OSTEOS NEWSLETTER

Newsletter of the Lebanese Society for Osteoporosis and Metabolic Bone Disorders

Editor-in-Chief: Asma Arabi, MD, MSc

Read in this issue

Fracture Risk & Chronic Kidney Disease.

Breastfeeding Protects against Hip Fracture.

How often Should We Monitor Bone Mineral Density?

Densitometry Corner.

Osteoporosis Academy Course.

Upcoming Meetings.

Welcome Note

Dear Colleagues,

It’s our pleasure to welcome you to this issue of your Newsletter. We hope you had

an enjoyable and great summer time, with plenty of sunlight and exercise in smoke

free places!! In this occasion, I would like to take the opportunity to invite you to

participate in the 4th annual meeting of the Lebanese Society of Osteoporosis and

Metabolic Bone Disorders that will be held November 30-December 1st, 2012 at

Movenpick Resort & Hotel in Beirut. Interesting and hot topics will be discussed

during the two-day meeting. These include, but not limited to, the 2012 update of

the Lebanese Osteoporosis assessment guidelines including fracture risk

assessment paradigm using the FRAX model, vitamin D, Fracture management, fall

prevention, and others....

We look forward to spending good time with you and with our speakers. So join us

and do not miss our high standard and thought-provoking conference.

.

Mission of Osteos

To enhance state-of-the-art knowledge and expert care for osteoporosis and other

metabolic bone disorders in Lebanon through education, research and service.

President

Rafic Baddoura, MD, MPH

Founding President

Ghada El-Hajj Fuleihan, MD, MPH

Vice-President

Muhieddine Seoud, MD

Secretary

Walid Saghir, MD

Treasurer

Jad Okais, MD

Executive Committee

Ghada El-Hajj Fuleihan, MD, MPH

Faisal El-Kak, MD

Georges Halaby, MD

Assaad Mohanna, MD

Jad Okais, MD

Walid Saghir, MD

Imad Uthman, MD

To join OSTEOS please

visit our website:

http://www.osteos.org.lb

For your suggestions,

please contact us:

osteos@osteos.org.lb

Double Issue No 5.1 & 5.2

Spring-Summer 2012

Read in this issue

• Does Osteoporosis Therapy Invalidate FRAX for Fracture Prediction?

• To FRAX or NOT To FRAX • Postmenopausal Osteoporosis Treatment With

Antiresorptives: Effects of Discontinuation or Long-Term Continuation on Bone Turnover and Fracture Risk

• Osteoporosis in Men: Endocrine Society Guideline • Glucocorticoid-Induced osteoporosis: American College of

Rheumatology Guidelines • Densitometry corner • Mark your calendar • Useful Links

Does Osteoporosis Therapy Invalidate FRAX for Fracture

Prediction?

“Ten-year fracture risk assessment with the

fracture risk assessment system (FRAX) is

increasingly used to guide treatment decisions.

Osteoporosis pharmacotherapy reduces

fracture risk, but the effect is greater than can

be explained from the increase in bone mineral

density (BMD). Whether this invalidates

fracture predictions with FRAX is uncertain. This

question of whether FRAX can be used in

patients receiving osteoporosis therapy was

addressed by Dr. William Leslie and his

colleagues. A total of 35,764 women (age ≥ 50

years) and baseline BMD testing (1996–2007)

had FRAX probabilities retroactively calculated.

A provincial pharmacy database was used to

identify osteoporosis medication use. Women

were categorized as untreated, current high

adherence users [medication possession ratio

(MPR) ≥0.80 in the year after BMD testing],

current low adherence users (MPR <0.80), and

past users. Fractures outcomes to 10 years

were established form a population-based

health data repository. FRAX and femoral neck

BMD alone stratified major osteoporotic and

hip fracture risk within untreated and each

treated subgroup (all p-values <0.001) with

similar area under the receiver operating

characteristic curve. In untreated and each

treated subgroup, a stepwise gradient in

observed 10-year major osteoporotic and hip

fracture incidence was found as a function of

the predicted probability tertile (all p-values

<0.001 for linear trend). Concordance

(calibration) plots for major osteoporotic

fractures and hip fractures showed good

agreement between the predicted and

observed 10-year fracture incidence in

untreated women and each treated subgroup.

Only in the highest risk tertile of women highly

adherent to at least 5 years of bisphosphonate

use was observed hip fracture risk significantly

less than predicted, though major osteoporotic

fracture risk was similar to predicted. In

summary, this work suggests that the FRAX tool

can be used to predict fracture probability in

women currently or previously treated for

osteoporosis. Although FRAX should not be

used to assess the reduction in fracture risk in

individuals on treatment, it may still have value

for guiding the need for continued treatment or

treatment withdrawal”. Copied verbatim from

Leslie et al, J Bone Miner Res,2012;27:1243-1240.

To FRAX or Not To FRAX

“The WHO Fracture Risk Assessment Tool

(FRAX) calculator is the most thoroughly studied

and widely used tool of fracture risk

assessment. FRAX is now available in 39

countries and is increasingly being used as a

guide for clinical decision-making. Despite the

scientific basis of FRAX and its strengths, several

limitations are recognized. FRAX treats all risk

factors as categorical, not taking into account

the dose or duration of glucocorticoid therapy

or the number, type, severity, or recency of a

fragility fracture, which are clinical variables

known to affect fracture risk. In patients with

risk factors for fracture that are not accounted

for in the FRAX model, such as diabetes, FRAX

estimates of fracture probability are less

accurate. Clinicians often use additional

information such as history of fall risk to make

treatment decisions. Although these are well-

recognized risk factors for fracture, they were

intentionally not included in the FRAX

calculator. When FRAX became available,

clinicians were advised not to use the tool in

patients receiving osteoporosis treatment.

Whether FRAX can be used in patients receiving

osteoporosis therapy was recently addressed by

Dr. William Leslie and his colleagues who

showed that, although FRAX should not be used

to assess the reduction in fracture risk in

individuals on treatment, it may still have value

for guiding the need for continued treatment or

treatment withdrawal. Certainly FRAX cannot

be used to monitor response to an osteoporosis

treatment. Many of us were making the

decisions about stopping treatment in patients

who did not need it or recommending a drug

holiday before FRAX was available. It is not clear

that knowing a patient’s FRAX score improves

our ability to make these decisions. However,

for clinicians who feel that the additional

information from FRAX would be useful, the

data from Leslie et al provide the basis to do so.

At least, the question of whether FRAX works in

patients on therapy can now be laid aside as

answered. Copied verbatim from McClung, JBMR

,2012;27:1243-1240.

Effect of Discontinuation or Long-Term continuation of

Antiresorptives on Bone Turnover & Fracture Risk

“Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3–4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered post discontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head ‘‘offset’’ data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation vs discontinuation vs alternative management strategies”. Copied verbatim from Boonen et al, J Bone Miner Res,

2012;27:963-974.

Osteoporosis in Men

Endocrine Society Clinical Practice Guideline

Nelson B. Watts, Robert A. Adler, John P. Bilezikian, Matthew T. Drake, Richard Eastell, Eric S. Orwoll, and Joel S. Finkelstein

J Clin Endocrinol Metab 97: 1802–1822, 2012 “Copied verbatim”

Recommendations

• We recommend that men with or at risk for osteoporosis consume 1000–1200 mg calcium daily, ideally from dietary sources, with calcium supplements added if dietary calcium is insufficient. (1|QQQE)

• We suggest that men with low vitamin D levels [_30 ng/ml (75 nmol/liter)] receive vitamin D supplementation to achieve blood25(OH) D levels of at least 30 ng/ml (75 nmol/liter). (2|QQQE)

• We suggest that men at risk of osteoporosis participate in weight-bearing activities for 30–40 min per session, three to four sessions per week. (2|QEEE)

• We suggest that men at risk of osteoporosis who consume three or more units of alcohol per day reduce their alcohol intake. (2|QEEE)

• We recommend that men at risk of osteoporosis who smoke cease smoking. (1|QQEE)

Sites to Measure

• We recommend dual-energy x-ray

absorptiometry (DXA) of the spine and hip in

men at risk for osteoporosis. (1|QQEE)

• We suggest measuring forearm DXA (1/3 or

33% radius) when spine or hip BMD cannot be

interpreted and for men with

hyperparathyroidism or receiving androgen

deprivation therapy (ADT) for prostate cancer.

(2|QQEE)

Evaluation

• We suggest a complete history and physical examination for men being evaluated for osteoporosis or considered for pharmacological treatment (e.g. those with low BMD and/or high fracture risk).

• Important information includes medications used, chronic diseases, alcohol or tobacco abuse, falls and/or fractures as an adult and family history of osteoporosis.

• Physical examination should assess patient height in comparison with maximum height, kyphosis, balance, mobility, overall frailty, and evidence of causes of secondary osteoporosis, including testicular atrophy, signs of hyperthyroidism, and evidence of chronic obstructive pulmonary disease.

• Men for whom bisphosphonate therapy is considered should have an examination of the teeth. (2|QQEE) • We suggest measuring serum calcium, phosphate, creatinine (with estimated glomerular filtration rate), alkaline phosphatase,

liver function, 25-hydroxyvitamin D [25(OH)D], total testosterone, complete blood count, and 24-h urinary calcium (creatinine and sodium) excretion in men being evaluated for osteoporosis or considered for pharmacological treatment with bone-active agents. (2|QQEE)

• If history or physical examination suggest a specific cause of osteoporosis, further testing should be done. Depending on the findings of the history and physical examination, such testing may include (but is not limited to) calculated free or bioavailable testosterone (using measurements of SHBG), serum protein electrophoresis with free _ and _ light chains and/or urine protein electrophoresis, tissue transglutaminase antibodies (for celiac disease), thyroid function tests, and PTH levels. (2|QQEE)

• In men with low bone mass (osteopenia) or osteoporosis who might have previously undiagnosed vertebral fractures, we recommend vertebral fracture assessment (VFA) using DXA equipment. If VFA is not available or is technically limited, lateral spine radiographs should be considered. (1|QQEE)

Indications to Measure BMD • We suggest testing men at increased risk for osteoporosis by

measurement of bone mineral density (BMD).

• Age 70 is a sufficient risk factor. Younger men (aged 50– 69) should be

tested if additional risk factors are present.

• A history of fracture after age 50 is a particularly important indication

for evaluation.

• Other reasons for testing men aged 50–69 include diseases/conditions

such as delayed puberty, hypogonadism, hyperparathyroidism,

hyperthyroidism, or chronic obstructive pulmonary disease; drugs

such as glucocorticoids or GnRH agonists; life choices such as alcohol

abuse or smoking; or other causes of secondary osteoporosis. FRAX,

Garvan, or other fracture risk calculators can improve the assessment

of fracture risk and the selection of patients for treatment. (2|QQEE)

Treatment

All Men We recommend pharmacological therapy for men at high risk for fracture including, but not limited to:

• Men who have had a hip or vertebral fracture without major trauma. (1|QQQE) • Men who have not experienced a spine or hip fracture but whose BMD of the spine, femoral neck,

and/or total hip is 2.5 SD or more below the mean of normal young white males. (1|QQEE) • In the United States, men who have a T-score between -1.0 and -2.5 in the spine, femoral neck, or

total hip plus a 10-yr risk of experiencing any fracture ≥ 20% or 10-yr risk of hip fracture ≥ 3% using FRAX; further studies will be needed to determine appropriate intervention levels using other fracture risk assessment algorithms.

• For men outside the US, region-specific guidelines should be consulted. (1|QQEE) • Men who are receiving long-term glucocorticoid therapy in pharmacological doses (e.g. prednisone

or equivalent ≥7.5 mg/d), according to the 2010 guidelines of the American Society of Rheumatology. (1|QQEE).

Selection of Therapeutic Agent • We recommend that men at high risk of fracture be treated with medication approved by regulatory

agencies such as the U.S. Food and Drug Administration (FDA) or the European Union (EU) European Medicines Agency (EMA) (at the time of this writing, alendronate, risedronate, zoledronic acid, and teriparatide; also denosumab for men receiving ADT for prostate cancer).

• The selection of therapeutic agent be individualized based on factors including: o fracture history, severity of osteoporosis (T-scores), o the risk for hip fracture, patterns of BMD [i.e. whether BMD is worse at sites where cortical

bone (e.g. 1/3 radius) or trabecular bone (e.g. spine) predominate], o comorbid conditions (e.g. peptic ulcer disease, gastroesophageal reflux, malabsorption

syndromes, malignancy, etc.), o cost, and other factors.

• In men with a recent hip fracture, we suggest treatment with zoledronic acid. • When teriparatide is administered, we suggest that it not be given with concomitant antiresorptive

therapy. • Agents that have not been approved by regulatory agencies for treatment of osteoporosis in men

(calcitonin, ibandronate,strontium ranelate, etc.) should be used only if the approved agents for male osteoporosis cannot be administered. (1|QQEE)

Management of Hypogonadal Men at High Risk of Fracture • For men at high risk of fracture who are receiving testosterone therapy, we suggest adding an agent

with proven antifracture efficacy (e.g. a bisphosphonate or teriparatide). (2|QEEE). • We suggest testosterone therapy in lieu of a “bone drug” for men at borderline high risk for fracture

who have serum testosterone levels below 200 ng/dl (6.9 nmol/ liter) on more than one determination, if accompanied by signs or symptoms of androgen deficiency (e.g. low libido, unexplained chronic fatigue, loss of body hair, hot flushes, etc.) or “organic” hypogonadism (e.g. due to hypothalamic, pituitary, or specific testicular disorder).

• If testosterone treatment does not alleviate symptoms of androgen deficiency after 3–6 months, it should be discontinued and other therapy considered. (2|QQEE).

• We suggest testosterone therapy for men at high risk for fracture with testosterone levels below 200 ng/dl (6.9 nmol/liter) who lack standard indications for testosterone therapy but who have contraindications to approved pharmacological agents for osteoporosis. (2|QQEE)

Men with Prostate Cancer Receiving ADT • We recommend pharmacological treatment for osteoporosis for men with prostate cancer receiving

ADT who have a high risk of fracture.

Monitoring Therapy

• We suggest that clinicians monitor BMD by DXA at the spine and hip every 1–2 yr to assess the response to treatment. If BMD appears to reach a plateau, the frequency of BMD measurements may be reduced. (2|QQQE) • We suggest that clinicians consider measuring a bone turnover marker (BTM) at 3–6 months after

initiation of treatment using a bone resorption marker [such as serum C-telopeptide of type I collagen (CTX) or serum or urine N-telopeptide of type I collagen (NTX)] for antiresorptive therapy and a bone formation marker [such as serum procollagen I N-propeptide (PINP)] for anabolic therapy. (2|QQQE)

American College of Rheumatology Recommendations for the Prevention & Treatment of

Glucocorticoid-Induced osteoporosis

Grossman J, Gordon R, Ranganat V, Deal C, Caplan L, Chen W, Curtis J, Furst D, McMahon M, Patkar N, Volkman E, Saag K

Arthritis Care & Research Vol. 62, No. 11, November 2010, pp 1515–1526

Despite the availability of therapies to reduce the risk of fractures, many patients receiving long-term glucocorticoid therapy do not receive any interventions to prevent or treat osteoporosis. In some populations, less than one third received BMD testing or had documented use of calcium and vitamin D supplementation. Similarly, the use of bisphosphonate therapy is low, particularly among men and younger women. In 2001, the American College of Rheumatology (ACR) published their Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. These guidelines were updated in 2010 and published in the Arthritis Care & Research. We reproduced below the Tables summarizing these guidelines published in the Arthritis Care & Research.

Recommendations on counseling for lifestyle modification and assessment of patients starting glucocorticoids at any dose with an anticipated duration >3 months

Recommendation Level of evidence Weight-bearing activities Smoking cessation Avoidance of excessive alcohol intake Nutritional counseling on calcium & vitamin D intake Fall risk assessment Baseline dual x-ray absorptiometry Serum 25-hydroxyvitamin D level Baseline height Assessment of prevalent fragility fractures Consider radiographic imaging of the spine or vertebral fracture assessment for those initiating or currently receiving prednisone ≥ 5 mg/day or its equivalent Calcium intake (supplement plus oral intake) 1,200–1,500 mg/day* Vitamin D supplementation*

C C C C C C C C C C A A

* Recommendations for calcium and vitamin D supplementation are for any dose or duration of glucocorticoids

Language and graphical descriptions of the strength of a recommendation & quality of evidence:

• Strong recommendations use the phrase “we recommend” and the number 1; • Weak recommendations use the phrase “we suggest” and the number 2. • Cross-filled circles indicate the quality of the evidence:

o QEEE denotes very low quality; o QQEE, low quality; o QQQE, moderate quality; o QQQQ, high quality.

Pharmacologic recommendations for postmenopausal women and men age >50 years starting glucocorticoid therapy

with prevalent glucocorticoid or an anticipated duration of >3 months

Recommendations Level of evidence Low-risk patient Alendronate for ≥7.5 mg/day prednisone OR Risedronate for ≥ 7.5 mg/day prednisone OR Zoledronic acid for ≥ 7.5 mg/day prednisone Medium-risk patient Alendronate for any dose of glucocorticoids OR Risedronate for any dose of glucocorticoids OR Zoledronic acid for ≥ 7.5 mg/day prednisone High-risk patient† Alendronate OR Risedronate OR Zoledronic acid OR Teriparatide‡

A A B A A B A A B B

† Any anticipated dose or duration of glucocorticoids justifies initiating prescription therapy for high-risk patients. ‡ For ≥5 mg/day prednisone with a duration ≤ 1 month and for any dose of glucocorticoids >1 month.

Recommendations of treatment for premenopausal women and men under age 50 years with a history of fragility

fracture Recommendations Level of evidence 1–3 MONTHS OF GLUCOCORTICOIDS Non-childbearing potential: Alendronate if receiving prednisone ≥ 5 mg/day OR Risedronate if receiving prednisone ≥ 5 mg/day OR Zoledronic acid if receiving prednisone ≥7.5 mg/day Childbearing potential: Inadequate data for recommendation ≥ 3 MONTHS OF GLUCOCORTICOIDS Non childbearing potential: Alendronate for any dose OR Risedronate for any dose OR Zoledronic acid for any dose OR Teriparatide for any dose Childbearing potential Alendronate if prednisone ≥7.5 mg/day OR Risedronate if prednisone ≥7.5 mg/day OR Teriparatide if prednisone ≥7.5 mg/day

A A B A A B B A C C

Recommended monitoring for patients receiving prevalent glucocorticoid therapy for >3 months

Recommendations Level of evidence

Consider serial bone mineral density testing Consider annual serum 25-hydroxyvitamin D measurement Annual height measurement Assessment of incident fragility fracture Assessment of osteoporosis medication Compliance

C C C C C

The strength of evidence was graded as follows: • For level of evidence A, data were derived from multiple RCTs or a meta-analysis, • For level B evidence, data were derived from a single RCT or nonrandomized study, • For level C evidence, data were derived from consensus, expert opinion, or case series.

Densitometry Corner

More Bone Density Testing is Needed, Not Less

“The study by Gourlay et al published in the New England Journal of Medicine earlier this year has raised questions about

intervals between BMD measurements in older postmenopausal women. Their study found that a higher baseline BMD

was associated with a longer time to develop osteoporosis and that women with normal bone density at the age of 67

years were unlikely to have subsequent rapid bone loss. This study generated considerable media attention, suggesting

that DXA was an expensive test that was overused and abused by physicians and that Medicare will save money if fewer

DXA studies are performed. In a Viewpoint published in the Journal of bone and Mineral Research, Lewiecki et al addressed

the controversy surrounding the proposed frequency for performing bone mineral density in older postmenopausal

women. According to the authors, overtesting with DXA is not a problem. The real problem is that far too few patients are

being screened for osteoporosis, and more BMD testing, not less, is needed to screen for osteoporosis. This is good clinical

practice, cost-effective, and will reduce the burden of osteoporotic fractures. However, current evidence-based guidelines

for BMD testing should be followed. Monitoring for treatment effect is recommended 1 to 2 years after starting or

changing therapy with consideration of longer testing intervals once a favorable treatment effect is confirmed. The ISCD

Official Positions state that intervals between BMD testing should be determined according to each patient’s clinical status;

the USPSTF suggests screening intervals of at least 2 years in women with normal baseline BMD. When screening shows

that BMD is normal or slightly low in women age ≥67 years, and there are no clinical risk factors for fracture or rapid bone

loss, a long interval until repeat testing is appropriate. For younger patients, for those with BMD values substantially below

normal, for those with prior fracture or clinical risk factors for fracture, and for those started on osteoporosis drug therapy,

a repeat BMD test should be done after a much shorter time interval”. Copied verbatim from Lewiecki M et al, J Bone Miner Res,

2012, 27: 739-742.

Date Event Location

Oct 5-6, 2012 Ten Topics In Rheumatology III Movempick Hotel, Beirut-Lebanon http://www.aub.edu.lb/fm/cme/activities/Documents/Rheumatology-III.pdf

Oct 12-15, 2012 American Society for Bone & Mineral Research

Minneapolis- Minnesota http://www.asbmr.org/Meetings/AnnualMeeting.aspx

Nov 9-14, 2012 ACR/ARHP 76th Annual Scientific Meeting Washington, D.C., USA http://www.acrannualmeeting.org/

Nov 10, 2012 The Diabetes Day 2012 Monroe Hotel – Beirut

Nov 15-17, 2012 International & Pan Arab Congress of the Lebanese Society of Obstetrics & Gynecology

Movempick Hotel, Beirut http://www.lsog.org.lb/admin/uploads/congress%20program_1209265251.pdf

Nov 25-30, 2012 RSNA 98th

Scientific Assembly Chicago, Illinois, USA http://rsna.org/

Nov 30- Dec 1, 2012 4th

Annual Meeting of the OSTEOS Movempick Hotel, Beirut http://www.trust-traders.com/registrationfrm.asp?id=134

Dec 9-12, 2012 25e Congrès Français de Rhumatologie La Défense, Paris http://sfr.larhumatologie.fr/congres/accueilcongres/index.phtml

Jan 18, 2013 XXVIème Journée Scientifique du GRIO Eurosites George V - PARIS – France http://www.grio.org/agenda-congres-details-25.php

Mark Your Calendar

Useful Links

Capture the Fracture: www.iofbonehealth.org/capture-fracture

World Osteoporosis Day, October 20, 2012

http://www.worldosteoporosisday.org/