Howard Fink, MD, MPH

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Parkinsons Disease and Skeletal Health

• Minneapolis VA Medicine Research Conference
• January 22, 2009
• Howard Fink, MD, MPH

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Summary

• There is accumulating evidence that PD is an
  important osteoporosis risk factor.

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Summary

• There is accumulating evidence that PD is an
  important osteoporosis risk factor.
• What is that evidence?
• By what mechanism(s) may PD be associated with
  osteoporosis?
• What should be done about this?

4
Summary

• There is accumulating evidence that PD is an
  important osteoporosis risk factor.
• What is that evidence?
• By what mechanism(s) may PD be associated with
  osteoporosis?
• What should be done about this?

5
Summary

• There is accumulating evidence that PD is an
  important osteoporosis risk factor.
• What is that evidence?
• By what mechanism(s) may PD be associated with
  osteoporosis?
• What should be done about this?

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Parkinsons Disease
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Parkinsons 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 gt55 yrs in 70 of
  patients
• Prevalence rises to 3 at gt80 yrs
• Slowly progressive

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Osteoporosis
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Osteoporosis

• Definition
• Skeletal disorder w/ reduced bone strength
  increased fracture risk

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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)

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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

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What is the evidence for Parkinsons Disease as a
risk factor for Osteoporosis?
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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 gt1 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

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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

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Association Between Parkinsons 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 5315591564, 2005
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MrOS Study Design

• Ongoing multi-site, prospective cohort study of
  predictors of osteoporosis and fractures in older
  men
• Enrolled 5995 men aged gt65, primarily from
  population-based sources

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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 Parkinsons disease?
• N52 with PD
• N5943 with no PD
• Measurement of BMD
• DXA Areal BMD (g/cm2) of lumbar spine, total hip
  hip subregions

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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

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Analyses

• ANCOVA to estimate cross-sectional association
  between PD and BMD measures
• Results expressed as mean percentage (95CI) BMD
  differences between men with and without PD
• Multivariate model construction
• Considered factors associated both with PD and
  the specific BMD measure (plt0.10)
• Variables also examined for clinical
  comprehensibility, correlation with other
  associated variables, and degree of missing data
• Step-wise selection (plt0.05 for retention)

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Association Between PD Areal BMD (DXA)
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Fall Risk

• After adjusting for age past falls, those w/PD
  had 2.3-fold increased risk of multiple future
  falls

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The association of Parkinsons 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 GroupOsteoporos Int
2008191093-97
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SOF Study Design

• Ongoing multi-site, prospective cohort studying
  predictors of osteoporosis and fractures in older
  women
• Enrolled 9704 women aged gt65, primarily from
  population-based sources
• 8105 attended study visit 4 and had known PD
  status

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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 Parkinsons disease?
• N73 with PD
• N8032 with no PD
• Measurement of BMD
• Areal BMD (g/cm2) of lumbar spine, total hip
  hip subregions with DXA

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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)

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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

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Hip BMD as a Function of PD Status
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Incident Hip Fracture Risk
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Fall Risk

• Among community-dwelling older women, after
  adjusting for age weight, those w/PD had
  3.7-fold increased risk of multiple future falls

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Association of Parkinsons 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
GroupOsteoporos Int 2008191277-82
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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 Parkinsons disease
• Visits 1 2 measurement of BMD
• Areal BMD (g/cm2) of lumbar spine, total hip
  hip subregions with DXA

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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

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Analyses

• Definition of PD Men reported PD at baseline,
  did not report no PD at follow-up (n46)
• Definition of No PD Men reported no PD at
  baseline, did not report PD at follow-up
  (n5891)
• Change in hip BMD estimable in 19 (41.3) men
  with PD and 4356 (73.9) of men without PD.

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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

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Analyses

• Age-adjusted annualized bone loss in men with
  without PD assessed using ANCOVA.
• Variables associated with PD status (plt0.10)
  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

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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

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• Why might PD be associated with osteoporosis?

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Postulated Mechanisms for PD-Osteoporosis
Association

• Reduced mobility or neuromuscular function
• Vitamin D deficiency
• Altered estrogen level
• Low weight / weight loss
• Parkinsons disease medications

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Postulated Mechanisms for PD-Osteoporosis
Association

• Reduced activity or neuromuscular function
• PD?reduced activity and neuromuscular
  function?increased bone resorption

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Postulated Mechanisms for PD-Osteoporosis
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
  200722461-8)
• Vit D receptors and 1-alpha hydroxylase
  distributed in brain, including most strongly in
  hypothalamus substantia nigra (Eyles DW, J Chem
  Neuroanat 20052921-30)
• Case report of improved PD symptoms with high
  dose 25-OH vit D (Derex L, Mov Disord
  199712612-13)

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Postulated Mechanisms for PD-Osteoporosis
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 MgtF, more common in women
  w/reduced endogenous estrogen exposure
• Aromatase KO mice more vulnerable to parkinsonian
  neurotoxin MPTP (Morale MC, Brain Res Rev
  200857431-43)
• Small trials suggest ERT may improve motor
  symptoms in PD (Nicolleti A, Clin Neuropharm
  200730276-80. Tsang KL, Neurology
  2000542292-8)

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Postulated Mechanisms for PD-Osteoporosis
Association

• Low weight / weight loss
• Weight loss strongly associated with bone loss in
  prospective studies
• Parkinsons 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 2008191277-82

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Postulated Mechanisms for PD-Osteoporosis
Association

• Parkinsons disease medications
• From case-control data1
• Inconsistent association between different
  classes of PD medications (levodopa, dopamine
  agonists, COMT inhibitors, MAO-B 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 200781153-61.

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• What, if anything, should be done about this?

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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.

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Amelioration of osteoporosis by menatetrenone in
elderly female Parkinsons Disease patients with
vitamin D deficiency.Sato Y, et al. Bone
200231114.

• 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 lt-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
  (plt.0001)
• Fractures
• 1 (1 hip) menatrenone grp vs. 10 (8 hip) no
  treatment grp (p.0082)

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Amelioration of osteopenia and hypovitaminosis D
by 1-alpha-hydroxyvitamin D3 in elderly patients
with Parkinsons disease. Sato Y, et al. J
Neurol Neurosurg Psychiatry 19996664.

• 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 lt-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 (plt.0001)
• Fractures
• 1 (1 hip) vit D grp vs. 8 (6 hip) placebo grp
  (p.0028)

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Alendronate and vitamin D2 for prevention of hip
fracture in Parkinsons Disease a randomized
controlled trial. Sato Y, et al. Movement
Disorders 200621924.

• Placebo-controlled, double-blind RCT
• 288 Japanese female PD patients aged gt65y (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 lt-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
  (plt.001)
• Hip fractures
• 4 alendronate grp vs. 14 placebo grp (RR 0.29,
  95CI0.10-0.85)

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Risedronate and ergocalciferol prevent hip
fracture in elderly men with Parkinsons Disease.
Sato Y, et al. Neurology 200768911.

• Placebo-controlled, double-blind RCT
• 242 Japanese male PD patients aged gt65y (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 lt-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
  (plt.001)
• Hip fractures
• 3 risedronate grp vs. 9 placebo grp (RR 0.33,
  95CI0.09-1.20)

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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-specifi
  c treatments reduce bone loss and prevent hip
  fractures in PD patients without osteoporosis.

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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 2006212265-66

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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

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Contact Information

• For information about this specific presentation
  please contact Howard Fink, MD, MPH at
  howard.fink_at_va.gov
• For any questions about the monthly GRECC Audio
  Conference Series please contact Tim Foley at
  tim.foley_at_va.gov or call [phone]
• 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_detai
  l.asp?id24985 and click the Handout
  Registration and Evaluation link