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Department of Internal Medicine and Biomedical Sciences (G.Pa., R.V., P.S., M.Pa., R.D., M.Pe.), University of Parma, 43100 Parma, Italy; Department of Experimental Pathology (G.Pi., C.F.), University of Bologna, 40126 Bologna, Italy; Italian National Research Center for Aging (C.F.), 60121 Ancona, Italy; Department of Biomedical Sciences (L.T.), University of Modena, 41100 Modena, Italy; and Department of Statistical Sciences (P.G.), University of Bologna, 40126 Bologna, Italy
Address all correspondence and requests for reprints to: Giovanni Passeri, M.D., Department of Internal Medicine and Biomedical Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: gpasseri{at}unipr.it.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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In the elderly, insufficient UV exposure and low dietary intake of both calcium and vitamin D are very common (9, 10, 11). Low circulating levels of calcitriol can be due to an impairment of renal conversion of 25-hydroxyvitamin D (25-OH vitamin D) to the active form (1,25-dihydroxyvitamin D). This may worsen the senile intestinal resistance to the vitamin due to the reduced number of vitamin D receptors, impaired binding of vitamin D to the vitamin D receptors, or postreceptorial defects (12). All of the above are often present in elderly subjects, inducing low serum calcium levels and increased PTH secretion and resulting in a negative bone balance.
It has also been shown that calcium supplementation can reduce bone loss in middle-aged postmenopausal women and lower the rates of new vertebral fractures in those with preexisting vertebral crushes (10). Moreover, dietary supplementation of calcium and vitamin D in elderly females (13) and in males and females aged 65–77 yr (14) has led to a reduction of nonvertebral fractures.
Considering the rapidly increasing average life expectancy, not only in the industrialized countries, the maintenance of self-sufficiency in the oldest olds is an extremely important goal. Those that reach an age close to the estimated limit of the human life span are unique models for studying the peculiar aspects of extreme longevity. In this regard, centenarians can be considered examples of successful aging. During the past decade, several interesting observations have emerged regarding peculiar neuroimmunoendocrine mechanisms and genetic aspects in these subjects (15, 16, 17, 18, 19, 20, 21, 22). However, little is known regarding bone status and metabolism of centenarians, despite the importance of prevention of fractures and disability in this frail population.
In this cross-sectional study, we considered bone status, mineral metabolism, and fractures in a group of centenarians. Our aim was to evaluate whether specific aspects of mineral metabolism in extreme longevity could offer suggestions, besides the prevention of falls, for preventing new fractures and the risk of disability. The peculiarities of centenarians can provide suggestions usable as preventive tools for the fast-growing elderly general population.
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Subjects and Methods |
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The study was performed between December 1998 and December 1999. The registry office lists of the provinces of Mantova and Parma, Italy (45° parallel North) reported at that time 266 subjects (221 females and 45 males) above 98 yr of age. The study protocol was approved by the committee on Human Research of the University of Parma. The subjects were recruited after a standardized procedure previously used (22). We were able to contact approximately half of the subjects through mail or by phone, and then through direct contact with the family and the family physician. Entry criteria included age above 98 yr (confirmed by a valid ID) and absence of acute illness in the previous 3 months; subjects were evaluated irrespective of chronic health situation (Table 1
) or level of self-sufficiency. We therefore studied 104 subjects ages 98–105 yr (90 females and 14 males) (Table 1). Median age was 100 yr, and subjects will be referred to as centenarians.
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Detailed information regarding all bone fractures sustained in their life, time of each event, and dynamic of the fracture was recorded to assess whether the event could be related to bone fragility or to major trauma. We also evaluated fracture risk factors, such as instability and tendency to fall.
A thorough physical/functional examination was performed (height, weight, blood pressure, pulse rate, sight and hearing ability). We performed a Mini-Mental State Examination (MMSE) and geriatric depression scale (23, 24, 25, 26). Physical function was evaluated using performance-based measures, such as the Epidemiologic Studies in the Elderly short battery, that integrate the following tests: rising from a chair, timed walk over 4.5-m course, and capacity to maintain balance in progressively more challenging standing position (balance tests) (27).
Biochemical parameters
Fasting peripheral blood was drawn from 0800–1000 h; 20–30 ml were collected and delivered within 2 h to the laboratory of the investigating centers (Parma or Modena university hospitals). Routine hematological and clinical chemistry tests [glucose, total cholesterol, triglycerides, serum proteins, albumin, 
-glutamyl transferase (GT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total alkaline phosphatase, creatinine] were performed using routine methods. An estimate of creatinine clearance was calculated using the Cockcroft-Gault formula. Plasma or serum was stored at -80 C for further evaluation. Serum PTH(1–84) and 25-OH vitamin D were measured by RIA (from Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum C-terminal fragment of collagen type I (S-CTX) (Osteometer Biotech A/S, Copenhagen, Denmark), IL-6, soluble IL-6 receptor (R&D Systems, Minneapolis, MN), and bone-specific alkaline phosphatase (Metra Biosystems, Mountain View, CA) were measured by ELISA.
Bone evaluation
Two portable ultrasound machines were used for bone measurement. The DBM Sonic osteosonographer (IGEA, Carpi, Italy) evaluates amplitude-dependent speed of sound (SoS) at proximal phalanges of the nondominant hand and considers a site formed of up to 70% of cortical bone. It provides a calculated variable of fracture risk defined as ultrasound bone profile index (UBPI). UBPI expresses the probability of having sustained an osteoporotic fracture as: 1, minimal probability; and 0, maximal probability. This method has been validated in 10,000 women of different ages, including centenarians (28). The Sahara ultrasonographer (Hologic, Walton, MA) evaluates calcaneal broadband ultrasound attenuation and SoS; it provides a numeric combination of these indices [quantitative ultrasound index (QUI)]. QUI is the numeric combination of SoS and broadband ultrasound attenuation, which is thought to reflect bone elasticity and stiffness (29). Osteosonography of phalanges was performed in 60 subjects, and ultrasonography of calcaneous in 28. No bone evaluation was performed in 16 centenarians due to atrophic retraction of the feet or arthritic deformation of the hands.
Statistical analysis
Comparisons between groups were made by Student’s t test. Correlation between variables were tested by Spearman test. SPSS for Windows (version 10; SPSS Inc., Chicago, IL) was used for statistical analysis; P value lower than 0.05 was considered significant.
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Results |
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). Only four males and three females were smokers; they had been smoking since their youth.
None of the centenarians had any acute disease at the time of the visit. More than half presented levels of dementia similar to those previously reported (30), as shown by the clinical examination and MMSE (23). Previous or chronic diseases (Table 1) were considered both by physical examination and by consulting the available medical files.
Fifty-four centenarians were unable to walk (Table 2), and of the remaining 50, 19 were walking without assistance; 9 were scored as stable by the self-perception of stability and by the specific tests performed (Table 2). Interestingly, among those able to walk, 60% did not show any sign of dementia, whereas dementia was prevalent (70%) among those unable to walk (Table 2). Falls are one of the most important factors related to hip fractures, especially in the elderly, and it was determined that 38 centenarians sustained at least one fall in the year before our visit (Table 2).
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shows fractures in centenarians according to gender, age of occurrence, and skeletal site. We found that 38 centenarians had sustained at least one fracture throughout their life, for a total of 55 events (Fig. 1A). Although the number of males studied was limited, we found that the percentage of subjects that sustained at least one fracture was similar in females and males. Through direct recall or relatives’ accounts, it was possible to evaluate the dynamics of most of the fractures and recognize those fractures due to fragility from those due to major trauma. We scored 42 events as fragility fractures that either followed falls from the standing position or occurred spontaneously. Considering the age of occurrence, two thirds of the total fractures took place after 80 yr of age, and all of these were fragility fractures (Fig. 1B). More than half of the fractures occurred at the femur, the most dangerous site in terms of self-sufficiency loss (Fig. 1C). Vertebral fractures were, very likely, underestimated, because we were not able to perform x-rays of the spine and only one vertebral crush was documented from hospital records. Twenty-two centenarians sustained at least one hip fracture, for a total of 28 events; it was striking that 14 of 28 hip fractures took place after 94 yr of age, and seven occurred between 80 and 93 yr (Fig. 1B).
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reports the impact of fractures on walking self-sufficiency. We observed that among the 31 subjects walking with either sticks or crutches, 61% sustained at least one fracture, whereas 12 of 19 subjects (63%) walking unassisted did not sustain any fracture. We were not able to assess, for 60% of the 54 subjects unable to walk, whether the fracture took place before or after the total loss of standing ability. Among the 22 hip-fractured centenarians (Fig. 2B), only two were walking self-sufficiently, whereas 14 were unable to walk.
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shows metabolic parameters of the centenarians studied. The mean levels of fasting glucose, cholesterol, triglycerides, serum albumin, total serum protein, and hepatic function markers (AST, ALT, GT) were all within normal ranges. Serum total alkaline phosphatase was close to the upper normal limit, and mean hemoglobin was in the lower range of normality. Serum creatinine was within the normal range in most centenarians, and only 11% had values over 1.5 mg/dl. Because simple serum creatinine can be misleading in subjects with low lean mass like the elderly, we also calculated the creatinine clearance, and the mean level was 24.1 ml/min (Table 3).
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Mean serum phosphate was in the lower quartile of normality; serum calcium was close to the lower limit and less than 9 mg/dl in 74% of the centenarians, whereas there was no significant difference when serum calcium was corrected for albumin (Table 3). Mean levels of PTH were twice the upper normal limit and significantly elevated in 64% of the centenarians (Table 3 and Fig. 3). Elevation of bone resorption was determined by S-CTX and was significantly above the normal limit in 92% of the subjects. Serum IL-6, a cytokine involved in osteoclastic proliferation that has been shown to correlate with PTH in animals as well as in humans (31, 32), was also elevated (Table 3 and Fig. 3). Mean serum IL-6 soluble receptor was just above the upper normal limit. Bone-specific alkaline phosphatase levels were, on average, coincident with the upper normal limit, and frankly elevated in 32 centenarians, further indicating the observed trend of elevated bone turnover. This intense bone resorption was particularly evident when the individual values of bone resorption markers (PTH, S-CTX, IL-6) and serum calcium were plotted (Fig. 3). A significant correlation was present between PTH and calcium (r = -0.33; P < 0.001), PTH and S-CTX (r = +0.37; P < 0.001), IL-6 and S-CTX (r = +0.37; P < 0.001), IL-6 and calcium (r = -0.35; P < 0.001), and PTH and IL-6 (r = +0.24; P = 0.019). We also considered, for each single individual, the relationship between the creatinine clearance and PTH, without finding any significant correlation (r = -0.167; P = not significant).
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Bone status was evaluated using ultrasound technology at the phalanges (60 subjects) or the heel (28 subjects). As expected, the ultrasonographic parameters were low at both bone sites, testifying to a situation of bone fragility. The t-score of the amplitude-dependent SoS at the phalanges was -3.7 ± 1.8, and the UBPI was 0.22 ± 0.18. At the calcaneus, the t-score of QUI was -2.78 ± 1.3.
A significant correlation was present between bone markers and ultrasonographic parameters: PTH or S-CTX vs. phalangeal UBPI (r = -0.38; P = 0.032; and r = -0.28; P = 0.036, respectively) and S-CTX vs. calcaneal SoS (r = -0.4; P = 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The most prevalent disease was dementia (57 of 104), with similar frequency of walking disability (54 of 104), and these two factors that are so important for self-sufficiency loss were both present in 38 subjects (Table 2). It is known that elderly people are at risk of fall due to visual impairment, poor stability, loss of muscular mass and strength, and slow neuromuscular reflexes, and the centenarians in the study did not differ from the general elderly population. Interestingly, 75% of the hip fractures (21 of 28) occurred after age 81 yr, and, in particular, 14 of 28 fractures occurred after the age of 94 yr. This indicates that most of the hip fractures occurred late in life, and this remarkable feature of centenarians should be considered in light of the bone catabolic state demonstrated in our study (33, 34). The significant correlation found between bone markers and osteosonographic/ultrasonographic parameters (PTH and S-CTX vs. phalangeal UBPI and S-CTX vs. calcaneal SoS) suggests that elevated bone resorption (Fig. 3) is probably responsible for the continuous loss of both trabecular and cortical bone, a leading factor in the occurrence of fractures.
The area where these subjects were living at the time of the study, and where 100 of 104 had lived all their lives, is the area where original Parmigiano-Reggiano cheese is produced. Parmigiano-Reggiano has the highest calcium content of cheeses produced worldwide and represents part of the daily diet of the inhabitants of the area. The average calcium intake assessed through the questionnaire was almost 750 mg/d (data not shown) and, although still low (35), was higher than that reported in other studies considering elderly subjects (36).
It is well known that active vitamin D tends to decrease in the elderly (37), but the severe hypovitaminosis D found here deserves some consideration. First of all, a progressive age-dependent decrease in the ability of the skin to produce vitamin D3 has been clearly documented in subjects above age 80 yr (38, 39). In Italy, as in many countries, milk is not fortified with vitamin D, and about half of the centenarians were visited (and blood was drawn) from April to September, when sun exposure is possible (40, 41).
In the area where the study was performed, the average days of rain are 70/yr (36 during the spring/summer time) plus 45 d of fog during the autumn/winter time (42).
It was not possible to make a reliable estimate of how much sun exposure these subjects were receiving. However, the centenarians unable to walk were not receiving any sun exposure, especially those living in nursing facilities. Most of those able to walk, on the other hand, spent at least 1 h outside during the summer time.
Moreover, elderly subjects often tend to have a low intake of milk and dairy food, due to chronic constipation or irritable bowel syndrome (43). The undetectable levels of 25-OH vitamin D observed in 99 of 104 centenarians indicate a real need for supplementation in the oldest olds at the population level. Serum creatinine was on average within normal range, but this parameter can be notoriously misleading, especially in elderly subjects with low lean mass. The calculated levels of creatinine clearance found in centenarians, although quite low, were not correlated with serum PTH, suggesting that secondary hyperparathyroidism was not due to chronic renal insufficiency.
In elderly women, an interrelationship of vitamin D insufficiency, secondary hyperparathyroidism, and femoral bone density has been shown (44).
It is likely that the severe hypovitaminosis of these centenarians can affect their self-sufficiency not just at the bone level but also by affecting muscle strength. It has been suggested that hypovitaminosis D may play an indirect role in the incidence of hip fracture, being associated with muscle weakness, limb pain, and impaired muscle function (45).
We evaluated bone status by peripheral ultrasonography at the phalanges and at the calcaneous, and low values were found in this aged population. Although central measurement of hip density with dual-energy x-ray absorptiometry may have furnished interesting information, we were unable to perform it. It would not be surprising, at this age, to find a good concordance of low values using either peripheral ultrasonography or central dual-energy x-ray absorptiometry.
Based on the findings of our study, we suggest that a lack of vitamin D is at the origin of the elevated bone turnover in centenarians. Hypovitaminosis D and the consequent trend to hypocalcemia can induce secondary hyperparathyroidism that is mirrored by elevation of IL-6 levels, as previously shown (31, 32). Bone catabolism, as demonstrated by high S-CTX levels in 92% of the subjects, although unable to restore normal level of serum calcium, perpetuates a vicious cycle that, overall, weakens the skeleton and increases the risk of fragility fractures. The bone status and metabolism of the centenarians considered here shows in a more definitive and convincing fashion what has been previously suggested for younger elderly subjects (46).
Our observations raise several questions: 1) Are hypovitaminosis D, the trend to hypocalcemia, and osteopenia general aspects of extreme longevity? 2) Are these abnormalities peculiar to extreme age, or are they related (completely or in part) to latitude, lifestyle (i.e. sun exposure and physical activities), or diet (i.e. calcium and vitamin D intake)? Further studies are needed in different populations of very old people to answer these questions. In any case, these observations constitute grounds for immediate and feasible intervention (i.e. appropriate supplementation of calcium and vitamin D) in the oldest olds, a frail population dramatically increasing, to prevent bone fractures together with fall-prevention strategies (47, 48). In conclusion, it may never be too late for the prevention of fractures, and an early start is, by far, advisable for the reduction of disability.
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Acknowledgments |
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Footnotes |
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Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; GT, -glutamyl transferase; MMSE, Mini-Mental State Examination; 25-OH vitamin D, 25-hydroxyvitamin D; QUI, quantitative ultrasound index; S-CTX, serum C-terminal fragment of collagen type I; SoS, speed of sound; UBPI, ultrasound bone profile index.
Received March 25, 2003.
Accepted August 12, 2003.
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References |
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are elevated in primary hyperparathyroidism and correlate with markers of bone resorption: a clinical research center study. J Clin Endocrinol Metab 81:3450–3454[Abstract]
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