Parkinson’s Disease and Skeletal Health

1. Parkinson’s Disease and Skeletal Health Minneapolis VA Medicine Research Conference January 22, 2009 Howard Fink, MD, MPH

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

3. 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?

6. Parkinson’s Disease

7. 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

8. Osteoporosis

9. Osteoporosis • Definition: • Skeletal disorder w/ reduced bone strength & increased fracture risk

10. 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)

11. 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

12. What is the evidence for Parkinson’s Disease as a risk factor for Osteoporosis?

13. 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

14. 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

15. 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

16. 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 population-based sources

17. 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

18. 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

19. 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)

20. Association Between PD & Areal BMD (DXA)

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

22. 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 GroupOsteoporos Int 2008;19:1093-97

23. 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

24. 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

25. 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)

26. 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

27. Hip BMD as a Function of PD Status

28. Incident Hip Fracture Risk

29. 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

30. 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 GroupOsteoporos Int 2008;19:1277-82

31. 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

32. 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

33. 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.

34. 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

35. 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

37. 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

38. Why might PD be associated with osteoporosis?

39. Postulated Mechanisms for PD-Osteoporosis Association • Reduced mobility or neuromuscular function • Vitamin D deficiency • Altered estrogen level • Low weight / weight loss • Parkinson’s disease medications

40. Postulated Mechanisms for PD-Osteoporosis Association • Reduced activity or neuromuscular function • PD→reduced activity and neuromuscular function→increased bone resorption

41. 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 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)

42. 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 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)

43. Postulated Mechanisms for PD-Osteoporosis 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

44. Postulated Mechanisms for PD-Osteoporosis Association • Parkinson’s 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 2007;81:153-61.

45. What, if anything, should be done about this?

46. 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.

47. 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)

48. 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)

49. 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)

50. 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)