Lebanese Society of Endocrinology Diabetes Lipids Monthly Meeting
Lebanese Society of Endocrinology, Diabetes & Lipids Monthly Meeting Osteoporosis in Men Where do we stand? Maya Barake, MD, MSc, CCD June 30, 2020
Osteoporosis: A disease of Men?
Outline • Epidemiology of osteoporosis in men: • • Worldwide data Arab/Lebanese data Mortality Undertreatment • Screening recommendations • Etiology/Work-up • Indications for treatment • Choice of therapy: • Approved Tx • Tx in hypogonadism • Tx in ADT
Worldwide Incidence of Osteoporotic Fractures above the age of 50 International Osteoporosis Foundation 39% of annual osteoporotic fractures occur in men www. iof. org
Average Annual Fracture Incidence Rate in Men v/s Women 44 74 Donaldson LJ et al, J Epidemiol Community Health 1990
Prevalence of Osteopenia and Osteoporosis in Men by Age 12% Trajanoska K et al, Bone 2018 30%
Age-standardized Hip Fracture Incidence Rates in Arab League Countries Barake M, Chakhtoura M, El Hajj Fuleihan et al, in press
Vertebral Fracture Prevalence Rates in Arab League Countries Author, Year Country El Maghraoui A et al. , 2012 Sample Size Age Mean (SD) (years) Prevalence of Morphometric Vertebral Fractures (excluding Grade 1) 791 62. 4 (8. 6) 14. 2% 216 63. 8 (8. 2) 13. 8% 432 73. 6 (5. 1) 12% Morocco El Maghraoui A et al. , 2008 Morocco Arabi A et al. , 2007 Lebanon Barake M, Chakhtoura M, El Hajj Fuleihan et al, in press
Prevalence of Osteoporosis & Vertebral Fractures in Lebanon 460 Elderly Patients (65 -85 years) Saad R, El Hajj Fuleihan et al slide courtesy Dr. El Hajj Fuleihan
Incidence per 100, 000 of Major Osteoporotic & Hip Fractures in Lebanese Men above the age of 50 Saad R, El Hajj Fuleihan et al slide courtesy Dr. El Hajj Fuleihan
Mortality after Hip Fracture is higher in Men v/s Women Survival estimates 106 Men v/s 264 agematched women 74% higher risk of death Trombetti et al, Osteoporos Int 2002
Mortality after Osteoporotic Fractures is higher in Men v/s Women Center J et al, Lancet 1999
Undertreatment of Osteoporosis after Hip Fx in Men v/s Women Kiebzak J et al, Arch Int Med 2002
Outline • Epidemiology of osteoporosis in men: • • Worldwide data Arab/Lebanese data Mortality Undertreatment - Osteoporosis/Osteoporotic Fractures are prevalent in men - Peak at a later age - Associated with worse outcomes (mortality) - Still undertreated
Outline • Epidemiology of osteoporosis in men: • • Worldwide data Arab/Lebanese data Mortality Undertreatment • Screening recommendations • Etiology/Work-up • Indications for treatment • Choice of therapy: • Approved Tx • Tx in hypogonadism • Tx in ADT
Mr. OF • 72 y. o. man, complained of back pain with no hx of trauma • Did thoracolumbar X-ray, showed L 1 Vertebral Fracture • Did DXA scan: T-score spine -2. 6, FN -2. 8, TH -2. 9 • MHx: HTN • Meds: Lisinopril 10 mg daily, D 10000 weekly • Social: smoker, social ethanol • FRAX: 10 -yr probability of major osteoporotic Fx: 11% of hip Fx: 7. 2%
Mr. OF Did we miss on screening him for Osteoporosis?
Indications for BMD measurement: The Lebanese Guidelines Definite Indications ØAge > 65 ØPresence of vertebral deformity or fragility fracture ØRadiologic evidence of demineralization All Other Indications ØBased on FRAX risk factors ØIf FRAX estimate > 10%, measure BMD Ø Androgen deprivation therapy Ø Chronic steroid therapy (>3 months) Chakhtoura M, El Hajj Fuleihan G, Baddoura R, Lebanese FRAX-based Osteoporosis Guidelines, 2013
Mr. OF Osteoporosis in a Man So what’s next? What is the needed work -up?
Risk Factors for Low Bone Mass-related Fractures in Men Drake et al, JCEM 2012
Work-up The Endocrine Society Guidelines Suggested • • Ca, Ph Cr CBC Alkaline Phosphatase LFTs 25(OH)Vitamin D Total Testosterone 24 -hr urinary calcium Optional • Free testosterone • Serum and/or urine protein electrophoresis • Tissue transglutaminase antibodies • TSH • PTH Watts et al, JCEM, 2012
Mr. OF The Work-up: • Hg 14. 2 • Cr 0. 8 • Ca 8. 9 Ph 3. 8 • TSH 3. 2 • 25(OH) Vitamin D 32 ng/dl • Total Testosterone 380 ng/dl (nl: 300 -1200)
Mr. OF What are the treatment indications? What are the treatment options?
Treatment Indications The Lebanese Guidelines Definite Indications Regardless of FRAX and BMD ØMen > 50 with history of fragility fracture: spine or hip or 2 or more other fragility fractures All Other Indications ØUse FRAX and treat at age-specific cutoffs Chakhtoura M, El Hajj Fuleihan G, Baddoura R, Lebanese FRAX-based Osteoporosis Guidelines, 2013
Effect of Osteoporosis Therapies on LS BMD in Men with Osteoporosis Randomized Placebo controlled trials Not Head To Head Mean age 62 -66 30 -55% VFx Difference in % change from baseline in Lumbar Spine BMD v/s Placebo 7 6 6. 1% 5. 3% 5 5. 3% 4. 8% 4. 5% 4 2. 6% 3 2 1 0 Alendronate Risedronate 2 Yrs Ibandronate 1 Yr Denosumab Zoledronic Acid Teriparatide 1 Yr 2 Yrs 11 months Orwoll et al, NEJM, 2000; Boonen et al, JBMR, 2009; Orwoll et al, Bone, 2010; Orwoll et al, JCEM, 2012; Orwoll et al, JBMR, 2003; Boonen et al, NEJM 2012
Effect of Osteoporosis Therapies in Men with Osteoporosis Placebo controlled trials Not Head To Head Mean age 62 -66 2 years (except 12 m Denosumab and 11 m Teriparatide) 30 -55% VFx • All trials showed increase in Total Hip BMD and Femoral Neck BMD with treatment compared to placebo (secondary endpoints) • Denosumab showed increase in 1/3 radius BMD compared to placebo (secondary endpoints) • By quantitative analysis, incidence of Vertebral Fractures less with Alendronate than with placebo (secondary endpoint) Orwoll et al, NEJM, 2000; Boonen et al, JBMR, 2009; Orwoll et al, JCEM, 2012; Orwoll et al, JBMR, 2003; Boonen et al, NEJM 2012
Effect of Osteoporosis Therapies on LS BMD in Men with Osteoporosis Yearly ZOL v/s Weekly ALN n = 302 Non Inferior ZOL 6. 1% ALN 6. 2% Patient Preference ZOL 74. 2% ALN 15. 3% Mean % change in BMD Orwoll et al, JBMR, 2010
Effect of Zoledronic Acid on Fracture Risk in Men with Osteoporosis 1199 men Mean age 66 (50 -85) 5. 4% T< 230 ng/dl Double-blind placebo-controlled trial 2 years ZA 5 mg/yr v/s Placebo clinical vertebral fractures and non vertebral fractures lower with Zoledronic Acid v/s Placebo morhpometric vertebral fractures Did not reach statistical significance Boonen et al, NEJM 2012
Effect of Romosozumab in Men with Osteoporosis n = 245 Double-blind placebo-controlled trial Significant increase Total Hip & Femoral neck CV serious AEs Romo 4. 9% Pl 2. 5% Lewiecki et al, JCEM 2018
Treatment Selection The Endocrine Society Guidelines “We recommend that men at high risk of fracture be treated with medication approved by regulatory agencies such as the FDA or the EMA (at the time of this writing, alendronate, risedronate, zoledronic acid, and teriparatide) and that the selection of therapeutic agent be individualized…” Watts et al, JCEM, 2012
Treatment Selection The Lebanese Guidelines • For men requiring treatment of osteoporosis, Alendronate, Risedronate, Zoledronic Acid and Denosumab can be used as firstline therapies for prevention of fractures • Teriparatide should be considered as a second-line therapy for men 65 years or older who have severe osteoporosis and prevalent fragility fractures Chakhtoura M, El Hajj Fuleihan G, Baddoura R, Lebanese FRAX-based Osteoporosis Guidelines, 2013
Treatment Duration, Treatment Holiday • No dedicated studies in Men • Extrapolation from studies in Postmenopausal Women • To consider treatment holiday with Alendronate after 5 years and Zoledronate after 3 years • Cannot give a holiday with Denosumab
Mr. OF The Work-up: • Hg 14. 2 • Cr 0. 8 • Ca 8. 9 Ph 3. 8 • TSH 3. 2 • 25(OH) Vitamin D 32 ng/dl 200 ng/dl • Total Testosterone 380 (nl: 300 -1200)
Mr. OF Is Testosterone a treatment option? Or do we need specific osteoporosis therapy? Do osteoporosis therapies work in hypogonadism?
Effect of Testosterone Therapy as a function of Testosterone level p < 0. 01 Snyder et al, JCEM, 1999
Effect of Testosterone Therapy on BMD in Older Men with Hypogonadism Randomized Placebo controlled trial n=48 Age > 60 Testosterone < 320 21 d significant Testo Enanthate 250 mg IM Q Not significant Basurto et al, The Aging Male, 2009
Treatment of Hypogonadal men with High risk of fracture The Endocrine Society Guidelines • Men at high risk of fracture + T < 200 ng/dl: testosterone (as per routine indication) + osteoporosis agent (due to lack of fractureprevention data in men treated with T) • Men at high risk of fracture + T < 200 ng/dl, with contraindication to osteoporosis agents: testosterone alone • Men at borderline risk of fracture + T < 200 ng/dl, with symptoms of hypogonadism or organic T deficiency: testosterone alone Watts et al, JCEM, 2012
Effect of Osteoporosis Therapies on LS BMD in Men with Osteoporosis Placebo controlled trials Not Head To Head Mean age 62 -66 2 years (except 12 m Denosumab and 11 m Teriparatide) 30 -55% VFx Difference in % change from baseline in Lumbar Spine BMD v/s Placebo 7 6 6. 1% 5. 3% 5 4. 8% 4. 5% 5. 3% 4 2. 6% 3 2 1 0 Alendronate 1/3 Low T Risedronate 9% T < 259 ng/dl Ibandronate Denosumab 15% T < 250 ng/dl Teriparatide 49% Low T Zoledronic Acid 5. 4% T < 230 ng/dl Except for Risedronate (benefit higher with low T), results were independent of testosterone level Orwoll et al, NEJM, 2000; Boonen et al, JBMR, 2009; Orwoll et al, JCEM, 2012; Orwoll et al, JBMR, 2003; Boonen et al, NEJM 2012
Effect of Zoledronic Acid on Fracture Risk in Men with Osteoporosis 1199 men Mean age 66 (50 -85) 5. 4% T< 230 ng/dl Double-blind placebo-controlled trial 2 years ZA 5 mg/yr v/s Placebo clinical vertebral fractures and non vertebral fractures lower with Zoledronic Acid v/s Placebo morhpometric vertebral fractures Did not reach statistical significance Total testosterone did not affect antifracture efficacy of zoledronic acid (P>0. 80 for interaction) Boonen et al, NEJM 2012
Mr. OF • 72 y. o. man, complained of back pain with no hx of trauma • Did thoracolumbar X-ray, showed L 1 Vertebral Fracture • Did DXA scan: T-score spine -2. 6, FN -2. 8, TH -2. 9 • MHx: HTN, Prostate Cancer on Androgen deprivation therapy • Meds: Lisinopril 10 mg daily, D 10000 weekly • Social: smoker, social ethanol
Denosumab in Men receiving ADT for non-metastatic Prostate CA 1468 men Mean age 75 BMD T score < -1 or Hx of Fracture Lumbar Spine BMD Vertebral Fractures 62% Similarly at the Total Hip, Femoral Neck, 1/3 Radius Smith et al, NEJM 2009
Thank you…
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