Osteoporos IntDOI 10.1007/s00198-008-0573-7 Additive benefit of higher testosterone levels and vitamin Dplus calcium supplementation in regard to fall riskreduction among older men and women H. A. Bischoff-Ferrari & E. J. Orav & B. Dawson-Hughes Received: 28 September 2007 / Accepted: 3 December 2007 # International Osteoporosis Foundation and National Osteoporosis Foundation 2008 uals also took vitD+cal, the fall reduction was enhanced Summary Higher physiologic testosterone levels among (men: OR=0.16; 95% CI [0.03,0.90] / women: OR=0.15; community dwelling older men and women may protect 95% CI [0.04,0.57]). Similarly, women in the top quartile against falls, and this benefit may be further increased of dihydroepiandrosterone sulfate (DHEA-S) had a lower among those taking additional vitamin D plus calcium.
risk of falling (OR =0.39; 95% CI [0.16,0.93]). Other sex Introduction The aim of this study is to investigate sex hormones and SHBG did not predict falling in men or hormone levels and fall risk in older men and women.
Methods One hundred and ninety-nine men and 246 Conclusions Higher testosterone levels in both genders and women age 65+ living at home were followed for 3 years higher DHEA-S levels in women predicted a more than 60% after baseline assessment of sex hormones. Analyses lower risk of falling. With vitD+cal, the anti-fall benefit of controlled for several covariates, including baseline 25- higher physiologic testosterone levels is enhanced from 78% hydroxyvitamin D, sex hormone binding globulin, and to 84% among men and from 66% to 85% among women.
vitamin D plus calcium treatment (vitD+cal).
Results Compared to the lowest quartile, men and women Keywords Falls . Older individuals . Sex hormones .
in the highest quartile of total testosterone had a decreased odds of falling (men: OR=0.22; 95% CI [0.07,0.72]/women: OR=0.34; 95% CI [0.14,0.83]); if those individ- An inverse association between sex hormone levels and hip Department of Rheumatology and Institute for Physical Medicine, fracture risk has been documented [explained by benefits on bone remodeling and bone density [, Additionally, lower sex hormone levels may be associated with increased fall risk as an alternative pathway explainingelevated hip fracture risk with age. Given that falling is a primary risk factor of hip fracture among older individuals, Jean Mayer USDA Human Nutrition Research Center on Aging,Tufts University, factors that relate to falling need careful evaluation, especially if deficiencies are amendable to treatment.
Testosterone levels decline with age in both men and women and testosterone replacement may increase lean Department of Biostatistics, Harvard School of Public Health,Boston, USA body mass [] and muscle strength [] in men with lowtestosterone levels. Among healthy older men with normal to mildly decreased testosterone levels, testosterone sup- strength and functional performance were unchanged with testosterone replacement in some studies performed in men day) plus calcium (500 mg per day) on bone mineral age 65 and older [, Regarding fall risk and density and fractures Of 848 persons who were testosterone levels, observational studies have been incon- prescreened with questionnaires, 545 were invited for sistent with an inverse association documented in one screening. The final study sample was 445 subjects (199 of two prospective studies ] among older men. Whether men and 245 women). Apart from DXA measurements and higher testosterone levels reduce fall risk among women, fractures, falls were assessed throughout the trial, as well as where levels of the hormone are far lower, is unclear , sex hormone levels at baseline. The latter data were used in Bioavailable and free estradiol levels decline with age in the present analyses. All participants provided written men and women ]. While some studies found that informed consent and the study protocol was approved by estrogen therapy may enhance muscle strength in older the Investigation Review Board at Tufts University.
women [others did not find a benefit , ].
Limited data from one observational study suggested no association between estrogen levels and muscle strength orfall risk in older men or women ].
The trial enrolled healthy ambulatory older men and women DHEA-S exerts its action indirectly after its conversion age 65 or older living in the community []. The trial to androgens and estrogens in peripheral tissues. Its excluded individuals with Parkinson's disease or hemiplegia, association with falling among older individuals is unclear cancer or hyperparathyroidism. The criteria of exclusion also with two observational studies suggesting a positive included a kidney stone in the past 5 years, renal disease correlation of the hormone with muscle strength in older (serum creatinine >1.2 mg/dl), liver disease, bilateral hip men and women [Whether sex hormone binding surgery, dietary calcium intake exceeding 1500 mg/day, globulin (SHBG) is associated with falling has not been therapy with testosterone, estrogen, tamoxifen, bisphospho- explored. However, SHBG may play an important adverse nate, fluoride or calcitonin in the past two years.
role in older individuals as it increases with age andpossibly contributes to a decreased bioavailability of sex Given the scarcity of studies on the role of sex hormone Of 445 subjects who were randomized, 389 attended the 3- levels and the risk of falling in older persons, we assess the year follow-up visit and 318 were still on study medication association of baseline sex hormone levels and subsequent at the 3-year follow-up visit. For this analysis, we used all risk of falling over a 3-year follow-up. Taking advantage of the blinded intervention with vitamin D plus calcium withinthis data set, we were able to explore a possible additive benefit of higher hormone levels and treatment withvitamin D plus calcium. Vitamin D, similar to testosterone Falls were ascertained by postcards. Participants were asked and estrogen, is a steroid hormone, and previous random- to send a postcard after every fall, which was then followed ized controlled trials suggested a significant improvement by a phone call from a staff member to assess the of strength ] and reduction of falls –with vitamin circumstances of the fall. In addition, falls were ascertained D treatment. In the same data set, vitamin D plus calcium significantly reduced the odds of falling in women (odds We included all reported fall events. Falls were defined ratio [OR], 0.54; 95% confidence interval [CI], 0.30–0.97), as “unintentionally coming to rest on the ground, floor, or but not in men (OR, 0.93; 95% CI, 0.50–1.72) [If there other lower level” [Falls due to severe trauma was an additive benefit, future intervention studies targeting involving external force or vehicles were not counted as a falls may optimize sex hormone levels and vitamin D plus fall. Falling at least once was the primary outcome of the calcium intake to decrease fall risk most efficiently. Finally, we studied the association of sex hormone levels with totaland leg lean body mass.
Baseline BMI is weight in kilograms divided by height in meters squared measured at the study center. Physicalactivity included leisure, household, and occupational activity as estimated by the Physical Activity Scale for theElderly (PASE) questionnaire ]. Tobacco use and use of The Boston Stop-It trial is a 3-year double-blind random- alcoholic beverages were assessed by a questionnaire at ized controlled trial on the effect of vitamin D3 (700 IU per Comorbid conditions assessed at baseline with a ques- 8.6%, respectively. Total testosterone was measured in serum tionnaire were summarized with a comorbidity score, which using radioimmunoassay kits from Diagnostic Products Corp represents the sum of the following comorbid conditions: (Los Angeles, CA). There are no significant cross-reactions diabetes, hyperthyroidism, hypertension, cancer, low back with other natural steroids. The intra- and inter-assay CVs surgery, previous hip fracture, and stomach surgery.
were 5.9% and 8.7%, respectively. Free testosterone was Total and leg lean body mass was measured by dual- measured by the method of Hammond et al. The energy x-ray absorptiometry using a DPX-L scanner (Lunar measurement was done with centrifugal ultrafiltration and Radiation, Madison Wisconsin). The reproducibility of lean the inter- and intra-assay CVs are 8.9% and 5.2%, tissue mass measurements was 1.0% ].
On the baseline visit, venous blood was collected between We used logistic regression to evaluate the effect of quartiles 7:00 and 9:30 a.m. after the subjects had fasted for at least of sex hormone levels with the lowest quartile as the 8 hours. Plasma 25-OHD levels were measured by reference on a person’s risk of falling at least once during competitive protein binding assay, as described by Preece the 3-year follow-up. In men and women, all analyses were et al., with intra- and interassay CVs of 5.6% to 7.7% ].
controlled for age in years, baseline BMI in kg/m2 (<25, 25– All following hormones were measured in the laboratory of 29, ≥30), baseline plasma 25-OHD levels, baseline PASE the late Dr. Christopher Longcope at the University of status for physical activity assessment, baseline smoking Massachusetts in Worcester. Estrone and estradiol were status (never, current, former smoker), baseline use of measured in serum by radioimmunoassay following solvent alcoholic beverages (yes/no), baseline number of comorbid extraction and celite chromatography. The intra- and inter- conditions, treatment with vitamin D plus calcium or assay CVs for estrone were 5.0 and 10.0% and for estradiol placebo, and length of follow-up in days. The analyses for were 7.0 and 13.2%, respectively. The estradiol assay had a total testosterone, estrone and estradiol were also controlled detection level of 5 to 7 pg/ml. Androstenedione was measured in serum using radioimmunoassay kits from In addition, we compared the baseline mean total lean Diagnostic System Laboratories (Webster, TX). This anti- body mass and the baseline mean leg lean body mass body is highly specific with negligible cross-reaction with among quartiles of baseline sex hormone levels using a other steroids. The intra- and inter-assay CVs were 7.3% multiple linear regression model while adjusting for age in and 9.8%, respectively. DHEA-S was measured in serum years, baseline BMI in kg/m2 (<25, 25–29, ≥30), baseline using radioimmunoassay kits from ICN Biomedical (Costa- plasma 25-OHD levels, baseline PASE, baseline smoking Mesa, CA) with relatively high cross-reactions, 30%–60%, status (never, current, former smoker), baseline use of with dehydroepiandrosterone and androstenedione. Since alcoholic beverages (yes/no) and baseline number of DHEA-S circulates at levels at least 1,000 times those of the comorbid conditions. Least square means were used to other two steroids, this cross-reaction does not interfere with express the adjusted mean and percent difference in lean the assay. The intra- and inter-assay CVs were 4.3% and body mass by quartiles of sex hormone levels.
Table 1 Characteristics of thestudy population All analyses were conducted with SAS (Version 8.2; SAS in the highest quartile of total testosterone with serum Institute Inc., Cary, NC, USA). All p-values were two-sided.
levels of 5.68 ng/ml or above had a 78% decreased odds offalling compared to men in the lowest quartile with totaltestosterone levels of 3.77 ng/ml or less (OR=0.22; 95% CI [0.07,0.72]). There was a significant trend between a lowerodds of falling and higher total testosterone levels (p= Baseline characteristics by sex are displayed in Table 0.005). See Fig. for exact boundaries of quartiles and While mean age was the same for men and women, women were less physically active, had lower 25-hydroxyvitamin Among women, similar to men, there was a significant D levels and were less likely to be ever smokers. Hormone trend between a lower odds of falling and higher testosterone levels, differed by sex significantly with one exception, levels (p=0.03). Women in the top quartile of testosterone estrone. Overall, 49% (97) of men and 57% (134) of with serum levels of 0.49 ng/ml and above had a 66% women fell during the 3-year follow-up.
decreased risk of falling compared to those in the lowestquartile with serum levels of 0.20 ng/ml or less (OR=0.34; 95% CI [0.14,0.83]). See Fig. for exact boundaries ofquartiles and illustration of the observed trend.
Among men, total testosterone levels independent of SHBG Also, women in the top quartile of DHEA-S had a 61% were significantly associated with the odds of falling. Men lower risk of falling compared to those in the lowest OR (95% CI) 0.75
Quartiles of total testosterone
OR (95% CI) 0.75
Quartiles of total testosterone
Fig. 1 Odds of falling by quartile of total testosterone in men and in women (test for trend: p=0.03) suggesting a decrease in the odds of women. Independent of age, body mass index, physical activity, falling with higher testosterone levels. In a comparison of the two SHBG levels, 25(OH)D levels, vitamin D plus calcium treatment, extreme quartiles, men in the highest quartile had a 78% and women number of comorbid conditions, smoking and alcohol consumption, had a 66% lower odds of falling. Results were similar with or without there was a significant trend in men (test for trend: p=0.005) and quartile (OR=0.39; 95% CI [0.16,0.93] (see Table There vitamin D plus calcium supplementation on fall prevention in appeared to be a threshold effect with a benefit in all Table Among men and women, there was an additional women reaching serum levels of above 0.30 μg/ml, the benefit of being in the sex-specific top quartile of serum upper end of the lowest quartile. Among men, there was a testosterone plus being randomized to vitamin D and calcium.
similar directionality with a decreased risk of falling withhigher DHEA-S levels. However, this was not significant.
Estrone, estradiol, free testosterone, androstenedione, and SHBG were not significantly associated with the odds There was a significant inverse association between baseline total and leg lean body mass, and quartiles of As this was a double-blind RCT with vitamin D plus SHBG in both men and women (see adjusted means in calcium compared to placebo ], we were able to explore a Fig. and b). All sex hormones were not appreciably possible additive benefit of higher testosterone levels and Table 2 Odds of falling across quartiles of estradiol, DHEA-S, and SHBG Effect women OR [95% CI] p-value for trend All analyses controlled for age, baseline BMI, baseline plasma 25-OHD levels, baseline PASE status for physical activity assessment, baselinesmoking status, baseline use of alcoholic beverages, baseline number of comorbid conditions, treatment with vitamin D plus calcium or placebo,and length of follow-up in days. Similar to estrone, there was no significant association between the odds of falling and estradiol andandrostenedione levels*p-value for trend test. **Significantly different from reference Table 3 Effect of higher testosterone levels on falling by vitamin D + calcium supplementation Sex-specific total testosterone quartiles All analyses controlled for age, baseline BMI, baseline plasma 25-OHD levels, baseline PASE status for physical activity assessment, baseline smokingstatus, baseline use of alcoholic beverages, baseline number of comorbid conditions, and length of follow-up in days. Our data suggest an additivebenefit of high testosterone levels and vitamin D (700 IU per day) plus calcium (500 mg per day) supplementation in older men and women density in men ] and women ], higher estrogen levelsmay not protect from falls in either sex.
We found that fall risk declines with higher physiological We found that higher DHEA-S levels may reduce the testosterone levels among older ambulatory men and odds of falling by 61% in women and there appeared to be women independent of age, SHBG levels, body mass a similar direction in men. Our study adds to the literature index, physical activity, smoking, alcohol consumption, suggesting that higher physiological levels, above 0.31 μg/l, number of comorbid conditions, vitamin D plus calciumtreatment, and length of follow-up. Men and women in thetop quartile of sex specific testosterone levels had a 78% respectively 66% lower risk of falling compared to individuals in the lowest quartile. This benefit was augmented if individuals in the top quartile had additional vitamin D plus calcium supplementation. In this subgroup fall risk was reduced by 84% in men and 85% in women.
The additional benefit of vitamin D plus calcium may be explained by evidence from several randomized controlled trials showing that vitamin D supplementation reduces the adjusted leg lean mass (SE)
risk of falls in older individuals by enhancing muscle strength and balance , , , From a clinical perspective the possible additive benefit of higher physio- Quartiles of SHBG
logic testosterone levels and vitamin D plus calcium supplementation is of interest as the additional benefit appears to be significant, applies to both sexes, and both *
components can be altered by treatment. In fact, in our earlier analyses of the RCT, which did not take testosterone levels into consideration, vitamin D plus calcium reduced falls among women (OR =0.54; 95% confidence interval [CI], 0.30–0.97), but not in men (OR=0.93; 95% CI, 0.50– *
1.72) compared to placebo ]. Thus, especially among men, the additional correction of testosterone levels to theupper end of the physiologic range may be important.
Adjusted lean total body mass (SE)
There was no association between estrogen levels and falls in either sex. Our findings are consistent with two Quartiles of SHBG
prospective cohort studies, which did not find an associa- Fig. 2 a Adjusted mean baseline leg. b Total body lean mass byquartiles of baseline SHBG. Mean adjusted lean mass by quartiles of tion between estrogen levels and incident falls among older SHBG is adjusted for age, physical activity, 25(OH)D levels, number men ] or women ]. Furthermore, one double- of comorbid conditions, smoking and alcohol consumption. P-values blind randomized controlled trial with falls as the outcome for comparison of quartiles with reference quartile (bottom quartile for did not find a protective effect of hormone replacement SHBG): *<0.05, **<0.001. Among men, the test for trend wassignificant for total body (p=0.005) and leg (0.03) lean mass. Among therapy in ambulatory older women [Thus, in contrast women, the test for trend was significant among women for total body to the previously documented benefit of estrogen on bone may be beneficial for fall prevention in women. Additional levels, as this may be sufficient for fall prevention data are needed in both men and women.
according to our results. The combined benefit of higher There was no association of the directly measured free testosterone and vitamin D plus calcium appears to be testosterone on falls in both genders. Physiologically, it is expected that free testosterone reflects the bioavailable part Based on our cross-sectional findings, body composition of total testosterone that enters the cells and is most is not associated with sex hormones but SHBG levels. Lean sensitive to outcomes, such as falls. However, it has been mass was highest among men and women with low SHBG suggested that measurement of free testosterone may levels. Thus, factors that impact on SHBG status may need present with difficulties or may not best represent the bioavailable fraction of testosterone ]. Alternatively, wecontrolled for SHBG when assessing the benefits oftestosterone, which may approximates the truly bioavailable fraction of testosterone. Androstenedione levels and SHBGlevels were not associated with falling in men or women.
Only SHBG showed a significant inverse association with total and leg lean body mass in men and women.
Specifically, based on our adjusted results, men in the topquartile of serum SHBG concentrations had a 6% lower leg This study was supported by a grant from the lean mass and women in the top quartile had a 9% lower Charles H. Farnsworth Trust, Boston, Mass (US Trust Company,trustee), and by grant AG10353 from the National Institutes of Health, leg lean mass. Higher SHGB levels have previously been Bethesda, Md, and a Swiss National Foundation Professorship Grant.
identified as a risk factor for hip fractures in the Study of Role of the Sponsors: No sponsors participated in the design and Osteoporotic Fracture (SOF) [Our results support these conduct of the study; in the collection, analysis, and interpretation of findings indirectly, as low leg lean body mass is a correlate the data; or in the preparation, review, or approval of the manuscript.
of quadriceps weakness [and poor structural parametersof bone [which are risk factors for hip fractures ].
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