Osteoporosis Puzzle: Next Steps Fractures with osteoporosis over - - PDF document

Osteoporosis Puzzle: Next Steps

Roger Long, MD

Professor of Pediatrics (and Internal Medicine) Division of Endocrinology University of California, San Francisco Disclosures: None 1

Burden of Osteoporosis

• Fractures with osteoporosis over the

age 50?

– 1 in 2 women – 1 in 4 men

• By 2020,

– 12.3 million in US older than 50 are expected to have osteoporosis (13.6 m by 2030)

• Prevalence:

– Highest: Mexican/American and non-Hispanic white – Lowest: Non-Hispanic blacks

NOF; USPSTF. JAMA 2018 319:2521

Normal Osteoporotic

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Burden of Osteoporosis

Osteoporotic fractures, effects of

– ~40% unable to walk independently at 1 yr – ~60% require assistance for at least 1 ADL

–Hip Fracture

• 20-30% mortality at 1 year

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When to screen?

USPSTF 2018

• Women:

– > 65 yo – < 65 yo, increased risk of fracture (using risk calculator tool)

• FRAX MOF > 8.4% (65 yo white female, no risk factors)
• Men:

– No screening recommendation as primary fracture risk is low – Per FRAX, MOF risk in 80 yo male equal to 65 yo female

NOF, ISCD, ACOG, Endocrine Society:

• Women: Similar recommendations

NOF, ISCD, Endocrine Society:

• Men:

– > 70 yo, < 70 yo with risk factors

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Who is at risk for fracture?

• Those with diagnosis of osteoporosis

– DXA scan: T scores < -2.5

• Modifiers of fracture risk:

– Previous fracture – Parent hip fracture – Female Sex – Age – Low BMI – Chronic illnesses – Glucocorticoids – Smoking – Alcohol – Falls

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WHEN to treat?

• Costs(risks) vs. benefits
• When is the risk of fracture high enough?

– Hip or vertebral fracture – T-score ≤ - 2.5 – 10 year fracture risk (FRAX)

≥ 3% hip fracture ≥ 20% major osteoporosis-related fracture*

* Generic bisphosphonate for cost-benefit analysis

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Sample FRAX Calculation:

Available at: www.shef.ac.uk/FRAX.

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WHY to treat?

• To reduce risk of fracture

» Can’t turn bones to steel, but can make them stronger 8

WHAT treatments?

Universal measures

Risk factor reduction

– Factors related to bone mass (meds, alcohol, smoking) – Factors related to falling (meds, environment)

Exercise

– Weight bearing aerobic exercise (target 30 min 3x/wk)

• Minimal skeletal loading is required to maintain skeletal mass

– Muscle strengthening (large muscle groups)

Optimize nutritional status

– Adequate protein and calories

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Calcium and Vitamin D

• Foundation for treatment regimens
• Presumed anti-fracture benefit

– When taken together

• Calcium intake (~1200 mg/day) –

ideally from diet

• Vitamin D (600-1000 units per day)

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Medication options

Anti-resorptive agent Reduce remodeling

• Bisphosphonate

Alendronate (approved 1995) Risedronate (approved 1998) Ibandronate (approved 2003) Zoledronate (Reclast) (approved 2007)

• Denosumab (approved 2010)

Anabolic agent Increase bone remodeling and modeling

• Teriparatide (approved 2002)
• Abaloparatide (approved 2017)
• Romosozumab (approved 2019)

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Bisphosphonates

• First line therapy for osteoporosis (without a high

risk of fracture)

– Fracture Risk Reduction (vs placebo)*:

• Vertebral:

33-52%

• Hip:

27-40%

• Nonvertebral: 16-22%

» Based on trials: Efficacy » Alendronate: up to 10 years » Risedronate: 7 years » Zoledronate: 6 years

*Barrioneuvo P, et al. JCEM 2019. 104:1623

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Bisphosphonate Effects

Report from ASBMR Task Force: Managing osteoporosis in patients on long term bisphosphonate therapy. JBMR 2016

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Adverse effects:

Atypical Femur Fracture (AFF)

• First reported association with BPs

in 2005

• Likely duration response

relationship

• Using previous figure (5yrs BP use):

– 2590 fractures averted for 16 AFF, Or 162 fractures/AFF

• Prodromal thigh/groin pain
• Risk likely higher in Asian

populations Osteonecrosis of the Jaw

• First reported association in 2003
• Incidence 1/10,000-100,000 pt-

years

• Advise regular dental care,

avoidance of invasive dental procedures

• Risk likely higher in Asian

populations

Adapted from Endocrinology Advisor

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Long term treatment approach: Post-menopausal women

Report from ASBMR Task Force: Managing osteoporosis in patients on long term bisphosphonate therapy. JBMR 2016

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When to restart?

• No guidelines to date
• Considerations:

– Decreasing BMD – Increasing bone turnover markers

• Suppression of BTM

– Alendronate 2-3 yrs – Risedronate/Ibandronate 1-2 yrs – Zoledronate ~3 yrs

When is there treatment failure?

• Fracture greater than 1 year into treatment
• BMD decrease > 5% or > LSC

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Alternative Therapies

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Denosumab

• Blocks osteoclast formation

– Consider in bisphosphonate intolerance or failure

• r renal insufficiency
• Fracture Risk Reduction (vs placebo)*:

– Vertebral: 68% – Hip: 44% – Nonvertebral: 20%

*Barrioneuvo P, et al. JCEM 2019. 104:1623

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FREEDOM trial

• Every 6 month

injection

• Uses immune

system to block formation of cells that resorb bone

• Similar concerns

about ONJ/atypical femur fractures Post-menopausal women, 60-90 yo, osteoporosis

Bone HG. Lancet 2017. 5:513

3 year RCT, 7 year extension/crossover

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Rebound Vertebral Fractures

• Caution when doses missed or medication
• discontinued. Vertebral fractures within 6 mo.
• Higher rates in those with prevalent fractures
• No difference in nonvertebral fracture rates
• Role of bisphosphonate to prevent

– Timing unclear

Cummings SR. JBMR 2018. 33:190

Any Multiple

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High Fracture Risk

• Severe osteoporosis

– T score < -3.5

• T score < -2.5 and fragility fracture

– Fragility fracture significance

• 1 in 5 will have another fracture in 2 years

– Vertebral fracture significance

• 5% with prevalent (date unknown) fracture and

20% with incidence (within 1 yr) will have another vertebral fracture in next year.

• Argument for first line anabolic therapy

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Anabolics

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Sclerostin secreted by osteocytes negatively regulates bone formation Romosozumab – monoclonal Ab against sclerostin

Sclerosteosis – homozygous LOF mutation

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Anabolics

• Treatment course

– Teri/Abalo: 18-24 months – Romo: 1 year

• Must follow treatment with antiresorptive

therapy to preserve gains.

• Fracture Risk Reduction (vs placebo):

Abalo Teri Romo Vertebral: 86% 73% 67% Hip: 76%* 36%* 56% Nonvertebral: 49% 38% 33% * not significant

*Barrioneuvo P, et al. JCEM 2019. 104:1623

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Teriparatide vs Risedronate

VERO study

• Post-menopausal women – high risk of

fracture – T score <-1.5 AND at least 2 moderate or 1 severe vertebral fracture.

• Randomized/double blind/double dummy
• 2 year duration
• 1366 enrolled.

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VERO: Fracture Outcome

Kendler DL. Lancet 2018. 391:230.

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Abaloparatide vs. Teriparatide

ACTIVE study

• Post-menopausal women – high risk of fracture

– T score <-2.5 AND at least 2 mild or 1 moderate vertebral fracture or fragility fracture within past 5 years. Or, > 65 yo with Tscore < -3 without fracture.

• Randomized to Abalo/Teri/Placebo
• 18 month duration
• 2463 enrolled.

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ACTIVE: Outcomes

• Equal vertebral fracture risk reduction

versus placebo

– Abalo: 86% Teri: 80%

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Romosozumab

New vertebral fractures

Langdahl BL. Lancet 2017. 390:1585; Cosman F . NEJM 2016. 375:1532; Saag KG. NEJM 2017. 377:1417.

3 trials: 29

Anabolic AEs

PTH/PTHrP

– Hypercalcemia – Hyperuricemia – Hypothetical Osteosarcoma risk

• Contraindicated in open growth plates, bone

tumors, Paget Disease, skeletal irradiation

Romosozumab

– Potential increase CV risk

• Do not use within 1 year of MI or stroke

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Questions?

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Vitamin K

• 2011: Japanese guidelines for

prevention and treatment of

• steoporosis

– Included Vitamin K treatment

• Largely based on studies that have been

retracted

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Vitamin K

• Updated meta-analysis
• In post-menopausal or osteoporotic

patients

• Vitamin K:

– Clinical fracture: OR 0.72 (0.55-0.95) – BMD and Vertebral Fx: no difference

Mott A, et al. Osteoporosis Int 2019. 30:1543

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