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Effects of Exercise & Pharmacological Therapy on Bone Density in Persons Post-Stroke Pummell, Kristen 2008

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Title Effects of Exercise & Pharmacological Therapy on Bone Density in Persons Post-Stroke Outline of Presentation • Introduction • Methods • Results • Discussion of findings • Clinical Implications • Limitations of Included studies Bone loss post stroke • BMD is decreased by 20-24%1 • Bone loss is a result of a high turn-over of bone with a disproportionate elevation of bone resorption2, 3 • Minimizing bone loss after stroke is critical in reducing the risk of fractures Mechanisms of Bone Loss post stroke • There are 4 main mechanisms that contribute to bone loss post stroke2-7: 1. Disuse due to paralysis 2. Vitamin D deficiency due to malnutrition, lack of sunlight exposure and immobilization induced hypercalcemia 3. Compensatory hyperparathyroidism 4. Vitamin K deficiency also due to malnutrition Falls and fractures • Reduced BMD makes stroke patients more susceptible to fracture resulting from falls8 • Patients with previous stroke constitute a large subgroup among patients with hip fracture – They must be considered to be of special interest in the prevention of falls and osteoporosis Falls Risk & Fracture Post-Stroke • More than 1/3 of stroke patients suffer a fall during their rehabilitation stay9 • Reasons for Falls9 – Deterioration in fall-protective reactions due to changes in intrinsic mechanisms: • Impaired balance • Postural instability • Impaired mobility • Cognitive impairment Implications of Fractures in the stroke population – Economic perspective • The incidence of hip fractures is 2-4 times higher in stroke patients compared to healthy normals9, 10 • more than 2/3 of patients experience paresis post- stroke and that fractures mainly occur on the paretic side10 • The cost of a hip fracture has been estimated as $20,000 in the first year after fracture11 – Patient perspective • Quality of Life Treatment of Low BMD Post-Stroke • Low BMD can be modified through different treatment options: •Pharmacological interventions – Bisphosphonates – Non-Bisphosphonates •Exercise therapy Pharmacological Intervention – Bisphosphonates • Bisphosphonates inhibit bone resorption through their effects on osteoclast recruitment, differentiation and action12 – Bisphosphonates in the included studies: • etidronate • risedronate • zolendronate Pharmacologic Therapy – Non-Bisphosphonates • There are numerous types of non- bisphosphonates that have been associated with effects on BMD – Non-bisphosphonates in the included studies: • Salmon calcitonin • Ipriflavone • Vitamin D • Calcium • Menatetrenone (vitamin K) Exercise Therapy • It has been shown that regular exercise is beneficial for bone health in the chronic stroke population13 • Exercise involving high impact loads positively influences skeletal bone mineral accrual and/or causes improvements in the structural characteristics of bone14,15 Knowledge Gap • There was no comprehensive systematic review investigating the effects of pharmacological and exercise interventions on BMD in the stroke population • There was a need for a systematic review to summarize the literature on the effect of pharmacological and exercise interventions on BMD post-stroke TitleMETHODS of the Review Eligibility Criteria • Pharmacological studies – Administration of a medication/supplement expected to improve BMD or to attenuate BMD loss • Exercise studies – Type and dose that could be expected to impact BMD or bone geometry – Control intervention had to be either: •Nothing, a sham/placebo •Therapy that was not expected to impact BMD or bone geometry Eligibility Criteria • Participants – Human subjects who had experienced a stroke •Acute stroke = less than one year •Chronic stroke = greater than one year • Outcome measures – Validated, reliable, and standardized measure of BMD and/or bone geometry •DXA, CXD or pQCT Study Identification • A literature search was conducted using multiple electronic databases: •OVID MEDLINE •OVID EMBASE •CINAHL •PEDro Study Identification • A grey literature search was performed with the use of: – Google – Google Scholar • Archival searches of all journals from which articles were retrieved by the original search • Exploring the references from those articles originally retrieved Qualitative Assessment • Two methods were used to evaluate each article’s quality and level of evidence: – RCTs: •PEDro scale •Sackett's modified Levels of Evidence – Non-RCTs: •Ten point scale developed using the evaluation criteria set out by the CDR •Sackett's modified Levels of Evidence Quantitative Assessment • The SES and a 95% CI were calculated for each study that contained the required information • The SES were classified as: – trivial (<0.2) – small (0.2-0.5) – medium (0.5-0.8) – large (≥0.8) TitleRESULTS Search Summary Literature search OVIDMEDLINE OVID EMBASE CINAHL 4049 Titles 33 Abstracts 19 Full text articles 12 Included studies Bisphosphonate Results • Poole et al. (2007)16 – Intervention: zoledronate – n = 14 – PEDro = 9 – Results: Intervention group • Did not experience the ↓ in BMD on the hemiplegic side • Experienced an ↑ in BMD on the non-hemiplegic side Bisphosphonate Results • Sato et al. (2005)17 females – Intervention: risedronate – n = 173 – PEDro = 9 – Results: Intervention group • Significant ↑ in BMD on the hemiplegic side (SES = 2.96) • Significant ↑ in BMD on the non-hemiplegic side (SES = 0.93) Bisphosphonate Results • Sato et al. (2005)18 males – Intervention: risedronate – n = 134 – PEDro = 8 – Results: Intervention group • Significant ↑ in BMD on the hemiplegic (SES = 3.2) • Significant ↑ in BMD on the non-hemiplegic side (SES = 0.69) Bisphosphonate Results • Sato et al. (2000)19 – Intervention: etidronate – n = 46 – PEDro = 7 – Results: • Etidronate attenuated the ↓ in BMD on the hemiplegic side  (SES = 0.66) • No significant change in BMD on the non-hemiplegic side Bisphosphonate Results • Ikai et al. (2007)20 – Intervention: etidronate – n = 35 – PEDro = 3 – Results: Intervention group • Smaller ↓ in BMD in the low ADL group on the hemiplegic side (SES = 0.84) • No significant change in BMD in the high ADL group on the hemiplegic side or in the low or high ADL group on the non-hemiplegic side Non-Bisphosphonate Results • Sato et al. (1997)21 – Intervention: 1α(OH)D3 (vitamin D3) – n = 30 – PEDro = 9 – Results: • Vitamin D3 prevented a ↓ in BMD on the hemiplegic side (SES = 0.86) • No significant changes on the non-hemiplegic side Non-Bisphosphonate Results • Uebelhart et al. (1999)22 – Intervention: salmon calcitonin – n = 11 – PEDro = 6 – Results: Intervention group • No significant difference in biochemical bone markers (BMD not measured) Non-Bisphosphonate Results • Sato et al. (1998)23 – Intervention: menatetrenone (vitamin K) – n = 51 – PEDro = 5 – Results: Intervention group • Significant ↑ in BMD on the hemiplegic side (SES = 1.01) • The intervention attenuated the ↓ in BMD on the non-hemiplegic side (SES = 0.55) Non-Bisphosphonate Results • Sato et al. (1999)24 – Intervention: ipriflavone or vitamin D3 – n = 30 and 32 – PEDro = 5 – Results: • Ipriflavone attenuated the ↓ in BMD compared to both the vitamin D3 and control groups on the hemiplegic side (SES = 0.79) • No significant difference between all groups on the non-hemiplegic side Exercise Results • Pang et al. (2005)25 – Intervention: 19 week exercise program; 3x/week – n = 30 – PEDro = 8 – Results: Intervention group • Did not experience the ↓ in BMD on the hemiplegic side (significant result) (SES = -0.11) • No significant difference in BMD on the non- hemiplegic side Exercise Results • Pang et al. (2006)26 – Intervention: 19 week exercise program; 3x/week – n = 30 – PEDro = 6 – Results: Intervention group • Significant ↑ in trabecular BMC (SES = 0.48) and cortical thickness (SES = 0.07) on the hemiplegic side • Non-significant ↑ on the non-hemiplegic side Exercise Results • Liu et al. (1999)27 – Intervention: stroke rehab exercise program; 5x/week, median length of 105.5 days – n = 80 – Cohort quality score = 9 – Results: • Discharge BMD was significantly lower than the BMD at admission for all sites except the unaffected radius, whole upper limb, and whole lower limb Exercise Results • Ikai et al. (2001)20 – Intervention: stroke rehab exercise program; 5x/week for 3 months – n = 37 – Cohort quality score = 7 – Results: • High ADL group experienced a significantly smaller ↓ in BMD compared to the low ADL group on the hemiplegic side (SES = 0.80) • No significant difference in BMD between the groups on the non-hemiplegic side TitleDISCUSSION Bisphosphonate Studies • All studies showed that either: – Treatment group experienced an increase in BMD on the hemiplegic side compared to the control group17, 18 • These studies had the largest effect sizes – Treatment group experienced a smaller decrease in BMD on the hemiplegic side compared to the control group16, 19, 20 Bisphosphonate studies • Bisphosphonate administration was also found to have an effect on the non- hemiplegic side – Three of the five studies using bisphosphonates showed an increase in BMD in the non- hemiplegic limb16-18 – Two studies reported no decrease in BMD in the intervention group when compared to controls19, 23 Bisphosphonate Studies • Implication: – bisphosphonate interventions have potential to beneficially affect bone metabolism in both the hemiplegic and non-hemiplegic side Non-bisphosphonate Studies • 75% of studies demonstrated beneficial effects of BMD on the hemiplegic side21, 23, 24 • Only 1 study found that the treatment (menatetrenone) attenuated, but did not prevent BMD loss on the non-hemiplegic side23 Non-Bisphosphonate Studies • Implication: – non-bisphosphonates appear to have the potential to maintain BMD on the hemiplegic side – non-bisphosphonates appear less able than bisphosphonates to affect BMD on the non- hemiplegic side Biochemical Markers • When both BMD & biochemical markers were measured, the markers of bone turn- over mirrored the changes in BMD on both the hemiplegic and non-hemiplegic side – approached reference values in treatment groups & remained abnormal in control groups • One study only measured biochemical markers and found no significant difference between treatment & control groups22 Challenges of Comparing Pharmacological Studies • Variety of drugs administered – each pharmacological intervention is featured in only two studies at the most, therefore not a large body of evidence to support the use of one drug over another • Variations in: – Dose – Administration route – Length of intervention Exercise studies • Two RCTs showed that BMD and/or BMC in the hemiplegic lower limb was maintained in the intervention group, while it decreased in the control group25, 26 Exercise Studies • A similar trend was seen in the cohort study carried out by Ikai et al. – participants with higher ADL functioning (and assumed higher levels of physical activity) maintained higher BMD on the hemiplegic side than participants with low ADL functioning20 • The cohort study by Liu et al. did not see a beneficial effect of the intervention on BMD – likely because exercise program was not of sufficient intensity to stimulate bone remodeling27 Exercise Studies • Implication: exercise may be able to prevent BMD loss on the hemiplegic side, but appears less able to affect BMD on the non-hemiplegic side Comparing Pharmacological & Exercise Studies • Smaller effect sizes were found for the exercise studies in comparison to the pharmacological studies •May be due to: – a difference in the effectiveness of the treatment – confounding factors such as: » lower study quality » shorter study duration » fewer participants » variations in type of exercise Comparing Pharmacological & Exercise Studies • Measurement sites varied between studies, making direct comparison difficult – Most pharmacological studies measured BMD at the second metacarpal, rather than at the hip Study Limitations • Sato et al.2-7 have found that BMD in post- stroke patients can be influenced by a number of factors including: – disuse due to paralysis – deficiencies in both vitamin D and K due to malnutrition – lack of sunlight exposure • None of the studies monitored or controlled all of these extraneous factors Study Limitations • Stroke duration:  Time since stroke for the included patients varied between the studies – Acute vs. chronic vs. strokes of varying duration • Mechanisms of bone loss may be different between these sub-populations • Response to a given treatment may vary between the groups Study Limitations • The most common BMD measurement site in the pharmacological studies was the second metacarpal using CXD • Easier and more cost effective, but the use of DXA to evaluate BMD is the current ‘gold standard’ • Since hip fracture is the outcome of interest, best evidence would be provided by using DXA to measure BMD at the hip Hip Fracture • Goal is to reduce number of fractures • The effectiveness of an intervention can be measured by BMD, but an increase in BMD is irrelevant if a fragility fracture still occurs Clinical implications • Only two of the studies in this review17, 18 used hip fracture incidence as an outcome measure as opposed to an adverse event • These two studies showed: – Number of falls was approximately the same in both the intervention group and controls – Number of fractures in the intervention group was significantly less than in the control group Hip Fracture • The remaining studies only reported hip fracture as an adverse event, rather than as an outcome measure: – In the pharmacological studies a higher incidence of hip fractures was reported in the control groups compared to the intervention groups – There were no reported fractures in the exercise studies • May be due to an improvement in fall-protective reactions and/or shorter study duration Future Directions • Need for studies that include: – long-term follow-up measurement – methodological consistency – longer duration RCTs for exercise interventions – greater number of subjects for exercise studies – clear definitions of exercise interventions – the combined effects of pharmacological & exercise interventions – hip fracture as an outcome measure Future Directions • Future studies will help determine: – potential adverse effects of pharmacological therapy – the most beneficial pharmacological treatment – ideal dosage and treatment schedules – ideal exercise parameters Conclusion • Both pharmacological and exercise treatment show promise – Based on the current literature, pharmacological treatment, especially bisphosphonates, appear to be more effective than exercise therapy in maintaining BMD post- stroke – However, exercise has benefits that stretch beyond BMD maintenance and should always be included in stroke rehabilitation Thank You • To Janice Eng and Maureen Ashe for their guidance and feedback throughout the course of this project • Thank you for your attention and don’t forget to drink your milk and weight-bear! References 1. Takamoto S, Masuyama T, Nakajima M, et al. (1995) Alterations of bone mineral density of the femurs in hemiplegia. Calcif Tissue Int 56:259-62 2. Sato Y, Fujimatsu Y, Honda Y, et al. (1998) Accelerated bone remodeling in the patients with post-stroke hemiplegia. J Stroke Cerebrovasc Dis 7(1):58-62 3. Sato Y, Kuno H, Kaji M, et al. (2000) Influence of immobilization upon calcium metabolism in the week following hemiplegic stroke. J Neuro Sci 175:135-39 4. Sato Y, Kuno H, Kaji M, et al. (1998) Increased bone resorption during the first year after stroke. Stroke 29:1373-77 5. Sato Y, Fujimatsu Y, Kikuyama M, et al. (1998) Influence of immobilization on bone mass and bone metabolism in hemiplegic elderly patients with long-standing stroke. J Neurol Sci 156:205-10 6. Sato Y, Honda Y, Kunoh H, et al. (1997) Long-term anti-coagulation reduces bone mass in patients with previous hemispheric infarction and non-rheumatic atrial fibrillation. Stroke 28:2390-94 7. Sato Y, Maruoka H, Oizumi K, et al. (1996) Vitamin D deficiency and osteopenia in the hemiplegic limbs of stroke patients. Stroke 27:2183-87 8. Demirbag D, Ozdemir F, Kokino S, et al. (2005) The relationship between bone mineral density and immobilization duration in hemiplegic limbs. Annals of Nuclear Medicine 19(8):695–700 9. Nyberg L, Gustafson Y (1995) Patient falls in stroke rehabilitation: a challenge to rehabilitation strategies. Stroke 26(5): 838-42 10. Ramnemark A, Nyberg L, Borssen B, et al. (1998) Fractures after stroke. Osteoporos Int 8:92-95 References 11. Ramnemark A, Nilsson M, Borssen B, et al. (2000) Stroke, a major and increasing factor for femoral neck fractures. Stroke 31(7): 1572-77 12. Brown JP, Josse RG (2002) 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 167: S1-S34 13. Pang MYC, Eng JJ, Dawson AS, et al. (2005) A community-based fitness and mobility exercise program for older adults with chronic stroke: a randomized controlled trial. J Am Geri Society 53:1667-74 14. Adami S, Gatti D, Braga V, et al. (1999) Site-specific effects of strength training on bone structure and geometry of ultradistal radius in postmenopausal women. Journal of Bone Mineral Research 14(1):120-4. 15. Martin RB, Burr DB (1989) Structure, Function and Adaptation of Compact bone. Raven; New York 16. Poole KES, Loveridge N, Rose CM, et al. (2007) A single infusion of zoledronate prevents bone loss after stroke. Stroke 38:1519-25 17. Sato Y, Iwamoto J, Kanoko T, et al. (2005) Risedronate therapy for prevention of hip fracture after stroke in elderly women. Neurology 64:811-16 18. Sato Y, Iwamoto J, Kanoko T, et al. (2005) Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med 165:1743-48 19. Sato Y, Asoh T, Kaji M, et al. (2000) Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone & Min Research 15(12):2487-94 20. Ikai T, et al. (2001) Prevention of secondary osteoporosis postmenopause in hemiplegia. Am J Phys Med Rehabil 80(3):169-74 References 21. Sato Y, Maruoka H, Oizumi K (1997) Amelioration of hemiplegia-associated osteopenia more than 4 years after stroke by 1 alpha-hydroxvitamin D sub 3 and calcium supplementation. Stroke 28(4):736-39 22. Uelbelhart D, Hartman DJ, Mermillod B, et al. (1999) A. Effect of calcitonin on bone and connective tissue metabolism in hemiplegic patients: a two-year prospective study. Clin Rehabil 13:384-91 23. Sato Y, Honda Y, Kuno H, et al. (1998) Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 23(3): 291-96 24. Sato Y, Kuno H, Kaji M, et al. (1999) Effect of ipriflavone on bone in elderly hemiplegic stroke patients with hypovitaminosis D. Am J Phys Med Rehabil 78(5): 457-63 25. Pang MYC, Eng JJ, Dawson AS, et al. (2005) A community-based fitness and mobility exercise program for older adults with chronic stroke: a randomized controlled trial. J Am Geri Society 53:1667-74 26. Pang MYC, Ashe MC, Eng JJ, et al. (2006) A 19-week exercise program from people with chronic stroke enhances bone geometry at the tibia: a peripheral quantitative computed tomography study. Osteoporos Int 17:1615-25 27. Liu M, Tsuji T, Higuchi Y, et al. (1999) Osteoporosis in hemiplegic stroke patients as studied with dual-energy x-ray absorptiometry. Arch phys Med Rehabil 80:1219-26

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