DNC NEWS: Stroke, bone loss and competing theories
March 6, 2005
Subject: Newly published research forces me to revise yesterday's newsletter on bone loss after stroke
Following a stroke a person's chance of fracturing a bone leaps up to 200-400% of what it was before the stroke. There are various theories which have been proposed to explain this phenomenon. The theories keep changing which prompts this rewrite of an article I almost mailed. In addition it prompts a number of ruminations on the nature of life, religion and science.
Yesterday morning I wrote a newsletter on the relationship between vitamin D and stroke recovery which I posted to our website at: http://www.denvernaturopathic.com/news/strokeandD.html
I felt rather accomplished having sorted through the existing science and coming to a satisfactory endpoint. I set it up as a newsletter scheduled to be mailed tomorrow morning.
This morning I noticed a new article in JAMA which strongly suggests an alternative explanation; everything I wrote needs to be rethought in a new context. This happens often in science. It's not the end of the world by any means. I could pretend I didn't notice the JAMA article, few of my readers will have seen it, and left things as they were. Instead I deleted the newsletter from the mailing queue and treated myself to a cup of Arabic coffee thick as mud with cardamom and sugar. I don't drink coffee often and the pleasant buzz sparked a few interesting side ruminations.
In science we learn that the truth is rarely constant. Today's knowledge is wrong by tomorrow morning. What if the same thing happened in religion? If today we learned that He created the world in six days but tomorrow the number was revised: “The world was created in six days, but he took time off on Thursday so it was really five days….” Or “If you count the overtime he put in with Adam and Eve, it was really seven days” Or if you count the days off counted by various religions, Saturday for the Jews, Friday for the Muslims, Sunday for the Christians, Thursday for the Hindus, in fact we are looking at a four day work week and…….” You see why I don't drink coffee everyday.
Back to the question at hand.
After a stroke people are 2-4 times as likely to fracture a hip. [i] Why is that? The first and most obvious explanation is that after a stroke people are less stable on their feet, more likely to totter, fall and break something. The second theory was that after a stroke people are confined to beds for extended periods, a known cause of bone loss. This results in more brittle bones, more easily broken in routine bumps and jars. As good as these explanations sound, the real answer is proving to be more complex. I wrote last year about the relationship between vitamin D levels and hip fractures. At the time new data was suggesting that it wasn't the variation in bone mineral density produced by vitamin D that was of benefit in preventing fractures, but over the short term it was the increase in leg muscle strength that protected the elderly from falling and breaking bones.
In the last year two lines of research are suggesting two possible causes of this increase in fractures, vitamin D deficiency that predisposes people to strokes and which is worsened during recovery and elevated homocysteine levels caused by vitamin B-12 and folate deficiencies. Dr. Bloom in hearing me fret about this of course poses her favorite question, “Couldn't it be an ‘And….' situation?” As usual she is probably right but let's look at these two competing theories one at a time.
Research now shows that people recovering from strokes have less vitamin D in their bodies than do healthy people their ages. The low vitamin D level could explain why stroke patients lose bone density so fast after a stroke. Elizabeth Warburton and her colleagues working in Cambridge , England looked at 34 stroke patients, average age 72 and 96 healthy people matched in age, gender, and other characteristics. Blood samples showed that the stroke patients had one third less vitamin D in their blood than non-stroke patients. In the first months after the stroke, vitamin D concentrations were so low as to be “off the scale.” [ii]
“Off the scale” sounds rather extreme. Yet it may be so. Following a stroke a patient is typically immobilized in a hospital bed. While in bed the skeletal bones lose calcium quickly. This increases blood levels of calcium. In response to this surge of calcium, the body responds by decreasing vitamin D production. Combine this with the fact that, while bedridden, these patients get no sunlight exposure and that these people started out with low vitamin D levels, then this ‘D drop' post stroke may be enough to push one off the scale. [iii]
Are low vitamin D levels a result of the stroke or a cause of the stroke in the first place? Low vitamin D levels have been theorized as contributing to strokes by increasing parathyroid hormone levels. The level of Vitamin D in the blood seesaws with parathyroid hormone. If vitamin D levels are low, parathyroid levels increase. Elevated parathyroid hormone often causes an increase in blood pressure [iv] and thus theoretically a stroke. It may be that low vitamin D actually may be a contributing factor in strokes. [v]
It looks like vitamin D deficiency is a far bigger problem than we thought especially in older populations. Estimates have ranged as high as 60% of hospitalized patients are Vitamin D deficient. A study done in Israel suggests that even in a sunny climate almost a quarter of hospitalized patients are vitamin D deficient. [vi] Yet as high as this sounds, these may be seriously underestimating the problem. For example in the Israeli study, low vitamin D was defined as serum 25(OH) vitamin D of less than 15 ng/ml or 37.5 nmol/L. Yet Last year, in a roundtable discussion at an osteoporosis conference in Lausanne , Switzerland , the big vitamin D researchers Vieth, Holick, Heaney, and others agreed that an optimal 25-D blood concentration for most people is 75 to 80 nmol/L. (1 nmol/L = 1 ng/mL x 2.5) This “ideal” is about twice as high as the amount commonly used in studies to mark between low and adequate.
We tend to view the world through colored glasses. Obviously our regular readers realize I have been somewhat fixated on Vitamin D these last few winter months. Thus I admit I may have been noticing articles related to vitamin D and not noticing other articles. This is certainly brought home in this particular situation. On March 2, 2005 JAMA published both an article and an editorial on homocysteine and post stroke fractures.
Yoshihiro Sato, M.D., from the Mitate Hospital, Tagawa, Japan, and colleagues investigated the occurrence of hip fractures in stroke patients who were given folic acid and vitamin B12, and those who received placebo. The researchers followed 559 Japanese stroke patients, aged 65 or over, for two years. All of the study volunteers had had a stroke at least one year before the start of the study, and none was taking any medication that affected bone metabolism.
The study volunteers were randomly split into two groups. Half were given 5 milligrams of folate, a water-soluble B vitamin, and 1,500 micrograms of vitamin B12 daily for two years, while the other half received two placebo pills daily. At the end of two years, homocysteine levels in the group that received the vitamin combination were reduced by 38 percent. Six people in the treated group suffered hip fractures during the study period compared to 27 in the placebo group -- a nearly five-fold difference. [vii]
But contrast these results with those of another Japanese study on exposing stroke patients to sunlight as a treatment. In a 12-month randomized and prospective study of stroke patients, 129 stroke patients received regular sunlight exposure for 12 months, and the remaining 129 did not. At the start of the study all the patients were vitamin D deficient. Bone density increased by 3.1% in the sunlight-exposed group and decreased by 3.3% in the sunlight-deprived control group. Blood vitamin D level increased 400% in the sunlight-exposed group. Six of the 129 patients in the sunlight deprived group fractured their hips during the one year study, while only one hip fracture occurred among the patients exposed to regular sunlight. That's a six-fold difference in fracture rates. [viii]
Both of these theories are probably true, vitamin D deficiency and elevated homocysteine levels probably are both contributing factors to the higher fracture rates for stroke patients. Both angles should be considered in any patient with a stroke or at risk of stroke.
If only reconciling differences in religious belief were as simple as this.
Vitamin B-12 and folate deficiencies are major problems which are under diagnosed. Often practitioners wait for the classical neurological symptoms of frank deficiency to appear before becoming concerned. The most blatant of these symptoms are a numbness or loss of fine vibratory perception in the hands and feet that have a classic “glove and stocking” distribution in contrast to the localized distribution along specific nerves, as seen in carpal tunnel syndrome. We may see earlier signs of the deficiency: I tend to jump to suspicion whenever I see even mild elevations of the mean corpuscular volume (MCV) on routine blood work.
Given the growing body of evidence of how widespread these deficiencies are and how much they increase risk of disease and mortality we should probably start screening for them more aggressively. The old standard tests, serum B-12 and serum folate levels, are being displaced by what appear to be more accurate screens measuring homocysteine and methylmalonic acid levels in the blood.
I think this subject deserves a newsletter of its own so I will stop now.
Want to read more about vitamin D? You can certainly read our past newsletters. There is an excellent article in two parts at Science News. Go to:
Here are links to our growing collection of past articles on Vitamin D:
Vitamin D and Cancer
Vitamin D, Multiple Sclerosis and Rheumatoid Arthritis
Vitamin D prevents falling in the Elderly
Vitamin D and Cardiovascular Disease
Vitamin D and migraines, PCOS, back pain, and Seasonal Affective Disorder
Vitamin D and Diabetes
Vitamin D Testing and Dosing: how to interpet lab tests
Vitamin D Summary: conditions, testing and dosing
[i] Stroke. 2001 Jul;32(7):1673-7
Vitamin D deficiency and risk of hip fractures among disabled elderly stroke patients.
Sato Y, Asoh T, Kondo I, Satoh K.
Department of Neurology, Kurume University Medical Center , Japan . firstname.lastname@example.org
BACKGROUND AND PURPOSE: Risk of hip fracture after stroke is 2 to 4 times that in a reference population. Osteomalacia is present in some patients with hip fractures in the absence of stroke, while disabled elderly stroke patients occasionally have severe deficiency in serum concentrations of 25-hydroxyvitamin D (25-OHD) (</=5 ng/mL). To determine the effects of vitamin D status on hip fracture risk, we prospectively studied a cohort of patients with hemiplegia after stroke who were aged at least 65 years. METHODS: We compared baseline serum indices of bone metabolism, bone mineral density, and hip fracture occurrence in stroke patients with serum 25-OHD </=25 nmol/L (</=10 ng/mL; deficient group, n=88) with findings in patients from the same cohort who had 25-OHD levels 26 to 50 nmol/L (10 to 20 ng/mL; insufficient group, n=76) or >/=51 nmol/L (>/=21 ng/mL; sufficient group, n=72). RESULTS: Over a 2-year follow-up interval, hip fractures on the paretic side occurred in 7 patients in the deficient group and 1 patient in the insufficient group (P<0.05; hazard ratio=6.5), while no hip fractures occurred in the sufficient group. The 7 hip fracture patients in the deficient group had an osteomalacic 25-OHD level of <5 ng/mL. Higher age and severe immobilization were noted in the deficient group. Serum 25-OHD levels correlated positively with age, Barthel Index, and serum parathyroid hormone. CONCLUSIONS: Elderly disabled stroke patients with serum 25-OHD concentrations </=12 nmol/L (</=5 ng/mL) have an increased risk of hip fracture. Immobilization and advanced age cause severe 25-OHD deficiency and consequent reduction of BMD.
PMID: 11441218 [PubMed - indexed for MEDLINE]
[ii] Poole , K.E., E.A. Warburton, et al . 2005. A contribution to bone loss in hemiplegic stroke patients may be vitamin D deficiency. International Stroke Conference 2005. Feb. 2-4. New Orleans
[iii] Bone. 2004 Apr;34(4):710-5.
Abnormal calcium homeostasis in disabled stroke patients with low 25-hydroxyvitamin D.
Sato Y, Kaji M, Honda Y, Hayashida N, Iwamoto J, Kanoko T, Satoh K.
Department of Neurology, Kurume University Medical Center , Japan . email@example.com
Disabled elderly stroke patients occasionally have very low serum 25-hydroxyvitamin D (25-OHD), which may be due to sunlight deprivation and malnutrition. Many of such patients have very low level of serum 1, 25-dihydroxyvitamin D (1, 25-[OH]2D; calcitriol), and immobilization-induced hypercalcemia may be responsible for inhibition of renal synthesis of calcitriol. To elucidate determinants of serum 1, 25-[OH]2D levels in elderly poststroke patients, we measured serum indices of bone and calcium metabolism and metacarpal bone mineral density (BMD). Patients whose serum 1, 25-[OH]2D concentration was below the mean-3 SD of normal control subjects were defined as the low 1, 25-[OH]2D group and the rest of the patients were designated as the normal group. Mean illness duration was 59 months in the normal group and 20 months in the low group. The Barthel index (BI), which predicts the degree of immobilization, was significantly lower in the low group than in the normal group. Mean serum 1, 25-[OH]2D and 25-OHD concentrations in the normal group were 36.7 pg/ml and 4.4 ng/ml, respectively; and those in the low group were 14.2 pg/ml and 1.8 ng/ml, respectively. Multiple regression analysis identified illness duration and calcium level as independent determinants of 1, 25-[OH]2D in both groups, and PTH in the normal group and 25-OHD in the low group were additional independent determinants. BMD in stroke patients was significantly lower than that in controls, and BMD in the normal group was lower as compared to the low group. BMD correlated negatively with 1, 25-[OH]2D and PTH in the normal group, and hyperparathyroidism may contribute to reduced BMD. These results suggest that treatment of decreased bone mass in stroke patients has to be individualized according to vitamin D status and calcium homeostasis.
PMID: 15050902 [PubMed - indexed for MEDLINE]
[iv] J Clin Invest. 2002 Jul;110(2):229-38
J Clin Invest. 2002 Jul;110(2):155-6.
1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.
Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP.
Department of Medicine, University of Chicago , Chicago , Illinois 60637 , USA . firstname.lastname@example.org
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
PMID: 12122115 [PubMed - indexed for MEDLINE]
[v] Neurology. 2003 Feb 25;60(4):626-9.
Does compensatory hyperparathyroidism predispose to ischemic stroke?
Sato Y, Kaji M, Metoki N, Satoh K, Iwamoto J.
Department of Rehabilitation Medicine, Institute of Brain Science, Hirosaki University School of Medicine, Japan . email@example.com
BACKGROUND: Parathyroid hormone (PTH) is vasoactive, and the endothelium is one of the target tissues of this hormone. Hyperparathyroidism is frequently associated with hypertension. OBJECTIVE: To determine if hyperparathyroidism, which develops particularly in elderly women as a compensatory mechanism to osteoporosis, may be a risk factor for ischemic stroke. METHODS: Serum PTH levels and bone mineral density (BMD) in 107 elderly patients with ischemic stroke (>or=65 years old) were assessed on the day of onset. The control group consisted of 107 healthy volunteers matched for age and sex. RESULTS: BMD was significantly lower and serum PTH higher in female stroke patients than in control subjects; there was a negative correlation between these two measurements. One-third of the female stroke patients had a serum PTH level higher than the mean + 2 SD of the control subjects (high PTH group), and the interval between menopause and the stroke was significantly longer in the high PTH group than in the normal PTH group. Multiple logistic analyses revealed hypertension and ischemic heart disease were more prevalent in the high PTH group. BMD and PTH were normal in male stroke patients. CONCLUSION: High serum PTH level may be associated with high incidence of ischemic stroke in women, possibly through the increased incidence of hypertension.
[vi] Isr Med Assoc J. 2004 Feb;6(2):82-7
Hypovitaminosis D among inpatients in a sunny country.
Hochwald O, Harman-Boehm I, Castel H.
Department of Pediatrics, Bnei Zion Medical Center , Haifa , Israel . firstname.lastname@example.org
BACKGROUND: Hypovitaminosis D is an important risk factor for osteoporosis and its complications. Previous studies found that the incidence of hypovitaminosis D among patients in an internal medicine ward reached up to 57%. OBJECTIVE: To determine the prevalence and determinants of hypovitaminosis D among patients in internal medicine wards in a sunny country. METHODS: We measured 25-hydroxyvitamin D, parathyroid hormone and various other laboratory parameters, and assessed the amount of sun exposure, dietary vitamin D intake and other risk factors for hypovitaminosis D in 296 internal medicine inpatients admitted consecutively to the Soroka University Medical Center , which is situated in a sunny region of Israel . RESULTS: We found hypovitaminosis D (serum 25-HO-D < 15 ng/ml) in 77 inpatients (26.27%). The amount of sunlight exposure, serum albumin concentration, being housebound or resident of a nursing home, vitamin D intake, ethnic group, cerebrovascular accident and glucocorticoid therapy were all significantly associated with hypovitaminosis D. Multivariate analysis showed a significant association between hypovitaminosis D and Bedouin origin, sun exposure, vitamin D intake, and stroke. Hypovitaminosis D was also found among inpatients who reported consuming more than the recommended daily amount of vitamin D. Parathyroid hormone levels were significantly higher in patients with 25-OH-D levels below 15 ng/ml. In a subgroup of 74 inpatients under 65 years old with no known risk factors for hypovitaminosis D, we found 20.3% with hypovitaminosis D. CONCLUSIONS: Hypovitaminosis D is common in patients hospitalized in internal medicine wards in our region, including patients with no known risk factors for this condition. Based on our findings, we recommend vitamin D supplementation during hospitalization and upon discharge from general internal medicine wards as a primary or secondary preventive measure.
PMID: 14986463 [PubMed - indexed for MEDLINE]
[vii] JAMA. 2005;293:1082-1088.
Effect of Folate and Mecobalamin on Hip Fractures in Patients With Stroke
A Randomized Controlled Trial
Yoshihiro Sato , MD ; Yoshiaki Honda, MD; Jun Iwamoto , MD ; Tomohiro Kanoko, PhD; Kei Satoh , MD
Context Stroke increases the risk of subsequent hip fracture by 2 to 4 times. Hyperhomocysteinemia is a risk factor for both ischemic stroke and osteoporotic fractures in elderly men and women. Treatment with folate and mecobalamin (vitamin B12) may improve hyperhomocysteinemia.
Objective To investigate whether treatment with folate and vitamin B12 reduces the incidence of hip fractures in patients with hemiplegia following stroke.
Design, Setting, and Patients A double-blind, randomized controlled study of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year following first ischemic stroke, who were recruited from a single Japanese hospital from April 1, 2000, to May 31, 2001. Patients were assigned to daily oral treatment with 5 mg of folate and 1500 µg of mecobalamin, or double placebo; 559 completed the 2-year follow-up.
Main Outcome Measure Incidence of hip fractures in the 2 patient groups during the 2-year follow-up.
Results At baseline, patients in both groups had high levels of plasma homocysteine and low levels of serum cobalamin and serum folate. After 2 years, plasma homocysteine levels decreased by 38% in the treatment group and increased by 31% in the placebo group (P<.001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (P<.001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment vs placebo groups were 0.20 (95% confidence interval [CI], 0.08-0.50), 7.1% (95% CI, 3.6%-10.8%), and 14 (95% CI, 9-28), respectively. No significant adverse effects were reported.
Conclusion In this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B12 is safe and effective in reducing the risk of a hip fracture in elderly patients following stroke.
[viii] Neurology. 2003 Aug 12;61(3):338-42.
Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in stroke patients.
Sato Y, Metoki N, Iwamoto J, Satoh K.
Department of Rehabilitation Medicine, Institute of Brain Science, Hirosaki University School of Medicine, Japan .
BACKGROUND: The authors' previous investigations have disclosed low serum 25-hydroxyvitamin D (25-OHD) concentrations in 45 patients during long-term hospitalization following stroke (mean 5.9 ng/mL). This 25-OHD deficiency resulted from sunlight deprivation. OBJECTIVE: To evaluate the efficacy of sunlight exposure in increasing serum 25-OHD, in reducing the severity of osteoporosis in bone mineral density (BMD), and in decreasing the risk of hip fractures in chronically hospitalized, disabled stroke patients. METHODS: In a 12-month randomized and prospective study of stroke patients, 129 received regular sunlight exposure for 12 months, and the remaining 129 (sunlight-deprived) did not. RESULTS: At baseline, patients of both groups showed vitamin D deficiency. BMD increased by 3.1% in the sunlight-exposed group and decreased by 3.3% in the sunlight-deprived group (p = 0.0001). 25-OHD level increased by fourfold in the sunlight-exposed group. Six patients sustained hip fractures on the hemiplegic side in the sunlight-deprived group, and one hip fracture occurred among the sunlight-exposed group (p = 0421; odds ratio = 6.1). CONCLUSION: Sunlight exposure can increase the BMD of vitamin D-deficient bone by increasing 25-OHD concentration.
Randomized Controlled Trial
PMID: 12913194 [PubMed - indexed for MEDLINE]