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Osteoporosis 2
1. Bisphosphonates
• Mechanism of Action: promotes bone formation and
decreases bone resorption.
• Application: considered first line treatment for osteoporosis in
both men and post-menopausal women.1
– Aledronate2, Risedronate3 and Zoledronic Acid4: are
approved in both sexes for the prevention and treatment of
osteoporosis.
2. Bisphosphonates
• Ibandronate (Boniva): only FDA approved for use
in the treatment (not prevention) of osteoporosis in
post-menopausal women
– Not FDA approved for males
• Paucity of studies1
• Similar pharmocokinetics in men and women2
• Similar efficacy in men and women probable3
(statement made in the Orwoll study)
Dr. Jenkins: the STRONG study is the only one of its kind that I could find for
Ibandronate testing in males– in the speaker notes I wronte that it’s “one of the only
studies”– I hestistate to write “the only study” of its kind though—do you know of
similar studies?
3. Ibandronate Efficacy in Males
Percent change in L1-L3 BMD Percent change in TH BMD
TH- Total Hip. BMD- Bone Mineral Density.
4. Ibandronate Efficacy in Males
Percent change in sCTX Percent change in BSAP
C-terminal telopeptide of type 1 collagen (sCTX); Bone-specific alkaline phosphatase (BSAP)
5. Bisphosphonates
Drug Vertebral
Fracture RR
Hip Fracture
RR
Non-
vertebral RR
Route/
Frequency
Indicated
for which
gender
Alendronate PO/QDay,
QWeek
Women
Men
Risedronate PO/QDay,
QWeek,
QMonth
Women
Men
Ibandronate NE NE PO/QMonth
IV/Q3Month
Women
Zoledronic
Acid
IV/QYear Women
Men
RR = Risk Reduction NE = No effect demonstrated
Side effects: Heartburn, nausea, bone pain, infusion reaction (zoledronic acid)
6. Other agents
Drug Vertebral
Fracture
RR
Hip
Fracture
RR
Non-
vertebral
RR
Route/
Frequency
Indicated
for which
gender
Raloxifene NE NE PO QDay Women
Calcitonin NE NE Nasal QDay
SQ QDay
Women
Teriparatide NE SQ QDay Women
Men
Denosumab SQ
Q6Months
Women
Men
RR = Risk Reduction NE = No effect demonstrated
Side Effects
• Raloxifene – hot flashes, edema, arthralgia, increased risk of thromoembolism
• Calcitonin – flushing, rhinitis, nausea, back pain, local site reaction (SQ)
• Teriparatide – hypercalcemia, orthostatic hypotension, dizziness, nausea,
injection site reaction
• Denosumab – dermatitis, arthralgia, edema, bone pain
7. Raloxifene
• Mechanism of Action: selective estrogen-receptor modulator,
– Benefits: shown to increase BMD of hip and spine in women1
• Application: approved for treatment and prevention of osteoporosis in
women; not approved for use in males2.
• Study disparities in males
• Narrow study contexts3,5
• Raloxifene is understudied in males was not shown to significantly
impact BMD in males4
Duschek study cited in the notes section is the only one I could find conducted in healthy
males—the sample size was only 30 men! Is there another study out there that I’m missing?
8. Salmon Calcitonin
• Mechanism: inhibits absorption of calcium from intestine and
renal tubules; inhibits osteoclast activity.
• Indications: approved for the treatment (not prevention) of
osteoporosis in women who are ≥5 years post-menopausal
• Approval- FDA doesn’t mention if it’s approved in men as
well– they only state post menopausal women– is Salmon
calcitonin used in men clinically?
10. Teriparatide (Forteo)
• Mechanism of Action: recombinant parathyroid hormone
(PTH); stimulates bone formation.
• Approval: approved for treatment and prevention of
osteoporosis in both men and postmenopausal women1 at high
risk for vertebral fracture. 2
16. Calcium & Vitamin D
• Efficacy: combination Calcium (1200 mg) and
Vitamin D (800 mg) reduces the risk of hip,
vertebral and total fractures in both men and
women1.
• Study flaws: men have not been adequately studied.
– 2010 DIPART Group Meta-Analysis: only14% of 68,500
subjects studied were men1.
– 2007 Tang et al2. Meta-Analysis included only 8% men3.
17. Tissue Selective Estrogen Complex
• Bazedoxifine/Conjugated Estrogen (Duavee)
– Mechanism of Action: SERM that selectively
stimulates lipid metabolism and bone, however, has
no effect on the uterus and breast.
– Benefits
• Increased hip and lumbar BMD
• Improves post menopausal vasomotor symptoms and
sleep disturbances.
18. Tissue Selective Estrogen Complex
• Bazedoxifene/Conjugated Estrogen (Cont’d)
– Application: approved2 for prevention of osteoporosis,
osteopenia & post menopausal vasomotor and sleep
disturbances in post-menopausal women.
– Men: None of the three major clinical trials included men,
despite that estrogen has been demonstrated to play a
significant role in bone formation3.
19. RANK-Ligand Inhibitor
• Denosumab
– Mechanism of Action: monoclonal antibody; prevents
osteoclast maturation.
– Benefits: significant increase in lumbar BMD and reduced
risk of vertebral fracture in both men and women
20. RANK-Ligand Inhibitor
• Indications
– Women: approved for treatment in women with non-
metastatic breast cancer and post-menopausal women with
osteoporosis at high risk for fracture.
– Men: approved for vertebral fracture prevention in men
with non-metastatic prostate cancer who are receiving
Androgen Deprivation Therapy.
22. Post-Operative Mortality
• Men have higher early post-operative mortality and are
less likely to return to independent living or mobility.
• Women are almost twice as likely to survive at 30 days
compared to men (OR 1.93; 95% CI 1.73 to 2.14)
• Women are almost twice as likely to survive at 120 days
compared to men (OR 1.98; 95% CI 1.84 to 2.14)
• Women are more likely to return to their home by 120 days
post-fracture (OR 1.19, 95% CI 1.06-1.32)
• Women are more likely to return to walking unaided at 120
days compared to men (OR 1.25; 95% CI 1.11 to 1.41)
23. Osteoporosis Research
• Research bias
– Majority of research focused on post-menopausal women
– Trials in men
• Outcome of interest rarely hip fracture
• FDA requires vertebral data in men}} CLARIFY THIS–
FIND THE DATA IN ONE OF THE ARTICLES MJ
SENT YOU.
• For agents with hip fracture data in women, if vertebral
BMD gains are similar in men to those seen in women,
data is extrapolated to hip fracture reduction for men
Put that 1 slide that had the Numbers of men v women that MJ sent you.
24. Osteoporosis Research
• Cost effectiveness and Screening
– Women: Cost effective screening methods in women have
been studied adequately and has lent to the use of FRAX
and WHO BMD T-Scores in identifying treatment
candidates.
– Men: Cost-effectiveness has not be adequately studied in
men.
• FRAX underestimates fracture in men.
• NOF guidelines for treatment should be used
conservatively in men.
25. Percentage of non-vertebral, hip, upper humerus and wrist fractures that occurred in men and women with osteoporosis, osteopenia
or normal BMD using gender specific T -scores.
Still need to ask for permission.
Notas do Editor
Speaker Notes
Mechanism of action: more specifically, inhibits apoptosis of osteoblasts and inhibits bone resorptive actions of osteoclasts.
Toxicities: all bisphosphonates are contraindicated in hypocalcemia, hypophosphatemia, Gastro-esophageal disorders (strictures, achalasia, reflux), osteonecrosis of the jaw and renal insufficiency (especially Zoledronic Acid). 1, 2
Calcium and Vitamin D should be replaced prior to treatment with bisphosphonates and maintenance should be continued throughout bisphosphonate therapy.
References
Ebeling, P.R. Osteoporosis in Men. New England Journal of Medicine 2008; 358: 1474-1482. (Level 1).
Orwoli et al. Alendronate for the treatment of osteoporosis in men. NEJM 2000. 343: 604-610.
Zhong et al. Anti-Fracture Efficacy of Riserdronic Acid in Men. Clin Drug Invest 2009; 29(5): 349-357. } Meta-analysis done looking at studies that adequately included men in Riserdronic Acid studies.
Lyles et al. Zoledronic acid and clinical fractures and mortality after hip fracture. NEJM 2007; 357:1799-1809.
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker notes
Ibandronate is an interesting case of paucity. The STRONG study is one of the only studies that has specifically investigated the effects of Ibandronate in men only.
Pharmacokinetics of Ibandronate is similar to other bisphosphonates and thus is expected to be similarly metabolised/eliminated in men.2
The STRONG study noted similar benefits of Ibandronate in men with osteoporosis as has been demonstrated in studies of post-menopausal women with osteoporosis2 (see following slides)
References
Orwoll et al. Efficacy and Safety of Monthly Ibandronate in Men with Low Bone Density. Bone 2010; 46: 970-976.
Barrett et al. Ibandronate: a clinical pharmacological and pharmocokinetic update. Journal of Clinical Pharmacology 2004; 44: 951-965.
Reginster et al. Efficacy and Tolerability of Once-Monthly Oral Ibandronate in Postmenopausal Osteoporosis: 2 year results from the MOBILE study. Annals of Rheumatic Disease 2006; 65:654-661.
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
The STRONG study demonstrated a significant increases in both L1-L3 BMD and Total Hip (TH) BMD from pre-treatment baseline in males treated with Ibandronate compared to placebo.
Reference
Orwoll et al. Efficacy and Safety of Monthly Ibandronate in Men with Low Bone Density. Bone 2010; 46: 970-976.
Speaker Notes
STRONG study also demonstrated a decrease in bone turnover markers sCTX and BSAP.
LG/MJ slide
Speaker Notes
Speaker Notes
Mechanism of Action: Raloxifene is a SERM that is agonistic to estrogen receptors in the bone and antagonistic to estrogen receptors in the breast and uterus; also approved for the prevention of invasive breast cancer in high risk women.
Disparity in studies: Pharmacotherapeutic studies for SERM application in osteoporosis have largely failed to adequately include men in the study design and hence have failed to adequately assess the risks/benefits of pharmacotherapies in men3. [DY SEX AND GENDER CONSIDERATIONS]
Raloxifene in males has been studied in narrow contexts, though males have estrogen receptors.
Duschek et al.conducted a study in 30 males and found no conclusive data on the benefits of Raloxifene
Most other studies are done in the context of males with non-metastatic prostate cancer receiving androgen deprivation therapy (as these patients are at risk for pathologic fracture).
Toxicities: venous thromboemoblism thus contraindicated in patients with history of thromboembolic events; caution advised in women with impaired hepatic or renal function; the incidence of drug toxicities associated with the pharmaceuticals mentioned thus far has been poorly noted between men and women, with the exception of osteonecrosis which seems to affect both sexes. {SOURCE}
References
(2013). Chapter 42. Drugs that Affect Bone Mineral Homeostasis. In Trevor A.J., Katzung B.G., Kruidering-Hall M.M., Masters S.B. (Eds), Katzung & Trevor’s Pharmacology: Examination & Board Review, 10e. Retrieved April 04, 2014 fromhttp://accesspharmacy.mhmedical.com/content.aspx?bookid=514&Sectionid=41817559. (LEVEL?)
Watts et al. Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2012; 97 (6): 1802-1822. (Level 1)
Finklstein et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004; 89: 3841-3846
Duschek et al. Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men. European Journal of Endocrinology 2004; 150: 539-546.
Dy et al. Sex and gender considerations in male patients with osteoporosis. Clin Orthop relat Res. 2011; 469 (7):1906-12. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
FDA notes that there’s an uncertain link between calcitonin and various cancer types (skin and breast were the majority malignancies seen, but others were also noted).
Toxicities: injected form is associated with hypocalcemic tetany; FDA warns that Salmon Calcitonin’s benefits in treatment of post-menopausal osteoporosis do not outweigh its cancer associations.
References
Sanders et al. Osteoporosis in Postmenopausal Women. Journal of the Southern Medical Association 2013; 106: 698-706. (Level 1)
(2013). Chapter 42. Drugs that Affect Bone Mineral Homeostasis. In Trevor A.J., Katzung B.G., Kruidering-Hall M.M., Masters S.B. (Eds), Katzung & Trevor’s Pharmacology: Examination & Board Review, 10e. Retrieved April 04, 2014 fromhttp://accesspharmacy.mhmedical.com/content.aspx?bookid=514&Sectionid=41817559. (LEVEL?)
Speaker Notes
Trovas et al. study demonstrated a significant increases in both lumbar spine and femoral neck BMD from pre-treatment baseline in males treated with salmon Calcitonin compared to placebo.
Additionally, Trovas et. al observed a significant decrease in urinary bone resorption markers (e.g., cTX and NTX) in male osteoporosis patients treated with salmon Calcitonin compared to placebo.
Reference
Trovas et al. A Randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. Journal of Bone and Mineral Research 2002; 17: 521-527.
Speaker Notes
Data regarding the effects of Teriparatide on extra-vertebral fracture risk is insufficient in men.
PTH analogs have been reported to be equally efficacious in both men and women in the prevention of fractures, however, data is much more limited for men due to under-enrolment in pharmacological studies.
References
Hadji et al. The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures. Osteoporosis International 2012; 23: 2141-50. (Level 3)
Murad et al. Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A systematic Review and Network Meta-Analysis. J Clin Endocrinol Metab 2012; 97 (6): 1871-1880. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
Teriparatide mediated change in spinal BMD is similar in males and females
Graph on the left represents the percent change in lumbar spine BMD from baseline to endpoint at 3, 6 and 12 months. The graph demonstrates a significant increase in lumbar spine BMD from baseline in both Teriparatide dosages (20μg and 40μg) compared to placebo.
Graph on the left demonstrates a decreased incidence of non-vertebral fractures in post-menopausal women receiving 20μg and 40μg Teriparatide treatment over a 20 month period.
References
Orwoll et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone mineral density in men with osteoporosis. Journal of Bone and Mineral Research 2003; 18: 9-17. (Level 2)
Neer et al. Effect of parathyroid hormone (1-34) on fractures and bone minderal density in postmenopausal women with osteoporosis. NEJM 2001. 344: 1434-1441.
LG/MJ slide
Speaker Notes
Monotherapy: Calcium or vitamin D monotherapies are ineffective for the prevention of total fractures in both men and women1, however, it is considered significant in fracture prevention patients deficient in either Calcium or Vitamin D2
Combination Therapy: has been demonstrated to significantly decrease fracture risk (vertebral, hip and total fractures) in both sexes1.
Reference
The DIPART Group. Patient level pooled analysis of 68,500 patients from seven major Vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463
Murad et al. Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A systematic Review and Network Meta-Analysis. J Clin Endocrinol Metab 2012; 97 (6): 1871-1880. (Level 1)
Speaker Notes
Combination therapy has been demonstrated to be especially effective in the prevention of hip fractures in both sexes1.
Reference
The DIPART Group. Patient level pooled analysis of 68,500 patients from seven major Vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463
Speaker Notes
Combination therapy, though demonstrated to be effective in fracture risk reduction, is still considered the least effective option in fracture prevention for both sexes4.
The DIPART Group’s Meta-Analysis utilized seven randomized control trials in the US and Europe, bearing a total of 68,500 study participants, only 14% of which were men.
The Tang et al. 2007 Meta-Analysis utilized 29 randomized trials, yielding 63,897 study participants, only 8% of which were men.
References
The DIPART Group. Patient level pooled analysis of 68,500 patients from seven major Vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463. (Level 1)
Tang et al. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370:657–666. (Level 1)
Becker. Does Supplementation with Calcium Alone or in Combination with Vitamin D Reduce the Risk of Osteoporotic Fracture? Nature Clinical Practice Endocrinology & Metabolism 2008; 4: 190-191. (Level 7)
Murad et al. Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A systematic Review and Network Meta-Analysis. J Clin Endocrinol Metab 2012; 97 (6): 1871-1880. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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References:
Gennari et al. Bazedoxifene for the prevention of postmenopausal osteoporosis. Therapeutics and Clinical Risk Management 2008; 4(6): 1229-1242. (Level 2)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
Toxicities: Overall well tolerated; abdominal pain, headache and flu-like symptoms1.
References
Gennari et al. Bazedoxifene for the prevention of postmenopausal osteoporosis. Therapeutics and Clinical Risk Management 2008; 4(6): 1229-1242. (Level 2)
U.S. Food and Drug Administration. (2013). FDA approves Duavee to treat hot flashes and prevent osteoporosis. Retrieved from http://www.fda.gov/drugs/newsevents/ucm370679.htm
Watts et al. Osteoporosis in Men: An Endocrine Societly Clinical Practice Guideline. J Clinical Endocrinol Metab. 2012; 97 (6): 1802-1822.
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
Toxicities: arthralgia, back pain, musculoskeletal pain the extremities and hypocalcemia.
Contraindicated with hypocalcemia; caution with renal insufficiency.
References:
U.S. Food and Drug Administration (2011). Denosumab (Prolia). Retrieved from: http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm272420.htm
Sanders et al. Osteoporosis in Postmenopausal Women. Journal of the Southern Medical Association 2013; 106: 698-706. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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References
U.S. Food and Drug Administration (2011). Denosumab (Prolia). Retrieved from: http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm272420.htm
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Comparative effectiveness of drug treatments to prevent fragility fractures:
a systematic review and network meta-analysis
LG/MJ slide
Speaker Notes
FRAX underestimates fracture in men;
Guidance for screening/treatment using BMD T scores is sufficient for women, however, underidenitifes men at risk. For example, the majority of men who experience fracture after age 60 have T scores > -2.5.
References
Schuit et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2003; 34: 195-202. (Level 2).
Watts et al. Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2012; 97 (6): 1802-1822. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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Speaker Notes
These graphs demonstrate that a significant proportion of women and especially men with normal BMD T-scores experience non-vertebral fractures.
Thus, though low BMD is a strong risk factor for non-vertebral fractures, relying solely on BMD T-scores for the identification of those at risk for fractures is insufficient.
References
Schuit et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2003; 34: 195-202. (Level 2).
Watts et al. Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2012; 97 (6): 1802-1822. (Level 1)
Submitted by: Sati Patel, MSII, TTUHSC School of Medicine; sati.patel@ttuhsc.edu
Date submitted: 4//2014
Last Revision date: 4/24/14
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