisphosphonates or teriparatide, the only treatment shown to specifically reduce hip fracture rate was Prolia®.28

Professor Papapoulos concluded his presentation by summarizing that in older, institutionalized women with vitamin D deficiency/insufficiency and low calcium intake, treatment with vitamin D and calcium supplementation effectively reduces the risk of hip fractures.18,19 However, this alone may not provide adequate protection against fracture in this patient population, and additional treatment is often required. It has been shown that in older women with osteoporosis receiving vitamin D and calcium supplementation, Prolia® treatment is associated with further reduction in the risk of hip fractures, sustained low incidence of hip fractures for up to 10 years, and a favourable safety profile,26,27 representing a promising treatment approach for this high-risk patient group.

PROLIA® CONTINUALLY INCREASES BMD OVER 10 YEARS WITHOUT THERAPEUTIC PLATEAU26,27

Long-term management of elderly patients with post-menopausal osteoporosis - Socrates Papapoulos | 5

References

1. Dimai HP, Svedbom A, Fahrleitner-Pammer A, et al. Epidemiology of hip fractures in Austria: evidence for a change in the secular trend. Osteoporos Int. 2011;22:685-92.

2. Dimai HP, Svedbom A, Fahrleitner-Pammer A, et al. Epidemiology of proximal humeral fractures in Austria between 1989 and 2008. Osteoporos Int. 2013;24:2413-21.

3. Dimai HP, Svedbom A, Fahrleitner-Pammer A, et al. Epidemiology of distal forearm fractures in Austria between 1989 and 2010. Osteoporos Int. 2014;25:2297-306.

4. Muschitz C, Kocijan R, Baierl A, et al. Preceding and subsequent high- and low-trauma fracture patterns-a 13-year epidemiological study in females and males in Austria. Osteoporos Int. 2017;28:1609-18.

5. Melton LJ, 3rd, Chrischilles EA, Cooper C, et al. Perspective. How many women have osteoporosis? J Bone Miner Res. 1992;7:1005-10.

6. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone. 2004;35:375-82.

7. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17:1726-33.

8. von Friesendorff M, Besjakov J, Akesson K. Long-term survival and fracture risk after hip fracture: a 22-year follow-up in women. J Bone Miner Res. 2008;23:1832-41.

9. von Friesendorff M, McGuigan FE, Wizert A, et al. Hip fracture, mortality risk, and cause of death over two decades. Osteoporos Int. 2016;27:2945-53.

10. Lems WF, Dreinhofer KE, Bischoff-Ferrari H, et al. EULAR/EFORT recommendations for management of patients older than 50 years with a fragility fracture and prevention of subsequent fractures. Ann Rheum Dis. 2017;76:802-10.

11. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Archives of internal medicine. 2004;164:1108-12.

12. Naismith GD, Smith LA, Barry SJ, et al. A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn's disease. J Crohns Colitis. 2014;8:1022-9.

13. Lundin H, Saaf M, Strender LE, et al. Gait speed and one-leg standing time each add to the predictive ability of FRAX. Osteoporos Int. 2017;28:179-87.

14. Ferreiro-Iglesias R, Barreiro-de AM, Otero SM, et al. Fecal Calprotectin as Predictor of Relapse in Patients With Inflammatory Bowel Disease Under Maintenance Infliximab Therapy. J Clin Gastroenterol. 2015;50:147-51.

15. McLellan AR, Gallacher SJ, Fraser M, et al. The fracture liaison service: success of a program for the evaluation and management of patients with osteoporotic fracture. Osteoporos Int. 2003;14:1028-34.

16. Akesson K, Marsh D, Mitchell PJ, et al. Capture the Fracture: a Best Practice Framework and global campaign to break the fragility fracture cycle. Osteoporos Int. 2013;24:2135-52.

17. Sandborn WJ, Feagan B, Wolf D, et al. A randomized, double-blind, placebo-controlled induction trial of an oral S1P receptor modulator (RPC1063) in moderate to severe Ulcerative Colitis: Results of the TOUCHSTONE study. European Crohn's and Colitis Organisation 10th Congress. 2015:OP024.

18. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992;327:1637-42.

19. Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002;13:257-64.

20. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-40.

21. McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res. 2007;22:135-41.

22. Papapoulos SE, Quandt SA, Liberman UA, et al. Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporos Int. 2005;16:468-74.

23. Boonen S, Black DM, Colon-Emeric CS, et al. Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc. 2010;58:292-9.

24. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.

25. Boonen S, Adachi JD, Man Z, et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96:1727-36.

26. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5:513-23.

27. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int. 2015;26:2773-83.

28. Yusuf A, Guo H, Balasubramanian A, et al. Effectiveness of bone therapies in routine clinical practice: two retrospective database analyses using US Marketscan and Medicare. Osteoporos Int. 2016;27(Suppl. 1):P190.

References | 6

Prolia® (denosumab) Abbreviated Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Prolia. Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60mg of denosumab in 1ml solution for injection for single use only. Contains sorbitol (E420). Indication: Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. Dosage and Administration: 60mg Prolia administered as a subcutaneous injection once every 6 months. Patients must be supplemented with calcium and vitamin D. No dosage adjustment required in patients with renal impairment. Not recommended in paediatric patients under 18 years of age. Give Prolia patients the package leaflet and patient reminder card. Contraindications: Hypocalcaemia or hypersensitivity to the active substance or to any of the product excipients. Special Warnings and Precautions: Hypocalcaemia: Identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia, within 2 weeks after the initial dose. Measure calcium levels if suspected symptoms of hypocalcaemia occur. Renal Impairment: Patients with severe renal impairment (creatinine clearance < 30ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Regular monitoring of calcium levels in these patients is especially important. Skin infections: Patients receiving Prolia may develop skin infections (predominantly cellulitis) requiring hospitalisation and if symptoms develop then they should contact a health care professional immediately. Osteonecrosis of the jaw (ONJ): ONJ has been reported rarely with Prolia 60mg every 6 months. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventative dentistry and an individual benefit:risk assessment is recommended prior to treatment with Prolia in patients with concomitant risk factors. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with Prolia. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to Prolia administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Atypical femoral fracture (AFF): AFF has been reported in patients receiving Prolia. Discontinuation of Prolia therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. Concomitant medication: Patients with rare hereditary problems of fructose intolerance should not use Prolia. Dry natural rubber: The needle cover of the

pre-filled syringe contains dry natural rubber (a derivative of latex) which may cause allergic reactions. Interactions: Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). There are no clinical data on the co-administration of denosumab and hormone replacement therapy (HRT), however the potential for pharmacodynamic interactions would be considered low. Pharmacokinetics and pharmacodynamics of Prolia were not altered by previous alendronate therapy. Fertility, pregnancy and lactation: There are no adequate data on the use of Prolia in pregnant women and it is not recommended for use in these patients. It is unknown whether denosumab is excreted in human milk. A risk/benefit decision should be made in patients who are breast feeding. Animal studies have indicated that the absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. No data are available on the effect of Prolia on human fertility. Undesirable Effects: The following adverse reactions have been reported: Very common (≥ 1/10) pain in extremity, musculoskeletal pain. Common (≥ 1/100 to < 1/10) urinary tract infection, upper respiratory tract infection, sciatica, cataracts, constipation, abdominal discomfort, rash, and eczema. Uncommon (≥ 1/1000 to < 1/100): Diverticulitis, cellulitis, and ear infection. Rare (≥ 1/10,000 to < 1/1,000): Osteonecrosis of the jaw, hypocalcaemia (including severe symptomatic hypocalcaemia) and atypical femoral fractures. In the postmarketing setting, musculoskeletal pain (including severe cases) rare cases of severe symptomatic hypocalcaemia, and rare events of hypersensitivity (including rash, urticaria, facial swelling, erythema and anaphylactic reactions) have been reported. Please consult the Summary of Product Characteristics for a full description of undesirable effects. Pharmaceutical Precautions: Prolia must not be mixed with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Prolia may be exposed to room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container. Once removed from the refrigerator Prolia must be used within this 30 day period. Do not freeze. Keep in outer carton to protect from light. Legal Category: POM. Marketing Authorisation Number: EU/1/10/618/003. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Limited, 240 Cambridge Science Park, Milton Road, Cambridge, CB4 0WD. Prolia is a registered trademark of Amgen Inc. Date of PI preparation: June 2015 (Ref: UKIE-P-162-0515-106061)

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Amgen Limited on +44 (0) 1223 436712

Adverse events should be reported to the appropriate health authority in your country

Local countries to insert approved PI

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Dammstrasse 23, CH-6301 Zug, Switzerland. Date of preparation: June 2017

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