Please complete the pre-assessment before the program begins

Please complete the pre-assessment before the program begins.

This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning.

This activity is supported by an educational grant from Amgen Inc.

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Faculty and Disclosures

Activity ChairLisa Cassidy-Vu, MDAssistant ProfessorDepartment of Family and Community MedicineWake Forest School of MedicineWinston-Salem, NC

Disclosure StatementDr. Cassidy-Vu has no financial relationship with any commercial interests to disclose.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Learning Objectives

• DEMONSTRATE appropriate screening approaches for patients who are at risk for osteoporosis, using tools such as Fracture Risk Assessment Tool (FRAX) scoring and dual-energy X-ray absorptiometry (DXA) bone mineral density scans

• IMPLEMENT accurate diagnostic decision-making based on patient-specific factors and results of tools such as FRAX scoring and DXA bone mineral density scans

• DESCRIBE updated guideline-recommended osteoporosis treatment algorithms, including risk stratification categories and possible drug treatment options

• SELECT appropriate patient-specific pharmacologic therapy for osteoporosis based on risk stratification and prior treatment experience

OsteoporosisDefinition, statistics, likely clinical outcomes

Osteoporosis: Definition

• A chronic progressive skeletal disorder characterized by:– Compromised bone strength predisposing to an

increased risk of fracture• Bone strength reflects the integration of 2 main features:

– Bone density– Bone quality

• Risk factors:– Estrogen deficiency and aging– Genetics: Family history, ethnicity– Chronic diseases and medications– Lifestyle: Nutrition, exercise, smoking, alcohol

2000 NIH Consensus Development Conference.

Normal Bone

Osteoporotic Bone

Sarafrazi N, et al. NCHS Data Brief, No 405. Hyattsville, MD: National Center for Health Statistics. 2021.

Lifetime Osteoporosis-Related Fracture Risk

1 in 2 women Up to 1 in 4 men

Each Year in the U.S.500,000 vertebral fractures400,000 wrist fractures300,000 hip fractures150,000 pelvic fractures700,000 other fractures (humerus, rib, patella, clavicle, etc.)

Hip Fracture Frequently Leads to Severe Consequences25% mortality in the first year after a hip fracture40% unable to walk independently 20% require temporary stay in nursing home60% require assistance a year later >50% permanently disabled>2-fold risk of becoming destitute

12.6% of Americans Over 50 Have Osteoporosis

Risk of Second Fracture10% within 1 year18% within 2 years31% within 5 years

Osteoporosis & Fractures

Prevalence of Spine Fractures by Age

Cosman F, et al. Osteoporos Int. 2017;28(6):1857-1866.

Overall prevalence is 5.4%(n=105)(n=81)

Self-Reported Spine Fracture History vs VFA Diagnosis

Of those reporting a history of spine fracture, 21% (95% CI 8.1 - 39.4) had a positive VFA Of those diagnosed with spine fracture by VFA, 8.2% (3.3, 16.3) reported a history of fracture

*Numbers in figure are unweighted.VFA, vertebral fracture assessment.Cosman F, et al. Osteoporos Int. 2017;28(6):1857-1866.

History of self-reported spine fracture*

VFA diagnosis

45 14 172

Screening for OsteoporosisOverview of evidence-based guidelines recommendations

Screening Guideline Recommendations

Clinical Practice Guideline Screening Recommendations

AACE/ACE Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis – 2020 Update

• All postmenopausal women ≥50 years of age should undergo clinical assessment for osteoporosis and fracture risk

• Women ≥65 years of age and younger women whose fracture risk is equal or greater than that of a 65-year-old white woman with no additional risk factors should undergo BMD testing

AACE, American Association of Clinical Endocrinologists; ACE American College of Endocrinology; BMD, bone mineral density.Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

Screening Guideline Recommendations (Cont’d)

Clinical Practice Guideline Screening Recommendations

Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement (2018)1

Screening with bone measurement testing is indicated to prevent osteoporotic fractures in:• Women ≥65 years of age • Women <65 years of age with increased risk of osteoporosis, as

determined by a formal clinical risk assessment tool (eg, FRAX®)There is insufficient evidence to assess the balance of benefits and harms of screening men for osteoporosis

National Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis (2014)2

• Measure height annually, preferably with a wall-mounted stadiometer• BMD testing should be performed in:

• Women ≥65 years of age and men ≥70 years of age• Postmenopausal women and men 50-69 years of age, based on

risk factor profile• Postmenopausal women and men ≥50 years of age who have had an

adult fracture to diagnose and determine degree of osteoporosis

BMD, bone mineral density; BMI, body mass index.1. US Preventive Services Task Force. JAMA. 2018;319(24):2521-2531. 2. Cosman F, et al. Osteoporos Int. 2014;25(10):2359-2381.

Available at: https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9

Risk Factors

Age The model accepts ages between 40 and 90 years. If ages below or above are entered, the program will compute probabilities at 40 and 90 years, respectively.

Sex Male or female. Enter as appropriate.

Weight This should be entered in kg.

Height This should be entered in cm.

Previous Fracture A previous fracture denotes more accurately a previous fracture in adult life occurring spontaneously, or a fracture arising from trauma which, in a healthy individual, would not have resulted in a fracture. Enter yes or no (see also notes on risk factors.

Parent Fractured Hip This enquires for a history of hip fracture in the patient’s mother or father. Enter yes or no.

Current Smoking Enter yes or no depending on whether the patient currently smokes tobacco (see also notes on risk factors).

Glucocorticoids Enter yes if the patient is currently exposed to oral glucocorticoids or has been exposed to oral glucocorticoids for more than 3 months at a dose of prednisolone of 5 mg daily or more (or equivalent doses of other glucocorticoids) (see also notes on risk factors).

Rheumatoid Arthritis Enter yes where the patient has a confirmed diagnosis of rheumatoid arthritis. Otherwise enter no (see also notes on risk factors).

Secondary Osteoporosis Enter yes if the patient has a disorder strongly associated with osteoporosis. These include type 1 (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition, or malabsorption and chronic liver disease.

Alcohol 3 or More Units/Day Enter yes if the patient takes 3 or more units of alcohol daily. A unit of alcohol varies slightly in different countries from 8-10 g of alcohol. This is equivalent to a standard glass of beer (285 mL), a single measure of spirits (30 mL), a medium-sized glass of wine (120 mL), or 1 measure of an aperitif (60 mL) (see also notes on risk factors).

Bone Mineral Density (BMD) Please select the make of DXA scanning equipment used and then enter the actual femoral neck BMD (in g/cm2). Alternatively, enter the T-score based on the NHANES III female reference data. In patients without a BMD test, the field should be left blank (see also notes on risk factors) (provided by Oregon Osteoporosis Center).

Available at: https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9

Limitations of FRAX®

• Underestimates risk of future fracture – Reports risk for major fractures only, which comprise ~50% of all fragility fractures– Underestimates risk in patients with multiple osteoporosis-related fractures, recent

fractures, significantly lower lumbar spine BMD than femoral neck BMD, secondary osteoporosis, and those at increased risk of falling

• Not valid to monitor patients on treatment• Only femoral neck BMD considered• Risk is “yes/no” without consideration of “dose” (e.g., glucocorticoids, smoking)• Not all risk factors included (eg, risk of falling)• Many diseases and medications not included• No consideration of time from fracture• No consideration for multiple fractures• Do patients with high FRAX® scores benefit from medication? (Unknown)

Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

Patient Case: Screening for Osteoporosis

• 67-year-old female new patient presents for annual preventive care visit• Medical history

– Significant for hypertension, hyperlipidemia, obesity, type 2 diabetes– No family history of osteoporosis and no bone fractures since childhood– A DXA scan performed 6 years previously showed no abnormalities

• Current medications:– Lisinopril 20 mg daily– Atorvastatin 40 mg daily– Metformin ER 500 mg 2 tablets twice daily– Insulin lispro 15 units 3 times daily– Aspirin 81 mg daily– Calcium-vitamin D3 600-400 units 1 tablet twice daily

Patient Case: Screening for Osteoporosis (Cont’d)

• Physical examination and lab test results:– BP: 124/74 (at goal)– eGFR: 85 mL/min/m2; no evidence of proteinuria

(indicating normal renal function)– A1c: 8.3%, increased from 7.1% 6 months ago– Metformin ER 500 mg 2 tablets twice daily

• Patient management plan:– Diabetes medication regimen adjusted– Recommendations provided to patient about low-carbohydrate

diet and exercise to promote blood glucose reduction– 3-month follow-up appointment

Were there any opportunities for better patient management that were missed during this visit?

?Please use the camera app on your smartphone or tablet to scan the QR code and answer the question.

A. No, because she does not have family history of osteoporosis or a history of adult fractures

B. No, because she is taking adequate doses of calcium and vitamin D and thus is not at risk for osteoporosis

C. Yes, because she meets guideline-recommended screening criteria and is at risk for osteoporosis

D. Yes, because obesity is a significant risk factor for osteoporosis

Were there any opportunities for better patient management that were missed during this visit?

Please use the camera app on your smartphone or tablet to scan the QR code and answer the question.

Rationale

• Patient meets evidence-based screening criteria in AACE/ACE 2020 Postmenopausal Osteoporosis Guidelines:– All postmenopausal women ≥50 years old should undergo clinical

assessment (e.g., FRAX®)– All postmenopausal women ≥65 should undergo BMD testing via

DXA• Obesity is not a risk factor for osteoporosis; low body weight

(<127 lbs.) is a risk factor• Lack of family history of osteoporosis or previous fractures as well as

adequate calcium and vitamin D supplementation do not negate patient’s fracture risk

This patient should be screened using the FRAX® scoring tool to determine 10-year risk of fracture. She should also undergo BMD testing with DXA.

Appropriately screening patients at risk for bone fractures and osteoporosis can help with early detection and treatment to prevent osteoporotic fractures.

!

Diagnosing OsteoporosisAppropriate evaluation for the patient

Diagnostic Criteria for Osteoporosis

Clinical Practice Guideline Diagnostic CriteriaAACE/ACE Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis – 2020 Update1

1. T-score ≤-2.5 in the lumbar spine, femoral neck, total proximal femur, or 1/3 radius

2. Low-trauma spine or hip fracture (regardless of BMD)3. T-score between 01.0 and -2.5 and fragility fracture of proximal humerus,

pelvis, or distal forearm4. T-score between 01.0 and -2.5 and high FRAX® (or if available, TBS-

adjusted FRAX®) fracture probability based on country-specific thresholdsNational Osteoporosis Foundation Clinician’s Guide to Prevention and Treatment of Osteoporosis (2014)2

1. Occurrence of adulthood hip or vertebral fracture in the absence of major trauma

2. BMD T-score ≤-2.5 (osteoporosis)3. BMD T-score ≤-2.5 with one or more fractures (severe or established

osteoporosis)

AACE, American Association of Clinical Endocrinologists; ACE American College of Endocrinology; BMD, bone mineral density; FRAX®, Fracture Risk Assessment Tool; TBS, trabecular bone score. 1. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46. 2. Cosman F, et al. Osteoporos Int. 2014;25(10):2359-2381.

Patients With Prior Fractures Are High Risk

• Prior fracture is the most important risk factor for another fracture1

• Approximately 60% of hip fracture patients have a prior fracture by history (often spine, wrist)2

– May be helpful to target younger patients for screening after the first fracture to prevent future hip fractures3

• Risk is highest within first few years after first fracture1

– Suggests an urgency for treatment

Hazard Ratios for Groups of Incident Fractures2

Previous fracture site Any bone Hip Spine

Any prior fracture 2.19 2.02 2.93

1 fracture 1.81 1.60 2.16

2 fractures 2.98 2.95 3.97

≥3 fractures 4.80 3.66 9.05

1. Kanis JA, et al. J Bone Miner Res. 2014;29:1926-1928. 2. Gehlbach S, et al. J Bone Miner Res. 2012;27(3):645-653. 3. Cosman F, et al. Osteoporos Int. 2014;25(10):2359-2381.

Most spine fractures do not come to clinical attention at the time of the event (75%).

Proactive targeted screening spine imaging recommended for those who fit certain criteria to identify those with spine fractures

Courtesy of the International Society for Clinical Densitometry.Cosman F, et al. Osteoporos Int. 2014;25(10):2359-2381.

Many Patients With Fractures Do Not Have “Osteoporosis” by BMD Criteria (Rotterdam Study)

Schuit SC, et al. Bone. 2004;34:195-202.

Women

Hip Fractures

MenNonvertebral Fractures

43%44%

13%

Normal BMD

Low BMD

Osteoporosis

31%

64%

5%

Normal BMD

Low BMD

Osteoporosis

18%

61%

21%

58%39%

3%

Osteoporosis

Low BMD

Osteoporosis

Low BMD

Normal BMD

Normal BMD

The Many Causes of Secondary Osteoporosis in Adults*

Endocrine or Metabolic Causes Nutritional/GI Conditions Drugs Other• Acromegaly• Diabetes mellitus (type 1 or 2)• Growth hormone deficiency• Hypercortisolism• Hyperparathyroidism• Hyperthyroidism• Hypogonadism• Hypophosphatasia• Porphyria• Pregnancy

• Alcoholism • Anorexia nervosa• Calcium deficiency• Chronic liver disease• Malabsorption syndromes/

malnutrition• Total parenteral nutrition• Vitamin D deficiency

• Anti-epileptic drugs• Aromatase inhibitors• Chemotherapy/

immunosuppressants• Medroxyprogesterone

acetate• Glucocorticoids• Gonadotropin-releasing

hormone agents• Heparin• Lithium• PPIs• SSRIs• SGLT2-inhibitors• Thiazolidinediones• Thyroid hormone (in

supraphysiologic doses)

• Disorders of collagen metabolism

• HIV/AIDS• Ankylosing spondylitis• Chronic obstructive pulmonary

disease• Gaucher disease• Hemophilia• Hypercalciuria• Immobilization• Major depression• Myeloma and some cancers• Organ transplantation• Renal insufficiency/failure• Renal tubular acidosis• Rheumatoid arthritis• Systemic mastocytosis• Thalassemia

*Not a comprehensive list. AIDS, acquired immunodeficiency syndrome; GI, gastrointestinal; HIV, human immunodeficiency virus; PPIs, proton pump inhibitors; SGLT, sodium-glucose cotransporter 2; SSRIs, selective serotonin-reuptake inhibitors. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

Consider Workup for Secondary Causes Before Initiating Treatment

• CBC, CMP, Vitamin D• TSH, PTH, Prolactin• HbA1c• Celiac disease• SPEP/UPEP• Urine studies: Calcium, cortisol• Review medications: lithium, corticosteroids, aluminum-

containing antacids, etc.CBC, complete blood count; CMP, complete metabolic panel; HbA1c, hemoglobin A1c; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone; SPEP/UPEP, serum and urine protein electrophoresis.Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

Patient Case: Osteoporosis Evaluation

• 67-year-old female patient returns for 3-month follow-up visit regarding her diabetes

• Patient is screened for osteoporosis, including by DXA scan• DXA scan results:

– Femoral neck T-score = -2.7– Lumbar spine T-score = -3.1

• Patient diagnosed with osteoporosis, based on both AACE/ACE and NOF criteria

Were any opportunities missed during this visit?

What else could you have done as part of the diagnostic workup for osteoporosis?


A. Conduct a FRAX® assessmentB. Obtain a comprehensive metabolic panelC. Obtain a complete blood countD. Measure the 25-hydroxyvitamin D levelE. All of the above

What else could you have done as part of the diagnostic workup for osteoporosis?


Rationale

• A FRAX® assessment can help elucidate the patient’s risk for future osteoporotic fractures and classify her into the appropriate risk category

• The AACE/ACE 2020 postmenopausal osteoporosis guidelines recommend analyzing potential secondary causes of osteoporosis as part of the diagnosis, including obtaining laboratory test results for the following:– Comprehensive metabolic panel – Complete blood count – 25-hydroxyvitamin D level – Intact parathyroid hormone– Phosphate measurement

• FRAX® scoring should always accompany BMD testing via DXA to assist with the diagnosis and to estimate the patient’s risk of fracture

• There is a high prevalence of secondary osteoporosis, even in apparently healthy individuals, and many secondary causes can be asymptomatic. Laboratory testing may be needed to detect secondary causes of osteoporosis. !

Treating OsteoporosisSelecting the right treatment for each patient

Lumbar spine or femoral neck or total hip T-score of ≤-2.5, a history of fragility fracture, or high FRAX® fracture probability*

Evaluate for causes of secondary osteoporosis

Recommend pharmacologic therapy / Educate on lifestyle measures, fall prevention, benefits and risks of medications

Correct calcium/vitamin D deficiency and address causes of secondary osteoporosis

Risk-stratification-based Treatment• High risk/no prior fractures • Very high risk/prior fractures

AACE/ACE 2020 Postmenopausal Osteoporosis Treatment Algorithm

*10-year major osteoporotic fracture risk ≥20% or hip fracture risk ≥3%Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

AACE/ACE 2020 Postmenopausal Osteoporosis Treatment Algorithm (Cont’d)

High Risk/No Prior Fractures* Very High Risk/Prior Fractures*

• Alendronate, denosumab, risedronate, zoledronate**

• Alternative therapy: ibandronate, raloxifene

• Abaloparatide, denosumab, romosozumab, teriparatide, zoledronate**

• Alternative therapy: alendronate, risedronate

Reassess yearly for response to therapy and fracture risk

Reassess yearly for response to therapy and fracture risk

*10-year major osteoporotic fracture risk ≥20% or hip fracture risk ≥3%. Non-US countries/regions may have different thresholds.**Indicators of very high fracture risk in patients with low bone density would include advanced age, frailty, glucocorticoids, very low T scores, or increased fall risk.Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

AACE/ACE 2020 Postmenopausal Osteoporosis Treatment Algorithm – High Risk/No Prior Fractures Treatment After Reassessment


Increasing or stable BMD and no fractures

Consider a drug holiday after 5 years of oral and 3 years of IV bisphosphonate therapy

Resume therapy when a fracture occurs, BMD declines beyond LSC, BTMs rise to pretreatment values, or patient meets initial treatment criteria

Progression of bone loss or recurrent fractures

• Assess compliance• Reevaluate for causes of secondary

osteoporosis and factors leading to suboptimal response to therapy

• Switch to injectable antiresorptive if an oral agent• Switch to abaloparatide, romosozumab, or

teriparatide if an injectable antiresorptive or at very high risk of fracture

• Assess factors leading to suboptimal response

AACE/ACE 2020 Postmenopausal Osteoporosis Treatment Algorithm – Very High Risk/Prior Fractures Treatment After Reassessment


Denosumab Romosozumab for 1 Year

Abaloparatide or Teriparatide

For Up to 2 yearsZoledronate

Continue therapy until the patient is no longer high risk and ensure transition with another antiresorptive agent

Sequential therapy with oral or injectable antiresorptive agent

Sequential therapy with oral or injectable antiresorptive agent

• If stable, continue therapy for 6 years

• If progression of bone loss or recurrent fractures, consider switching to abaloparatide, teriparatide, or romosozumab

Whom to Treat: NOF Guidelines 2014

Cosman F, et al. Osteoporos Int. 2014;25:2359-2381.

Women ≥65 and Men ≥70 (younger with risk factors)

DXA Test

T-score Between -1.0 and -2.5T-score ≤-2.5 in the Lumbar Spine, Total Hip, or Femoral Neck or

Hip or Spine Fracture (clinical or radiographic)

≥3% for Hip Fracture or≥20% for Major Osteoporotic Fractures

FRAX®

10-y fracture risk

Candidate for TREATMENT

YES

YES

ACP Guidelines

Pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce risk for hip and vertebral fractures in women with known osteoporosis

Treat osteoporotic women with pharmacologic therapy for 5 years, but some may benefit from extended treatment

BMD screening not recommended during the 5-year treatment period for osteoporosis in women

Menopausal estrogen therapy ± progesterone therapy or raloxifene not recommended for the treatment of osteoporosis in womenConsider treatment in osteopenic women ≥65 years of age who are at high risk for fracture based on patient preferences, fracture risk profile, and benefits, harms, and costs of medications

The 2017 ACP guidelines are endorsed by the AAFP.*Expert opinion. ACP, American College of Physicians.Qaseem A, et al. Ann Intern Med. 2017;166(11):818-839.

Limitations*• No treatments without specific hip fracture efficacy were included• Recommends a treatment holiday for denosumab• No discussion of long-term treatment decisions beyond 5 years• Anabolic therapy not included

2020 AACE/ACE Guideline Recommendations for Lifestyle Issues

Ensure adequate intake of calcium

Ensure adequate intake of vitamin D

Consume a balanced diet

Regularly perform weight-bearing and balance exercises

Avoid tobacco use

Limit alcohol consumption

Take measures to avoid falls


Evidence for Reduction of Fracture Risk by Pharmaceutical Agents

Drug Vertebral Fracture Nonvertebral Fracture Hip Fracture

Calcitonin

Raloxifene

Ibandronate

Alendronate

Risedronate

Zoledronic acid

Denosumab

Teriparatide

Abaloparatide

Romosozumab * *

*Clinical fracture reduction was shown in both trials. Nonvertebral and hip fracture reductions were shown at month 24 for patients receiving 12 months of romosozumab followed by 12 months of alendronate compared with patients receiving 24 months of alendronate.Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46.

Efficacy of Zoledronic Acid (HORIZON Trials)

Recurrent Fracture Trial2

• Included patients who had experienced a hip fracture and were unable or unwilling to take an oral bisphosphonate

• Zoledronic acid significantly reduced subsequent risk of clinical fracture, nonvertebral fracture, and clinical vertebral fracture (but not hip fracture) over time versus placebo

• Zoledronic acid significantly reduced risk of all-cause mortality by 28% over time versus placeboAlso, significant reduction in hip fracture versus placebo at 3 years (HR 0.59, P<0.002)

*P<0.001, relative risk reduction vs placebo (95% confidence interval). 1. Black DM, et al. N Engl J Med. 2007;356(18):1809-1822. 2. Lyles KW, et al. N Engl J Med. 2007;357(18):1799-1809.

% P

atie

nts

With

New

Ve

rteb

ral F

ract

ures

60%*

71%*

0

10

0-1 0-2 0-3Years

5

15

1.5%(42/2822)

3.7%(106/2853) 2.2%

(63/2822)

7.7%(220/2853)

3.3%(92/2822)

10.9%(310/2853) 70%*

Zoledronic acid Placebo

Pivotal Fracture Trial1

Zoledronic Acid – Safety Information

Contraindications– Hypocalcemia– Creatinine clearance <35 mL– Acute renal impairment

US FDA. CDER. Zoledronic acid NDA 021817. Label 7/7/17.

– Myalgia– Diarrhea– Pain in extremities– Eye inflammation– Arthralgia

Adverse Reactions– Pyrexia– Flu-like symptoms– Nausea– Headache– Vomiting

Other Concerns– Osteonecrosis of the jaw (ONJ)– Atypical femur fracture– Severe bone, joint, and muscle pain

Denosumab Treatment on Lumbar Spine and Total Hip BMD Through 10 Years1

BMD data are LS means and 95% confidence intervals. aP<0.05 vs FREEDOM baseline. bP<0.05 vs FREEDOM and Extension baselines. cPercentage change while on denosumab.1. Bone HG, et al. Lancet Diabetes Endocrinol. 2017;5(7):513-523. 2. Ferrari S, et al. Bone. 2020;124:115268.

There is recent data on denosumab in postmenopausal

women with type 2 diabetes, generally consistent with original

findings with the broader population.2

Cross-over DenosumabLong-term DenosumabPlacebo

Denosumab – Safety Information

Contraindications– Hypocalcemia

Other Concerns– Skin rash– ONJ– Atypical femur fracture (AFF)– Multiple vertebral fractures upon withdrawal

US FDA. CDER. Denosumab NDA 125320. Label 6/1/2010.

Adverse Reactions– Back pain– Pain in extremities– Hypercholesterolemia– Musculoskeletal pain– Cystitis

PTH and PTH-Related Protein Analogs

• Both PTH analog teriparatide and PTH-related protein (PTHrP) analog abaloparatide are potent stimulators of bone remodeling, increasing BMD and reducing the risk of vertebral and nonvertebral fractures

• PTH and PTHrP analogs bind to the PTH/PTHrP receptor, which is expressed on osteoblasts and osteocytes among other cell types

• Intermittent administration of PTH and PTHrP analogs leads to anabolic pharmacologic efficacy, preferentially enhances bone formation

• Intermittent administration has a net positive effect on calcium balance and increases bone mass, particularly in trabecular bone

• While PTH and PTHrP analogs are classified as “anabolic,” they can also stimulate osteoclastic bone resorption

Leder BZ. Curr Osteoporos Rep. 2017;15(2):110-119.

ACTIVE: Risk of New Vertebral Fractures1

0

1

2

3

4

5

Prop

ortio

n (%

) of P

atie

nts

With

N

ew V

erte

bral

Fra

ctur

es

Modified ITT Population* N=2118

*Includes all ITT patients who had pretreatment and post-baseline evaluable radiologic assessments. †P<0.001 vs placebo; ITT, intention-to-treat.1. Miller PD, et al. JAMA. 2016;316:722-733. 2. Cosman F, et al. Mayo Clin Proc. 2017;92:200-210. 3. Bone HG, et al. J Clin Endocrinol Metab. 2018;103:2949-2957.

Placebon=711

Full ACTIVExtend Study (3.5 years)2,3

• Sustained reduced risk for vertebral, nonvertebral, clinical, and major osteoporotic fractures• Similar incidence of adverse effects, no cases of AFF or ONJ

Abaloparatiden=690

Teriparatiden=717

4.22%(n=30)

0.58%(n=4)

0.84%†

(n=6)

Relative Risk Reduction vs

Placebo

0

1

2

3

4

5

0 100 200 300 400 500Pr

opor

tion

(%) o

f Pat

ient

s W

ith

Non

vert

ebra

l Fra

ctur

es

ITT Population N=2463

Time to Event (days)

Kaplan-Meier Curve Placebo

Note: No significant difference between abaloparatide and teriparatide

TeriparatideLog-rank P value=0.22 vs placebo

AbaloparatideLog-rank P value=0.22 vs placebo

Abaloparatide & Teriparatide – Safety Information

• Rodent osteosarcoma• Hypercalcemia• Hypercalciuria• Hyperuricemia• Orthostatic hypotension• Adverse reactions

– Arthralgia– Pain– Nausea

US FDA. CDER. Teriparatide NDA 021318. Label 04/06/20.US FDA. CDER. Abaloparatide NDA 208743. Label 2/5/18.

Romosozumab

• Monoclonal antibody that binds and inhibits sclerostin1

• Sclerostin inhibition has dual effect on bone, increasing BMD markedly:1– Stimulates bone formation by promoting

osteoblast number and activity– Reduces bone resorption by inhibiting RANK

ligand expression

• Black box warning for increased risk of myocardial infarction, stroke, and cardiovascular death2

1. Sølling ASK, et al. Ther Adv Musculoskel Dis. 2018;10(5-6):105-115.2. EVENITY® (romosozumab-aqqg) prescribing information, April 2020.

Romosozumab Lowers Risk of Clinical Fracture Through Month 12: FRAME Trial

n/N1 = number of subjects with fractures/number of subjects in the primary analysis set for vertebral fracture.P value based on logistic regression model adjusted for age (<75, ≥75) and prevalent vertebral fracture.Cosman F, et al. N Engl J Med. 2016;375:1532-1543.

Subj

ect I

ncid

ence

(%)

n/N1 = 26/3262 14/3265 59/3322 16/3321

RRR=73%P=<0.001

RRR=46%P=0.056

Through Month 6 Through Month 12

0.8%

1.8%

0.4%0.5%

0.0%

0.5%

1.0%

1.5%

2.0% Placebo (N=3591)

Romosozumab (N=3589)

Romosozumab Lowers New Vertebral Fracture Incidence in Higher-Risk Population: ARCH Trial

Saag KG, et al. N Engl J Med. 2017;377:1417-1427.

Patients in the ARCH trial had a much higher risk for fracture than those in the FRAME trial.

RRR=37%P=0.003

Through Month 12

6.3%

4.0%

0.0%

5%

10%

15%

0.0%

RRR=48%P=0.003

Month 13 Through Month 24

11.9%

6.2%5%

10%

15%

Subj

ect I

ncid

ence

(%)

Subj

ect I

ncid

ence

(%)

Alendronate (N=2047)

Romosozumab (N=2046)

Alendronate Alendronate (N=2047)

Romosozumab Alendronate (N=2046)

Romosozumab – Safety Information

• Contraindications– Hypocalcemia

• Adverse Reactions– Arthralgia– Headache

• Other Concerns– Major adverse

cardiac events– Hypersensitivity– ONJ– AFF

1. US FDA. CDER. Romosozumab NDA 761062. Label 4/9/19. 2. Cosman F, et al. N Engl J Med. 2016;375:1532-1543.3. Saag KG, et al. N Engl J Med. 2017;377:1417-1427. 4. Lewiecki EM, et al. J Clin Endocrinol Metab. 2018;103:3183-3193.

• 12 months: Placebo = 41/3576 (1.1%), Romosozumab = 44/3581 (1.2%)• 24 months: Placebo Denosumab 79/3576 (2.2%),

Romosozumab Denosumab 82/3581 (2.3%)

FRAME2

• 12 months: Alendronate 38/2014 (1.9%), Romosozumab = 50/2040 (2.5%)• 24 months: Alendronate Alendronate 122/2014 (6.1%),

Romosozumab Alendronate 133/2040 (6.5%)

ARCH3

• Placebo = 2/81 (2.5%)• Romosozumab = 8/168 (2.9%)

BRIDGE4

Cardiovascular RiskLabel Warnings1

Limitations of Antiresorptives for the High-Risk Patient

• Nonvertebral fracture risk reductions for antiresorptives are at best 20%-25% – Takes 3 years to see significant decline

• Long-term efficacy of antiresorptives is unclear

• Rare but significant long-term safety risks for both bisphosphonates and denosumab (AFFs, ONJ)1

Bisphosphonates • Effect on fractures beyond 3-4 years inconsistent • BMD plateaus after 3-4 years

– If T-Score remains <-2.5, patients still at risk1

Denosumab • Continued increase in BMD years 3-102

• Low fracture rates during the extension study years (but no long-term placebo group)2,3

• Hip BMD attained during denosumab treatment is predictive of lower risk of subsequent incident nonvertebral fracture3

1. Cosman F, et al. J Clin Endocrinol Metab. 2014;99:4546-4554. 2. Bone HG, et al. Lancet Diabetes Endocrinol. 2017;5:513-523. 3. Ferrari S, et al. J Bone Miner Res. 2019;34:1033-1040.

Rationale for Anabolic Therapy First Line

• If imminent fracture risk is high –Anabolic agents provide fastest protection against fractures

• 12 to 18 months for both vertebral and nonvertebral risk reductions

• If very low BMD (i.e., T-score <-3) even without prior fracture–Best initial treatment may still be anabolic

• Increased skeletal mass and improved microarchitecture• Largest effects when anabolic followed by antiresorptive

Cosman F, et al. J Bone Miner Res. 2017;32:198-202.

Potential Osteoporosis Treatment Targets

• Remain free of fracture (first or recurrent) for 5 years1

– For recurrent fracture, fracture-free duration target might vary based on site of initial fracture

• After incident spine or hip fracture, possibly a longer target– Must include assessment of vertebral fracture

• Vertebral imaging needed at beginning and ‘end’

• Attain BMD T-scores above osteoporosis range1

• Reduce fracture probabilities to below treatment indications1

• An ASBMR/NOF task force has been formed to determine the feasibility of formulating “treat-to-target” goals2

1. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1046. 2. Cummings SR, et al. J Bone Miner Res. 2017;32:3-10.

Treatment Targets Affect Treatment Sequence Decisions and Decisions About Drug Holidays1-4

*Grade A.1. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46. 2. Cosman F, et al. J Bone Miner Res. 2017;32:198-202. 3. Leder BZ. JBMR Plus. 2018;2:62-68.4. Cummings SR, et al. J Bone Miner Res. 2017;32:3-10.

• Anabolic agents provide fastest protection against fractures • 12 to 18 months for both vertebral and nonvertebral risk reductions• Increased skeletal mass and improved microarchitecture

Highest Risk Patient (Imminent fracture risk

or T-score <-3)

• Produce rapid reduction in osteoporosis-related fracture risk• Provide foundation for greater strengthening effect and BMD improvement Anabolic

• Help achieve fracture-free interval of 3-5 years• Help achieve BMD goals (T-scores above -2.5)Nonresorptive BPN

• Use bisphosphonates at end of treatment sequence, especially if at very high risk of fracture or very low BMD

• Monitor fractures/BMD/biochemical turnover markers*• Repeat sequential monotherapy as needed

BPN

Drug Holidays – AACE/ACE 2020

1. Camacho PM, et al. Endocr Pract. 2020;26(suppl 1):1-46. 2. Langdahl BL. Eur J Endocrinol. 2018;180:R29-R35. 3. Bindon B, et al. Endocr Pract. 2018;24:163-169.

High Risk1 Very High Risk1

• Oral bisphosphonate treatment after 5 years• IV bisphosphonate treatment after 3 years

Patients should receive a treatment duration of:• 10 years for oral bisphosphonates• 6 years of IV bisphosphonates treatment • Non-bisphosphonate treatment (teriparatide) may be

offered during the holiday from bisphosphonate

• The optimal duration of a bisphosphonate holiday has not been established; patient selection and monitoring during BP holidays are important

• Bisphosphonates remain adhered to bone surfaces and exert effect over years after discontinuation– Rank order for binding affinity: zoledronate > alendronate > risedronate

• Intermittent bisphosphonates can be used to maintain BMD (e.g., single zoledronic acid infusion)– Repeat treatment when/if needed

• Restart if decrease in BMD or fracture2,3

• Not with denosumab– Rebound bone turnover with discontinuation

Patient Case: Treating Osteoporosis

• 67-year-old female patient has been diagnosed with osteoporosis. Her HCP is considering treatment options, taking into account the following information:– No bone fractures since she was a child– No family history of osteoporosis– Normal BMD based on DXA 6 years ago– Current DXA results:

• Femoral neck T-score = -2.7• Lumbar spine T-score = -3.1

– Current FRAX® scores:• 35% FRAX® 10-year risk of major osteoporotic fracture• 2% FRAX® 10-year risk of hip fracture

• The HCP initiates treatment with alendronate 70 mg 1 oral tablet once weekly

Did the HCP choose the most effective treatment option?


A. Classify the patient as high fracture risk and initiate abaloparatideB. Classify the patient as high fracture risk and initiate denosumabC. Classify the patient as very high fracture risk and initiate zoledronic acidD. Classify the patient as very high fracture risk and initiate romosozumab

Did the HCP choose the most effective treatment option?


Rationale

• According to the 2020 AACE/ACE guideline recommendations, the patient is classified as very high fracture risk because:– T-score <3.0– >30% FRAX® 10-year risk of major osteoporotic fracture

• Evidence shows that treating very high facture risk patients with anabolic therapy leads to improved fracture reduction, compared to treatment with antiresorptive therapy

• Romosozumab has anabolic and antiresorptive properties, and it is appropriate for this patient because she is a very high fracture risk patient. PTH analog teriparatide and PTH-related protein analog abaloparatide, which are also anabolic therapies, are also appropriate for this patient

• The maximum duration for PTH analogs is 2 years

!

• Risk stratification into high fracture risk or very high fracture risk categories per 2020 AACE/ACE guideline recommendations helps guide initial treatment selection

• Romosozumab, FDA-approved in 2019, is a new treatment option for very high fracture risk patients– Romosozumab has anabolic and antiresorptive properties– Can be taken for 12 consecutive months– May be taken by patients who have already received

2 years of PTH analog therapy

Therapies Vary Significantly in Cost*

Therapy BCBS1 GoodRx2

Abaloparatide (30-day supply) $80-611 (Tymlos) N/A

Alendronate (84-day supply) $376 (Fosamax)$10-20 (generic) $13-77 (generic)

Denosumab (30-day supply) $60-390 (Prolia)$60-718 (Xgeva)

$1299-1412 (Prolia)$2460-2594 (Xgeva)

Ibandronate (90-day supply) $556 (Boniva)$10-20 (generic)

$553-601 (Boniva)$22-38 (generic)

Raloxifene (90-day supply) $576 (Evista)$10-20 (generic) $37-226 (generic)

Risedronate (90-day supply) $1010 (Actonel)$15-30 (generic)

$1064-1156 (Actonel)$91-180 (generic)

Romosozumab (30-day supply) $80-557 (Evenity) N/A

Teriparatide (28-day supply) $60-1089 (Forteo)$60-713 (generic)

$3795-3992 (Forteo)$844-967 (generic)

Zoledronate (30-day supply) $2.54-8.45 (generic) $916-971 (Zometa)$38 (generic)

*2021 prices (current as of April 5, 2021) for Zip Code 222021. https://www.fepblue.org/pilot/rx-cost-tool/search. 2. https://www.goodrx.com.

Opportunities to Minimize Costs• Manufacturer discount programs• Prior authorizations• Other discount programs

(e.g., GoodRx)

Take-Home Messages

• Osteoporosis is a common disease with serious consequences due to fractures– Fracture numbers are expected to hit crisis range

• Tools to diagnose osteoporosis and identify patients for pharmacological therapy are available – cheap and without risk

• Risk stratification can help guide treatment selection• Pharmacological agents reduce fracture risk

– Treatment decisions for initiating and continuing therapy should be individualized based upon the expected benefit and potential risk for each patient

– Different medications are appropriate at different ages and stages of disease• Secondary fracture prevention should be a priority

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