Osteoporos Int (2005) 16: 302–305 DOI 10.1007/s00198-004-1682-6 O R I GI N A L A R T IC L E Rapid long-term bone loss following stroke in a man with osteoporosis and atherosclerosis Kenneth E. S. Poole Æ Elizabeth A. Warburton Jonathan Reeve Received: 15 December 2003 / Accepted: 19 May 2004 / Published online: 10 June 2004 Ó International Osteoporosis Foundation and National Osteoporosis Foundation 2004 Abstract Bone loss in humans has been reported where there is reduced mechanical loading such as in space flight, spinal cord injury, and stroke. Whether osteoporotic patients are susceptible to further bone loss in states of underloading such as hemiparesis is unknown. Here we report the case of a 64-year-old man with established idiopathic osteoporosis and atherosclerosis who presented with a right middle cerebral artery territory stroke. Annual bone mineral density measurements were made at the left hip and spine before and after left hemiparesis. The left total hip T-score was )3.2 before the stroke. Following stroke, there was rapid and sustained bone loss with a reduction in bone mineral density (BMD) of 21.6% over 3 years despite oral bisphosphonate therapy. There was also an unexpected decline in vertebral BMD after the stroke. This is the first report of the accelerated effect of hemiplegia on bone loss in an already osteoporotic skeleton. Keywords Bone densitometry Æ Hemiplegia Æ Male osteoporosis Æ Mechanical loading Æ Stroke Introduction A combination of secondary bone loss, increased falls, and impaired protective arm reflexes leads to an increased risk of hip fractures, greatest in the 1st year K.E.S. Poole (&) Æ J. Reeve MRC Bone Research Group, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Level 5, Box 157, Cambridge, CB2 2QQ, UK E-mail: kesp2@cam.ac.uk Tel.: +44-1223-330104 Fax: +44-1223-330105 E.A. Warburton Department of Stroke Medicine, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK following stroke [1, 2]. A reduction in bone mineral density (BMD) following stroke has been widely reported, particularly during that 1st year [3]. Osteoporosis and vascular diseases often coexist [4], and the association between the conditions continues to generate interest [5]. However, no studies to date have reported how patients with osteoporosis respond to the skeletal challenge of hemiplegia. The case history that follows illustrates the potential for accelerated bone loss following hemiplegia in a patient who was already osteoporotic. Materials and methods BMD testing was performed annually for 5 years using the Lunar Expert densitometer (GE Lunar, Madison, WI, USA) in the Metabolic Bone Unit at Addenbrooke’s Hospital. The sites reported were the total hip region and the L3 vertebra only (due to fractures at other levels). The operator 1-year precision error in healthy controls is as follows: total hip, 2%; lumbar spine L3 vertebra, 2%; giving least-significant changes of 5.6% at either site per year. Where T-scores are presented, the reference range is the Lunar UK Femur male reference population, young adult ages 20–40. Case report A 60-year-old man was under investigation in the metabolic bone disease clinic for episodes of severe lumbar back pain. The pain had occurred suddenly on coughing and gradually improved over a 6 week period. He had felt a similar pain 8 years previously while lifting a heavy container. Spinal X-rays were graded using a semiquantitative method [6]. This confirmed a grade 3 crush fracture of L5, with other fractures evident at T6, T11, L1, L2 (all grade 1 anterior wedge) and L4 (grade 1 biconcave) [6]. Figure 1 is a plain lateral radiograph of the lumbar spine. Past medical history included myocardial infarc- 303 90-day cycle, 400 mg daily for 14 days followed by 76 days of calcium carbonate 1.25 g/day. He reported strict compliance with his medication. Between the years 1998 and 1999, BMD remained stable, with an upward trend at L3, but no change in the total hip BMD. There were no further clinical or radiological fractures. In May 2000, the patient developed a sudden leftsided weakness. On examination there was evidence of left arm and leg weakness, left hemianopia, dysphagia, and left hemineglect. A CT brain scan illustrated a hypodense area consistent with cerebral infarction in a right middle cerebral artery distribution. Ultrasound of the carotid arteries revealed a completely occluded right internal carotid artery. There followed a period of 5 months of inpatient rehabilitation on the stroke unit. Persistent hemineglect was a significant factor complicating recovery. At the time of discharge (October 2000) he was still wheelchairdependent for most of the day, weight-bearing only to transfer and while washing. Etidronate was stopped directly after the stroke because of dysphagia and concern over the risks of aspiration as well as esophageal dysmotility. Etidronate was recommenced in clinic 5 months after the stroke. Alendronate 70 mg (Fosamax Once Weekly, MSD) replaced etidronate in August 2001 (due to decreasing BMD), and calcium supplementation continued. Results Fig. 1 Lateral X-ray of the lumbar spine indicating vertebral fractures at L2, L4, and L5. L3 vertebra is preserved. Note the aortic calcification anterior to L4 and L5 tion (1985), mild chronic obstructive pulmonary disease (no history of inhaled or oral corticosteroid use), and intermittent claudication with angiographic evidence of bilateral femoral artery atherosclerosis (1998). He had been a cigarette smoker (30 pack years) but stopped in 1985. He was investigated for secondary causes of osteoporosis and vertebral fracture, but none was found. In particular, there was no evidence of hyperthyroidism, liver disease, malabsorption, myeloma, osteomalacia, or hypogonadism. Corrected calcium, phosphate, and alkaline phosphatase were in the middle of the normal range. He had a good diet and an active manual laboring job outdoors . His body mass index was 20.5 kg/m2 (18.5–24.9). A bone scintigram indicated increased isotope uptake at L1 only, consistent with recent vertebral collapse. A Lunar Expert dual-energy X-ray absorptiometry (DXA) scan confirmed established osteoporosis at the lumbar spine and left total hip region. Only the L3 vertebra was analyzed in view of the prevalent fractures elsewhere in the lumbar spine. At L3 the BMD was 0.822 g/cm2 (T-score )3.5). Total hip BMD was 0.680 g/ cm2 (T-score )3.20). Disodium etidronate (Didronel PMO; Proctor and Gamble) was commenced on a DXA scanning of the affected left hip continued annually after the stroke. The total hip BMD of the hemiplegic lower limb decreased precipitously, by a total of 21.6% over the period of investigation despite antire- Fig. 2 Bone mineral density (left total hip and L3 vertebra) in a man with idiopathic osteoporosis pre- and post-stroke 304 sorptive therapy. Figure 2 is a plot of T-score at the hip and L3 vertebra against year. At L3 vertebra there was a steep decline in BMD, but after commencing alendronate there was an increase of 3.8%. Annual percentage change in BMD at total hip, femoral neck, and L3 vertebra are presented in table form (Table 1). At 1 year, corrected calcium, phosphate, and alkaline phosphatase remained normal. Serum vitamin D was 6.3 lg/l (seasonally adjusted normal range for East Anglian adults 10–54 lg/l), and 800 IU colecalciferol with calcium (Calcichew D3 Forte; Shire) replaced calcium alone. His weight decreased in the year following stroke, from 54 kg to 48.1 kg (BMI 18.7 kg/m2), but in the subsequent year had recovered to 57.4 kg (BMI 21.6 kg/m2). Discussion The case presented is interesting since it is the first report of the effect of hemiplegia on bone loss in an already osteoporotic skeleton. The most striking observations are the rapidity of the bone loss at the hip and vertebra, and that the loss of hip BMD has continued beyond 2 years despite treatment with oral antiresorptives (albeit interrupted for 5 months). The patient also demonstrated stable BMD prior to the stroke, data which has not been available from observational studies to date. Immediately following stroke, patients have lower BMD when compared with age-matched controls [4] but having a low BMD did not predict stroke in men or women [7]. Several studies of stroke have concluded that BMD falls in the hemiplegic limbs, particularly within the 1st year [8, 9]. BMD reduction at the hip is greatest in patients (such as the patient described) who do not bear weight or relearn to walk within the first 2 months after stroke [10]. The lower half of the femoral neck (which is loaded by repetitive compressive forces during a normal gait cycle) seems particularly vulnerable to the effects of hemiplegia [10]. In this patient, this localized bone loss occurred in the setting of reduced nutrition, hypovitaminosis D, and widespread atherosclerosis. An unexpected finding is the rapid loss of bone from the spine after the stroke. The few studies that have examined vertebral BMD after stroke [8, 11] did not report bone loss at this site. These investigators determined vertebral BMD from whole body DXA scans and not region-specific lumbar spine BMD measurements, so further work may be necessary. To explain the rapidity of the spine BMD loss in the case described, it is important to remember that the recovery of walking function was very much delayed, such that the patient was bed or chair-bound for 5 months and did not receive bisphosphonate during that time. Generalized bone loss (including the spine) in this patient may also have been associated with poor nutrition which led to a 6-kg reduction in weight in the year following the stroke [12]. It is interesting to consider the relative contributions of atherosclerosis to osteoporosis in this patient who (before his stroke) had angiographic evidence of bilateral femoral artery atherosclerosis and coronary atherosclerosis (myocardial infarction). Ultrasound evidence of carotid occlusion post-stroke also implied pre-stroke carotid atherosclerosis. The patient presented originally with a clinical vertebral fracture, with further incident fractures discovered on radiological examination. Osteoporotic vertebral fractures in men share certain risk factors with stroke and atherosclerosis, such as reduced physical activity [13], excessive alcohol consumption [14, 15], smoking [15, 16], and poor calcium intake [17]. Where associations between osteoporosis and stroke do exist (as shown in epidemiological studies), they may be due to these shared risk factors and/or common pathophysiological processes. As an example, peripheral vessel atherosclerosis can influence bone metabolism directly. Men with symptomatic atherosclerotic occlusion of one leg have reduced BMD in the affected femoral neck and trochanter (independently of smoking and body mass index) [5]. A negative correlation between the degree of carotid atheroma (in postmenopausal women) and total body BMD has also been reported [18]. The main novel aspects of this case are the rapidity of the bone loss, its duration after hemiplegia and the concomitant loss at L3 vertebra. With this degree of hemiplegia and loss of function, one would expect to see a roughly 5–10% loss in BMD at the total hip within 6 months which begins to plateau at 12 months [9]. In addition to the initial prolonged bed rest, muscular dysfunction, poor nutrition, and reduced ipsilateral Table 1 Annual change in BMD at hip and spine in g/cm2 and in percentage change Year Left total hip BMD, g/cm 1998 1999 2000a 2001 2002 Overall % change a 0.680 0.671 0.616 0.585 0.533 Stroke occurred in May 2000 2 Left femoral neck % per year BMD, g/cm 0 )1.3 )8.1 )4.6 )7.6 )21.6 0.545 0.540 0.508 0.485 0.452 2 L3 vertebra % per year BMD, g/cm2 % per year 0 )0.9 )6.8 )4.2 )6.0 )17.0 0.822 0.838 0.730 0.713 0.735 0 +1.95 )13.15 )2.1 +2.7 )10.6 305 weight-bearing, it is possible that the vitamin D insufficiency and coexisting arterial disease could have contributed to the severity and profundity of the bone loss. Region-specific bone loss after stroke may be explained in part by altered blood flow in hemiplegic bones [19], and those with arterial insufficiency may be at greater risk. Vitamin D insufficiency is also common following stroke [20] and is associated with low BMD in the hemiplegic finger [21] and post-stroke hip fracture [22]. There are additional subtler derangements of the vitamin D / parathyroid hormone axis following stroke which have been implicated in bone loss [23, 24]. This case serves as a reminder of the potential for vitamin D insufficiency to occur following stroke, as sunlight exposure and diet can be inadequate. One would expect bisphosphonates to be successful in attenuating bone loss after stroke [2], and yet the study patient had a 6% decrease in BMD in the hemiplegic hip after commencing oral alendronate. In a randomized placebo-controlled study of oral etidronate versus placebo treatment in 93 patients with acute stroke, oral etidronate more than halved the reduction in BMD observed at the hemiplegic metacarpal ()2.3% ±0.3 SD) when compared with placebo ()4.8% ±0.7 SD) at 1 year [25]. Reasons why alendronate might not have been effective in this patient include poor compliance with therapy or timing of administration and a mineralization defect as a result of unaddressed vitamin D insufficiency. Conclusion This case demonstrates the potential adverse effects of stroke on the adult skeleton in established osteoporosis, with a profound reduction in BMD in the hip of the hemiplegic lower limb in the setting of widespread atherosclerosis. More work is necessary to understand the mechanisms determining individual skeletal responses to hemiplegia. Acknowledgements K.E.S.P. has a fellowship from the National Osteoporosis Society and the Sackler Foundation. E.A.W. is supported by the Stroke Association, the Health Foundation, and the National Osteoporosis Society. References 1. Kanis J, Oden A, Johnell O (2001) Acute and long-term increase in fracture risk after hospitalization for stroke. Stroke 32:702–706 2. Poole KE, Reeve J, Warburton EA (2002) Falls, fractures, and osteoporosis after stroke: time to think about protection? Stroke 33:1432–1436 3. Hamdy RC, Moore SW, Cancellaro VA, Harvill LM (1995) Long-term effects of strokes on bone mass. Am J Phys Med Rehabil 74:351–356 4. Jorgensen L, Engstad T, Jacobsen BK (2001) Bone mineral density in acute stroke patients: low bone mineral density may predict first stroke in women. Stroke 32:47–51 5. Laroche M, Moulinier L, Leger P, Lefebvre D, Mazieres B, Boccalon H (2003) Bone mineral decrease in the leg with unilateral chronic occlusive arterial disease. Clin Exp Rheumatol 21:103–106 6. Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148 7. Mussolino ME, Madans JH, Gillum RF (2003) Bone mineral density and stroke. Stroke 34:E20–22 8. Ramnemark A, Nyberg L, Lorentzon R, Englund U, Gustafson Y (1999) Progressive hemiosteoporosis on the paretic side and increased bone mineral density in the nonparetic arm the first year after severe stroke. Osteoporos Int 9:269–275 9. Jorgensen L, Jacobsen BK, Wilsgaard T, Magnus JH (2000) Walking after stroke: does it matter? Changes in bone mineral density within the first 12 months after stroke: a longitudinal study. Osteoporos Int 11:381–387 10. Jorgensen L, Crabtree NJ, Reeve J, Jacobsen BK (2000) Ambulatory level and asymmetrical weight bearing after stroke affects bone loss in the upper and lower part of the femoral neck differently: bone adaptation after decreased mechanical loading. Bone 27:701–707 11. Hamdy RC, Krishnaswamy G, Cancellaro V, Whalen K, Harvill L (1993) Changes in bone mineral content and density after stroke. Am J Phys Med Rehabil 72:188–191 12. Hannan MT, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson PW, Kiel DP (2000) Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res 15:710–720 13. Gillum RF, Mussolino ME, Ingram DD (1996) Physical activity and stroke incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 143:860–869 14. Palomaki H, Kaste M (1993) Regular light-to-moderate intake of alcohol and the risk of ischemic stroke: is there a beneficial effect? Stroke 24:1828–1832 15. Scane AC, Francis RM, Sutcliffe AM, Francis MJ, Rawlings DJ, Chapple CL (1999) Case-control study of the pathogenesis and sequelae of symptomatic vertebral fractures in men. Osteoporos Int 9:91–97 16. Whisnant JP, Wiebers DO, O’Fallon WM, Sicks JD, Frye RL (1996) A population-based model of risk factors for ischemic stroke: Rochester, Minnesota. Neurology 47:1420–1428 17. Abbott RD, Curb JD, Rodriguez BL, Sharp DS, Burchfiel CM, Yano K (1996) Effect of dietary calcium and milk consumption on risk of thromboembolic stroke in older middle-aged men. The Honolulu Heart Program. Stroke 27:813–818 18. Uyama O, Yoshimoto Y, Yamamoto Y, Kawai A (1997) Bone changes and carotid atherosclerosis in postmenopausal women. Stroke 28:1730–1732 19. Van Ouwenaller C, Uebelhart D, Chantraine A (1989) Bone metabolism in hemiplegic patients. Scand J Rehabil Med 21:165–170 20. Sato Y, Kuno H, Asoh T, Honda Y, Oizumi K (1999) Effect of immobilization on vitamin D status and bone mass in chronically hospitalized disabled stroke patients. Age Ageing 28:265– 269 21. Sato Y, Maruoka H, Oizumi K, Kikuyama M (1996) Vitamin D deficiency and osteopenia in the hemiplegic limbs of stroke patients. Stroke 27:2183–2187 22. Sato Y, Asoh T, Kondo I, Satoh K (2001) Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients. Stroke 32:1673–1677 23. Sato Y, Kaji M, Saruwatari N, Oizumi K (1999) Hemiosteoporosis following stroke: importance of pathophysiologic understanding and histologic evidence. Stroke 30:1978–1979 24. Sato Y, Oizumi K, Kuno H, Kaji M (1999) Effect of immobilization upon renal synthesis of 1,25-dihydroxyvitamin D in disabled elderly stroke patients. Bone 24:271–275 25. Sato Y, Asoh T, Kaji M, Oizumi K (2000) Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner Res 15:2487–2494