POSTMENOPAUSAL OSTEOPOROSIS handout.pdf · • Osteoporosis-related fractures can lead to pain, disability, and deformity. They reduce quality and quantity of life. • Hip fractures

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POSTMENOPAUSAL OSTEOPOROSIS

MARCH 2020

Copyright © 2019 American Associa7on of Clinical Endocrinologists

1

Postmenopausal Osteoporosis

Copyright © 2019 American Association of Clinical Endocrinologists

C:\Users\Richard\OneDrive\Documents\PMO 2-2020 MSU.pptx

Copyright © 2019 American Association of Clinical Endocrinologists 2

A Major Public Health Problem

• Osteoporosis is a major public health problem. More than 10 million Americans have osteoporosis, and an additional 43 million have low bone mass, according to data from the U.S. National Health and Nutrition Examination Survey.

• More than 2 million osteoporosis-related fractures occur each year in the United States, and more than 70% of these occur in women.

• More than 20% of postmenopausal women have prevalent vertebral fractures. As the most common osteoporotic fracture, vertebral fractures are a hallmark of the disease and indicate a high risk for future fractures. They are also associated with impaired pulmonary function and increased mortality risk, especially respiratory deaths. However, the majority of vertebral fractures (2/3) are asymptomatic.

Camacho PM, Petak SM, Binkley N et al. American Associa7on of Clinical Endocrinologists and American College of Endocrinology Clinical Prac7ce Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl 4):1-42.Wright NC, Looker AC, Saag KG, Cur7s JR, Delzell ES, Randall S, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014;29:2520-2526.Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.Puisto V et al. Vertebral fracture and cause-specific mortality: a prospec7ve popula7on study of 3,210 men and 3,730 women with 30 years of follow-up. Eur Spine J 2011; 20:2181–2186.

Prevalence of Osteoporosis Increases With Age

34Copyright © 2019 American Association of Clinical Endocrinologists

• Age is an independent risk factor for osteoporotic fractures. The risk increases progressively with age, doubling every 5 to 10 years. Nearly one-quarter (24.8%) of women 65 and older have osteoporosis. For women 80 and older, that figure rises to more than one-third (35.6%), according to a report from the CDC.

• In addition, more than half (52.3%) of women 65 and older have low bone mass (osteopenia). Although fracture risk is highest in women with osteoporosis, most women who experience a fracture have osteopenia, because there are many more women in this category.

The Centers for Disease Control and Prevention. “Percentage of Adults Aged 65 and Over With Osteoporosis or Low Bone Mass at the Femur Neck or Lumbar Spine: United States, 2005–2010.” h`ps://www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.htm. Accessed August 2, 2018.Ross PD. “Risk Factors for Osteoporo7c Fracture.” New England Journal of Medicine 1998; 27: 289-301.

http://www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.htm

Most Women with Osteoporosis Are Not Treated

35Copyright © 2019 American Associaton of Clinical Endocrinologists

• Postmenopausal osteoporosis is preventable and treatable, but only a small proportion of women at increased risk for fracture are evaluated and treated.

• Even among women with fractures, lack of treatment is common. Fewer than 1 in 4 women age 67 or older with an osteoporosis-related fracture undergoes bone density measurement or begins osteoporosis treatment.

Camacho PM, Petak SM, Binkley N et al. American Associa7on of Clinical Endocrinologists and American College of Endocrinology Clinical Prac7ce Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Kanis JA, Melton LJ 3rd, Chris7ansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994;9:1137-1141.

Diagnosing Osteoporosis

• Postmenopausal osteoporosis can be diagnosed based on the World Health Organization (WHO) definition: a bone mineral density (BMD) T-score of -2.5 or below in the lumbar spine, femoral neck, total hip, and/or 33% (one-third) radius.

Note: this is table 4 from the AACE Guidelines.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Copyright © 2006 AACE. Endocr Pract. 2016;22(Suppl 4):1-42. Reprinted with permission from American Associa7on of Clinical Endocrinologists.


Additional DiagnosticCriteria


• In addition to the WHO bone mineral density criteria, these may also be used to diagnose osteoporosis:

• Low-trauma spine or hip fracture, regardless of BMD• Osteopenia or low bone mass (T-score between –1 and

–2.5) with a fragility fracture of proximal humerus, pelvis, or possibly distal forearm

• Low bone mass or osteopenia and high FRAX® (Fracture Risk Assessment Tool) fracture probability based on country-specific thresholds

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practce Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

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The Fracture Risk Assessment Calculator• The FRAX calculator is available online from the University of Sheffield, UK

Copyright © 2019 American Associaton of Clinical Endocrinologists 7

Screening for Postmenopausal Osteoporosis


• All postmenopausal women age 50 or older should undergo clinical assessment for osteoporosis and fracture risk, including a detailed history and physical examination. Tools such as FRAX should be used when available.

• BMD testing is the gold standard in diagnosing osteoporosis. However, this test is not always available. The decision to measure BMD should be based on an individual’s clinical fracture risk profile and skeletal health assessment.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl 4):1-42.

ScreeningRecommendations


• Both the AACE and the U.S. Preventive Services Task Force recommend BMD testing for all women aged 65 and older as well as younger postmenopausal women at increased risk for bone loss and fracture based on fracture risk analysis.

• BMD measurement is not recommended in children, adolescents, healthy young men, or premenopausal women, unless there is a significant fracture history or there are specific risk factors for bone loss.

Nelson HD, Haney EM, Dana T, Bougatsos C, Chou R. Screening for osteoporosis: an update for theU.S. Preventive Services Task Force. Ann Intern Med. 2010;153: 99-111.


ClinicalPresentation


• Fracture is the single most important manifestation of postmenopausal osteoporosis. Osteoporotic fractures are usually caused by low-energy injuries such as a fall from standing height.

• Vertebral fractures, however, may occur during routine daily activities, without a specific fall or injury. In clinical practice, it may be difficult or impossible to reconstruct the mechanical force applied to bone in a particular fall.


• PATIENTS WITH VERTEBRAL FRACTURES ARE HIGH OR VERY HIGH RISK FOR FUTURE FRACTURE

• HOWEVER 2/3 ARE ASX• NEED TO BE FOUND WITH IMAGERY• SPINE IMAGING IS PROBABLY AS IMPORTANT AS DXA



















ClinicalPresentation


• Osteoporosis-related fractures can lead to pain, disability, and deformity. They reduce quality and quantity of life.

• Hip fractures are the most serious consequence of postmenopausal osteoporosis. Women with hip fracture have an increased mortality of 12% to 20% during the subsequent two years. More than 50% of hip fracture survivors are unable to return to independent living. Many survivors require long-term nursing home care

• Other low-trauma, osteoporosis-related fractures include those of the proximal humerus, pelvis, and in some cases the distal forearm.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Prac7ce Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Black DM and Rosen CJ. Postmenopausal Osteoporosis. The New England Journal of Medicine 2016; 374:254-262.

Copyright © 2019 American Associa7on of Clinical Endocrinologists1

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Treatment• To identify coexisting medical conditions that cause or contribute to bone loss, an appropriate

medical evaluation is indicated for all women with postmenopausal osteoporosis. Some causes of secondary osteoporosis include the following.

Endocrine or metabolic causes Nutritional/GI conditions Drugs Disorders of collagen metabolism Other

Acromegaly

Diabetes mellitusType 1Type 2

Growth hormone

deficiency

Hypercortisolism

Hyperparathyroidism

Hyperthyroidism

Hypogonadism

Hypophosphatasia

Porphyria

Pregnancy

Note: This is table 11 from the AACE gu

Alcoholism

Anorexia

nervosa

Calcium

deficiency

Chronic liver

disease

Malabsorption syndromes/ malnutrition (including celiac disease, cystic fibrosis, Crohn’s disease, and gastric resection or bypass)

Total parenteral

nutrition Vitamin D

deficiency

Antiepileptic

drugsa Aromatase

inhibitors

Chemotherapy/ immunosuppressants

Depo-

Provera

Glucocortic

oids

Gonadotropin-releasing hormone agents

He

par

in

Lith

ium

Proton pump inhibitors

Selective serotonin reuptake inhibitors

Thiazolidinediones

Thyroid hormone (in supraphysiologicdoses)

Ehlers-Danlos syndrome

Homocystinuria due to cystathioninedeficiency

Marfan syndrome

Osteogenesis

imperfecta

AIDS/HIVa

Ankylosing spondylitis

Chronic obstructive pulmonary disease

Gaucher

disease

Hemophilia

Hypercalciuria

Immobilizatio

n Major

depression

Myeloma and some

cancers Organ

transplantation Renal

insufficiency/ failure

Renal tubular acidosis

Rheumatoid arthritis

Systemic mastocytosis

Thalassemia

Copyright © 2019 American Astiocia7on of Clinical Endocrinologists 12

Treatment


• Because causes of secondary osteoporosis are common even in apparently healthy, postmenopausal women, laboratory testing should be considered for all women with osteoporosis. Laboratory evaluation could include:

• Complete blood cell count (CBC)• Comprehensive metabolic panel (includes calcium, albumin,

and creatinine tests)• Serum 25-hydroxyvitamin D• Phosphate• 24-hour urine collection for calcium, sodium, and creatinine.

Camacho PM, Petak SM, Binkley N et al. American Associa7on of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Treatment


• If medical history, physical findings, or laboratory test results suggest causes of secondary osteoporosis, additional laboratory evaluation is warranted and may include, but is not limited to, the following.

• Serum intact parathyroid hormone (PTH) concentration for possible primary or secondary hyperparathyroidism

• Serum thyrotropin• Tissue transglutaminase antibodies for suspected celiac disease• Serum protein electrophoresis and free kappa and lambda light chains for suspected myeloma

• Urinary free cortisol or other tests for suspected adrenal hypersecrettion• Serum tryptase, urine N-methylhistidine, or other tests for mastocytosis• Bone marrow aspiration and biopsy to look for marrow-based diseases• Undecalcified iliac crest bone biopsy with double tetracycline labeling (recommended for

patients with bone disease and renal failure to establish the correct diagnosis and direct management)

• Genetic testing for unusual features that suggest rare metabolic bone diseases

Camacho PM, Petak SM, Binkley N et al. American Associiation of Clinical Endocrinologists and American College of Endocrinology Clinical Pratiice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Note: This is taken from table 12 in the AACE guidelines.

Treatment


• Lifestyle modifications may improve musculoskeletal integrity and balance, preserve bone strength, and prevent future fractures. These include:

• An adequate intake of calcium and vitamin D• Daily supplementation with vitamin D3 at a dose of 1,000 to 2,000 IU is typically

needed to maintain an optimal serum 25(OH)D level.• For adults age 50 and older, the recommended calcium intake (dietary plus

supplements if necessary) is 1,200 mg/day.

• Lifelong participation in regular, weight-bearing, resistance exercise

• Balance-improving exercises to minimize falls

• Avoiding tobacco and excessive use of alcohol• Eliminating potential risk factors for falling.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endticr Pract. 2016;22(Suppl4):1-42.


Treatment


• The AACE strongly recommends pharmacologic therapy for the following patients:

• Those with osteopenia or low bone mass and a history of fragility fracture of the hip or spine.

• Those with a T-score of –2.5 or lower in the spine, femoral neck, total hip, or 33% radius.

• Those with a T-score between –1.0 and –2.5 in the spine, femoral neck, total hip, or 33% radius, if the FRAX® 10-year probability for major osteoporotic fracture is ≥20% or the 10-year probability of hip fracture is ≥3% (in the U.S.) or above the country-specific threshold in other countries or regions.



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Drug Prevention Treatment

Alendronate 5 mg PO daily35 mg PO weekly

10 mg PO daily70 mg POweeklyb 70 mg + Dc

Calcitonin — 200 IU intranasally once daily, or 100 IU SQqod

Denosumab — 60 mg SQ every 6 mo

Estrogen (multiple formulations) Multiple regimens —

Ibandronate 2.5 mg PO daily 150 mg POmonthly

2.5 mg PO daily 150 mg POmonthly 3 mg IV every 3mo

Raloxifene 60 mg PO daily 60 mg PO daily

Risedronate5 mg PO daily35 mg PO weekly 150 mg POmonthly

5 mg PO daily35 mg PO weekly 150 mg POmonthly

Abaloparatid — 80 mcg subcutaneously daily

Teriparatide — 20 μg SQ daily

Zoledronic acid 5 mg IV every 2nd y 5 mg IV once yearly

Camacho PM, Petak SM, Binkley N et al. American Associa7on of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.

Copyright © 2006 AACE. Endocr Pract. 2016;22(Suppl 4):1-42. Reprinted with permission from American Association of Clinical Endocrinologists.

Copyright © 2019 American Assticia7on of Clinical Endocrinologists 17

Treatment


• Four agents (alendronate, risedronate, zoledronic acid, and denosumab) have evidence for broad anti-fracture efficacy (spine, hip, and non-vertebral fracture risk reduction). These should be considered as initial options for most patients who are candidates for pharmacologic therapy.


Treatment


• Patients who have lower or moderate fracture risk can be started on oral agents.

• Injectable agents such as teriparatide,abaloparatide romosozumab, denosumab, or zoledronic acid can be considered as initial therapy for those who have the highest fracture risk.


Treatment


• For patients at high risk of spine fracture but not at risk for hip or non-vertebral fractures, ibandronate and raloxifene may be appropriate. Raloxifene has the additional benefit of reducing breast cancer risk.

• Denosumab is the agent of choice for patients with renal insufficiency. The AACE cautions against using in dialysis patients and those with stage 5 kidney disease due to risk of hypocalcemia.


© 2019 American Associaton of Clinical Endocrinologists2

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Sequential Therapy: Follow Anabolic Therapy with Antiresorptive Agents

• Treatment with anabolic agents (teriparatide, abaloparatide, romosozumab) should always be followed by antiresorptive therapy to prevent bone density decline and loss of fracture efficacy. The rationale for using an antiresorptive agent after anabolic therapy is based on both the limited period that anabolic therapy is used and on data showing that bone mineral density declines if antiresorptivetherapy is not initiated.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl4):1-42.Leder BZ. Optimizing sequential and combined anabolic and antiresprptive osteoporosis therapy. Journal of Bone and Mineral Research 2018; 2:62-68.

sts 21

Copyright © 2019 American Association of Clinical Endocrinologists 22

Combination Therapy:Under Investigation

• Combination therapies for osteoporosis are being evaluated, but there are as yet no studies showing that treatment with two or more osteoporosis drugs has a greater effect on fracture reduction than treatment with a single agent.

• Studies of bisphosphonate/PTH analog combinations suggest they do not provide substantial clinical benefit compared with monotherapy. The most promising combination studied to date is teriparatide and denosumab. The DATA study showed that bone mineral density at the spine and hip increased significantly more in postmenopausal women on this combination compared to either drug alone.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl 4):1-42.Leder BZ. Optimizing sequential and combined anabolic and antiresprptive osteoporosis therapy. Journal of Bone and Mineral Research 2018; 2:62-68.Leder BZ et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (the DATA Extension Study): a randomized controlled trial.J Clin Endocrinol Metab 2014; 99:1694–700.Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382:50–56.

Combination Therapy: AACE Recommendation

Copyright © 2019 American Associaton of Clinical Endocrinologists2

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s

• Combination therapy substantially raises the cost and probably increases the potential for side effects. Until the effect of combination therapy on fracture risk is better understood, the AACE does not recommend combination therapy for prevention or treatment of postmenopausal osteoporosis.

• However, in certain situations when the patient needs a stronger agent because fracture risk is especially high or there is demonstrated suboptimal effect from raloxifene or hormone replacement therapy (i.e., recurrent fractures, high bone resorption markers, or progression of BMD loss), yet the patient has specific non-bone reasons to continue with these agents, another antiresorptive agent or anabolic therapy could be added to the therapy.

Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016 Update. Endocr Pract. 2016;22(Suppl 4):1-42.Leder BZ. Optimizing sequential and combined anabolic and antiresprptive osteoporosis therapy. Journal of Bone and Mineral Research 2018; 2:62-68.Leder BZ et al. Two years of denosumab and teripara7de administration in postmenopausal women with osteoporosis (the DATA Extension Study): a randomized controlled trial.J Clin Endocrinol Metab 2014; 99:1694–700.Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382:50–56.

Discontinuation of Denosumab: ClinicalConsiderations

Copyright © 2019 American Association of Clinical Endocrinologists2

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ts

• Denosumab is a fast-acting and potent antiresorptive agent. However, its effects are rapidly reversible. When denosumab is discontinued, bone turnover rates increase to levels above pretreatment baseline.

• Clinicians should be aware that this post-denosumab “rebound” has been linked to an increased risk of vertebral fractures. In addition, evidence suggests that switching from denosumab to teriparatide in particular can lead to bone loss in postmenopausal women.

Treatment• The AACE has

developed the following treatment algorithm as part of its 2016 clinical practice guidelines.

• The full guidelines are available at https://www.aace.com/ files/postmenopausal-guidelines.pdf.

Copyright © 2006 AACE. Endocr Pract. 2016;22(Suppl 4):1-42. Reprinted with permission from American Association of Clinical Endocrinologists.


http://www.aace.com/

BISPHOSPHONATESFIRST LINE TREATMENT FOR POSTMENOPAUSAL OSTEOPOROSISBIND TO BONE SURFACE AND INHIBIT OSTEOCLAST MEDIATED BONE RESORPTIONORAL ALENDRONATE AND RISEDRONATE AND IV

ZOLEDRONATE LOWER VF AND NVF INCLUDING HIP FXFIRST CORRECT HYPOCALCEMIA AND VITAMIN D DEFICIENCYNOT RECOMMENDED IF CREATININE CLEARANCE LESS THAN 35 ML/MIN

POTENTIAL HARMS OF BP TREATMENT

RARE BUT SERIOUSONJ-EXPOSED BONE IN THE MAXILLO-FACIAL REGION THAT FAILS TO HEAL WITHIN 8 WEEKS; INCIDENCE BETWEEN 1/10000 AND 1/100000 PER YEAR OF USE AFF- LOW TRAUMA SUBTROCHANTERIC OR FEMORAL SHAFT FRACTURES; ABSOLUTE RISK OF WITH 5 YEARS TX LOWFOR EVERY 10000 WOMEN TXED FOR 3 YRS, 130 HIP FXS PREVENTED AT THE COST OF ONE AFF1.8/10000/YR AFTER 2 YRS; INCREASES WITH LONGER DURATION TO 113/10000/YR AFTER 8 YEARSCONSIDER THE RISK OF NOT TREATING

DENOSUMABA BIOLOGIC RANK LIGAND INHIBITORANTIRESORPTIVEPOSSIBLY SUPERIOR TO BP’SCONTRAINDICATION OR INTOLERANCE TO BP’SONJ AND AFF RAREEFFICACY RAPIDLY WANES AFTER TX LEADING TO HIGHER RATES OF VF’SEITHER CONTINUE INDEFINITELY OR TRANSITION TO ALTERNATIVE TX

DRUG ADHERENCEEASY TO MONITOR WITH ZA AND DENOSUMAB AND ROMOSOZUMABA MAJOR PROBLEM WITH ORAL BISPHOSPHONATES

OOC World Health Organization. World Health Organ Tech Rep Ser 1994;843:1-129

Images courtesy of Drs DavidDempster

and Roger Zambesi

Osteoporosis is a condition of low bone mass, microarchitectural deterioration and impaired bone strength, resulting in an increased risk for fractures1

Normal Osteoporosis

To correct the skeletal abnormalities of osteoporosis, bone-forming therapies are required to restore bone mass and strength

ANABOLIC AGENTSTERIPARATIDEABALOPARATIDEROMOSOZUMAB

OOC

PTH and Antiresorptive Therapies:Different Mechanisms of Action

12

-50

-100

250

200

150

100

50

0

0 1 12

250

200

150

100

50

0

-50

-100*

Teriparatide

3 6Months

0 1 3 6Months

Alendronate

P1NPNTx

McClung MR, et al. Arch Intern Med. 2005;165:1762-8.

Anabolics: First Line Osteoporosis Treatment for

Patients at High Risk of Fracture

Who are the Highest Risk Patients?• Prior fracture is most important risk factor for another fracture1

• Recent Fx suggest very high risk (Osteoporosis Emergency)- In over 377,000 women with first fx, absolute risk of

another fracture:- 10% first year , 18% first 2 years, 31% first 5 years2

• Multiple Fractures also very high risk3

• Proactive Spine Imaging Required to find Vertebral Fractures- In NHANES VFA Study 2017, vertebral Fx prevalence:- 5% in the 60s, 10% in the 70s, 20% in the 80s4

• People with very low BMD: high long-term risk for fracture• not necessarily high imminent risk

1. Kanis J Bone 20042. Balasubramanian A OI 2018

3.Gehlbach et al OI 20007 4.Cosman F et al OI 2017

Treatment of High Risk Patients: Limitations of Most Potent Antiresorptives

For zoledronic acid1 and denosumab2: nonvertebral fracture risk reductions at best 20%-25%

No significant fracture risk reduction seen before 3 years

*STRATA I and II1. Black DM et al. N Eng J Med. 2007;356:1809. 2. Cummings SR et al. N Engl J Med. 2009;361(8):756-65.

HORIZON1* FREEDOM2

Treatment of High Risk Patients: Limitations of Antiresorptives

• Longterm bisphosphonates- Effect on fractures beyond 3-4 years inconsistent- BMD plateaus after 3-4 years and if <-2.5, patients still at risk 1-2

• Longterm Efficacy with denosumab- low fracture rates after 3 years and continued increase in BMD

after 3 yrs3

- higher hip BMD predicts lower risk of future fx4, but may require very longterm therapy

• Longterm safety risks (AFF, ONJ) with both Dmab and BPs

1 Cosman F et al JCEM 20143 Bone H et al. Lancet Diab Endo.2017.

2 Black DM JAMA 20064Ferrari S et al. ASBMR 2016

Anabolic Agents Produce Rapid Fracture Reduction

• From respective pivotal clinical trials:

• Over median 19 months, Teriparatide1

- Reduced vertebral fracture by 65%

- Reduced nonvertebral fragility fx by 53%

• Over 18 months, Abaloparatide 2

- Reduced vertebral fracture by 86%

- Reduced nonvertebral fracture by 43%

• Over 12 months, Romosozumab3

- Reduced vertebral fracture by 73%- Reduced nonvertebral fracture by 25% (P=0.096)

- 42% for ROW, excluding LA (p<0.05)

1 Neer R et al NEJM 2001 2 Miller P et al JAMA 20163 Cosman F et al. NEJM. 2016

Comparing Anabolic and Antiresorptive Agents

• Comparing across different studies with differentpopulations, varying baseline characteristics andbaseline risk problematic.

• What about data comparing anabolic withantiresorptive agents in head to head trials?

Fracture Outcome Studies Anabolic vs Antiresorptive Agents

• Two Studies (Fracture Outcomes Not Primary Endpoints):• In Glucocorticoid Induced Osteoporosis:

• Teriparatide reduced vertebral fractures by 90% compared to Alendronate over 18 months1

• In Patients with acute painful vertebral fractures:• Teriparatide reduced vertebral fractures by 50%

compared to Risedronate over 1 year2

• Two New Studies Where Fracture Outcomes Were Primary Endpoints:• VERO: Compared Teriparatide with Risedonrate 3

• ARCH: Compared Romosozumab with Alendronate4

1 Saag et al NEJM 20073 Kendler et al Lancet2017

2 Hadji et al OI 20124 Saag et al ASBMR 2017, NEJM 2017

VERO: Teriparatide vs Risedronate in Severe Osteoporosis

Patients: Key Inclusion Criteria• Ambulatory postmenopausal women aged ≥45 years

• Radiographic evidence for at least 2 moderate (i.e. a reduction invertebral body height of 26% to 40%) or 1 severe (more than 40%reduction) prevalent vertebral fragility fractures

• BMD T-score ≤-1.5 standard deviations at the lumbar spine, total hip, or femoral neck

Protocol• Women randomized to receive:

- Teriparatide 20 mcg/day plus blinded oral Risedronate placebo or- Risedronate 35 mg orally once weekly plus blinded Teriparatide placebo

Kendler DL et al. Lancet. 391:230, 2018Trial Sponsor:

VERO: Teriparatide vs Risedronate in Severe OsteoporosisPrimary Endpoint

• Percentage of patients with at least 1 new vertebral fracture during the 24-month study

Key Secondary Endpoints• Pooled new and worsened vertebral fractures.• Clinical fractures (composite of clinical vertebral and non-vertebral

fragility fractures).• Non-vertebral fragility fractures*.• Major non-vertebral fragility fractures**

* excluding pathologic fractures and fractures of the skull, face, fingers, metacarpals, or toes.** hip, radius, humerus, ribs, pelvis, tibia, or femur

Kendler DL et al. Lancet. 391:230, 2018Trial Sponsor: Lilly


Analysis at 12 months was apre-specified exploratory endpoint.ARR = Absolute Risk Reduction; RRR = RelativeRisk Reduction CI = confidence interval NNT = number needed totreat


VERO: Teriparatide vs Risedronate in Severe Osteoporosis Incidence of Nonvertebral Fx

Risedronate

Teriparatide

No. at RiskTeriparatide 680 625 592 565 513Risedronate 680 622 595 570 518

Cum

ulat

ive

Inci

denc

e(%

)

Time(Months)

CI = confidence interval.* Fractures of the clavicle, scapula, ribs, sternum, sacrum, coccyx, humerus, radius, ulna, carpus, pelvis, hip, femur, patella, tibia, fibula, ankle,calcaneus, tarsus, or metatarsus (excluding pathologic fractures and fractures of skull, face, fingers, metacarpals, and toes).

Trial Sponsor: Lilly Kendler DL et al. Lancet. 391:230, 2018


Number of Incident Nonvertebral FracturesTeriparatide

(N=680)Risedronate

(N=680)

Patients with at least 1 non-vertebral fragility fracture, 25 (3.7) 38 (5.6)n (%)

with 1 non-vertebral fragility fracture 23 (3.4) 28 (4.1)

with 2 non-vertebral fragility fractures 2 (0.3) 10 (1.5)

Total number of non-vertebral fragility fractures 27 48

N = total number of patients; n = number of patients in the specified category

Adjusted rate ratio for teriparatide vs risedronate: 0.56 (0.35; 0.90) p=0.017*

*Non-longitudinal analysis of fracture occurrence was carried out using a Poisson regression model (Poisson distribution and log link) including the following variables: treatment, antecedent of recent clinical vertebral fractures, and recent use of bisphosphonate.


OOC

Sequential Therapy:

20

15

5

10

Combo

DMab

TPTD

48

18.3%

16.0%

14.0%

6 12 24Months

% C

hang

e fr

omB

asel

ine

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DMab0

6

3

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0

3

9 Total Hip

1/3 Radius

Lumbar Spine

24 Mo

48 Mo

% C

hang

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omBa

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Denosumab and TeriparatideBaseline 24 Mo 48 Mo

Teriparatide Denosumab YESCombination Denosumab YESDenosumab Teriparatide NO

Leder BZ et al. Lancet. 2015. pii: S0140-6736_61120-5.

T to D C to D D to T6

-3 T to D C to D D to T

OOC

• TPTD increases cortical porosity in radius and tibia1

• TPTD increases bone formationin human femoral neck2

• Denosumab after TPTD improvesBMD3

• TPTD after denosumab results in decreased BMD in hip (atmonth 12) and radius3

• TPTD should be added to denosumab therapy rather than switching

Teriparatide:Recent information

1. Tsai J et al. J Clin Endo Metab 2016;101:2023-302.Cosman F et al. J Clin Endo Metab 2016101:1498-1501 3. Leder BZ et al. Lancet. 2015. pii: S0140-6736_61120-5

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• Abaloparatide: a synthetic analog of PTHrP

• a selective activator of PTH type 1 receptor

• less stimulation of bone resorption thanteriparatide

• greater increase in BMD vs teriparatide in Phase 2 study

Abaloparatide

Horwitz MJ et al. J Bone Miner Res. 2013; 28:2266-76 Leder BZ et al. J Clin Endocrinol Metab. 2015;100:697-706

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2463 women withpostmenopausal osteoporosis

0

4

8

% C

hang

e fro

mba

selin

eLumbar spine Totalhip

Placebo APTD-80 TPTD-20

12

ACTIVE Trial: Abaloparatide and TeriparatideBone Mineral Density : 18months

Interventions:Abaloparatide 80 ugm SQ QD Teriparatide 20 ugm SQ QD* Placebo

* Open label

Miller PD et al. JAMA 2016;316:722-33

1

0

3

2

4

5

80%

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RRR RRR86%

Placebo TPTD 20 ABALO 80

Frac

ture

Rat

e (%

)at

18m

onth

s

N=711 N=690N=717

Morphometric Vertebral Fractures


1

0

2

3

5

4


28%RRR RRR

43%

P=0.21 P=0.44

Non-vertebral FracturesP=0.049

ACTIVE Trial: Abaloparatide and Teriparatide

0

1

3

2

5

4

OOC RRR = Relative risk reduction

HR HR0.71 0.57


Frac

ture

Rat

e (%

)at

18m

onth

s


0

1

2

3

4

5


HR 0.67 HR

0.30

P=0.14

Major Osteoporotic FracturesP=0.001

ACTIVE Trial: Abaloparatide and Teriparatide

P=0.11

Clinical FracturesP=0.02

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Abaloparatide

• Well tolerated: less frequent hypercalcemia

• placebo 0.4%

• abaloparatide 3.4%

• teriparatide 6.4%

• Daily SQ injections for 18months

• No need for refrigeration

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Sclerostin Inhibition

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Increased bone mass throughout skeleton.

Very low fracture risk

Photo: Janssens and Van Hul.Hum Mol Genet. 2002;11:2385-93.

Normal

Sclerosteosis / van Buchem’s

Sclerosteosis

due to absence of sclerostin (SOST) - a bone formation inhibitor

heterozygotes have normal phenotype except high bone mass

RomosozumabPhase 2 Study: Bone Mineral Density

Perc

enta

ge C

hang

e Fr

omBa

selin

e

10

8

6

4

2

0

–2

0 3

OODCata are LS means and 95% CIs.

9 12

*†ʌ

*†ʌ

*†ʌ11.3%

6Month

Lumbar Spine*P < 0.0001 vsplacebo

12 †P < 0.0001 vsALNʌP ≤ 0.0025 vs TPTD

–1

–2

0

4

3

2

1

0 3

*

*†ʌ

4.1%5 *P < 0.0001 vs placebo

†P < 0.0001 vs ALNʌP < 0.0001 vs TPTD

*†ʌ

6 9 12Month

Placebo ALN TPTD Romosozumab 210 mg QM

Total Hip

McClung et al. NEJM 2014;370:412-420.

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Bone Mineral Density –Year2Continued Romosozumab Therapy

TotalHip

30 3612 18 24

15

10

5

0

-530 36 BL 3 6

MonthBL 3 6 12 18 24

24

16

8

0

-8

Lumbar Spine

Romosozumab 210 mgQM* Placebo*

15.7%

6.0%

McClung MR et al. ASBMR 2014.

Perc

ent C

hang

e fr

omB

asel

ine

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Bone Mineral Density – Year 3Romosozumab Discontinuation: Transition toDenosumab

TotalHip

30 36

10

5

0

-530 36 BL 3 6 12 18 24

MonthBL 3 6 12 18 24

24

16

8

0

-8

Lumbar Spine

Romosozumab 210 mgQM* Placebo*

Denosumab 60 mgQ6MPlacebo Q6M

15.7%

19.4% 15

6.0%7.1%

McClung MR et al. ASBMR 2014.

Perc

ent C

hang

e fr

omB

asel

ine

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Romosozumab Phase 3 FRAMEStudyTop-line Results

• Year 1: romosozumab 210 mg Q month vs placebo• Year 2: open label denosumab 60 mg Q6 months

• At 12 months• 73% reduction in vertebral fracturerisk• 36% reduction in clinical fracturerisk• non-vertebral fracture risk: not significantly reduced

• p=0.10 at 12 months, 0.06 at 24 months• 42% reduction outside Latin America

• At 24 months: 75% reduction in vertebral fracturerisk• During second year: 25 vertebral fractures in DMab-PBO vs

5 in Romo-DmabCosman F et al. New Engl J Med 2016;375:1532-43







ANABOLICS

• ANTIFRACTURE EFFECTS ARE FASTER AND LARGER VS ANTIRESORPTIVE AGENTS

• EFFECTS SUSTAINED AFTER TRANSITION TO ANTIRESORPTIVES• VF, HIP AND NVF LOWER WITH ROMOSOZUMAB VS ALENDRONATE• THESE TRIALS DEMONSTRATE THAT IMPROVING TOTAL HIP BMD

ASSOCIATED WITH IMPROVED BONE STRENGTH AND RESISTANCE TO FRACTURE

• GREATEST HIP BMD GAINS OCCUR WHEN ANABOLICS USED FIRST

WHEN TO SWITCH TO AN ANABOLIC

• FROM BISPHOSPHONATE• WITH INCIDENT HIP FX OR VERY LOW HIP BMD CAN ADD ABALOPARATIDE OR

SWITCH TO ROMOSOZUMAB

PMO 2020

• REMEMBER EVIDENCE CONTINUES TO SUGGEST A SUPERIOR BENEFIT OF ANABOLIC FIRST FOR HIGH RISK PATIENTS

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Thankyou