osteoporosis medications - american association of...

Osteoporosis Medications: A Case-Based Discussion

Laila S. Tabatabai, MD August 5, 2017

Disclosures

Eli Lilly

Radius

Objectives

Determine which patients with low bone density require treatment, along with optimal duration of treatment

Select antiresorptive agents based on the patient's individual characteristics and preferences

Recognize the benefits of anabolic agents in specific subpopulations of osteoporosis patients

Case 1 Gemma, a 52-year-old Caucasian woman presents to her primary care provider (PCP), for her annual physical examination

She is 5'2" and weighs 103 lb. BMI 18.8

Gemma reports irregular menses and occasional hot flashes. She is not on HRT

She says that she has “a couple of glasses of wine” most weekends and smokes 1-2 cigarettes daily

She does not regularly take any prescription medication. Uses NSAIDS as needed for “aches and pains,” usually in the evening

She takes a daily multivitamin supplement. She avoids dairy foods due to GI symptoms

The best next step in evaluation would be:

No recommendation at this time

Make a note on her file to monitor her for bone loss at her next annual exam

Order a DXA scan

Recommend calcium supplementation

Gemma’s risk factors for Osteoporosis

Caucasian race

Perimenopause/post-menopause – accelerated bone loss

Low BMI, small frame

Smoking

Calcium-deficient diet

Risk factors for Osteoporosis

Caucasian or Asian race/ethnicity

Female sex

History of fragility fracture

Parental hip fracture

Long-term steroid use (greater than 5 mg prednisone for 3 weeks or longer)

3 or more alcoholic beverages daily

Tobacco use

Secondary causes (type 1 DM, rheumatoid arthritis, chronic malnutrition, longstanding hyperthyroidism, hypogonadism, chronic liver disease)

Fragility fracture (fall from standing height)

Loss of height (>2 inches)

Visible dorsal kyphosis

Radiographic osteopenia, vertebral compression fracture

Indications for Evaluation of BMD

DXA

DXA scan reveals that Gemma has a L1-L4 T-score of -1.5, right femoral neck T-score -2.2, right total hip T-score -1.8.

What is the best next step in assessing her fracture risk?

No further assessment is necessary, the DXA scan gives all the information needed

Use the FRAX fracture risk assessment tool

Obtain a x-rays of the entire skeleton to rule out all possible occult fractures

Ask Gemma her back pain level from 0-10 out of 10 while she stands, sits, and then lies supine on the examination, to assess for vertebral compression fracture

DXA

DXA scan reveals that Gemma has a L1-L4 T-score of -1.5, right femoral neck T-score -2.2, right total hip T-score -1.8.

What is the best next step in assessing her fracture risk?

No further assessment is necessary, the DXA scan gives all the information needed

Use the FRAX fracture risk assessment tool

Obtain a x-rays of the entire skeleton to rule out all possible fractures

Ask Gemma to rate her back pain level from 0-10 out of 10 while she stands, sits, and then lies supine on the examination, to assess for vertebral compression fracture

FRAX (WHO Fracture Risk Assessment Tool)

Risk Factors

Risk Assessment

FRAX Threshold To Treat

10-year risk of major osteoporotic fracture > 20%

10-year risk of hip fracture > 3%

Risk Assessment

Trabecular Bone Score (TBS)

Derived from the texture of the DXA image and has been shown to be related to bone microarchitecture and fracture risk.

Computed from the antero-posterior spine DXA examination file by a software (TBS iNsight)

The lumbar spine texture analysis using TBS is a risk factor for osteoporotic fracture.

The predictive ability of TBS is independent of FRAX clinical risk factors and femoral neck BMD.

The calculated probabilities of fracture have been shown to be more accurate when computed including TBS.

FRAX Limitations

Lacks dose-response effects (years of smoking, amount of glucocorticoid exposure, number of fractures, etc.)

Does not accommodate all known risk factors (falls, biochemical markers, etc.)

Only applicable to untreated patients

Limited country models available

Does not replace clinical judgment

Interactive – use FRAX calculator

https://www.sheffield.ac.uk/FRAX/

Objectives




Helga

68 y.o German lady with active tobacco use, COPD with long-term steroid use, GERD with Barrett’s esophagus under annual surveillance

Tells you she tried the “Sally Field drug” and “hated it”

No fractures, no significant height loss, no parental hip fracture

Takes no calcium or vitamin D supplements. Makes her own goat cheese and kefir – has 3-4 servings of dairy foods daily

DXA: lowest T-score -2.6 at R femoral neck, FRAX: 10-yr major fracture risk 14% and 10-yr hip fracture risk 7.3%

Labs: Creatinine 1.4, GFR 32, 25-hydroxyvitamin D 27, PTH 78, calcium 9.1. SPEP nl, celiac panel neg.

Helga

Does she need treatment?

Which medication should you choose?

What concerns do you have?

FDA-Approved Medications Drug PMO GIO Men

Prevention Treatment Prevention Treatment

Estrogen Raloxifene Calcitonin Alendronate Risedronate Ibandronate Zoledronic acid Denosumab Teriparatide

PMO: post-menopausal osteoporosis GIO: glucocorticoid-induced osteoporosis

FDA-Approved Medications Drug Fracture Efficacy Possible Side Effects

Spine Hip

Estrogen (PO, TD) Stroke, CV, DVT, breast Ca Raloxifene (PO) DVT Calcitonin (SQ, nasal) Nasal irritation (nasal) Alendronate (PO) ONJ, AFF, GI Risedronate (PO) ONJ, AFF, GI

Ibandronate (PO, IV) ONJ, AFF, GI (PO) Zoledronic acid (IV) ONJ, AFF, renal

Denosumab (SQ) Immune, ONJ, AFF Teriparatide (SQ) Hypercalcemia, GI

ONJ: osteonecrosis of the jaw AFF: atypical femoral fracture

Denosumab

Biologic – monoclonal antibody

Mechanism

Inhibits receptor activated nuclear factor kB

Prevents osteoclast formation

Short half life, not bound to skeleton

Subcutaneous every six months

Denosumab Advantages

Does not persist in skeleton, reversible

Not cleared by kidney: can use with creatinine clearance below 30

ml/min

Fracture efficacy spine, hip, non-vertebral

May help adherence in some patients

Disadvantages

Immune effects: infections may be increased

Marked suppression of bone turnover

Long term safety issues: ONJ, atypical fractures

Hypocalemia (CKD pts, prostate cancer w/ bone mets)

Increase in rebound vertebral fracture rate

McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL et al. Osteoporos Int 2013; 24:227-235

Denosumab: 8 Year Data Extension study: All on denosumab at 48 months

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Denosumab

Placebo

Months

McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL et al. Osteoporos Int 2013; 24:227-235

Denosumab: 8 Year Data Extension study: All on denosumab at 48 months

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DenosumabPlacebo

Formulate Tailored Treatment Plans Oral bisphosphonates

PROS – cheap, effective (osteoporotic fracture risk reduction ~50%), no significant rebound with discontinuation CONS – GI side effects (even in patients without GERD/gastritis/ulcers), AFF and ONJ with long-term/uninterrupted use, requires bisphosphonate holiday, lack of long-term adherence,

Up to 50% of patients on oral bisphosphonates abandon therapy within the 1st year1

12-month persistence rates were 47.5% for monthly ibandronate and 30.4% for weekly bisphosphonates2

Compliance (MPR, medication possession ratio) was significantly higher in the monthly cohort (MPR=85%) than in the weekly cohort (MPR=79%)2

1. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Huybrechts KF et al. Bone. 2006. June;38(6):922-8. 2. Adherence to monthly and weekly oral bisphosphonates in women with osteoporosis. Cotte FE et al. Osteoporos Int (2010) 21:145–155.

Formulate Tailored Treatment Plans Parenteral Anti-resorptives (IV zoledronic acid, SC denosumab)

PROS – improved adherence, highly potent, effective (osteoporotic fracture risk reduction ~50-70%), no significant GI side effects

CON – ONJ, AFF with long-term/uninterrupted use, significant acute phase reaction with IV zoledronic acid (usually 1st dose only)

CON – significant increase in rebound vertebral fracture rate with discontinuation of denosumab1,2

absent microdamage repair during therapy and excess reactivation of osteoclasts, rapid bone resorption

“Rebound-associated vertebral fractures” (RVF) - multiple new clinical vertebral fractures, associated with either no or low trauma, in the context of high bone turnover and rapid loss of lumbar spine bone mineral density (BMD) occurring within 3 to 12 months after discontinuation of denosumab

1. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Popp AW et al. Osteoporosis Int 2016 May;27(5):1917-21. 2. Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: 9 Clinical Cases Report Lamy O et al. JCEM 2017 Feb;102(2)354–358.

When selecting a medication for treatment of osteoporosis, consider this…

Fracture risk

Comorbidities

Contraindications (relative and absolute)

Patient preference

Adherence

Duration of treatment

Helga

68 y.o German lady with active tobacco use, COPD with long-term steroid use, GERD with Barrett’s esophagus under annual surveillance

Tells you she tried the “Sally Field drug” and “hated it”

No fractures, no significant height loss, no parental hip fracture

Takes no calcium or vitamin D supplements. Makes her own goat cheese and kefir – has 3-4 servings of dairy foods daily

DXA: lowest T-score -2.6 at L1-L4, FRAX: 10-yr major fracture risk 28% and 10-yr hip fracture risk 4.1%

Labs: Creatinine 1.4, GFR 32, 25-hydroxyvitamin D 27, PTH 78, calcium 9.1. SPEP nl, celiac panel neg.

Helga

Does she need treatment?



Helga

Does she need treatment? YES



Helga


Which medication should you choose? DENOSUMAB


Helga


Which medication should you choose? DENOSUMAB

What concerns do you have? Renal disease and vitamin D deficiency – risk of hypocalcemia

Adherence to therapy – rebound vertebral fracture risk

Objectives




Osteoporosis Treatment: Anabolic Agents


Mainstay of treatment for patients who have suffered a fragility/osteoporotic/pathological fracture (non-malignancy)

Should be first-line treatment in fracture patients without contraindications to anabolic therapy

Only treatment available for patients with atypical fractures related to long-term bisphosphonate use


Only 22% of fragility fracture patients receive treatment for osteoporosis1

Fracture risk is elevated for several years after the initial fracture: 10% in 1st year, 18% in 2nd year2 and stays elevated for 15 years3

Almost 2/3 of women age 50+ with hip fracture were not started on osteoporosis treatment within 12 months of discharge4

1. Solomon DH et al. Am J Med 2003 115(5):398-400. 2. Balasubramanian et al, JBMR, 2016; 31(suppl 1). 3. Van Geel TA et al., Ann Rheum Dis, 2009;68:99-102. 4. Solomom DH et al. JBMR. 2014. 29:1929-1937.

Teriparatide

Summary of Effects1: Increase in spine BMD of 10-14%, 96% of postmenopausal women showed an increase Increase in femoral neck BMD 3-5% Reduced risk of vertebral fractures by up to 69% Reduced risk of nonvertebral fracture by up to 54%

1. Neer R et al. NEJM. 2001; 344:1434.

Teriparatide

Teriparatide is much more efficacious at increasing lumbar spine bone density than hip bone density

No early separation in incidence of nonvertebral fractures in teriparatide-treated groups versus placebo-treated groups In clinical use for over 15 years

Novel Osteoporosis Agents: Abaloparatide

Only the 2nd anabolic agent approved for treatment of osteoporosis

Approved on 4/28/17

Indication: for treatment of postmenopausal women with a recent osteoporotic fracture

Designed by insertion of residues into the PTH– related peptide amino-terminal fragment between residues 22 and 34.


Resulting peptide is a selective activator of the PTH type 1 receptor pathway, more anabolic effects & less bone resorption than teriparatide.

High affinity binding to the bone formation configuration of the PTH type 1 receptor, and lower affinity binding to the resorptive configuration.

This results in less calcium mobilization and net greater anabolic effect than PTH (teriparatide) or PTH-rp.


Phase 2 study: abaloparatide produces rapid bone mineral density increases at the lumbar spine and at primarily cortical skeletal sites, including the hip.

Phase 3 results from the ACTIVE trial (Abaloparatide Comparator Trial In Vertebral Endpoints): abaloparatide treatment for 18 months reduced new vertebral fractures by 86% and nonvertebral fractures by 43%, with rapid separation in nonvertebral fracture risk between the abaloparatide and placebo groups.


Safety concerns: As with teriparatide, use of abaloparatide is associated with a dose-dependent increase in osteosarcoma in rats This effect was observed at doses between 4 – 28 the exposure in humans using the 80 mcg dose Use is not recommended in patients at increased risk for osteosarcoma, including Paget’s disease, those with unexplained elevations in alkaline phosphatase, open epiphyses, prior skeletal irradiation (external beam or implant), skeletal malignancies. Boxed warning is identical to warning on teriparatide

Mayo Clinic Proceedings 2017 92, 200-210DOI: (10.1016/j.mayocp.2016.10.009) Copyright © 2016 Mayo Foundation for Medical Education and Research

Lumbar spine Total hip

Femoral neck

http://www.elsevier.com/termsandconditions

http://www.elsevier.com/termsandconditions

Teriparatide or Abaloparatide?

Cost

Approval

BMD site of concern

ACTIVE data: Early increase in s-PINP and the less prominent increase in s-CTX with abaloparatide compared with teriparatide1

1. Miller P et al. JAMA. 2016;316(7):722-733.

Teriparatide or Abaloparatide?

Despite being lower in the abaloparatide group vs the teriparatide group, bone formation (s-PINP), still remained 50% above baseline in the abaloparatide group at 18 months.

Abaloparatide: It may be that smaller increases in formation coupled with a lesser increase in markers of bone resorption, are consistent with early increases in BMD and earlier fracture protection.

Further research is needed

Miller P et al. JAMA. 2016;316(7):722-733.

AACE Clinical Practice Guideline for the Diagnosis and Treatment of

Postmenopausal Osteoporosis - 2016

Novel Osteoporosis Agents: Romosozumab

Developed by Amgen. Awaiting approval.

Sclerostin deficiency leads to sclerostosis (high bone mass and resistance to fracture)

Sclerostin is secreted by osteocytes, inhibits Wnt signaling, thus reducing osteoblast activity

MoA: Monoclonal antibody that binds and inhibits sclerostin

Increases bone formation and reduces bone resorption (“uncoupling effect”)

Novel Osteoporosis Agents: Romosozumab

Phase 3 study safety data:

Increase in positively-adjudicated serious cardiovascular adverse events in romosozumab group 2.5% of romosozumab patients suffered cardiovascular SAE versus 1.9% in the alendronate group.

References

Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, Kleerekoper M, Lewiecki EM, Miller PD, Narula HS, Pessah-Pollack R, Tangpricha V, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis – 2016. Endocrine Practice. 2016 Sep 2; 22(Suppl 4):1-42.

Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med 2016 Jan 21:374(3):254-62.

Lewiecki EM, Miller PD, Harris ST, Bauer DC, Davison KS, Dian L, Hanley DA, McClung MR, Yuen CK, Kendler DL. Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis. J Clin Densitom. 2014 Oct-Dec; 17(4):490-5.

Adler RA, El-Hajj Fuleihan G, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016 Jan;31(1):16-35.

“Medicine is only for those

who cannot imagine

doing anything else.”

Luanda Grazette, MD

Keck School of Medicine, USC

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