Osteoporosis

Amanda Keith, PharmD, BCPS

Centra - Lynchburg General Hospital

April 8, 2015

Objectives

• Evaluate DEXA and FRAX scores to assess bone status.
• Recognize new pathophysiologic pathways of bone health and the relevant pharmacotherapy options.
• Identify adverse effects and risks related to pharmacotherapy options.
• Develop a medication therapy plan and subsequent monitoring plan based on a patient vignette.

Epidemiology

• >10 million Americans (3% population)
• 34 million more with low bone mass
• 80% cases in women
• 50% white females with OP/LBM by 60yo
• Est. by 2025, OP-related fx will increase to 3 million with total cost of $25 billion
• LTC 20% fractures
• 60% don’t regain independence

Pathophysiology

http://www.webmd.com/osteoporosis/guide/picture-of-osteoporosis

Pathophysiology

• Peak bone mass in 2^nd/3^rd decades
• Bone remodeling maintains bone health
• Continuous, coupled process that balances bone resorption, formation, & maintains Ca/Phos balance
• Osteoclasts
• responsible for bone resorption to meet metabolic needs of body
• Osteoblasts
• stimulate bone formation & collagen production to increase BMD

FRAX

• Fracture Risk Assessment Tool
• Estimates fracture risk at 10yrs
• No need for DXA (good when tech not avail)
• Use only if postmenopausal or men >50
• Treatment naïve
• Without fracture history
• High fracture risk
• >20% for any fracture
• >3% for hip fracture

FRAX

FRAX Website

Diagnosis

Adapted from Forinash

DXA Monitoring

Adapted from NOF page 20

BMD testing Q1-2 years after starting medical therapy & then every 2 years

More frequent in some situations

Longer interval if higher initial T-score & no risk factors

Universal Recommendations

• Diet with Ca, supplement if needed
• 1000mg QD men 50-70
• 1200mg QD women 51+ & men 71+
• Vitamin D intake, supplement if needed
• 800-1000 IU QD age >50
• Regular weight-baring & muscle-strengthening exercise
• Assess risk factors for fall & modify
• Tobacco cessation

NOF Guidelines

Treatment Guidelines

• Hip or vertebral fracture
• clinical or asymptomatic
• T-score ≤ -2.5 at hip/neck/spine
• Postmenopausal women & men 50+ with:
• LBM at femoral neck/hip/spine by DXA AND
• 10yr hip fx probability ≥ 3 percent or 10-yr major osteoporosis-related fx probability ≥ 20% based on FRAX

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NOF/AACE Guidelines

Approved Indications

Bisphosphonates

• Alendronate
• 5mg QD & 35mg weekly (prevention only)
• 10mg QD, 70mg weekly, 70mg weekly with D3, 70mg weekly effervescent
• Risedronate
• 5mg QD, 35mg weekly, 35mg weekly delayed release, 35mg with CaCarbonate, 75mg on two consecutive days every month, 150mg monthly
• Ibandronate
• 150mg monthly & 3mg IV Q3months
• Zoledronic Acid
• 5mg IV over 15 mins yearly (Q2 years for prevention)

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Bisphosphonate MOA

• Inhibit bone resorption via actions on osteoclasts or on osteoblast precursors
• Decreases the rate of bone resorption, leading to an indirect increase in BMD

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Bisphosphonates

Bisphosphonate Administration

• All oral meds:
• Empty stomach, 1^st thing in morning, upright 30 minutes
• Alendronate & risedronate oral
• Full 8 ounces water
• Binosto (effervescent alendronate)
• Dissolve in 4 ounces of room temp water
• Atelvia (delayed release risderonate)
• Immediately after breakfast with at least 4 ounces before eating/drinking/meds

Bisphosphonate Administration

• Ibandronate
• sit upright 60 mins
• Check Scr before each Q3month IV injection
• Zolendronic acid
• Well hydrated
• pretreat with APAP (acute phase reaction)
• 32% occurrence with 1^st dose, 7% after second

Bisphosphonates

• Similar adverse effects
• GI related
• difficulty swallowing, esophagus inflammation
• watch renal function
• Contraindicated with GFR <30-35ml/min
• Zolendronic Acid with <35ml/min or AKI

Denosumab (Prolia)

• Monoclonal antibody with affinity for RANKL
• Osteoblasts secrete RANKL
• RANKL activates osteoclast precursors & subsequent osteolysis
• Causes release of bone-derived growth factors which increase serum Ca levels
• Denosumab binds to RANKL, blocks interaction with RANK, prevents osteoclast formation
• Leads to ↓ bone resorption and ↑ bone mass

Denosumab (Prolia)

http://openi.nlm.nih.gov/detailedresult.php?img=3459574_cia-7-363f1&req=4

Denosumab (Prolia)

• Other indications
• Tx bone loss in women with breast cancer on aromatase inhibitor therapy
• Tx bone loss in men on meds for prostate CA
• MD office administration
• 60mg SQ Q6 months
• Cause hypocalcemia, ⇧ risk of cellulitis
• ↓Vertebral fx 68%, ↓hip fx 40%, ↓ non-vertebral fx 20% over 3 years

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Raloxifene (Evista)

• SERM – acts like estrogen to prevent bone loss
• ↓ bone resorption, ↑ BMD
• ↓ risk of vertebral fx by ~30% in those with prior vert fx & ↓ 55% in those without fx in pvs 3 years
• 60mg QD with or without food
• Increases DVT risk (similar to estrogen), hot flashes, leg cramps

Teriparatide (Forteo)

• Recombinant formulation of endogenous PTH
• Stimulates osteoblast function,GI Ca absorption, increase renal tubular reabsorption of calcium
• ↓ vertebral fx by ~ 65% & non-vertebral fx by ~53% after average 18 months therapy

Teriparatide (Forteo)

• Avoid with risk of osteosarcoma in (those with Paget’s or prior radiation), bone mets, hypercalcemia, hx skeletal malignancy
• 20 micrograms SQ daily
• Rec. max duration 18-24 months
• When stop therapy, bone loss can be rapid – need to start alternate therapy
• SE: leg cramps, nausea, dizziness

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Calcitonin

• Miacalcin/Fortical
• ↓ vertebral fx ~30% in those with hx vert. fx
• 200 IU intranasal daily
• AE: rhinitis, epistaxis, allergic reaction (salmon allergy)
• Functionally antagonizes the effects of PTH
• Directly inhibits osteoclastic bone resorption

Estrogen – In or Out

• Once was DOC
• FDA - “when prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate”

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MOA Review

http://openi.nlm.nih.gov/detailedresult.php?img=3549483_ijcp0066-1139-f2&req=4

Potential New Drug Pathways

• Cathepsin K

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• Sclerostin

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• Drugs in Development

Cathepsin K

• Lysosomal cysteine protease made by osteoclasts
• Primary enzyme involved in bone resorption
• Degrades collagen leading to bone breakdown
• Excessive breakdown during bone remodeling is key step in causing post-menopausal osteo

Drugs In Development

• Odanacatib
• Selective, reversible cathepsin K inhibitor
• Significantly ⇧ lumbar spine & hip BMD
• Phase 3 trial (LOFT) completed late 2014 – NDA expected early 2015
• Oral, once weekly

PDF Print

Sclerostin

• Osteocyte-secreted protein
• Inhibits osteoblast-mediated bone formation
• Sclerostin inhibition attractive MOA
• gene that encodes sclerostin is expressed only in skeletal tissue therefore off-target effects limited

Drugs in Development

• Romosozumab
• Phase 2 study completed 1/2014
• ⇧ bone formation by binding to sclerostin
• Current drugs don’t restore bone architecture & anabolic agent teriparatide limited by inconvenient dosing, high cost, and a black box warning about osteosarcoma
• SQ injection every 1 or 3 months over 12 months

Tucker

Myth vs Fact

• Calcium & Cardiovascular Disease
• Drug Holidays with Bisphosphonates
• Bisphosphonate-Associated ONJ & Dental Procedures
• Esophageal Cancer with Bisphosphonates
• PPIs & Osteoporosis

Calcium & CV Death

• RCT 2008 found ↑ risk of MI & composite death after 5 years of 1gm Ca supplement
• CV risk wasn’t primary outcome
• 2 Meta-analyses afterwards

1) ↓ risk in dialysis pts/no effect in general pop

2) placebo-controlled trials (excluded if Vit D) – ↑ risk of MI/composite death stroke MI; no risk of stroke/death alone

• Doses 700-899/day asstd with ↑ MI risk

Calcium & CV Death

• Ca supplementation alone may ↑ MI risk & composite MI/stroke/sudden death
• Ca+D doesn’t appear to affect risk
• Risk may ↑ with impaired renal or elderly
• Encouarge goal Ca through diet
• Supplement only if needed

Estimating Dietary Calcium

Bisphosphonate Drug Holiday

• Theory: long half-life in bone & AE (ONJ, esophageal CA, atypical fx)
• FLEX trial
• 10 yrs vs 5 on/5 off
• Only benefit: women with osteoporosis but no prior vertebral fx
• Continuation of bisphosphonate associated with significant ↓ in nonvertebral fx risk

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Bisphosphonate Drug Holiday

• Z3P3
• Lacked power
• Showed may be safe unless woman at high risk of fracture
• FDA Analysis 2011
• Pooled data
• No difference in those with 1+ fx between bisphos vs placebo at years 4-5, 6-9, or >9
• Fx related to BMD but also bone quality

Bisphosphonate Drug Holiday

• No consensus recommendations
• AACE – consider holiday after 3-5 years
• FDA – consider after 3-4 years (if continue, no risk or benefit found)
• Expert opinion:
• Low fx risk – consider after 5 yrs & stay off until BMD decreases or fx occurs
• Mod fx risk – bisphos 5-10 years, holiday 2-3 yrs
• High fx risk – consider holiday up to 2 years,

but start non bisphos therapy when stop bisphos

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Bisphosphonates & ONJ

• ONJ = exposed necrotic bone in the jaw >8 weeks in a pt w/bisphosphonate exposure, no history of radiation
• Oral bisphosphonates - 0.1%
• IV bisphosphonates (non OP indications) - 0.8-1.2%
• Higher BA (50% vs 1% po); larger doses
• Usually procedure prior, spontaneous rare

Bisphosphonates & ONJ

• Risk factors

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• Recommend dental exam before start
• If invasive procedure – provider decision- ?hold
• Discontinue 6-12 months with debridement if develops (risk/benefit)

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Esophageal Cancer & Bisphosphonates

• 2011 FDA reviewed case series of 23 reports from 1995-2008
• 31 other reports from Japan/Europe
• UK database
• 1^st trial - no ↑ risk b/t users & non-users
• 2^nd trial – ↑ risk with bisphos therapy (higher risk with more rxs filled)
• use >3yrs greater risk than <1yr
• Couldn’t assess adherence

Esophageal Cancer & Bisphosphonates

• Danish cohort showed significantly ↓ risk of esoph. CA compared to controls
• Inconclusive evidence
• Benefit outweighs risk
• Esophageal CA rare, esp. in women
• Educate on appropriate administration

Morden

PPIs & Osteoporosis

• PPIs commonly used (?overused)
• 2011 FDA advisory:
• Potential ↑ risk of fracture in hip, wrist & spine with high-dose &/or long-term PPI use
• In vitro – PPIs interfere with bone metabolism, leading to ↑ risk
• FDA looked at 4 Meta-analyses

Takada & Jo

PPIs & Osteoporosis

• Lack of consistency in studies in the MA
• Observational design = limitation
• Exact mechanism is unknown, presume from ↓ calcium absorption w/chronic use
• Calcium citrate doesn’t require acidic environment for absorption
• Evaluate PPI use periodically

Leontiadis

References

• Chiha M, Myers LE, Ball CA, et al. (2013) Long-term follow-up of patients on drug holiday from bisphosphonates: real-world setting. Endocrinology Practice, 19(6):989-94. http://dx.doi.org/10.4158/EP12425
• Forinash, A.B. and Abigail Yancey. Osteoporosis. In: Murphy J, Lee M, eds. Pharmacotherapy Self-Assessment Program, 2013 Book 1. Cardiology and Endocrinology. Lenexa, KS: American College of Clinical Pharmacy, 2013: 51-77.
• Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 remcommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 2010;62:1515-26.
• Jo Y, Park E, Ahn SB, et al. (2014) A proton pump inhibitor’s effect on bone metabolism mediated by osteoclast action in old age:a prospective randomized study. Gut and Liver, published online December 5, 2014, 1-8. http://dx.doi.org/10.5009/gnl14135
• Leontiadis G, Moayyedi P. (2014). Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol, 12(4):414-23. http://dx.doi.org/10.1007/s11938-014-0030-y.
• Lexi-Comp, Inc (Lexi-Drugs). Lexi-Comp, Inc.; March 31, 2015.

References

• Mordern NE, Munson JC, Smith J, et al. (2015) Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury. Osteoporosis International, 2015 Feb; 26(2):663-72. http://dx.doi.org/10.1007/s00198-014-2925-9
• National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2014.
• PDF Print. (September 15, 2014). Merck announces data from pivital phase 3 fracture outcomes study for odanacatib, an investigational oral, once-weekly treatment for osteoporosis. Retrieved from http://www.mercknewsroom.com/news-release/research-and-development-news/merck-announces-data-pivotal-phase-3-fracture-outcomes-st.
• Tanaka M, Itoh S, Yoshioka T, et al. (2014) The therapeutic effectiveness of the coadministration of weekly risedronate and proton pump inhibitor in osteoporosis treatment. Journal of Osteoporosis, 2014, 1-5. http://dx/doi.org/10.1155/2014/607145
• Tucker ME. (January 3, 2014) Romosozumab ‘potential breakthrough’ in osteoporosis. Retrieved from http://www.medscape.com/viewarticle/818651
• Watts NB, Bilezikian HP, Camacho PM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010a;16(suppl3):s1-s37.

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Question 1

Martha is a 70yo female who is being assessed for osteoporosis by her rural MD. The office doesn’t have DEXA technology. The physician desires to use FRAX to assess her fracture risk and potential need for treatment. Which part of her past medical history would prevent FRAX from being accurate for Martha?

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• Finger fracture at age 15
• Hip fracture at age 65
• Postmenopausal
• Previously on bisphosphonate therapy, but discontinued it 4 years prior

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Question 1

Martha is a 70yo female who is being assessed for osteoporosis by her rural MD. The office doesn’t have DEXA technology. The physician desires to use FRAX to assess her fracture risk and potential need for treatment. Which part of her past medical history would prevent FRAX from being accurate for Martha?

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• Finger fracture at age 15
• Hip fracture at age 65
• Postmenopausal
• Previously on bisphosphonate therapy, but discontinued it 4 years prior

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Question 2

The next potential drug for osteoporosis treatment to enter the market is odanacatib. The novel mechanism of this agent is:

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• Binding to RANKL preventing osteoclast formation
• Inhibition of osteoclastic bone resorption
• Sclerostin inhibition
• Selective, reversible cathepsin K inhibition

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Question 2

The next potential drug for osteoporosis treatment to enter the market is Odanacatib. The novel mechanism of this agent is:

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• Binding to RANKL preventing osteoclast formation
• Inhibition of osteoclastic bone resorption
• Sclerostin inhibition
• Selective, reversible cathepsin K inhibition

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Question 3

Which of the following principles is not part of thorough counseling for oral bisphosphonate therapy in regards to prevention of adverse effects?

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• Doses may be taken at any time of day as long as consistent
• Doses should be taken on an empty stomach
• Drink a full glass of water with each dose
• Remain upright at least 30 minutes after each dose

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Question 3

Which of the following principles is not part of thorough counseling for oral bisphosphonate therapy in regards to prevention of adverse effects?

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• Doses may be taken at any time of day as long as consistent
• Doses should be taken on an empty stomach
• Drink a full glass of water with each dose
• Remain upright at least 30 minutes after each dose

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Question 4

Susan is a 68 year old post-menopausal female with a history of TIAs, Zollinger-Ellison syndrome, & hypertension. She is currently on aspirin, protonix, and lisinopril. Her allergies are to penicillin, peanuts, and fish. Based on your knowledge of existing therapies and her PMH, which agent would be the most appropriate for initiating prevention of osteoporosis?

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• Alendronate
• Calcitonin
• Denosumab
• Estrogen therapy

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Question 4

Susan is a 68 year old post-menopausal female with a history of TIAs, Zollinger-Ellison syndrome, & hypertension. She is currently on aspirin, protonix, and lisinopril. Her allergies include penicillin, peanuts, & fish. Based on your knowledge of existing therapies and her PMH, which agent would be the most appropriate for initiating prevention of osteoporosis?

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• Alendronate
• Calcitonin
• Denosumab
• Estrogen therapy

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