Editorial

Synergistic effect of vitamin D and calcium in preventing proximalfemoral fractures in older patients

The steady increase in life expectancy has propelled os-teoporosis to the forefront of public health concerns in indus-trialized countries. Osteoporotic fractures cause sufferingand excess mortality, affect quality of life, and result inenormous healthcare costs [1–5]. Among osteoporotic frac-tures, the most devastating are those of the proximal femur,which are associated with high mortality rates, temporary orpermanent loss of self-sufficiency and, in some cases, insti-tutionalization [1,2,5–10]. The huge economic burden oftreating proximal femoral fractures includes the direct costsof surgery, intensive care, care on the ward, and rehabilita-tion, as well as the costs associated with institutionalizationor home care. Although decreases in mortality and morbidityrates have been achieved, the cost savings provided by im-provements in the management of proximal femoral frac-tures (with shorter hospital stays, earlier rehabilitation, andgreater use of home care) do not exceed 20% [11,12]. Fur-thermore, specialized rehabilitation therapy remains costlyand does not consistently improve the functional recovery[13]. Clearly,prevention of proximal femoral fractures is theonly means of achieving large reductions in mortality andmorbidity while substantially reducing costs.

Among risk factors amenable to intervention, secondaryhyperparathyroidism related to calcium and vitamin D defi-ciencies is extremely common. In older individuals, severalmechanisms act together to produce vitamin D deficiency.Limited exposure to sunlight and age-related skin alterations(primarily thinning of the epidermis) decrease the productionof vitamin D (cholecalciferol) by the skin, which normallycovers about two-thirds of vitamin D requirements [14,15].The dietary intake of vitamin D is often low in older individu-als [16,17]. As a result, hepatic output and serum levels of25-hydroxycholecalciferol (25OHD) drop significantly withadvancing age. A decline in the activity of the renal enzyme1a-hydroxylase is another age-related change and decreasesthe conversion of 25OHD to 1a,25-dihydrocholecalciferol(1a,25(OH)2D), which is the only active form of vitamin D[18]. In response to the drop in serum 1a,25(OH)2D, theparathyroid glands increase their output of parathyroid hor-mone (PTH). This elevates the serum level of PTH, whichstimulates the renal 1a-hydroxylase, thereby maintaining1a,25(OH)2D levels [19]. Serum 25OHD is low, whereasserum PTH is elevated. These changes are more pronouncedin winter, when exposure to sunlight is minimal [16,20–23].

Seasonal variations in 25OHD and 1a,25(OH)2D levels oc-cur even in sunny climates [24,25].

1a,25(OH)2D increases active calcium absorption by theproximal jejunum (primarily the duodenum), steps up theexpression of the proteins involved in transcellular calciumtransport [26–28], and stimulates rapid transport of calciumthrough enterocytes (transcaltachia) [29]. Enterocytes losevitamin D receptors during the aging process, causing intes-tinal calcium absorption to decrease, even when1a,25(OH)2D levels remain stable [30,31].

In addition to vitamin D deficiency, an inadequate calciumintake is common in older individuals and can be a compo-nent of general undernutrition [16]. In one study, a lowcalcium intake was noted in two-thirds of institutionalizedwomen [32]. In older women living at home (French EPI-DOS cohort of women older than 75 years of age), the meancalcium intake was only 570 mg/d [21]. Older individualsmay deliberately reduce their intake of dairy products be-cause they are concerned about hypercholesterolemia or havelactose maldigestion [33,34]. The conjunction of a low cal-cium intake and decreased intestinal calcium absorption re-sults in hypocalcemia, which further stimulates the produc-tion of PTH. Fardellone et al. [35] reported a highlysignificant negative correlation between PTH levels and cal-cium intake in older women who had calcium intakes of lessthan 786 mg/d, but not in those with higher calcium intakes.That this has a biological impact was confirmed by thefinding that older women with low calcium intakes and lowintestinal calcium absorption rates were at increased risk forproximal femoral fractures [36].

Older individuals who are institutionalized or house-bound, patients with undernutrition or other disorders, andlow-income individuals are at high risk for calcium andvitamin D deficiency and for secondary hyperparathyroid-ism. Calcium intake and exposure to sunlight are very low inthis population [22,37–39]. As a result, serum levels of25OHD and even 1a,25(OH)2D decline, whereas serum lev-els of PTH rise sharply [21,38,40,41]. Furthermore, thesepatients are at high risk for falls. These factors converge toproduce a markedly higher incidence of proximal femoralfractures in institutionalized individuals than in same-agecommunity-dwelling individuals [42]. Conversely, manyelderly individuals who remain active, eat a healthy diet, and

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are free of disease have normal 25OHD and PTH levels[43,44].

Thus, two factors contribute to the development of sec-ondary hyperparathyroidism: vitamin D deficiency and aninadequate intake of calcium. The high output of PTH in-creases bone resorption and overall bone remodeling, par-ticularly in the cortical component. Increased porosity anddecreased thickness of the cortical bone develop, diminish-ing the mechanical strength of long bones, most notably thefemoral neck and proximal humerus. Several studies foundthat bone mineral density was negatively correlated withPTH levels [45,46]. Patients with proximal femoral fractureshad lower 25OHD levels and higher PTH levels, as comparedto older women with osteoporosis but no fractures [47].

The major contribution of PTH overproduction to thepathogenesis of bone frailty in older patients indicates thatkeeping PTH levels as low as possible is the key to optimalbone protection. PTH levels rise when 25OHD levels fallbelow 26–28 ng/ml (65–70 nM/l) [48–50]. It is probably safeto assume that 25OHD levels should not be allowed to dropbelow 25 ng/ml (62.5 nM/l) if PTH levels are to be kept low.The concentration of 10 or 12 ng/ml (25 or 30 nM/l) oftenused as the lower level of the normal range is probably notsufficiently sensitive for detecting vitamin D deficiency thatis mild but nevertheless potentially associated with an in-creased risk of proximal femoral fracture. 25OHD levelsbetween 10 and 25 ng/ml (25–62.5 nM/l) may indicate vita-min D deficiency requiring supplementation [51]. This con-siderably broadens the field of calcium-vitamin D supple-mentation as a prophylactic therapy for proximal femoralfractures.

These pathophysiological data have been confirmed bytherapeutic trials of calcium and vitamin D therapy for pre-venting osteoporotic fractures. In studies where the mean25OHD level exceeded 30 ng/ml (75 nM/l), PTH levelsdropped, BMD values stopped declining or increased, andthe incidence of proximal femoral fractures and fractures atother sites decreased significantly [32,52,53]. These studiesused vitamin D dosages of 700–800 IU/d, in combinationwith calcium. Conversely, studies in which patients receivedlower vitamin D dosages (300–400 IU/d) showed that mean25OHD levels remained lower than 25 ng/ml and that PTHlevels declined byonly 20% at the most [54–57]. In thesestudies, the fracture incidence was similar in the supple-mented and placebo groups, regardless of the treatment dura-tion.

Serum 25OHD levels rise sharply during the first monthson supplementation and subsequently level off with continu-ing treatment in a fixed dosage. However, the accumulationof vitamin D is short-lived, and supplementation does notcorrect age-related biological alterations. Consequently, ifthe treatment is stopped, bone mineral density decreases,reaching levels comparable to those in the placebo groupafter 2 years [58]. This militates in favor of lifelong calciumand vitamin D supplementation. This treatment is both inex-pensive and safe [32]. Laboratory tests may be in order

before treatment initiation or during follow-up. Prolongedhypercalciuria carries a risk of renal lithiasis and requires adecrease in the calcium dosage. Persistent high PTH levelsdespite a rise in 25OHD levels and normal or slightly el-evated serum calcium levels may indicate primary hyperpar-athyroidism. Hypercalcemia developing during supplemen-tation may reveal another condition associated withincreased bone resorption, such as myeloma or sarcoidosis.

In an article published in this issue, Fardellone et al. [59]report the effects of vitamin D (800 IU/d) and calcium (1200mg/d) supplementation on bone mineral density and bio-chemical parameters in a group of elderly women with verylow vitamin D levels (<12 ng/ml) at baseline. Although thisstudy largely supports the previously published data, severalpoints deserve comment. Severe vitamin D deficiency isextremely common in older women in France, even thosewho live at home and are relatively self-sufficient. This sug-gests that periodic screening for, and routine prevention of,vitamin D deficiency may be appropriate in individuals olderthan 70 years of age. The potentially severe consequences ofvitamin D deficiency on the health of individuals lends ur-gency to this issue, particularly as supplementation is inex-pensive and devoid of major side effects.

The second point is the effect of treatment. Fardellone etal. used the same vitamin D dosage as Chapuy et al. in theDECALYOS I study [43,50,51], in which the mean 25OHDlevel rose above 30 ng/ml and PTH levels decreased tonormal on treatment. However, the DECALYOS study wasnot confined to women with severe vitamin D deficiency: inthe first phase, the mean baseline 25OHD level was 16 ng/mland in the second phase, 23% of the women had 25OHDlevels above 12 ng/ml. In contrast, in the study by P. Fardel-lone et al., the 25OHD level achieved on supplementationwas lower than 29 ng/ml in 50% of the women, and theimprovement in bone resorption markers was only partial.These results suggest that even 800 IU of vitamin D per daymay be inadequate to elevate 25OHD levels above 29 ng/mlin women with severe vitamin D deficiency (25OHD <12 ng/ml).

In summary, secondary hyperparathyroidism related tovitamin D deficiency is extremely common in older womenin France and is a major risk factor for proximal femoralfractures. Vitamin D supplementation in a daily dosage of800 IU, in combination with calcium supplementation, in-creases 25OHD levels, returns PTH levels to normal, andsignificantly reduces the incidence of appendicular os-teoporotic fractures. However, this dosage may be too low inwomen with severe vitamin D deficiency.

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Pawel SzulcPierre Jean Meunier *

INSERM Unit 403, Hôpital Edouard-Herriot, Pavillon F,Place d’Arsonval, 69437 Lyon cedex 3, France

E-mail address: pierre.meunier@laennec.univ-lyon1.fr(P.J. Meunier)

Received 20 December 2002; accepted 15 January 2003

* Corresponding author.Present address: Unité INSERM 403, FacultéLaënnec,

8, rue Guillaume-Paradin, 69008 Lyon, France.

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