family medicine refresher course april 2, 2019 · 2019. 3. 5. · janet a. schlechte, m.d. janet a....
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OsteoporosisWhich Drug, When to Start,
How Long to Treat
Family Medicine Refresher Course
April 2, 2019
Janet A. Schlechte, M.D.
Janet A. Schlechte, M.D.
has no relationships with any proprietary entity producing
health care goods or services consumed by or
used on patients.
Disclosure of Financial Relationships
•Pathogenesis of post menopausal bone loss has been elucidated
•BMD can be measured reproducibly by DXA and diagnostic criteria are established
•Tools for estimating individual fracture risk are available
•Fracture protection occurs rapidly
THE GOOD NEWS
• Number of patients treated for osteoporosis has declined by 40% since 2008
• Patients often stop medication because of safety concerns
• Most drugs are anti-remodeling agents• Physicians are uncertain about when
to treat and for how long
THE BAD NEWS
• Which drug is best?
• How long to treat?
• Concerns about AFF and ONJ
• Drug holiday
Issues
JCEM 2012;97:311
Remodeling and Modeling of Bone
Bisphosphonates RANKLAlendronate DenosumabRisedronateIbandronateZoledronic Acid
PTH PTHrPTeriparatide Abaloparatide
Treatment of Osteoporosis
NEJM 2007;356:1809
Effect of Bisphosphonate on Hip Fractures
Antifracture Efficacy of Bisphosphonates
Vertebral Hip Nonvertebral
Alendronate + + +
Risedronate + + +
Ibandronate + – –
Zoledronic Acid + + +
Year
BM
D C
han
ge
Fro
m B
asel
ine,
Mea
n, %
0
FIT
1 2 3 4 0 1 2 3 4 5
16
14
12
10
8
6
4
2
0
-2
FLEX
Begin Flex
BisphosphonatesHow long to treat?
Placebo
Alendronate
JAMA 296:2927, 2006
Bisphosphonates Time to First Fracture
JAMA 296:2927, 2006
Time to First Fracture, mo
0 12 24 36 48 60 720
5
10
15
20
Time to First Fracture, mo
0 12 24 36 48 60 720
5
10
15
20
Placebo
AlendronateAlendronate
Placebo
Cu
mu
lati
ve In
cid
ence
(%
)
Cu
mu
lati
ve In
cid
ence
(%
)
Nonvertebral Clinical Vertebral
RR, 1.00 (95% CI, 0.76-1.32) RR, 0.45 (95% CI, 0.24-0.86)
Consider a drug holiday when
• T score >-2.5
• No fractures
• No new risk factors
• Patient agrees to close follow-up and repeat DXA
There are no guidelines for when to withdraw a bisphosphonate
Bisphosphonate Drug Holiday
• Consider in low risk patients after 5 years of treatment with alendronate or risedronate and after 3 years of therapy with zoledronic acid
• FDA has not identified subgroups of patients who will benefit from therapy with bisphosphonates for >3-5 years
• Usefulness of bone markers and DXA surveillance not established
NEJM 2009;361:756
Should I Start with Denosumab Instead?
Freedom Trial
• 3 year RCT of Denosumab• 7800 postmenopausal women 60-90• T score -2.5, some had vertebral
fractures• 68% reduction in new vertebral
fractures• 20% reduction in non vertebral
fractures• 40% reduction in hip fracture
NEJM 36:958, 2009
Osteo Intl 2017;28:1723
Effect of Stopping Denosumab
• 52 patients treated for 8 years had decrease of ~6.7% in hip and spine BMD during 1 year of observation
• 10% experienced fractures
• Case reports 5 patients treated for 2-3 years, 8% fractured
Effect of Stopping Denosumab
Curr Osteo Report 2015 Osteo Intl 28:1723, 2017
Drug Holiday for Denosumab?
• 50 women treated with Deno or PTH or both then switched at 2 years
• After 4 years women counseled to reinstitute their previous therapy
• 28 returned for follow-up
• With no follow-up therapy BMD ↓ by 4.2% in hip and 10% in spine
• In those who received follow-up treatment BMD was maintained
Bone 2017
A 70 y.o. female has a T score of -2.9 in her femoral neck. She has taken a bisphosphate for 2 years and announces today that she has stopped the drug.
“My osteoporosis drug is too risky.”
Atypical Femoral Fracture
T score BMD (gm/cm2)
2010 -1.6 0.656
2005 -1.4 0.660
2003 -1.5 0.659
2000 -1.4 0.664
Hip Fracture Sites
BMR 25:2267, 2010
• OR 2.7 (1.2-6.0) 716 cases vs 3580 controls
• 9723 fractures vs 48564 in controls
• Treating 1000 women for 5 years would
- Prevent 30-50 nonvertebral fx
- Prevent 50-115 vertebral fx
- Cause 5 atypical fx
JAMA 305:783, 2011
Atypical Fractures and Bisphosphonates
JBMR 2012;27:2544
Atypical Femoral Fractures and Duration of Bisphosphonate Exposure
• Defects in cholesterol synthetic pathway
• Vitamin D deficiency• Glucocorticoids• PPI?• Normal or low BMD• Comorbid illness• Combination of antiresorptive agents
Causes of Atypical Fractures
• If a patient taking a bisphosphonate develops thigh or groin pain
• X-ray both femurs
• If radiographs normal consider bone scan or MRI to look for stress reaction
Bone and Mineral Research 25:2267, 2010
After Atypical Femur Fractures
• When/if to restart therapy is individual decision based on risk factors
• Do yearly clinical assessment
• ? bone markers
• Monitor BMD
Bisphosphonates and Osteonecrosis
Osteonecrosis of the Jaw
• 1 in 10,000 to 1 in 60,000 patient years compared to 1-10/100 patients with cancer
• Usually associated with high dose therapy with pamidronate and zoledronic acid
• Bone markers do not identify at-risk patients
• Stopping drug pre-procedure not likely helpful
Reassure Your Patients
• Typical intertrochanteric fractures more common than subtrochanteric fractures
• Extended therapy with antiresorptive agents can be associated with ↑ risk of subtrochanteric fracture but overall risk is low
• Concern about subtrochanteric fracture should not deter providers from using bisphosphonate therapy in appropriate patients
Resting
Activation
OsteoclastRecruitment
Resorption
Reversal
OsteoblastRecruitment
Repair
Resting
Osteoid
Bone
Denuded Bone SurfaceOC
MP
POBMC
New Osteoid
OC
OB
PM PO
24
20
-4
16
12
8
0 6 12 18
4
0
24 30
Alendronate
Combination therapy
Parathyroid hormone
Time (months)
Per
cent
cha
nge
Effect of PTH and Alendronate on Spinal BMD
NEJM 349:1216, 2003
Parathyroid Hormone Therapy
• Not first line therapy• Severe osteoporosis or failure of
other therapy• Don’t use if patient has secondary
hyperparathyroidism, hypercalcemia, evidence of skeletal malignancy
• PTH decreases vertebral fracturesbut fracture reduction is slow to develop (9 months)
• Need an anabolic agent with more rapid onset of action
• Analog of PTHrP recently approved
Abaloparatide
• Synthetic analog of PTHrP
• Binds more selectively than PTH to the PTH-1 receptor which stimulates anabolic activity with modest stimulation of resorption
• Transient binding favors bone formation and minimizes bone resorption, also less calcium mobilization
Sclerostin and Osteoblast Proliferation
• Monoclonal antibody against sclerostin
• Multicenter, randomized, placebo controlled
• 419 postmenopausal women
• Romosozumab, teriparatide, alendronate or placebo
• Primary endpoint - percent change in spine BMD at 1 year
Romosozumab
• A 70 y.o. who is taking calcium and vitamin D calls to discuss the safety of calcium therapy.
• She takes 2500 mg of calcium carbonate and 1000 IU of vitamin D daily.
• She is worried about an increase in CV disease due to calcium.
Effect of Calcium/Vitamin D on CVDThe Women’s Health Initiative
Hsia et al. Circulation 2007; 115:846-854
MI + Coronary Death Stroke
What to do
• Link between calcium supplementation and CV events inconclusive
• Promote dietary calcium
• Don’t stop calcium supplement
• Reserve supplements for those unable or unwilling to achieve adequate dietary intake
Take Home Points
• Therapy for osteoporosis is effective and can be targeted to affect bone formation and bone resorption
• Need tools for assessing bone quality and additional anabolic agents
• Use drug holiday in patients taking a biphosphonate
• Reassure patients about safety of available drugs
KEEPCALM
AND
TRUST YOURENDOCRINOLOGIST
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