Lifetime high calcium intake increases

osteoporotic fracture risk in old age

Thijs R. Klompmaker. 


Medical Hypotheses 2005; 65(3): p552-558

(also available in pdf)

Abstract in PubMed






Caloric restriction prolongs life span. Calcium restriction may preserve bone health.
In osteoporosis, bone mineral density (BMD) has significantly decreased, due to a lack of osteoblast bone formation. Traditional osteoporosis prevention is aimed at maximizing BMD, but the lifetime effects of continuously maintaining a high BMD on eventual bone health in old age, have not been studied. Strikingly, in countries with a high mean BMD, fracture rates in the elderly are significantly higher than in countries with a low mean BMD. Studies show that this is not based on genetic differences. Also, in primary hyperparathyroidism, on the brink of osteoporosis, BMD levels may be significantly higher than normal. 
Maybe, BMD does not represent long term bone health, but merely momentary bone strength. And maybe, maintaining a high BMD might actually wear out bone health.
Since osteoporosis particularly occurs in the elderly, and because in osteoporotic bone less osteoblasts are available, the underlying process may have to do with ageing of osteoblastic cells. 
In healthy subjects, osteoblastic bone cells respond to the influx of calcium by composing a matrix upon which calcium precipitates. In the process of creating this matrix, 50 to 70% of the involved osteoblasts die. The greater the influx of calcium, the greater osteoblast activity, and the greater osteoblast apoptosis rate. An increased osteoblast apoptosis rate leads to a decrease in the age-related osteoblast replicative capacity (ARORC). In comparison to healthy bone, in osteoporotic bone the decrease in the replicative capacity of osteoblastic cells is greater. Due to the eventual resulting lack of osteoblast activity, micro-fractures cannot be repaired. Continuously maintaining a high BMD comes with continuously high bone remodeling rates, which regionally exhaust the ARORC, eventually leading to irreparable microfractures.
Regarding long time influences on bone health, adequate estrogen levels are known to be protective against osteoporosis. This is generally attributed to its inhibiting influence on osteoclast activity. Instead, its net effects on osteoblast metabolism may be the key to osteoporosis prevention. Adequate estrogen levels inhibit osteoblast activity, calcium apposition and osteoblast apoptosis rate, preserving the ARORC. 
Conclusion: Regarding osteoporosis prevention, ARORC better than BMD represents bone health. Regarding ARORC, adequate estrogen levels are protective, opposing the similar effects of hyperparathyroidism and a high calcium diet.
Tests need to be performed in mice to assess the lifetime effects of a high versus a low calcium diet, on eventual bone fracture toughness.


Osteoporosis represents a major public health problem. Efforts to prevent osteoporosis have not been successful, which is demonstrated by increased incidence of age-adjusted osteoporotic fractures. For decades, prevention of osteoporosis has been aimed at increasing peak bone mass, but in countries with a high mean bone mineral density (BMD), osteoporosis incidence is high as well. 
In Europe, BMD of healthy female adults in Poland are lower than those in French, Italian and Spanish populations (1); and the age-adjusted incidence of hip fractures is lower as well (2). In Sweden the mean BMD is higher (3), and so is hip fracture incidence (2).
Japanese subjects have lower peak bone mass than their European counterparts and also hip fracture incidence is lower in Japan than in the West (4). This lower BMD is not due to genetic differences; U.S.-born Japanese-American women have BMD values equivalent to those of white normals (5).
Women in China have lower BMD and much lower risk of hip fracture than women in Europe or North America (6). This lower BMD is not due to genetic differences; Chinese premenopausal women who immigrated to Denmark more than 12 years ago have a similar BMD to that of Danish premenopausal women (7).
In Gambia, calcium intake, mean BMD and osteoporosis incidence are all very low (8). Again, this has no genetic cause. There are no significant differences in BMD in Gambian and Caucasian adults living in the UK (9).

Might maintaining a low BMD preserve long-term bone health?
Maybe, BMD does not represent long term bone health, but merely momentary bone strength. And maybe, maintaining a high BMD might actually wear out bone health, eventually causing poor bone strength; in as much as constantly speeding will cause your car to break down sooner. 



Caloric restriction elongates life span (10)(11)(12)(13) by retarding age-related physiological and biochemical changes (14)(15)(16). Calcium restriction may preserve bone-health by retarding the decrease in the age-related osteoblast capacity to form new bone. 

The short-term effects of a high calcium intake have been well established. In our bones, osteoblasts create the matrix upon which calcium precipitates. A high calcium intake leads to an increased activity of osteoblasts and increased bone formation rates, which, depending on bone resorption rates, may increase BMD, and thus create stronger bones. 
In maintaining a higher BMD, both bone formation and bone resorption are increased. Unfortunately, 50 to 70% of the composing osteoblasts die in the composition of new matrix (17), and osteoblasts have a limited proliferative capacity (18)(19)(20). Increased osteoblast activity and cell differentiation coincide with increased osteoblast apoptosis rate (21)(22), which is specific for the proliferating zone (21)(23)(24). Increased osteoblast apoptosis rates accelerate the decrease in the age-related osteoblast replicative capacity (ARORC). 
Osteoblasts from osteoporotic bone have a severely reduced replicative capacity (25)(26). Therefore, in osteoporotic bone, less osteoblasts are available (27)(28)(29) and/or osteoblast activity is impaired (28)(29)(30)(31)(32), as in ‘exaggeratedly aged’ bones (25)(33). Due to this lack of osteoblast activity, less pre-calcified matrix is available (34) and micro-fractures cannot be repaired (35).
In osteoporotic patients, there is no occurrence of a generalized premature cellular aging (36). Instead, the decrease in osteoblast activity is regional (27)(28), indicating external factors, such as the regional over-use of osteoblasts. 


It has been well-established that optimum estrogen levels are protective against osteoporosis. This is generally attributed to predominant inhibitory effects on bone resorption, but the influence of adequate estrogen levels on osteoblast metabolism may be key to understanding the etiology of osteoporosis.
It has often been claimed that estrogen stimulates osteoblast activity, but these findings may have been the result of the previous use of inadequate methods. After verification and characterization of the reported anabolic effects of estrogen on bone formation in growing rats, the compiled data consistently demonstrated that estrogen inhibits bone formation (37).
Other studies reported anabolic effects in the first six days of estrogen administration (38) or when added intermittently (39)
On the longer haul, estrogen does not stimulate, but suppresses osteoblastogenesis (40), attenuating osteoblast birth rate (41)(42), inhibits human osteoblast cell proliferation, differentiation and activity (43)(44)(45)(46), bone formation, (47)(48)(49) and prevents osteoblast cell death (42)(50)(51), thereby increasing osteoblast lifespan (40)(42)(52). Partly, estrogen may inhibit osteoblast activity by modifying the effects of parathyroid hormone (PTH) (53).
More importantly, as osteoporosis is particularly prevalent in postmenopausal women, estrogen deficiency is responsible for increased osteoblastogenesis (54), increases the number of osteoblasts (55) and osteoblast activity (56), accelerating bone formation (49)(54)(57)(58)(59)(60)(61) (and predominantly bone resorption), increasing osteoblast apoptosis rate (62), shortening the lifespan of osteoblasts (63)(64)
Regarding understanding the etiology of osteoporosis, the net effects of estrogen on BMD are not the issue, because BMD only represents momentary bone strength. Instead, the net effects of adequate and inadequate estrogen levels on osteoblast activity, apoptosis rate and the ARORC are essential, explaining the possible detrimental effects of a high calcium diet on eventual bone health.


Opposed to and inhibited by adequate estrogen levels, prolonged hyperparathyroidism (HPTH) is a well-known cause of osteoporosis, which is often attributed to its stimulating effects on bone resorption. Osteoblasts, however, are the main target cells for parathyroid hormone (PTH) (65). Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. (66) PTH stimulates osteoblast proliferation (67)(68)(69)(70)(71), enhances osteoblast differentiation (70)(72)(73), increases osteoblast number and mineral apposition rate (74)(75), stimulating bone formation (76)(77)(78). PTH supplementation may induce a net gain of bone mass (79)(23)(80)(81)(82), similar to the effects of a high calcium diet. 
In HPTH, bone formation (and resorption) rate is markedly elevated (83) and increases in formative and resorptive markers seem to be of equivalent size (84). Therefore, In HPTH, BMD values widely differ (85), depending on the regional balances between increased osteoblast and osteoclast activity. Some BMD values may be significantly higher than in controls (86). The resulting BMD values, however, are not the issue, because they only reflect momentary bone strength. The issue is long term bone health, which is compromised by increased osteoblast apoptosis rates. 
PTH-induced osteoblast apoptosis is specific for the proliferating zone (23)(24), indicating that the effects of PTH on apoptosis can only be explained on the basis of its anabolic effect on osteoblast proliferation, similar to the effects of a high calcium diet.
HPTH eventually leads to exhaustion of the ARORC, causing osteoporosis. HPTH enhances fracture risk (87)(88)(89)
Regardless of the net effects on BMD, estrogen inhibits, and a high calcium diet and HPTH increase bone turnover. Regarding ARORC, estrogen is therefore protective, opposing the effects of HPTH and a high calcium diet.


The protective or opposite effects of 1,25 dihydroxycholecalciferol (Calcitriol) on the ARORC depend on coexisting PTH levels. Similar to PTH, but to a lesser extent, Calcitriol directly stimulates osteoblast differentiation and activity, increasing osteoblast apoptosis (22), accelerating the decrease in the ARORC. Indirectly, however, Calcitriol may be protective due to its inhibitory effects on PTH levels, net downregulating both osteoclast and osteoblast activity (90), which attenuates the decrease in the ARORC. 


Long-term glucocorticoid therapy promptly induces osteoporosis, whose severity depends on the dose and duration of the treatment (91)
Glucocorticoids directly stimulate an increase in the apoptosis of mature osteoblasts (92)(93)(94), unlike the indirect effects of HPTH and a high calcium diet, which increase osteoblast apoptosis by stimulating osteoblast proliferation and activity.
Glucocorticoids decrease BMD by inhibiting osteoblast activity, and simultaneously accelerate the decrease of the ARORC by inducing osteoblast apoptosis. 


Exercise is positively associated with BMD of the hip, but often osteoporosis patients cannot increase their BMD through exercise (95). The possible exercise-induced bone mass gain is far less than the disuse-induced bone loss (96), which may indicate exhaustion of the ARORC.
Exercise is essential to maintain the shock-absorbing effects of strong muscles (97). In the short term, in older adults, exercise can partially (20 – 40%) decrease hip-fracture risk (98), but this will accelerate the decrease in the ARORC. In elderly women who had previously been diagnosed with hip fracture, a protective effect was found for women who were moderately active recently. In women, however, who were very active recently, hip fracture risk was slightly elevated (99), which might indicate a lack of osteoblast capacity to repair loading-induced microfractures. The later in life, the smaller the effects of exercise (100), due to the decrease in the ARORC. In elderly with a mean age of 73, exercise was not protective for osteoporotic fracture (101). In women of about the same age, with a history of postmenopausal fractures, exercise did not affect BMD or fracture rates either (102).
Regarding osteoporotic fracture risk, exercise may have long-term beneficial effects by focusing on increasing muscle strength rather than bone strength.


Regarding osteoporosis, BMD represents momentary bone strength and ARORC represents long-term bone health. Regarding ARORC, adequate estrogen levels are protective, preserving osteoblast viability, opposing the pro-apoptotic effects on osteoblasts of glucocorticoid therapy, hyperparathyroidism and a high calcium diet. Maintaining a high BMD has adverse effects on long-term bone health, explaining the positive correlation between mean BMD and age adjusted osteoporotic fracture incidence, per country.
Osteoporosis prevention may be successful by aiming to reduce mean calcium intake to the level of countries where osteoporotic fracture incidence is lowest, approximately 300 to 500 mg / day.
Tests need to be performed in mice (half the population at 90% and the remaining at 100% of average life-expectancy) to assess the lifetime effects of a very high (3%), high (1.5%), moderate (0.5%), low (0.2%) and very low calcium diet (0.1%) respectively (Ca/P=1.5, Ca/Mg=10, Mg>0.02%), on eventual bone fracture toughness.
More beneficial effects of exercise may be obtained by focusing on increasing muscle strength rather than bone strength.
If this theory is correct, worldwide millions of people may have been treated wrongly, and traditional prevention may have had, and will continue to have, strong adverse effects on the health of hundreds of millions of people. Even the most conservative estimates of costs are astronomical.


The first version of this theory was published at in 2000. To obtain inspirational criticism, the theory was submitted to the online science forum of The Guardian, where M. Robert Showalter encouraged me to dig deeper in various directions, and to contact scientists specialized in all related fields.
In long fax-discussions, H.M. Frost (Southern Colorado Clinic) showed me how seemingly oppositional approaches may still be intertwined, confined by one common dogma. Not until 2004, Nobel Prize-winner for physics in 1989, Prof. Hans Dehmelt, finally convinced me to submit my theory to Medical Hypotheses.
I would like to thank Nathalie Augustina for her support, and Janice Gloster, PhD, for her editorial work.


For a detailed explantion of this theory, check out the original version.




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