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Effects of Exercise & Pharmacological Therapy on Bone Density in Persons Post-Stroke Pummell, Kristen; Lammers, Steven; Dewailly, Tim; Kurtakis, Melina; Mattiello, Christina Aug 21, 2008

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Effects of Exercise & Title 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 poststroke 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 nonbisphosphonates 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  Title METHODS 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)  Title RESULTS  Search Summary Literature search OVID MEDLINE  OVID EMBASE 4049 Titles 33 Abstracts 19 Full text articles 12 Included studies  CINAHL  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 nonhemiplegic 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  Title DISCUSSION  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 nonhemiplegic side – Three of the five studies using bisphosphonates showed an increase in BMD in the nonhemiplegic 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 nonhemiplegic side  Biochemical Markers • When both BMD & biochemical markers were measured, the markers of bone turnover 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 poststroke 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 poststroke – 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. 2. 3. 4. 5. 6. 7. 8. 9. 10.  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 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 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 Sato Y, Kuno H, Kaji M, et al. (1998) Increased bone resorption during the first year after stroke. Stroke 29:1373-77 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 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 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 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 Nyberg L, Gustafson Y (1995) Patient falls in stroke rehabilitation: a challenge to rehabilitation strategies. Stroke 26(5): 838-42 Ramnemark A, Nyberg L, Borssen B, et al. (1998) Fractures after stroke. Osteoporos Int 8:92-95  References 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.  Ramnemark A, Nilsson M, Borssen B, et al. (2000) Stroke, a major and increasing factor for femoral neck fractures. Stroke 31(7): 1572-77 Brown JP, Josse RG (2002) 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 167: S1-S34 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 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. Martin RB, Burr DB (1989) Structure, Function and Adaptation of Compact bone. Raven; New York Poole KES, Loveridge N, Rose CM, et al. (2007) A single infusion of zoledronate prevents bone loss after stroke. Stroke 38:1519-25 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 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 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 Ikai T, et al. (2001) Prevention of secondary osteoporosis postmenopause in hemiplegia. Am J Phys Med Rehabil 80(3):169-74  References 21. 22. 23. 24. 25. 26. 27.  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 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 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 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 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 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 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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