osteoporosis, beyond diagnosis and first line treatment ... c... · 10-year probability of a major...

$: Osteoporosis, Beyond Diagnosis And First Line Treatment ... C... · 10-year probability of a major osteoporosis-related fracture ≥ 20% based on the US-adapted WHO algorithm National$
Osteoporosis, Beyond Diagnosis and First Line Treatment:

Drug Holidays & Treatment Failure

Dr Anuradha Negi Dr Ester Yeoh Registrar Consultant Department of Medicine, Division of Endocrinology Khoo Teck Puat Hospital

Case Study 1

• Mdm. S

• 75 year old Chinese female

• No past medical history

• Non smoker

• No previous fractures

• Requests for Osteoporosis

evaluation

Case Study 1 • Mdm. S

• 75 year old Chinese female

• No past medical history

• Non smoker

• No previous fractures

• Menopause at 50 years

• Requests for Osteoporosis evaluation

INDICATION FOR BMD TESTING : Women age >65 Years regardless of clinical risk factors

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010.

Indications for BMD • Women age 65 and older and men age 70 and older,

regardless of clinical risk factors

• Younger postmenopausal women and men age 50 to 69 about whom you have concern based on their clinical risk factor profile

• Adults who have a fracture after age 50

• Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for ≥ three months) associated with low bone mass or bone loss

• Anyone being treated for osteoporosis, to monitor treatment effect


BMD - Hip

BMD - Spine

Should treatment be considered in this

situation ?

In postmenopausal women and men age 50 and older, consider treatment if :

• A hip or vertebral (clinical or morphometric)

fracture • T-score ≤ -2.5 at the femoral neck or spine after

excluding secondary causes • Low bone mass (T-score between -1.0 and -2.5 at

the femoral neck or spine) and 10-year probability of a hip fracture ≥ 3% or 10-year probability of a major osteoporosis-

related fracture ≥ 20% based on the US-adapted WHO algorithm


TEST Value Reference

Hemoglobin 12.4 12-16 g/dl

Platelet 124 140-440

TBW 9.2 4-10 X 10(9)

Creatinine 58 40-85

ALT 13 7-36U/L

AST 17 15-33U/L

Albumin 42 37-51 g/l

ALP 54 32-103U/L

25 OH VITAMIN D 25.9 <30 Ug/L

Calcium. corrected 2.38 2.10-2.55 MMOL/L]

PTH 1.1 0.9-6.2 PMOL/L

Free T4 13 8.8-14.4 PMOL/

TSH 0.964 0.65-3.75 mu/L

Search for Secondary cause

What are the treatment options?

Adequate intake of Calcium ie. 1200mg per day

Dietary and Lifestyle Measures

Dietary and Lifestyle Measures

• Vitamin D 800-1000 IU/day Sources : Vitamin D-fortified milk (400 IU per quart, although

certain products such as soy milk are not supplemented with vitamin D) and cereals (40 to 50 IU per serving), egg yolks, salt-water fish and liver.

(Sun exposure ~25 min, 3x/week with 6% BSA – face and both arms)

• Weight-Bearing Exercise • Fall prevention • Avoidance of tobacco and alcohol • Treatment of secondary cause • Pharmacologic treatment

FDA-Approved Medications

ANTIRESOPTIVE ANABOLIC

STRONTIUM

MIXED AGENT

Pharmacologic Therapy Drug Class Examples Side effects

Bisphosphonates

Alendronate, tablet 70 mg once a week

-Oesophageal ulcer -ONJ (Particularly following intravenous bisphosphonates ) -Atrial fibrillation

Risedronate/ Actonel tablet 35 mg once week

Zoledronic acid, intravenous 5 mg over 15 minutes once a year

How will you follow-up?

Approach to Monitoring

• Monitor compliance, review risk factors and,

exercise, fall prevention and other lifestyle measures

• Serial central DXA BMD • Interval between BMD is determined by clinical

status • Repeat 1 year after initiation or change of

therapy. Longer interval once therapeutic effect is established

• More frequent testing in conditions associated with rapid bone loss such as glucocorticoid therapy

• Rates of bone loss or gain are most often modest compared to the errors incurred in the measurement of BMD

• The change in BMD that can be confidently detected is termed the least significant change (LSC)

– Know the facility’s LSC in g/cm2

Approach to Monitoring- How much of a difference in BMD is real?

How much of a difference in BMD is real?

• Look at the DXA images on the two studies.

The region of interest must be same

Change in BMD : Absolute LSC = Recent BMD - Initial BMD % Change = [(Recent BMD – Initial BMD)/ Initial BMD] X 100%

Hip Neck of femur Spine

BMD

T-score

%change BMD T-score %change BMD T-score

%change

2013 0.610 -2.6 0.552 -2.4 0.798 -1.8

2014 0.695 -2.2 +14 0.589 -2.1 +6.7 0.837 -1.4 +4.8

2015 0.698 -2.2 +0.4 0.612 -1.9 +3.9 0.845 -1.4 +0.9

Hip

NOF Spine

% LSC 5 6.2 3.1

Absolute LSC g/cm2

0.036 0.039 0.025

LSC FOR KTPH

Bone turnover markers

Bone Formation Markers

Bone Resorption Markers

Alkaline Phosphatase (ALP)

NTX

P1NP

CTX

• Greater biological and analytical variability • Biological variability can be reduced by obtaining samples in the early morning after an overnight fast. • Serial measurements at the same time of day (and preferably during the same season of the year)

How long should we treat for?

Drug Holiday

• Bisphosphonates bind to hydroxyapatite in bone and remain for years.

• Bisphosphonate exposure for 3-5 years in postmenopausal women provides protection from fractures for a variable period of time when therapy is withdrawn.

• Risk of adverse effects of long term therapy

Black DM, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938 Black DM, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012; 27(2):243-254

• Currently no strong evidence to provide guidance in terms of how long to treat, how long the holiday should be, and when the holiday should be stopped.

• Therapy needs to individualised based on the individual’s current fracture risks

• Revaluate need for holiday after 3-5 yr.

Bisphosphonate drug holiday: who, when and how long. Therapeutic Advances in Musculoskeletal Disease

RECOMMENDATION FOR DRUG HOLIDAY FROM BISPHOSPHONATES

PATIENT CATEGORY RECOMMENDATION

High-risk of fracture

T-score < -2.5 at hip Previous fracture of the hip or spine Ongoing high-dose glucocorticoid therapy

Treat with bisphosphonates for 10 years. Offer drug holiday for 1-2 years A non- bisphosphonate treatment (e.g. raloxifene or teriparatide) may be offered during the ‘holiday’.

Moderate-Risk

Treat for 5–10 years. Offer a ‘drug holiday’ of 3–5 years or until there is significant loss of BMD or the patient has a fracture, whichever comes first. Eg: 72yearold woman, menopause at age 48, lowest initial Tscore –2.8, no risk factors, bisphosphonate therapy for 7 years, BMD increased over that time so lowest Tscore now is –2.3. Treatment was indicated but after 7 years of treatment, a drug holiday might be considered.


RECOMMENDATION FOR DRUG HOLIDAY FROM BISPHOSPHONATES

PATIENT CATEGORY

RECOMMENDATION

Mild- Risk Factor Treat with bisphosphonate for 3–5 years, then stop Example: 68yearold woman, menopause at age 50, initial lowest Tscore –2.3, parent with a hip fracture, bisphosphonate treatment for 5 years, BMD stable over that time.

Low risk of fracture: Did not meet current treatment criteria at the time of treatment initiation Discontinue treatment


Monitoring during Drug Holiday

• Decrease in BMD might be used to decide when to end a drug holiday.

• Reassessment of risk should occur sooner for drugs with lower skeletal affinity

– Suggest: Reassess after 1 year for risedronate, 1–2 years for alendronate, and 2–3 years for zoledronic acid

– BMD after 1st year of stopping, 2 yearly BMD thereafter

Case Study 2

SITE 16Dec 2005

BMD T-SCORE

Left Femoral Neck 0.38g/cm2 -4 SD

Lumbar Spine L1-L4 0.50g/cm2 -4.4

Mdm. TSH 86 year old Chinese female Past Medical history : Osteoporosis, f/up another hospital Family history : Daughter has osteoporosis

Rx: Alendronate (FOSAMAX) 70 mg once a week Calcium and Vitamin D 2 tab OM

DATE SITE BMD Medication

Left Femoral Neck Left Total Hip Lumbar Spine L1-l4

BMD g/cm2

T-score

LSC BMD T-score

LSC BMD T-score

LSC

2005 SGH

0.38 -4 SD 0.50 -4.4 Alendronate 70 mg once a week Calcium carbonate/ Vit D 2 tab OM

2006 SGH

0.405 -3.8 +6.5% 0.50 -4.4 0%

2008 SGH

0.395 -3.9 -2.4% 0.455 -4 0.481 -4.5 -3.8%

2009 SGH

0.396 -3.9 +0.2% 0.467 -3.9 +2.6%

0.478 -4.6 -0.6%

2011 SGH

0.388 -3.9 -2% 0.472 -3.8 +1% 0.487 -4.5 +1.8%

• Presented with a Fall in 2011 • Low trauma, standing height • XR left Hip: Shortening of the neck of the left femur,

with sclerosis across the neck region suggesting sub-acute fracture line.

• Underwent left hip cancellous screw insertion March 2011

Is this treatment failure ?

What other investigations would you consider?

DEFINITION

1. Two or more incident fragility fractures; 2. One incident fracture and decrease in serum βCTX or PINP < LSC 3. One incident fracture and decrease in BMD >LSC 4. Decrease in serum βCTX or PINP < LSC and decrease in BMD > LSC

Before Switching Therapy

• Fractures of the hand, skull, digits, feet and ankle are not considered as fragility fractures

• When using sequential bone turnover markers, use the same assay.

• Falls are an important driver of fractures. Consider risk of falls when analyzing treatment response

- Review Adherence

- Screen for secondary causes

Approach to treatment Failure

Endocrinopathies Drugs

Hypogonadism (Hyperprolactinemia) Hyperparathyroidism Hyperthyroidism Cushing’s syndrome Acromegaly

Glucocorticoids Excess thyroid hormones Anticoagulants Anticonvulsants Thiazolidinediones Alcohol Rifampicin Methotrexate

GI-Tract DIsorders Bone Marrow Disorders

Gastrectomy IBD Coeliac disease Intestinal bypass surgery Primary biliary cirrhosis Pancreatic insufficiency

Multiple Myeloma Hemolytic Anemia Hemoglobinopathies Myelo and lympho-proliferative disorder

P. Tannirandorn Osteoporos Int. 2000;11:637




TBW 9.2 4-10 X 10(9)

Creatinine 57 40-85

ALT 21 7-36U/L

AST 33 15-33U/L


ALP 54 32-103U/L

25 OH VITAMIN D 32.2 10.1-40.3 Ug/L

Calcium. Total 2.38 2.10-2.60 MMOL/L]

PTH 1.1 0.9-6.2 PMOL/L

Free T4 12.2 8.8-14.4 PMOL/

TSH 0.964 0.65-3.75 mu/L

Search for Secondary cause was undertaken

• Developed progressive worsening left hip pain secondary to avascular necrosis.

• Cancellous screws were removed and left hip bipolar hemiarthroplasty was performed in 2011.

• Bisphosphonates discontinued in 2012

Subsequent course …

• Re-admitted in 2014 with another fall

• Was trying to sit up when grand daughter jumped on her and patient fell to her right

a. Right Humerus Fracture b. Right Neck of Femur fracture




TBW 10.23 4-10 X 10(9)

Creatinine 46 40-85

ALT 27 10-36U/L

AST 23 10-30U/L


ALP 197 22-104U/L

25 OH VITAMIN D 16.9 <30 Ug/L

Calcium. 2.12 2.15-2.50 mmol/L]

Phosphate 0.85

Free T4 13.2 12-22 pmol/L

TSH 2.63 0.27-4.20 mu/L

Again, no secondary cause found

Treatment Strategy

Three general rules :

• A weaker anti-resorptive can be replaced by a more potent drug of the same class

• An oral drug can be replaced by an injectable drug

• A strong anti-resorptive can be replaced by an anabolic agent

FDA-Approved Medications

ANTIRESOPTIVE ANABOLIC

STRONTIUM

MIXED AGENT

DENOSUMAB

• Monoclonal antibody

• Binds and inhibits RANKL

• BMD : increases at spine and hip

• S/C injection every 6 months

• Side effects : Hypocalcemia, infections and ONJ – Risk factors for hypoCa (severe) – CKD, Vit D

deficiency

RANK Ligand : An Essential Mediator of Osteoclast Formation, Function, and Survival

Osteoblasts

Activated Osteoclast

CFU-GM Prefusion Osteoclast

Multinucleated Osteoclast

Hormones Growth Factors Cytokines

Bone Formation

Bone Resorption Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

RANKL

RANK

Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival

RANKL

RANK

OPG

Denosumab

Bone Formation Bone Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-GM Prefusion Osteoclast

Osteoblasts

Hormones Growth Factors Cytokines

.

Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342 McClung ER, et al. N Engl J Med. 2006;354:821-831.

DATE SITE BMD Medication

Left Femoral Neck Left Total Hip Lumbar Spine L1-l4

BMD g/cm2

T-score

LSC (%)

BMD T-score

LSC (%)

BMD T-score

LSC (%)

2005 0.38 -4 SD 0.50 -4.4 Alendronate 70 mg once a week Calcium carbonate/ Vit D 2 tab OM

2006 0.405 -3.8 +6.5 0.50 -4.4 0

2008 0.395 -3.9 -2.4 0.455 -4 0.481 -4.5 -3.8

2009 0.396 -3.9 +0.2 0.467 -3.9 +2.6 0.478 -4.6 -0.6

2011 0.388 -3.9 -2 0.472 -3.8 +1 0.487 -4.5 +1.8

2014 KTPH

0.463 -4.7 NA S/C Denosumab Lynae D3 1000 IU Calcium 900 mg OD

2014 KTPH

0.487 -4.5 +5.1

Take Home Messages

• Bisphosphonates as first-line therapy

– Consider oral and IV

– Determine length of treatment based on risk stratification

• Drug holiday

• Defining treatment failure

– Consider adherence to therapy

– Other options of therapy

THANK YOU

QUESTIONS?

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