Orthopaedics

Osteoporosis Update: Advances in Treatment

Incidentally Discovered Vertebral Fracture

A 70 year old female smoker being evaluated for a cough presents for discussion of recently order chest xray. You explain that the CXR shows no infiltrates or masses in the lung tissue itself but there is an incidental vertebral compression fracture at T12 noted.

What do you ask next?

Delving Deeper

Upon further discussion you ascertain:

•She remembers a 2 month history of significant back pain that spontaneously resolved after a fall from standing height while working in the yard 3 years ago shortly after she retired

•She is 2 inches shorter than her peak adult height

•No previous fractures

Delving Deeper: Secondary Causes

•No current or past history use of steroids

•Alcohol intake is one glass of wine daily

•50 pack year history of smoking

•Menopause age 52

•No weight gain or weight loss

•No diarrhea or malabsorption symptoms

•Physically active and rarely falls

•Normal renal function with no kidney stones

Medical History

•PMH: –Hypertension –Hyperlipidemia

•Medications: amlodipine 5 mg, simvastatin 20 mg, multiple vitamin for “seniors”

•SH: retired school teacher

•FH: no hip fractures in either parent, mother developed Dowager’s hump

Physical Exam

•P=75, BP=135/80, Wt: 150 lbs, Ht: 66 inches, BMI=24.2

No Cushing Features

No kyphosis or pain on spinal palpation

No goiter, tremor, thyroid eye finds

Laboratory and Imaging

•DXA –Lumbar Spine Tscore -1.6 –Femoral Neck T score -1.5 –Total Hip Tscore -1.3 –FRAX 10 year Probability MOF 16%, HF 3.7%

•Secondary Evaluation is normal –CMP, phos, CBC, TSH, 24hr urine calcium/creatinine, 25D, PTH, SPEP/UPEP

What do you Advise?

Counsel for smoking cessation

Treat with appropriate calcium and vitamin D

Counsel about Fall prevention

A. Initiate treatment with pharmacotherapy

    OR

B. Reassure the patient that no intervention is needed

Smoking Cessation Reduces Fracture Risk

–FRAX 10 year Probability MOF 16%, HF 3.7%

–No Smoking: FRAX 10 year Probability MOF 16%, HF 2.2%

Fracture is a Powerful Risk Factor for Future Fracture

Relative Risk
•Thinness 1.3 If BMI <21
Smoking       1.5   If current
•Family history         
     of hip fracture      
1.6Sister
Family history         
     of hip fracture    
1.3Mother

    Spine     Non-Spine

Fractures

•Non-spine   2.2      1.5        

•Spine     
1 fracture            3.2        1.6
>/= 2 fractures  8.0       2.0

    Spine           Non-Spine
2.21.5
3.21.6
8.02.0

Mortality Following Clinical Fractures Fracture Intervention Trial

Cauley JA, et al. Osteoporos Int. 2000;11:556-561

Outcomes of Hip Fractures 

300,000 hip fractures annually1

24% excess mortality in 12 months2

50% do not recover baseline function3

25% require long-term nursing home care4

Guidelines for Osteoporosis Screening

Indication for Pharmacologic Treatment

•Initiate pharmacologic treatment in:

Those with clinical or asymptomatic hip or vertebral fracture

–Those with a T score <-2.5 at the hip, spine or femoral neck

–Those with osteopenia and a FRAX 10 yr probability >20% of major osteoporotic fracture or >3% of hip fracture

Take Home Points

•A fragility fracture is skeletal failure

•Initiate pharmacologic treatment in:

Those with clinical or asymptomatic hip or vertebral fracture regardless of T score

–Those with a T score <-2.5 at the hip, spine or femoral neck

–Those with osteopenia and a FRAX 10 yr probability >20% of major osteoporotic fracture or >3% of hip fracture

Advances in Treatment

Outline

•New long term data for Denosumab

•New data about treatment of Osteopenia

•New treatments: Abaloparatide

•New treatments: Romosozumab

Normal Bone Remodeling

FDA-Approved Osteoporosis Medications

Antiresorptives

Estrogen/HRT*

Bisphosphonates

Alendronate (Fosamax)*

Risedronate (Actonel)*

Ibandronate (Boniva)

Zoledronic Acid (Reclast)*

SERMS:Raloxifene (Evista)

Bazedoxifene (Duavee)

Calcitonin (Miacalcin)

Denosumab(Prolia)*

Anabolics

Parathyroid Hormone (Teriparatide, Forteo)

PTHrP Analogue (Abalopartide, Tymlos)*

Romosozumab(Evenity)

Denosumab New Long Term Data

Denosumab Mechanism

FREEDOM Extension

FREEDOM EXTENSION: 10 yr Data

Incidence of New Fractures in Long Term Group

Bone Markers Rebound within 3 months of Stopping Dmab

Bone Density Drops within 6 months of Stopping Dmab

Vertebral Fractures Increase when Dmab is Stopped

With Prevalent Vertebral Fracture

Take Home Points

•Denosumab must be administered in a timely and continuous fashion

•No medication holiday with denosumab

•Best practice for transitioning off treatment is being studied

Treatment Efficacy in Osteopenia

Zoledronic Acid in Women with Osteopenia    

•6 year, double-blind, placebo controlled trial

•2000 women, age 65+

•Osteopenia (T score -1 to -2.5 in the total hip/femoral neck)

•Zoledronic acid 5 mg every 18 months (4 infusions) OR Placebo

•Vitamin D administered and 1 gram calcium intake encouraged

•Primary endpoint: time to first occurrence of a fracture

Study Design and Baseline Characteristics

                

Zoledronic Acid in Osteopenia: Fracture Outcomes

Adverse Events

Bisphosphonates and Mortality

•RCT of ZA in men and women after hip fracture demonstrated a 28% decrease in mortality (Lyles K, NEJM, 2007) •Meta-analysis of 8 osteoporosis trials with duration >12 months showed a 11% reduction in mortality (Bolland M, JCEM, 2010)

•Observational study of 209 post-hip fracture subjects reported a 63% reduction in mortality (Beaupre LA, Osteoporosis Int, 2010) •Observational study of nursing home subjects showed 27% reduction on mortality in BP users (Sambrook PN, Osteo Int, 2010)

•Prospective, cohort study of 2043 men and women over 60 demonstrated a 69% reduction in mortality in women on BPs (Center J, JCEM 2011)

Take Home Points

•ZA is effective in reducing fracture in older osteopenic women

•4 infusions over 6 years was sufficient

•Decreased mortality and decreased cancer incidence in ZA treated women