osteoporosis for primary
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Osteoporosis for primary care physician
Harold Rosen, MDDirector- Osteoporosis Prevention and
Treatment CenterBeth Israel Deaconess Medical CenterCOPYRIG
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Potential conflicts of interestNone
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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NOF GUIDELINESScreen– women after 65, and men after 70–>50 if additional risk factors are present
Treat men or women after age 50 if –Vertebral or hip fx, OR–Any T-score <-2.5, OR–T-score –1 to –2.5 and
10 year MOF risk >20% OR hip fracture risk >3%, http://www.shef.ac.uk/FRAX/
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http://www.shef.ac.uk/FRAX/index.htm
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Audience question #1
Patient had a BMD showing osteopenia with T-score -1.7, and she does not qualify for treatment. When should the next BMD be done?–A. 1 year–B. 5 years–C. 10 years–D. 17 years
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Audience question #1
Patient had a BMD showing osteopenia with T-score -1.7, and she does not qualify for treatment. When should the next BMD be done?–A. 1 year–B. 5 years–C. 10 years–D. 17 years
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Interval to 10% of patients getting osteoporosis
Initial T-score Interval in years-2 to -2.49 1-1.5 to -1.99 5-1 to -1.49 17
Gourlay et al. NEJM 2012;366:225
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WHAT interval is 1, 5, or 17 years?
This is the scanning interval in patients who do NOT qualify for treatment.This is not the scanning interval in patients who ARE ON treatment!COP
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Following pts on Rx for osteoporosis-Aggressive approach
A small percentage of patients on antiresorptive therapy may be losing BMD, so follow patients with serial BMDs.Some pts losing BMD on Rx have a secondary cause, like celiac disease.Following patients with serial markers and/or densitometry may provide reinforcement that would improve long-term compliance.
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Following pts on Rx for osteoporosis-Conservative approach
Patients with osteoporosis treated with anti-resorptive Rx have a decrease in turnover, increase in BMD, and reduction in fracture risk. Verify that patient is taking the medication, compliant with usual precautions, is taking adequate vitamin D and calcium, and has no other conditions that cause bone loss.Even if we identify pts with suboptimal BMD response to Aln, we do not need to change therapy, because they still have fewer fx than with placebo.
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RR of VCF in pts in FIT accdg to changes in hip BMD on Rx, compared with placebo pts in the
corresponding percentile (OI 2005;16:842)
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Leslie et al., JBMR 2019;34:1808
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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VFA (vertebral fracture analysis)
The densitometer can do an AP and lateral thoraco-lumbar view which is excellent for checking for vertebral fracturesExcellent resolution up to T7This is a separate test with its own CPT code, but costs very little (~$20)COPYRIG
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On the left we see a normal lateral VFA showing no VCF as high as we can see (T6).On the right, we see a lateral VFA with a wedge deformity of T12
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Why was VFA developed?
Vertebral fractures are common even among patients who otherwise have no indication for treatment based on BMD and FRAX– 18% of such patients had unsuspected vertebral
fracturesGreenspan et al., JCD 2001;4:373
So the value of VFA is that it identifies patients with skeletal fragility who would benefit from treatment even if the BMD is OK and FRAX are not bad.
18 C
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Who should have VFA?
Reasonable pretest probability of finding the VFA (>10%?)The finding of vertebral fracture will influence clinical management
19
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1147 men from Geelong had VFA, considered VCF only if ≥ grade 2. Prevalence of VCF in men climbs >10% over age 80.
Pasco et al., OI 2009;20:787.
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VFA guidelines – ISCD (International Society for Clinical Densitometry
Patients should have a VFA if they fulfill ≥1 of the following 4 criteria:–Age (≥70 for women or ≥80 for men), OR–Historic height loss ≥ 4 cm (1.5 inches), OR–Steroid use (5 mg/d prednisone for 3 months), OR–Self-reported but unconfirmed vertebral fractureCOPYRIG
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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Studies that show little effect of ca usually are in the A zone (not giving enough to see an effect), or C zone (already sufficient)
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Calcium and vitamin DCalcium and vitamin D have the most effect on BMD and fx risk in patients most deficientModest doses of calcium do not cause heart disease; this is especially clear when given as dietary calciumYou cannot give antiresorptives to patients deficient in calcium and vitamin D; if they are not getting calcium and you stop them from pulling calcium out of the bone, they are susceptible to hypocalcemia.
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Calcium conclusionsEstimate dietary calcium intake– 1 serving (300 mg) =
1 cup of milk, yogurt, beans, collard greens, or almonds2 cups of ice cream, cottage cheese, or broccoli1 oz of hard cheese 1 can of sardines or salmon (with bones)
if >1000 mg/d, OK (NEJM 1990;323:878)Add in supplemental calcium citrate TO GET INTAKE OVER 1000 mg/d1000 units of D daily
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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ScorecardDrug abbreviation Brand name classAlendronate aln Fosamax PO bisRisedronate ris Actonel PO bisIbandronate ibn Boniva PO/IV bisZoledronate zol Reclast IV bisRaloxifene ralox Evista SERMCalcitonin calc Miacalcin nasal Denosumab den Prolia ab to RANKLPTH PTH Forteo anabolicAbaloparatide Abalo Tymlos anabolicRomosozumab Romo Evenity anabolic
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Guidelines for treatment of osteoporosisMild osteoporosis:– First line – Aln-vs others, longer track record, hip fx
efficacy, better BMD data, and cheap generic– Second line – IV zoledronate (better hip fx and BMD data
than ralox or ibn) or SQ denosumab– Third line- ralox or ibn
Severe osteoporosis:– Anabolics should be given first to raise BMD as high as
possible before “locking in” with antiresorptive. – Prefer ROMO because the others are cumbersome (daily
SQ) and osteogenic sarcoma in rats.
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Tips about medsAlendronate (Fosamax)- 70 mg PO weekly, taken on an empty stomach, full glass of water, wait ½ hrbefore eating.–Typically taken for a 5 year course–Stop and contact MD if GI upset
Zoledronate (Reclast) - 5 mg IV over ½ hr yrlyx3–Common side effect is fever and achiness for a
few days, Rx tylenol. Denosumab (Prolia) - 60 mg SQ every 6 months
Side effects- 3% eczema, 0.3% cellulitis
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Audience question #2
What is the incidence of overtreatment syndromes such as ONJ (osteonecrosis of the jaw) and atypical subtrochanteric femur fracture within the first 5 years of bisphosphonate use for osteoporosis?–A. 10%–B. 1%–C. 0.1%–D. negligible
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Audience question #2
What is the incidence of overtreatment syndromes such as ONJ (osteonecrosis of the jaw) and atypical subtrochanteric femur fracture within the first 5 years of bisphosphonate use for osteoporosis?–A. 10%–B. 1%–C. 0.1%–D. negligible
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Bone et al., NEJM 2004;350:1189
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Black et al., JBMR 2012;27:243
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Ruggiero SL et al. J Oral Maxillofac Surg. 2004 May;62(5):527-34.
Exposed Necrotic Bone in a Patient Receiving Zoledronic Acid for 6 Months: Maxillary Extractions 4 Months Earlier
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ONJ incidence in pts with cancer on monthly IV
bisphosphonates.NEJM 2005;353:99
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Almost all of the cases of ONJ or
spontaneous femur fractures are in pts on alendronate for
>5 years!
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ARR = absolute risk reduction.1. Black D et al. J Bone Miner Res. 2004;suppl 1:S45.2. Data available on request from Merck & Co., Inc. Please specify 20650700(1)–FOS.
Cumulative Incidence of Clinical Vertebral Fractures With Alendronate Supports the Safety of
Long-Term Treatment
Years of Treatment Since FIT
0
2
4
6
8
10
5 6 7 8 9 10
Cum
ulat
ive
Inci
denc
e, %
Risk Reduction
55%
ALN/PlaceboALN/ALN (Pooled)
ALN/Placebo, N:ALN/ALN, N:
437 436 428 425 419 412 404 398 392 387662 660 651 646 638 631 626 615 606 597
5.4%
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Bisphosphonate RxTry to get any jaw SURGERY done prior to bisphosphonate Rx (AIM 2006;144:753)Oral surgeons guidelines:If extractions needed on Rx– If <4 yrs on Rx, no need to stop ALN or delay– If >4 yrs on Rx, hold ALN for 2 months, restart after healed
After 5 yrs of 70 mg Aln, there substantial residual effect for at least 5 yrs after d/c (Fosamax pension). So d/c Aln after 5 yrs for low-risk pts, and after 10 years for high-risk pts.Restart Rx if we see convincing bone loss and a rise in bone resorption (fasting serum CTX).
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The duration of the drug holiday comes from the gut, not from the
headBut no drug holiday for
denosumab, or bone loss resumes with a vengeance!
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GOALSWhen to screen/treat?–BMD–FRAX–VFA
Rx–Ca/D-–Drugs - antiresorptives
Bisphosphonate concernsBisphosphonate duration
–Drugs – anabolicsOld – PTH, abaloparatideNew – Romosozumab
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Anabolic Rx for osteoporosis1. Indications for anabolic Rx
2. Options for anabolic Rx–PTH (teriparatide, or Forteo)–Abaloparatide (Tymlos)–Romosozumab (Evenity)
3. Anabolics after antiresorptives and vice versa
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When to consider anabolics?
Especially severe osteoporosis– Nontraumatic vertebral fractures– T-score <-3.5– Treat to target
Osteoporosis despite long course of antiresorptivesOsteoporosis with low but stable BMD (such as idiopathic male osteoporosis) where antiresorptivesdon’t make much sense.Anabolics work best when given ab initio.
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Available anabolicsForteo– Analog of PTH, PTH 1-34– Stimulates bone formation and resorption, but more
formation
Tymlos– PTHRP analog
Evenity (romosozumab, or ROMO)– Sclerostin is a circulating protein which suppresses bone
formation– Romosozumab is an antibody to sclerostin, binding an
inhibitor of bone formation, promoting bone formation– The enemy of my enemy is my friend
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Summary of anabolicsPTH (Forteo)– Improvement of spine BMD and fx risk better than with BIS– Downsides of daily injection, cancer in rats, and expense
Abaloparatide (Tymlos)– Improvement of BMD and fx risk better than with PTH– Less hypercalcemia, stable at room temperature– Downsides of daily injection, cancer in rats, and expense– PTH 2.0!
Romosozumab (Evenity, or ROMO)– Improvement of BMD and fx risk better than with PTH– MONTHLY injection, NO cancer in rats, but still expensive,
and black box warning for CVD.
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Phase III Active-controlled fx study in postmenopausal women at high fracture risk (ARCH)
4093 postmenopausal women with osteoporosis and prior fx.Randomized to ROMO vs ALN for 1 yr, f/b 2 yr of ALN for all.Improvement in BMD on ROMO
Saag et al., NEJM 2017;377:1417
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Phase III Active-controlled fx study in postmenopausal women at high fracture risk (ARCH)
4093 postmenopausal women with osteoporosis and prior fx.Randomized to ROMO vs ALN for 1 yr, f/b 2 yr of ALN for all.Reduction in VCF and non-VCF
Saag et al., NEJM 2017;377:1417
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CV side effects with ROMO
Side effect Romo vs ALN Odds ratio with CISerious CV events 2.5%vs 1.9% 1.31 (0.85-2.00)CV ischemic events 0.8% vs 0.3% 2.65 (1.03-6.77)Stroke 0.8% vs 0.3% 2.27 (0.93-5.22)
Saag et al., NEJM 2017;377:1417
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Cosman et al. NEJM 2016;375:1532
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Black box warning in the Romo PI
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Continuation of the Phase II trial of ROMOLeft panel shows that in subjects who take ROMO for 2 years and then stop, the BMD goes back to baseline within a yr.Right panel shows that the rise in BMD with ROMO is more modest when taken after ALN. McClung et al., JBMR 2018;33:1397
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Summary (1)BMD screening at 65F/70M, sooner if high risk. VFA if 70F/80M, sooner if ht loss >1.5 inches or steroids.Rx pts with spine or hip fx, or T-score <-2.5, or osteopenia with >3% 10-yr hip fx risk by FRAXGive 1000 units of D, and supplemental ca to achieve TOTAL ca intake of 1000 mg/d.Can follow pts on Rx with BMD, mainly to
help reinforce compliance
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Summary (2)First line Rx is usually a PO bisphosphonate (Aln), or IV – DMAB is a great drug, but must be given forever
Keep ALN course 5 yrs in low risk patients because of RARE concerns about ONJ or atypical femur fx after 5 yrsAnabolics should be considered for patients with severe osteoporosis; Romo is effective and easier to use than the other anabolics.
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