Transcript Document

Parkinson’s Disease and
Skeletal Health
Minneapolis VA Medicine Research Conference
January 22, 2009
Howard Fink, MD, MPH
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Summary
•
There is accumulating evidence that PD is an important
osteoporosis risk factor.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Summary
•
There is accumulating evidence that PD is an important
osteoporosis risk factor.
1.
2.
3.
What is that evidence?
By what mechanism(s) may PD be associated with osteoporosis?
What should be done about this?
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Summary
•
There is accumulating evidence that PD is an important
osteoporosis risk factor.
1.
2.
What is that evidence?
By what mechanism(s) may PD be associated with
osteoporosis?
What should be done about this?
3.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Summary
•
There is accumulating evidence that PD is an important
osteoporosis risk factor.
1.
2.
3.
What is that evidence?
By what mechanism(s) may PD be associated with osteoporosis?
What should be done about this?
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Parkinson’s Disease
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Parkinson’s Disease
• Clinical presentation:
– Tremor, rigidity, bradykinesia
– Postural instability & gait disorder
– Dementia may occur at late stages
• Course:
– Usually mid- to late-life onset
• First symptoms occur at >55 yrs in 70% of patients
• Prevalence rises to ~3% at >80 yrs
– Slowly progressive
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Osteoporosis
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Osteoporosis
• Definition:
– Skeletal disorder w/ reduced bone strength & increased fracture
risk
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Osteoporosis
• Bone strength reflects dynamic bone remodeling
– Bone breakdown is coupled to subsequent bone formation
– Skeleton repairs & adapts to changes in its strain exposure
• Bone strength is function of:
– Bone mineral density (BMD)
– Bone geometry
– Bone quality (i.e. architecture, turnover, damage)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Osteoporosis
• Epidemiology:
– There is no existing clinical measure of bone strength
– Defined by BMD criteria (strong predictor of fracture risk)
– FRAX calculator of absolute fracture risk to help define treatment
thresholds: http://www.shef.ac.uk/FRAX/
– Most who might be considered for treatment based on BMD or
FRAX are undiagnosed
• Consequences:
– ~1.5 million “osteoporotic” fractures/yr in U.S., most commonly
spine, hip and wrist
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What is the evidence for
Parkinson’s Disease as a risk
factor for Osteoporosis?
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Association of PD with
Osteoporosis
• Multiple case-control or retrospective studies published
1987-2002 reported PD associated with lower BMD
– None reported consistent findings at >1 skeletal site
– Half examined BMD measures not in wide clinical use
– No studies examined whether factors other than age &
sex could have accounted for observed findings
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Association of PD with
Osteoporosis
• In prospective data from the Study of Osteoporotic
Fractures (SOF)1:
– PD associated with ~2-fold increased hip fracture risk
partially attenuated by adjustment for age & baseline
BMD
• Association between PD & fractures assumed attributable
in part to increased falls risk
1Taylor
BC, JAGS 2004
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Association Between Parkinson’s Disease and Low
Bone Density and Falls in Older Men:
The Osteoporotic Fractures in Men (MrOS) Study.
Fink HA, Kuskowski MA, Orwoll ES, Cauley JA, Ensrud KE.
J Am Geriatr Soc 53:1559–1564, 2005
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
MrOS Study Design
• Ongoing multi-site, prospective cohort study of predictors
of osteoporosis and fractures in older men
• Enrolled 5995 men aged >65, primarily from populationbased sources
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Baseline Data Collection
• Ascertainment of PD:
– Subject self-report to questionnaire:“Has a doctor or
other healthcare provider ever told you that you had
or have Parkinson’s disease?”
• N=52 with PD
• N=5943 with no PD
• Measurement of BMD
– DXA: Areal BMD (g/cm2) of lumbar spine, total hip & hip
subregions
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Other Baseline Measurements
•
•
•
•
•
•
Age, height, weight
PMH/comorbidities (e.g. DM, stroke, CHF, fractures, falls)
Medications
Habits (e.g. activity, diet, smoking, alcohol)
Self-reported function (e.g. QOL, IADLs)
Physical/mental performance (e.g. leg power, walking speed,
balance)
• Cognition, vision
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Analyses
• ANCOVA to estimate cross-sectional association between
PD and BMD measures
• Results expressed as mean percentage (95%CI) BMD
differences between men with and without PD
• Multivariate model construction:
– Considered factors associated both with PD and the specific BMD
measure (p<0.10)
– Variables also examined for clinical comprehensibility, correlation
with other associated variables, and degree of missing data
– Step-wise selection (p<0.05 for retention)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Association Between PD
& Areal BMD (DXA)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Fall Risk
• After adjusting for age & past falls, those w/PD
had 2.3-fold increased risk of multiple future falls
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
The association of Parkinson’s disease with
bone mineral density and fracture in older
women
Schneider JL, Fink HA, Ewing SK, Ensrud KE, Cummings SR,
for the Study of Osteoporotic Fractures (SOF) Research
Group
Osteoporos Int 2008;19:1093-97
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
SOF Study Design
• Ongoing multi-site, prospective cohort studying predictors
of osteoporosis and fractures in older women
• Enrolled 9704 women aged >65, primarily from
population-based sources
• 8105 attended study visit 4 and had known PD status
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
SOF Visit 4 Data Collection
• Ascertainment of PD:
– Self-report questionnaire: “Has a doctor or other
healthcare provider ever told you that you had or have
Parkinson’s disease?”
• N=73 with PD
• N=8032 with no PD
• Measurement of BMD
– Areal BMD (g/cm2) of lumbar spine, total hip & hip subregions
with DXA
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Other SOF Measurements
Measured at visit 4
•
•
•
•
•
•
Age, height, weight
PMH/comorbidities (e.g. DM, stroke, CHF, fractures, falls)
Medications
Habits (e.g. activity, diet, smoking, alcohol)
Self-reported health status (e.g. QOL, IADLs)
Cognition
Measured at visit 2
• Neuromuscular function (e.g. leg power, walking speed, balance)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Analyses
• Linear regression to estimate cross-sectional association
between PD and hip BMD
– Results for mean age-adjusted BMD in men with and without PD
were compared with t-tests
• Cox proportional hazards to estimate risk of incident hip,
and nonspine nonhip fractures
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Hip BMD
as a Function of PD Status
Figure 1. Age Adjusted Total Hip and Femoral Neck BMD
by Parkinson's Disease Status
0.800
0.74(0.73, 0.74)
PD
0.68 (0.64, 0.72)
0.700
BMD (g/cm2)
0.63 (0.63, 0.64)
0.59 (0.55, 0.62)
0.600
0.500
0.400
Total Hip
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Femoral Neck
Non-PD
Incident Hip Fracture Risk
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Fall Risk
• Among community-dwelling older women, after
adjusting for age & weight, those w/PD had 3.7fold increased risk of multiple future falls
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Association of Parkinson’s disease with
accelerated bone loss, fractures and
mortality in older men: the Osteoporotic
Fractures in Men (MrOS) study
Fink HA, Kuskowski MA, Taylor BC,
Schousboe JT, Orwoll ES, Ensrud KE,
for the Osteoporotic Fractures in Men (MrOS) Study Group
Osteoporos Int 2008;19:1277-82
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
MrOS Data Collection
• PD status ascertained at visits 1 & 2 (mean 4.6y interval):
– Subject self-report to questionnaire:“Has a doctor or
other healthcare provider ever told you that you had
or have Parkinson’s disease
• Visits 1 & 2 measurement of BMD
– Areal BMD (g/cm2) of lumbar spine, total hip & hip subregions
with DXA
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
MrOS Visit 1 & 2 Measures
• Age, height, weight (weight change from baseline
calculated)
• Comorbidities (including recent falls)
• Medications
• Habits (e.g. activity, diet, smoking, alcohol)
• Self-reported function (e.g. QOL, IADLs)
• Physical/mental performance (e.g. leg power, walking speed,
balance)
• Cognition
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Analyses
• Definition of PD: Men reported ‘PD’ at baseline,
did not report ‘no PD’ at follow-up (n=46)
• Definition of No PD: Men reported ‘no PD’ at
baseline, did not report ‘PD’ at follow-up
(n=5891)
• Change in hip BMD estimable in 19 (41.3%) men
with PD and 4356 (73.9%) of men without PD.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Analyses
• Hip BMD change could not be determined in 27
PD men:
– 16 (34.8%) died prior to visit 2
– 1 terminated prior to visit 2
– 2 refused to attend visit 2 due to health problems
– 7 completed visit 2 questionnaire but no BMD
measurement
– 1 whose contralateral hip was measured at visit 2
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Analyses
• Age-adjusted annualized % bone loss in men with &
without PD assessed using ANCOVA.
• Variables associated with PD status (p<0.10) examined as
covariates in separate age-adjusted models
• Multivariate modeling not performed as only a small
number of PD subjects had both baseline & follow-up
BMD measures
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Impact of patient population
on results
Volunteer cohort
+ Prospective studies allow collection of
extensive pre-fx measures
– Results may not be representative for all men
with fx
• Participants likely healthier, community-dwelling,
more well-educated, etc
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Why might PD be associated
with osteoporosis?
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Reduced mobility or neuromuscular
function
• Vitamin D deficiency
• Altered estrogen level
• Low weight / weight loss
• Parkinson’s disease medications
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Reduced activity or neuromuscular function
– PD→reduced activity and neuromuscular
function→increased bone resorption
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Vitamin D deficiency
– PD and osteoporosis both epidemiologically associated with
vitamin D deficiency
– Conventional thinking:
• PD→decreased sun exposure & dietary vit D intake→decreased
calcium absorption→secondary hyperparathyroidism→increased
bone resorption
– Recently theorized:
• Vit D deficiency→decreased activation of 1,25-OH vit D in
substantia nigra→disruption of brain cell function (Newmark HL, Mov
Disord 2007;22:461-8)
– Vit D receptors and 1-alpha hydroxylase distributed in brain, including
most strongly in hypothalamus & substantia nigra (Eyles DW, J Chem
Neuroanat 2005;29:21-30)
– Case report of improved PD symptoms with high dose 25-OH vit D
(Derex L, Mov Disord 1997;12:612-13)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Altered estrogen level
– Estrogen deficiency known to cause bone loss
– Data suggestive that estrogen deficiency also may
contribute to development of PD
• PD more common in M>F, more common in women
w/reduced endogenous estrogen exposure
• Aromatase KO mice more vulnerable to parkinsonian
neurotoxin MPTP (Morale MC, Brain Res Rev 2008;57:431-43)
• Small trials suggest ERT may improve motor symptoms in PD
(Nicolleti A, Clin Neuropharm 2007;30:276-80.Tsang KL, Neurology
2000;54:2292-8)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Low weight / weight loss
– Weight loss strongly associated with bone loss in
prospective studies
– Parkinson’s disease associated with weight loss, both
before and after diagnosis
– In older men, adjustment for concurrent weight loss
attenuated association between PD and bone loss
more than any other variable, but did not eliminate the
association1
1 Fink
HA, Osteoporos Int 2008;19:1277-82
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Postulated Mechanisms for PDOsteoporosis Association
• Parkinson’s disease medications
– From case-control data1
• Inconsistent association between different classes of PD
medications (levodopa, dopamine agonists, COMT inhibitors, MAOB inhibitors, anticholinergics) and fracture risk
• No evidence that association varied by dose or duration of
use
– Interpretation complicated by confounding by
indication
1Vestergaard
P, Calcif Tissue Int 2007;81:153-61.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What, if anything, should be
done about this?
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What to Do: Clinical?
• Treat PD patients to reduce bone loss, prevent
fractures?
– There is some evidence that osteoporosis-specific
treatments reduce bone loss and prevent hip fractures
in PD patients.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Amelioration of osteoporosis by menatetrenone in
elderly female Parkinson’s Disease patients with
vitamin D deficiency.
Sato Y, et al. Bone 2002;31:114.
• Double-blind RCT
• 120 postmenopausal Japanese PD patients (mean 72y)
– Exclusions: nonvertebral fx, recent or regular use of bone active meds,
known cause of osteoporosis
– Mean baseline BMD 2.2 mm Al in both groups (mean T-scores <-2.5)
• 45 mg daily menatrenone (vitamin K2) vs. no treatment x 12m
• Bone loss:
– Change in 2nd metacarpal BMD (mm Al, CXD)
• +0.9% menatrenone grp v. -4.3% no treatment grp (p<.0001)
• Fractures:
– 1 (1 hip) menatrenone grp vs. 10 (8 hip) no treatment grp
(p=.0082)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Amelioration of osteopenia and hypovitaminosis D
by 1-alpha-hydroxyvitamin D3 in elderly patients with
Parkinson’s disease.
Sato Y, et al. J Neurol Neurosurg Psychiatry 1999;66:64.
• Placebo-controlled, double-blind RCT
• 86 Japanese PD patients (mean 71y; 51 women)
– Exclusions: nonvertebral fx, recent or regular use of bone active meds,
known cause of osteoporosis
– Mean baseline BMD 2.0-2.1 mm Al in both groups (mean T-score <-2.5 vs.
normal Japanese ref range)
• 1 mcg vit D vs. placebo daily x 18m
• Bone loss:
– Change in 2nd metacarpal BMD (mm Al, computed radiographic
densitometry, i.e. CXD)
• -1.2% vit D grp v. -6.7% placebo grp (p<.0001)
• Fractures:
– 1 (1 hip) vit D grp vs. 8 (6 hip) placebo grp (p=.0028)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Alendronate and vitamin D2 for prevention of hip
fracture in Parkinson’s Disease: a randomized
controlled trial.
Sato Y, et al. Movement Disorders 2006;21:924.
• Placebo-controlled, double-blind RCT
• 288 Japanese female PD patients aged >65y (mean 72y)
– Exclusions: nonvertebral fx, recent or regular use of bone active meds,
known cause of osteoporosis
– Mean baseline BMD 2.1-2.2 mm Al in both groups (mean T-score <-2.5)
– 5 mg alendronate + 1000 IU ergocalciferol vs. placebo + 1000 IU
ergocalciferol daily x 24m
• Bone loss:
– Change in 2nd metacarpal BMD (mm Al, CXD)
• +3.1% alendronate grp vs. -2.8% placebo grp (p<.001)
• Hip fractures:
– 4 alendronate grp vs. 14 placebo grp (RR 0.29, 95%CI=0.10-0.85)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Risedronate and ergocalciferol prevent hip fracture in
elderly men with Parkinson’s Disease.
Sato Y, et al. Neurology 2007;68:911.
• Placebo-controlled, double-blind RCT
• 242 Japanese male PD patients aged >65y (mean 72y)
– Exclusions: nonvertebral fx, recent or regular use of bone active meds,
known cause of osteoporosis
– Mean baseline BMD 2.25 mm Al in both groups (mean T-score <-2.5)
– 2.5 mg risedronate + 1000 IU ergocalciferol vs. placebo + 1000 IU
ergocalciferol daily x 24m
• Bone loss:
– Change in 2nd metacarpal BMD (mm Al, CXD)
• +2.2% risedronate grp v. -2.9% placebo grp (p<.001)
• Hip fractures:
– 3 risedronate grp vs. 9 placebo grp (RR 0.33, 95%CI=0.09-1.20)
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What to Do: Clinical?
• Treat PD patients to reduce bone loss, prevent
fractures?
– Trials suggest that supplemental vit D and vit K2 each
reduce bone loss, and that alendronate and risedronate
each prevent hip fracture
– All published trials from single investigator in Japanese
osteoporotic patients with PD; generalizability to other
osteoporotic PD populations unknown
– There is no evidence yet that osteoporosis-specific
treatments reduce bone loss and prevent hip fractures
in PD patients without osteoporosis.
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What to Do: Clinical?
• Screen PD patients for osteoporosis?
– Though at increased risk for osteoporosis, accelerated bone loss,
falls, and fractures, patients with PD are infrequently screened for
osteoporosis1
– There is no direct evidence on the cost-effectiveness of screening
this population for osteoporosis, but demonstrating this will be
difficult
– Recommendation: In addition to implementing fall prevention
measures, clinicians should consider osteoporosis screening in
older patients with PD
1Eng
ML, Mov Disord 2006;21:2265-66
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
What to Do: Research?
• Examine PD-bone loss association in larger PD populations,
including evaluation of RF for bone loss in PD patients
• RCT to examine whether PD-specific treatment reduces BMD
loss, falls & fractures
• RCT to examine whether osteoporosis-specific treatment
reduces BMD loss & fractures in nonosteoporotic PD patients
• RCT to examine whether vitamin D and/or estrogen improve
PD symptoms
• Consider inclusion of PD as RF in absolute fracture risk models
to be utilized for BMD screening, fracture prevention decisions
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009
Contact Information
• For information about this specific presentation
please contact Howard Fink, MD, MPH at
[email protected]
• For any questions about the monthly GRECC
Audio Conference Series please contact Tim Foley
at [email protected] or call (734) 222-4328
• For the link to the evaluation form for this
conference that will confer CE credit please go to
http://vaww.sites.lrn.va.gov/vacatalog/cu_detail.asp
?id=24985 and click the “Handout: Registration
and Evaluation” link
Howard Fink, MD, MPH
Minneapolis VA Medicine Research Conference
January 22, 2009