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Home , Pamidronic acid

‘Keeping strength in the face of adversity’: -induced

Mo Aye Consultant Endocrinologist Centre for Metabolic Disease Hull Royal Infirmary

Q Can you name a medical specialty that doesn’t use systemic steroids at all? Q Who is this?

In: J.F.K. File, Hidden Illness, Pain and Pills. New York Times 17 November 2002

Christine …

• Dr CM 4/11/1946 (70y) • Previous polymyalgia rheumatica (2010) • Iatrogenic hypoadrenalism and ‘withdrawal syndrome’ • Current dose: prednisolone 15 mg • Fractures: fibula (51y), ulna (59y), *humerus (66y)

Does not wish to have any treatment for GIO Q What is the fracture risk?

10-year risk of osteoporotic fractures 100%

90%

80%

70% 60% 60%

50% 40% 40% 30% 30% 20% 20% 10% 10% 5%

0% Q What level of risk is ‘acceptable’?

10-year risk of osteoporotic fractures 100%

90%

80%

70% 60% 60%

50% 40% 40% 30% 30% 20% 20% 10% 10% 5%

0% Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects Epidemiology

• UK General Practice Research Database (now Clinical Practice Research Datalink) • 0.9% of UK adult population (GPRD) • 2.5% of those aged 70-79

• US epidemiological data: • 1% of all adults • 3% of adults > 50 years

• Second most common form of osteoporosis • 1:5 steroid users will fracture in 1y • 30-50% of steroid users will fracture Risk of fractures: dose duration relationship

• Fractures risk rises within 3 months, peaks at 12 months [van Staa 2000]

• Prednisolone 2.5-7.5 mg/d [De Vries 2007] • Vertebral fractures 2 x • Femoral fractures 1.5 x

• Prednisolone 30mg/d, cumulative 5 g (~6mo) • Vertebral fractures 14 x • Femoral fractures 3 x

van Staa TP et al. Rheumatology 2000;39:1383 De Vries F et al. Arthritis Rheum 2007;56:208 Why do fractures matter?

• Vertebral fractures • Pain — wide-range (painless fractures to bed-bound) • Deformity — posture, chest expansion • Loss of independence – decompensation • Increased risk of fractures: 5 x

• Femoral fractures • 10% die in 1 month, 30% die in 1 year • 50% of survivors institutionalised RR of fractures: pred (≥15/d), cumulative

de Vries F. Arthritis & Rheumatism. 2007;56(1):208 DOI 10.1002/art.22294 Q Why is the risk not linear? Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects

Q How should we assess fracture risk?

• DXA scan?

• Risk algorithm: FRAX https://www.sheffield.ac.uk/FRAX ?

• Both? Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects Densitometric diagnosis

2

1

0

-1 T-score -2 Z-score -3

-4

-5 20 30 40 50 60 70 80 90 100 Densitometric diagnosis

2

1

0

-1 T-score Z-score -2 Z-score -3

-4

-5 20 30 40 50 60 70 80 90 100 T -4.0

T -2.0 Fracture risk assessment tool (FRAX) https://www.sheffield.ac.uk/FRAX

27%

6.2%

https://www.sheffield.ac.uk/FRAX/ Fracture risk assessment tool (FRAX) Q Do you believe it?

What are the limitations of FRAX? Limitations of FRAX: age

• Not applicable if <40 y

• Antiresorptive agents are relatively contraindicated in women of reproductive potential Limitations of FRAX: previous fracture

• Previous fracture: • Vertebral fracture: 3-5 x • Femoral fracture: 2-3 x

• Fractures beget fractures Limitations of FRAX: steroid dose

• FRAX assumes 2.5-7.5 mg pred

• If >7.5mg: • ↑ Major #risk by 15% • ↑ Hip # risk by 20%

• If <2.5mg: • ↓ Major # risk by 20% • ↓ Hip # risk by 35% T -4.0

T -2.0 Limitations of FRAX: lumbar spine BMD

• FRAX uses femoral neck BMD

• LS BMD is (usually) lower

• Increase/decrease fracture probability by 10% for each one standard deviation T-score difference between lumbar spine and total hip Adjusted risk

Major fractures Hip fracture Calculated by FRAX 27% 6.2% Adjusted for steroid dose Revise up by 15% Revise up by 20% (Prednisolone >7.5mg) +4.05% +1.24% Adjusted for LS BMD Revise up by 20% LS T-score -4.0 — Cf NOF T-score -2.0 +5.40% Adjusted risk for fractures 36.45% 7.44% Adjusted risk

Major fractures Hip fracture Calculated by FRAX 27% 6.2% Adjusted for steroid dose Revise up by 15% Revise up by 20% (Prednisolone >7.5mg) +4.05% +1.24% Adjusted for LS BMD Revise up by 20% LS T-score -4.0 — Cf NOF T-score -2.0 +5.40% Adjusted risk for fractures 36.45% 7.44% Adjusted risk

Major fractures Hip fracture Calculated by FRAX 27% 6.2% Adjusted for steroid dose Revise up by 15% Revise up by 20% (Prednisolone >7.5mg) +4.05% +1.24% Adjusted for LS BMD Revise up by 20% LS T-score -4.0 — Cf NOF T-score -2.0 +5.40% Adjusted risk for fractures 36.45% 7.44% Adjusted risk

Major fractures Hip fracture Calculated by FRAX 27% 6.2% Adjusted for steroid dose Revise up by 15% Revise up by 20% (Prednisolone >7.5mg) +4.05% +1.24% Adjusted for LS BMD Revise up by 20% LS T-score -4.0 — Cf NOF T-score -2.0 +5.40% Adjusted risk for fractures 36.45% 7.44% Q What is Christine’s fracture risk?

10-year risk of osteoporotic fractures 100%

90% 80% 36.45% 70% 60% 60%

50% 40% 40% 30% 30% 20% 20% 10% 10% 5%

0% Q Should we treat Christine? Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects Guidelines

• National Osteoporosis Guideline Group — 2017 • American College of Rheumatology — 2017 • Scottish Intercollegiate Guideline Network (SIGN) 142 — 2015 • IOF/ECTS Glucocorticoid-induced osteoporosis Guidelines Working Group — 2012 • EULAR – 2007 • Royal College of Physicians — 2003 GIO Guidelines

RCP NOGG SIGN 142 EULAR IOF/ECTS ACR Age >65 >70 >70 and taking <40 with T <- pred 7.5-15 3.0 and pred >7.5 Dose-duration >15 mg/d Pred > 7.5 or Pred > 7.5 Pred >15 Pred ≥ 7.5 mg Over 30 y and Any dose ≥ 3 for ≥ 3 mo Any ≥ 3 mo Pred >30 mg or mo >5g/y Fracture Treat if # Treat if # Treat if # Treat if # Treat if # Treat if # T-score ≤-1.5 Part of FRAX ‘High T-score’ Above ≤-2.5 treatment threshold Bone loss — — — — — > 10%/y FRAX — Depends on Above Major OP#: age treatment 20% threshold Hip #: 3% Consider 10- 19% major OP or 1-2% hip Pragmatically,

Treat if: • Previous, recent, recurrent or multiple fractures • Age (at least 65) • At least pred 7.5 mg or > • T-score ≤ -1.5 [RCP 2003] • Corrected FRAX risk: 20% / 3% • Individualised care Q Should we advise Christine to have treatment?

• Previous fractures: • Humerus while on steroids, • Fibula and ulna in her 50s

• Age >70 • Pred >15 • Duration > 3 months • T-score -4.0 • FRAX: 36.45% | 7.44% Managing GIO

• Minimise steroid exposure: • Lowest dose/shortest time

• Treat/control the underlying condition: • May not be possible: e.g. immunosuppression

• Physical activity: • Weight-bearing activities to strengthen bone • Strength-training to improve muscle strength

• : • No outcome data of efficacy in GIO • May address sarcopenia

• Prevent falls • Treat hypogonadism (?) Q What drugs can we use? Treatment options

Class Agents Oral Parenteral bisphosphonates [Ibandronic acid] [Pamidronic acid] Selective oestrogen-receptor modifier (SERM) Raloxifene Bazedoxefene Anabolic agents – (rhPTH 1-34) [] (PTHrP) [] [] [HRT] Oral bisphosphonates

Advantages Disadvantages

Alendronate 70 mg/week (or • Affordable • GI side effects 10 mg/d) • Cost effective • Pill burden • Poor adherence Risedronate 35 mg/week • Proven outcome: • Contraindicated in poor renal (or 5 mg/d) RRR 43% for vertebral function (eGFR 30-35) fractures, NNT 31 [Allen 2016] • No data on hip fracture Ibandronate 150 mg/mo. reduction in GIO • Non-anabolic

Allen CS, Yeung JH, Vandermeer B, Homik J. Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst Rev 2016;10:CD001347-CD001347. Zoledronate (vs. RIS): HORIZON

Treatment Prevention

Reid DM, Devogelaer JP, Saag K, et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 2009;373:1253-63. Zoledronate

Advantages Disadvantages

Zoledronate • Cost effective • Requires attendance to health (Aclasta) • Adherence, not facility 5mg/y questioned • More convenient? • Contraindicated in poor renal • Avoids GI side effects function (eGFR <35) • Risk of hypocalcaemia esp. if low vitamin D <50 nmol/L • Acute phase reaction

• Risk of MRONJ • Risk of atypical femoral fractures • Non-anabolic Teriparatide, rhPTH 1-34 (vs. ALN) Vertebral fractures: 0.6% vs. 6.1%, RR 0.098, NNT 18.18

Saag KG, Shane E, Boonen S, et al. Teriparatide or Alendronate in Glucocorticoid-Induced Osteoporosis. N Engl J Med 2007;357:2028-39. Teriparatide

Advantages Disadvantages

Teriparatide • The only anabolic agent • Cost 20 µg SC daily for 2 • Reduces vertebral fractures • Daily SC injections years • Quick onset • No hip fracture data • Analgesic effect • Uncertain effect where PTH is raised (SHPT, CKD) (vs. RIS)

Saag KG, Wagman RB, Geusens P, Adachi JD, Messina OD, Emkey R, Chapurlat R, Wang A, Pannacciulli N, Lems WF: Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol 2018. Denosumab

Advantages Disadvantages

Denosumab • Potent anti-resorptive • Requires administration by a health 60 mg SC every 6 professional months • Not contraindicated in low renal • Strict 6-month schedule clearance (eGFR ≤30 ) • Risk of hypocalcaemia esp. if low vitamin D <50 nmol/L • Rapid onset/offset • Risk of MRONJ • Risk of atypical femoral fracture • Non-anabolic Outline …

• Epidemiology • Pathogenesis • Fracture risk assessment • Management • Risks/side effects Q What is this condition?

MRONJ • Previous MRONJ • Poor dental health or hygiene • Smoking • Alcohol • Steroid use •

1 in 10 000 to 1 in 100 000 (but much higher in steroid users) Q What is this condition?

Atypical femoral fracture

• Prolonged antiresorptive therapy • Potent antiresorptive • Vascular and genetic factors

1 in 1000