Vitamin D and Osteoporosis

Vitamin D and Osteoporosis

Iris Thiele Isip Tan MD, FPCP, FPSEMClinical Associate Professor, UP College of Medicine

Section of Endocrinology, Diabetes & MetabolismDepartment of Medicine, Philippine General Hospital

Disclosure

Merck Sharp & Dohme (MSD)

Honoraria as RTD speaker

Travel grant for regional endocrine meeting

How much vitamin D is enough?


Should vitamin D levels be measured?






Does supplemental vitamin D reduce fractures and falls?

How much vitamin D is

enough?

Vitamin D and Bone Metabolism

Gut

Renal distal tubule

In vitamin D-deficient state, calcium absorption decreases Low calcium causes

increase in PTH secretion

PTH

Low Levels of Vitamin DCalcium reservoir of bone is depleted to correct for low calcium absorption in gut

Mobilization of calcium from bone

PTH

Balanced SystemCalcium absorption meets metabolic demands

Normal bone mineralization is maintained

Dietary calcium

Circulation

Calcium reabsorption

1

23

4

Vitamin D

Vitamin D

Adapted from Holick M. Curr Opin Endocrinol Diabetes. 2002;9:87–98; DeLuca HF. Am J Clin Nutr. 2004;80(suppl 1):1689S–1696S; Lips P. Endocr Rev. 2001;22:477–501; Holick MF. J Nutr. 2005;135:2739S–2748S.

Parathyroid

Canonical FunctionThe canonical function of vitamin D, described briefly in the

previous section, is the facilitation of calcium absorptionthrough the endocrine pathway of Figure 1. Figure 3 illustratesthe relationship of absorption fraction in healthy adults toserum 25(OH)D, showing a plateau effect at serum 25(OH)Dlevels of approximately 80 nmol/L (9). Below that level, cal-cium absorption is impaired, as Figure 3 shows. It might beinferred from Figure 3 both that 25(OH)D is itself responsiblefor directly increasing absorption efficiency and that maximalabsorption amounts to approximately 30%. Both are probablyincorrect. Even at full vitamin D repletion [i.e., 25(OH)D levels!80 nmol/L), absorption fraction may be higher or lower thanthe plateau level shown in Figure 3, depending solely on cal-citriol production, which reflects calcium need. (Calcitriol, inturn, is regulated by parathyroid hormone, itself reacting toperceived calcium need.) Below 80 nmol, absorption dependson both 25(OH)D and calcitriol. Although 25(OH)D has beenshown to alter absorption directly (7), the size of that effect istoo small to account for the ascending limb of the curve inFigure 3. What Figure 3 shows is not so much what vitamin Ddoes as what it permits. Vitamin D enables the physiologicregulation of absorption so that vitamin D supply is not ratelimiting. In one key study (10), participants with 25(OH)Dconcentrations averaging 86 nmol/L (34 ng/ml) absorbed atnearly 70% higher efficiency than did the same women studiedat 50 nmol/L (20 ng/ml).

Prevailing Vitamin D StatusSeveral population-based studies have reported vitamin D

status in age groups from children to centenarians, as well as inisolated groups of individuals with discrete diseases (11–15).Individuals who would otherwise be considered healthy typi-

cally have serum 25(OH)D levels averaging in the range of 50 to65 nmol/L, and from 65 to 100% of such populations havelevels !80 nmol/L. As just noted, values of !80 nmol/L arenecessary to optimize the canonical role of vitamin D. Outdoorworkers in the tropics typically have serum 25(OH)D levelsranging from 120 to 200 nmol/L. These observations suggestthat vitamin D deficiency is perhaps the most widespreaddeficiency condition in developed nations. It is important alsoto understand that the term “deficiency” in this sense does notnecessarily connote clinically explicit disease (as would theterm “deficiency” for nutrients such as vitamin C [scurvy] orthiamin [beriberi]). Rather it connotes an increase in risk forcertain untoward outcomes, such as those reviewed brieflybelow in Vitamin D and Chronic Disease. This explains theseeming paradox that individuals who are ostensibly healthytoday may nevertheless be “deficient.”

Vitamin D RequirementThe last published recommendations for vitamin D intake (1)

are 200 IU/d for children and for adults up to age 50, 400 IU/dfrom age 50 to 70, and 600 IU/d thereafter. (The rise in therecommendations with age is an explicit reflection of the factthat, although cutaneous synthesis is understood to be occur-ring in most individuals, the efficiency of that synthesis de-clines with age [16,17].) These recommendations are explicitlypegged to the prevention of rickets in children and are presum-ably adequate for the prevention of osteomalacia in adults butare otherwise unconnected with any of the other disorders orfunctions reviewed in this article. At the time the recommen-dations were published, there was no clear evidence of howmuch vitamin D was typically synthesized in the skin, and,indeed, vitamin D presents a unique challenge among all of thenutrients because it is not typically present in most foods andbecause people with ample sun exposure have, effectively, noneed at all for oral vitamin D.

Quantitative studies performed since the publication of thethese recommendations have made it clear that at a presumablyoptimal level of !80 nmol/L, daily metabolic utilization ofvitamin D is on the order of 4000 IU (18). Because dietarysources account for typically for no more than 5 to 10% of thattotal, the rest must be coming from skin or, lacking that, mustresult in a suboptimal 25(OH)D concentration.

Much work is being done (16,19,20) with respect to cutaneoussynthesis of vitamin D and its relative role in the total vitaminD economy, but, for the moment, emphasis has to be on the oralsupplementation that may be needed to achieve desired serum25(OH)D concentrations. The quantitative work alluded to pre-viously (18) has resulted in a “rule of thumb” to the effect thateach 100 IU of additional daily oral vitamin D intake producesan elevation of serum 25(OH)D of approximately 1 ng/ml (2.5nmol/L). Thus, a patient with a starting value of 15 ng/ml (37.5nmol/L) would require approximately 1500 IU/d to bring hisor her serum 25(OH)D level up to 30 ng/ml (75 nmol/L). At thesame time, it must be stressed that individual response tostandard dosages varies widely, and the rule of thumb is onlyan approximation.

Figure 3. Relationship of calcium absorption fraction to vitaminD nutritional status [as measured by serum 25(OH)D] (9).Note that efficiency rises up to 25(OH)D levels of approxi-mately 80 nmol/L (32 ng/ml), above which regulation of ab-sorption is no longer limited by vitamin D status. (CopyrightRobert P. Heaney, 2005. Used with permission.)

Clin J Am Soc Nephrol 3: 1535–1541, 2008 Vitamin D in Health and Disease 1537

Calcium Absorption: Threshold Effect

32 ng/dL

Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

Vitamin D metabolic utilization

4,000 IU/day

Vitamin D-fortified milk (400 IU/quart)Cereals (40-50 IU/serving)Egg yolksSaltwater fishLiver

Clinician’s Guide to the Prevention & Treatment of Osteoporosis National Osteoporosis Foundation, 2008

Chief Dietary Sources of Vitamin D

Vitamin D: Recommended daily intake

The Hormone Foundation 2009

Recommended daily intake

Vitamin D Calcium

Under age 50 400-800 IU at least 1,000 mg

Over age 50 800-1,000 IU at least 1,200 mg

• 10/11 RCTs: ↑ serum 25(OH)D

• Response depends on baseline level‣ Greater if baseline 25(OH)D <50 nmol/L

• 0.7 nmol increase in serum 25(OH)D in healthy young men for each 1 ug (40 IU) of vitamin D

Brannon et al, Am J Nutr 2008;88:483S-90S

Response to Fortified Food

+ 100 IU oral vitamin D intake

= + 1 ng/mL (2.5 nmol/L)

serum 25(OH)D

Rule of Thumb

Patient with a starting serum 25(OH)D of 15 ng/mL would require 1,500 IU/d to bring his level to 30 ng/mL

Heaney R. Clin J Am Soc Nephrol 2008;3:1535-41

Individualize requirements for vitamin D supplementation

Sunlight

exposureSkin

pigmentation

Baseline vitamin D level

Intestinal

absorption

rates

Type of vit D supplement

(D3 is 3x more potent

than D2)

Age (reduced photo-

conversion of

7-dehydrocholesterol

to vit D)

Genetic variation in vitamin D receptor activity

Brown S, Alternative Medicine Review 2008

TOXICITYVitamin D supplementation

Trial characteristics

22 vitamin D trials with AE outcomes

19 trials: adults only

Many too short to observe AEs

400-4,000 IU/d vit D3 (n=19)

5,000-10,000 IU/d vit D2 (n=2)

Cranney et al, Am J Clin Nutri 2008;88(suppl):513S-9S

Most frequently reported

Hypercalcemia HypercalciuriaMore events in vit D group but difference with placebo group NS

Asymptomatic

TOXICITYVitamin D supplementation

Trial characteristics

7 trials reported kidney stone incidence

5 trials had no cases

1 trial reported NS difference

1 reported increase in stones (WHI)


Women’s Health Initiative

n = 36,282

400 IU vitamin D3 + 1000 mg Ca vs Ca alone

5.7 events/10,000 women-years exposure

Institute of MedicineTolerable Upper

Intake Level (TUIL)2,000 IU/day

No-observed-adverse-effect-level (NOAEL)

10,000 IU/day

Heaney R. J Musculoskelet Neuronal Interact 2006:6(4):334-

Serum 25(OH)D 32 ng/mL = minimum

daily intake of 2,600 IU vitamin D

(US residents)

80-90% of vitamin D is cutaneously produced

from sunlight

Limited by

age

higher latitudes

working indoors

use of sunscreen

skin pigmentation

cultural practices precluding skin exposure

Bathing suit exposure during summer

until skin just begins to turn pink

⬇skin production of

10,000 - 50,000 IU of vitamin D3

Adams et al. NEJM 1982;306:772-775

Effect on serum 25(OH)D

4 RCTs using artificial UVB light source

4 RCTs using solar exposure

Nursing home residents with low baseline 25(OH)D

Suberythemal UV light exposure = 25(OH)D 28-42 nmol/L after 3 mos.


“Fair evidence to suggest that artificial and solar exposure increases 25(OH)D levels in vitamin D-deficient and replete persons, including the elderly.”

Brannon et al, Am J Nutr 2008;88:483S-90S

TOXICITYSun exposure

“Is a specific level of sunlight exposure sufficient to maintain adequate vitamin D levels without increasing the risk of non-melanoma skin cancer or melanoma?”


No studies!

Should vitamin D levels be

measured?

National Osteoporosis Foundation

Measure serum 25(OH)D in those at risk of deficiency

elderly

malabsorption (i.e. celiac disease)

chronic renal insufficiency

housebound

chronically ill

limited sun exposure

Low Vit D Status Despite Abundant Sun Exposure

Binkley et al, JCEM 2008; 92;2130-5

Serum 25(OH)D and PTHSkin color: reflectance colorimetrySun exposure index: amount of skin exposed X reported average sun exposure per week without sunscreen

University of HawaiiA’ala Park Board Shop

Convenience sample of adults in Honolulu, Hawaii (lat 21 ̊ )n = 93 (63 ♂, 30♀)

Mean self-reported sun exposure without sunscreen use 22.4 h (range 2-96)28.9 + 1.5 h/wk



51% of subjects had low vit D status with serum 25(OH)D cutpoint of 30 ng/mL

Evolutionary?

Genetic differences: Optimal amount of vit D

Cytochrome P450

Inadequate D3 Inadequate cutaneous production

Enhanced cutaneous destruction of previt D3 or D3

Downregulation of cutaneous synthesis by sun-induced melanin production

Abnormalities of transport from skin to circulation


Sun exposure to the hands and face for 15 minutes may not be enough

Measure serum 25(OH)D?


Measure serum 25(OH)D in otherwise healthy women with osteoporosis?

Tannenbaum et al, JCEM 2002:87;4431-7

Objective:Identify most useful/ cost-efficient screening tests in detecting secondary contributors to osteoporosis

24-h urine Ca for all

If urine Ca abn, serum Ca and PTH

Serum TSH for all on T4 replacement 1 2

3

2

4 5

24-h urine Ca & serum Ca for all

If urine Ca or serum Ca abn, serum PTH

Serum TSH for all on T4 replacement

24-h urine Ca, serum Ca & PTH for all


24-h urine Ca, serum Ca, PTH and 25(OH)D for all


Serum Ca, PTH and 25(OH)D for all


n = 173 postmenopausal women, no known contributors to osteoporosis on past medical history



Disorders identified:

56/173 women

Hypercalciuria most common (9.8%; n=17)

vitamin D deficiency (4.1%; n=7)

24-h urine Ca ➜ serum Ca & PTH


1 2

3

2

4 5

24-h urine Ca & serum Ca ➜ PTH


24-h urine Ca, serum Ca & PTH


24-h urine Ca, serum Ca, PTH and 25(OH)D for all


Serum Ca, PTH and 25(OH)D for all


n = 173 postmenopausal women, no known contributors to osteoporosis on past medical history

n=33 n=35

n=48 n=55 n=37



24-h urine Ca ➜ serum Ca & PTH

Serum TSH if indicated 1 2

24-h urine Ca & serum Ca ➜ PTH

Serum TSH if indicated

24-h urine Ca, serum Ca & PTH


3

24-h urine Ca, serum Ca, PTH, 25(OH)D

Serum TSH if indicated 4

Serum Ca, PTH, 25(OH)D


5

n=33 (59%)

$22/patient

$116 per diagnosis

n=35 (63%)

$30/patient

$148 per diagnosis

n=48 (86%)

$75/patient

$272 per diagnosis

n=55 (98%)

$116/patient

$366 per diagnosis

n=37 (66%)

$108/patient

$506 per diagnosis

1999: 24h urine Ca $8, serum Ca $7, PTH $57, serum 25(OH)D $41, TSH $23

Vitamin D Deficiency: A Common Occurrence in Both High- and Low-energy Fractures

Steele et al, HSSJ 2008:4;143-8

44 orthopedic trauma in-patients (20♂, 24♀)

Low-energy fracture fracture from a fall of standing heightHigh-energy fracturefracture from a fall greater than standing height or motor vehicle impact

Multiple studies have shown a high prevalence ofvitamin D de!ciency among various subgroups of patients;postmenopausal women [7, 12, 14, 15, 17], general medicalin-patients [24], and geriatric patients [5, 10, 11, 18, 21].The prevalence of vitamin D insuf!ciency among male andfemale orthopedic patients with fractures has been limited tolow-energy fractures [1, 22]. Given vitamin D’s multitudeof positive effects on bones and muscular function, itsimportance to patients who have undergone traumatic injuryto the bones may be critical. What is the prevalence ofvitamin D insuf!ciency, de!ned as a serum level of 25(OH)D below 32 ng/ml, among both high- and low-energyfracture patients? How does gender in"uence vitamin Dinsuf!ciency in fracture patients? What is the relationshipbetween age and 25(OH)D level for high-energy fracturepatients compared to low-energy fracture patients?

Patients and methods

This institutional review board approved retrospectivereview analyzed 44 orthopedic trauma in-patients admittedfrom June 1, 2006 to February 1, 2007 for fracture care. The44 patients comprised a consecutive series of patients seenby one physician on the metabolic bone disease team. Asstandard protocol, all patients admitted to the trauma serviceat this hospital were seen by both the orthopedic traumaservice and the metabolic bone disease team. This standardof care was established based on an increased awareness ofvitamin D de!ciency and osteoporosis seen in orthopedicarthroplasty patients [7]. Patients were included if theysustained a documented fracture, had a 25-hydroxyvitaminD level drawn after surgery in the hospital, and were greaterthan or equal to 18 years of age. Patients were excluded ifthey had any known risk factors for vitamin D de!ciency,such as renal insuf!ciency (as indicated by a creatininelevel of !2 mg/dl), malabsorption, gastrectomy, active liverdisease, acute myocardial infarction, alcoholism, anorexianervosa, or steroid dependency. In this study, the 25(OH)Dmetabolite was used as a measurement of vitamin D status.Although calcitriol (1,25-dihydroxvitamin D) is the mostpotent vitamin D metabolite, the metabolite 25(OH)Dprovides a more accurate account of vitamin D status [9,20, 26, 29]. Serum 25(OH)D levels were measured throughthe use of liquid chromatography/mass spectrometry.

Age, gender, and type of fracture were recorded for eachpatient. This study included a total of 44 patients, 45.5%men (n=20) and 54.5% women (n=24). The mean age forall patients was 59±20 years, range 19–95 years. The meanage for men was younger at 51±21 years than for women,which was 66±17 years (p=0.02). The fractures wereclassed as low-energy fracture vs. high-energy fracture.Low-energy fractures were de!ned as fractures sustainedfrom a fall of standing height or less, while high-energyfractures resulted from a fall greater than standing height ora motor vehicle impact.

Univariate analysis was run on all variables; means,standard deviations, medians, frequencies, etc., as appropri-ate. All demographic and clinical variables were assessed

statistically for an association with the occurrence ofvitamin D depletion. Differences between groups wereassessed using the Student’s t test for normally distributeddata, and the Mann–Whitney test for non-parametric data.Categorical data were analyzed using a two-tailed Fisher’sExact test. Alpha was set to 0.05. The results reported hereare not adjusted for multiple comparisons due to the smallsample size, but was powered to test the concept of vitaminD de!ciency. Data analysis was conducted using SPSSversion 14 (SPSS Inc., Chicago, IL) and StatXact v7 (Cytel,Cambridge, MA).

Results

This study showed that there was a high prevalence ofvitamin D insuf!ciency among fracture patients on theorthopedic trauma service, not limited to only low-energyfractures. We found vitamin D insuf!ciency, 25(OH)D<32 ng/ml, in 59.1% (26/44) of the patients. The mean25(OH)D was 30 ng/ml ± 13 and the median was 29.5 ng/ml (Fig. 1).

The women in this series were more likely to be vitaminD insuf!cient than the men, (p=0.03). Seventy !ve percent(18/24) of women and 40% (8/20) of men were vitamin Dinsuf!cient. Speci!cally, this gender difference was seenwithin the high-energy fracture group in which signi!cantlymore women (80%, 8/10) than men (25%, 4/16) werevitamin D insuf!cient (p=0.01; Table 1a). There was a

Median 33.5

Median 27.5

32

Mean 29.8Mean 30.3

0

10

20

30

40

50

60

70

Men Women

25

(OH

)D [

ng

/ml]

Fig. 1. Vitamin D levels in this patient population sorted by patientgender

144 HSSJ (2008) 4: 143–148

26/44 (59%) vit D deficient

18/24 (75%)

8/20 (40%)

Vitamin D Deficiency: A Common Occurrence in Both High- and Low-energy Fractures

Steele et al, HSSJ 2008:4;143-8

higher prevalence of vitamin D insuf!ciency in low-energyfractures (77.8%, 14/18) vs. high-energy fractures (46.2%,12/26) when both sexes were combined (p=0.06). Therewas no signi!cant difference between vitamin D insuf!-ciency among men vs. women with low energy fractures,(p=0.5) as 100% (4/4) of men and 71.4% (10/14) of womenwere insuf!cient (p=0.5; Table 1b). In the women in thissample, both high- and low-energy fractures present withcomparable vitamin D insuf!ciency: 80% (8/10) and 71.4%(10/14), respectively (p=0.999). In men, signi!cantly morevitamin D insuf!ciency was seen in low energy fractures vs.high energy fractures: 100% (4/4) vs.25% (4/16), respective-ly (p=0.01; Table 1c). In men, the median vitamin D levelwas signi!cantly lower for low energy fractures (19.5 ng/ml)compared to high energy fractures (34 ng/ml; p=0.007).

Overall, the low energy fracture group (mean 71 years)was signi!cantly older than the high-energy fracture group(mean 51 years; p<0.001). In addition, men with lowenergy fractures were signi!cantly older (mean 73 years)than men with high-energy fractures (mean 46 years; p=0.02) (Table 2a). Women with low-energy fractures (mean71 years) were older than those with high-energy fractures(mean 58 years; p=0.053). For women, there was nodifference in the median vitamin D level for high-energyfractures (27 ng/ml) vs. low energy fractures (28 ng/ml; p=0.7) (Table 2b). The mean 25(OH)D level for women andmen by fracture type is shown in Fig. 2. Women showed asigni!cant correlation between age and 25(OH)D (rho=0.46; p=0.2). Older women had higher values of 25(OH)Dthan younger women. For men, there was no signi!cantcorrelation between age and 25(OH)D (rho=!0.2; p=0.2)(Fig. 3).

Discussion

In the present study, a high percentage (59%) of adultfracture patients were vitamin D insuf!cient, de!ned as aserum 25(OH)D level less than 32 ng/ml. Our results areconsistent with data from previous studies indicating thatlow-energy fracture patients are often associated withvitamin D insuf!ciency [1, 22]. The present study also

demonstrated a large subset of high-energy fracture patientswho were also vitamin D insuf!cient. Though one may nothave previously suspected vitamin D insuf!ciency in apatient that sustained a high-energy fracture, this studyindicates that any fracture patient has a considerable risk forvitamin D insuf!ciency, not just low-energy fractures in thecommon osteoporotic sites. The in"uence of vitamin Dinsuf!ciency on muscle strength and bone health may beincreasing the fracture risk among both high- and low-energy impacts.

This study had several limitations. Our study waslimited to a small sample size, and the 25(OH)D levelswere drawn after surgery since this test was ordered aspostoperative fracture care. The differences between vita-min D insuf!ciency (25(OH)D <32 ng/ml) and vitamin Dde!ciency (25(OH)D <20 ng/ml) could not be assessed dueto the small sample size. Also, the quality vs. quantity ofbone could not be assessed in this retrospective review. Inaddition, we included patients into this study irrespective oftheir previous treatment history of calcium and/or vitaminD. The bene!t of including all these patients was to reportthe prevalence of vitamin D insuf!ciency among fracturepatients, regardless of whether they were replete due toprior supplementation. The disadvantage is that somepatients may have been on supplementation prior to theirfracture and the length of time on treatment and how itcorrelated to their 25(OH)D level and bone health was notassessed.

A standard vitamin D treatment protocol was used totreat all patients identi!ed with vitamin D insuf!ciency. Theprotocol consisted of 50,000 IU of vitamin D2 given atvarying frequencies depending on the severity of insuf!-ciency. Patients with 25(OH)D levels in the range of 25–35 ng/ml were treated with 50,000 IU of vitamin D2monthly for 2 months; 25(OH)D levels in the range of 15–25 ng/ml were treated with 50,000 IU every other week fora total of 8 weeks. Patients with 25(OH)D levels less than15 ng/ml were treated with 50,000 IU weekly for 8 weeks,in addition to vitamin D3 1,200 IU maintenance daily. Allvitamin D insuf!cient patients were either treated with thisprotocol and followed by the metabolic bone disease teamor the treatment protocol was recommended to their primary

Table 1 Vitamin D status vs. gender

Men Women Men vs. Womenp valuea

a. High-energy fracturesRepleteb 12 2 0.01De!cientc 4 8

b. Low-energy fracturesRepleteb 0 4 0.5De!cientc 4 10

c. High-energy fractures vs. low-energy fracturesp valuea 0.01 0.999

a p values were calculated using the Fisher’s Exact testb "32 ng/mlc < 32 ng/ml

Table 2 Age and 25(OH)D level vs. fracture etiology

Low-energyfractures

High-energyfractures

p value

a. MenAgea 72.5±16 45.9±19 0.02c

25(OH)Db 19.5 34 0.007d

b. WomenAgea 71.1±14 57.8±18 0.053c

25(OH)Db 28 27 0.7d

aMean age in years ± standard deviationbMedian 25(OH)D ng/mlc p values were calculated using the t testd p values were calculated using the Mann–Whitney test

HSSJ (2008) 4: 143–148 145

What cut-off value defines low vitamin D status?

Serum 25(OH)D

<25 nmol/L 25-75 nmol/L >75 nmol/L

Deficiency Insufficiency Sufficiency

Dawson-Hughes B, Am J Clin Nutr 2008:88(suppl);537S-40S

Variability of vit D concentration by geographical location

Differences in assay methodology

Optimal level of 25(OH)D 30 ng/mL determined in a Caucasian population

Goal of vit D supplementation?

Serum 25(OH)D greater than an accepted cutpoint (e.g. 30 ng/ml)

Upper limit of normal (a value that varies between laboratories)


Does supplemental

vitamin D reduce fractures

and falls?

ObjectiveTo review the effect of vitamin D

on bone density

and fractures in

postmenopausal

women

Data SourceMEDLINE and EMBASE from 1966 to 1999

25 trials

Study Selection

Standard or

hydroxylated vitamin

D with or without Ca

suppl vs control

Measured bone

density or fracture

incidence >1 year

Meta-analysis of the Efficacy of Vitamin D Treatment in Preventing Osteoporosis in

Postmenopausal Women

Guyatt et al, Endoc Rev 2002; 23(4);560-9

Meta-analysis of the Efficacy of Vitamin D Treatment in Preventing Osteoporosis in

Postmenopausal Women

25 trials

Vitamin D (n=4017) vs control (n=4107)

Patients with ↓bone density (17 trials)

Standard vitamin D (10 trials)

Hydroxylated vitamin D (14 trials)

Both forms of vitamin D (1 trial)

Follow-up: 1-5 y

Loss to follow-up<10% (2 trials)10-20% (8 trials)>20% (13 trials)unknown (2 trials)

Blinded (18 trials)

Unblinded (5 trials)

Blinding unclear (2 trials)


Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women

RR with 95%CI for vertebral fractures

combined forearm bone density. Larger effects were seen instudies that did conduct an intention-to-treat analysis. Thesmall number of studies makes inferences from these anal-yses insecure.

For all bone density analyses, we found only one instancesuggesting publication bias, the investigation of the effect of

hydroxylated vitamin D on forearm bone density. One trial,appreciably larger than the rest, showed a negligible effect ofhydroxylated vitamin D on forearm bone density. A numberof small trials showed a substantial effect (Fig. 5). Althoughby no means definitively demonstrating publication bias,these results do raise the possibility.

FIG. 2. RR with 95% CI for vertebral fractures after treatment with vitamin D.

TABLE 2. Weighted RR with 95% CI after treatment with vitamin D

Fracture sites Type standard/hydroxylated

No. oftrials

No. ofpatients RR (95% CI) RR P

valueHeterogeneity P

value

Vertebral Combined 8 1130 0.63 (0.45, 0.88) !0.01 0.16Standard 1 160 0.33 (0.01, 8.05) 0.49 –Hydroxylated 7 970 0.64 (0.44, 0.92) 0.02 0.11

All nonvertebral Combined 6 6187 0.77 (0.57, 1.04) 0.09 0.09Standard 3 5399 0.78 (0.55, 1.09) 0.15 0.05Hydroxylated 3 788 0.87 (0.29, 2.59) 0.80 0.19

We interpreted P ! 0.05 as indicating important between-study differences in results.

FIG. 3. RR with 95% CI for nonvertebral fractures after treatment with vitamin D.

Guyatt et al. • Meta-Analyses of Osteoporosis Therapies Endocrine Reviews, August 2002, 23(4):560–569 565

by on October 18, 2009 edrv.endojournals.orgDownloaded from


Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women

RR with 95%CI for nonvertebral fractures

combined forearm bone density. Larger effects were seen instudies that did conduct an intention-to-treat analysis. Thesmall number of studies makes inferences from these anal-yses insecure.

For all bone density analyses, we found only one instancesuggesting publication bias, the investigation of the effect of

hydroxylated vitamin D on forearm bone density. One trial,appreciably larger than the rest, showed a negligible effect ofhydroxylated vitamin D on forearm bone density. A numberof small trials showed a substantial effect (Fig. 5). Althoughby no means definitively demonstrating publication bias,these results do raise the possibility.

FIG. 2. RR with 95% CI for vertebral fractures after treatment with vitamin D.

TABLE 2. Weighted RR with 95% CI after treatment with vitamin D

Fracture sites Type standard/hydroxylated

No. oftrials

No. ofpatients RR (95% CI) RR P

valueHeterogeneity P

value

Vertebral Combined 8 1130 0.63 (0.45, 0.88) !0.01 0.16Standard 1 160 0.33 (0.01, 8.05) 0.49 –Hydroxylated 7 970 0.64 (0.44, 0.92) 0.02 0.11

All nonvertebral Combined 6 6187 0.77 (0.57, 1.04) 0.09 0.09Standard 3 5399 0.78 (0.55, 1.09) 0.15 0.05Hydroxylated 3 788 0.87 (0.29, 2.59) 0.80 0.19

We interpreted P ! 0.05 as indicating important between-study differences in results.

FIG. 3. RR with 95% CI for nonvertebral fractures after treatment with vitamin D.

Guyatt et al. • Meta-Analyses of Osteoporosis Therapies Endocrine Reviews, August 2002, 23(4):560–569 565

by on October 18, 2009 edrv.endojournals.orgDownloaded from


Proposed Scientific and Ethical Guidelines for Clinical Trials on Vitamin D and Fracture

Osteoporosis Education Project

Vitamin D levels achieved should

be 32 ng/mL

Achievement of vit D sufficiency

should be verified by 25(OH)D

Only those with 25(OH)D >32 ng/

mL should be included

Vit D supplementation

must be continued for at least 12 mos

Vit D3 (cholecalciferol) should be used

1 2 3

4 5


Trial Trial Overview (All RCTs)

Trial Compliance

Serum Vit D (Therapeutic

threshold is 32 ng/mL)

% Fracture Reduction

French Decalyos I Study

3270 ambulatory elderly French women18-month trial800 IU D3 w/ tri-calcium phosphate (1,200 mg elemental Ca)

1,762 (54%) completed the trialGood supplement compliance

16 ng/mL average Vit D level at baseline42 ng/mL average vit D level at completion of trial

32% ↓ in all non-vertebral fractures43% ↓ in hip fractures

French Decalyos I Study Extension

3270 ambulatory elderly French women18-month extension of trial800 IU D3 w/ tri-calcium phosphate (1,200 mg elemental Ca)

Supplement compliance unclear but appears adequate



Vitamin D and Fracture Trials



Trial Compliance




French Decalyos II Study

610 ambulatory French women2-year trial800 IU of D3 with tri-calcium phosphate (1,200 mg elemental Ca)

422 (69%) completed the trial95% supplement compliance


Non-significant ↓ in all non-vertebral fractures31-38% ↓ in hip fractures

British study of vit D and osteoporotic fracture

2,686 community living men and women aged 65-855-year trial100,000 IU tablets of vit D3 every 4 months

75% of participants took the vit D at least 80% of the time66% compliance for final dose

At 4 years29 ng/mL average Vit D level in those on supplements21 ng/mL average vit D in placebo group

33% overall ↓ of fractures (hip, wriat, spine, forearm)




Trial Compliance




Boston area study

389 community dwelling men & women (mean age 74)3-year trialIntervention: 700 IU D3 and 500 mg elemental Ca (as citrate maleate)

318 (82%) completed the trialSupplement compliance appears good



Japanese study of sunlight exposure on BMD & hip fracture incidence among vit D deficient stroke patients

258 stroke patients12-month trial50% of patients had 15 minutes/day of sunlight exposure to face and hands50% were sunlight deprived

Compliance with sunlight exposure appears good

6.8 ng/mL average Vit D level at baseline20.8 ng/mL average vit D level at completion of trial

Sixfold ↓ in hip fracture incidence in the sunlight-exposed group3.1%↑ in BMD in sunlight-exposed3.3% ↓ in BMD in sunlight-deprived




Trial Compliance




Japanese study of hip fracture reduction among Alzheimer’s patients through sunlight exposure

284 Alzheimer’s patients12-month trial1,200 mg elemental calcium 2x/day to both groups; 50% of patients had 15 min/day of sunlight exposure to face, hands and forearms (total exposed skin area 426 +32 cm3); 50% of patients were sunlight deprived

Compliance with sunlight exposure appears good

9.6 ng/mL average Vit D level at baseline20.8 ng/mL average vit D level at completion of trial

4x more frequent non-vertebral fractures in sunlight-deprived group (11 vs 3)4x more frequent hip fractures in sunlight deprived-group (9 vs 2)2.7% ↑ in BMD in sunlight-exposed5.6% ↓ in BMD in sunlight-deprived



Vitamin D and Fracture Trials Some observations


Supplementation with 400 IU vitamin D repeatedly found to have no impact

on fracture incidence

Bischoff-Ferrari et al meta-analysisPooling of 12 studies with 400 IU vitamin D daily failed to influence fracture incidence700-800 IU daily of vitamin D ↓ hip fracture by 26%↓ all fractures by 23%

Vitamin D and Fracture Trials Some observations


Vitamin D at an 800 IU daily dose leads to 25(OH)D

levels of 32 ng/mL in some but not

all subjects

Less than half of adults will achieve 25(OH)D of 32 ng/mL with 700-1,000 IU vitamin D supplementation x 8 weeks

British RECORD trial800 IU vitamin D in older adults raised vit D to an average of 24.8 ng/mLSwiss studyVit D levels increased from 12.3 ng/mL to 26.2 ng/mL in ambulatory elderly given 800 IU D3 daily x 3 months

Vitamin D Status and Treatment of Postmenopausal Osteoporosis with Bisphosphonates

25 (OH) D : 93 [3.3] nmol/L 25 (OH) D : 50 [1.9] nmol/L

#

112 womenOn bisphosphonateEtidronate (n=30)Alendronate (n=64)Risedronate (n=38)Serum 25(OH)D <70 nmol/L (53%)

Deane et al, Alternative BMC Musculoskeletal Disorders 2007

ObjectiveTo evaluate how

supplementation

with vit D alone

affects risk of falling, primarily in

postmenopausal

women

Data SourceMEDLINE, EMBASE, BIOSIS and Cochrane database from Jan 1985 to June 2005

5 studies

Study Selection

Vitamin D vs placebo

Vit D + Ca vs calcium

alone

Studies which

enrolled both men

and women included

Risk of falls

Meta-analysis: Vitamin D and the Risk of Falls

Jackson et al, QJM 2007;100:185-192

5 trials

All RCTs except 1

D3 used in all D3 + Ca (4 trials)

Postmenopausal women only (3 trials)

Mean baseline 25(OH)D were inadequate (defined as <76.2 nmol/L)

Duration 18 weeks to over 5 years

D3 dose from 300 to 800 IU except 1 trial (oral capsule of 100,000 IU vit D3 q4 months)




group: calcium or placebo). However, there was noclear evidence on the effect of vitamin D3 on the riskof non-vertebral and vertebral fractures. Our resultsdiffer from those presented by Bischoff-Ferrari et al.9

who, although not assessing the risk of falls,demonstrated a significant 26% reduction in riskof sustaining a hip fracture and a significant23% reduction in risk of sustaining any

Review: Vitamin D3 reviewComparison: 01 FallsOutcome: 01 Falls including calcium

Study Vitamin D3 (+/! Ca) Control RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Graafmans 62/177 66/177 16.82 0.94 [0.71, 1.24]Pfeifer 11/70 19/67 4.95 0.55 [0.29, 1.08]Bischoff 14/62 18/60 4.66 0.75 [0.41, 1.37]Trivedi 100/270 92/255 24.11 1.03 [0.82, 1.29]Grant 161/1306 196/1332 49.46 0.84 [0.69, 1.02]

Total (95% CI) 1885 1891 100.00 0.88 [0.78, 1.00]Total events: 348 (Vitamin D3 (+/! Ca)), 391 (Control)Test for heterogeneity: Chi! = 4.36, df = 4 (P = 0.36), I! = 8.3%Test for overall effect: Z = 1.95 (P = 0.05)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Figure 1. Results of the meta-analysis for falls.

Review: Vitamin D3 reviewComparison: 01 FallsOutcome: 02 Falls including calcium in post-menopausal women

Study Vitamin D3 (+/! Ca) Control RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

Pfeifer 11/70 19/67 14.67 0.55 [0.29, 1.08]Bischoff 14/62 18/60 13.82 0.75 [0.41, 1.37]Trivedi 100/270 92/255 71.50 1.03 [0.82, 1.29]

Total (95% CI) 402 382 100.00 0.92 [0.75, 1.12]Total events: 125 (Vitamin D3 (+/! Ca)), 129 (Control)Test for heterogeneity: Chi! = 3.59, df = 2 (P = 0.17), I! = 44.2%Test for overall effect: Z = 0.82 (P = 0.41)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Figure 2. Results of the meta-analysis for falls in post-menopausal women only.

Table 2 Results reported in included studies for biochemical markers

Author Fallsa (Y/N) Fracturesa (Y/N) 25(OH)D (nmol/l) n

Baseline Final

Lips et al., 199627

Vitamin D3 N Y 27.00 NR 270c

Placebo N Y 26.00 NR 270c

Meyer et al., 200228

Vitamin D3 N Y 47.00 64.00 34Placebo N Y 51.00 46.00 31Peacock et al., 200029

Vitamin D3 N Y 57.50 NR 95c

Placebo N Y 60.00 NR 95c

Pfeifer et al., 200031

Vitamin D3 Y Y 25.65 NR 148c

Calcium Y Y 24.63 NR 148c

Bischoff et al., 20033

Vitamin D3 Y N 30.75b 65.50b 61 at baseline; 45 at follow-upCalcium Y N 29.00b 28.50b 59 at baseline; 44 at follow-up

Y, measured; N, not measured; aRR reported in forest plots. bMedian value (mean reported unless otherwise stated). cTotalnumber of subjects in both groups.

Vitamin D, falls and fractures 189

Pooled RR for D3 preventing falls 0.88 (95%CI 0.78-1.00)

Postmenopausal women only Pooled RR 0.81 (95%CI 0.48-1.34)


Vitamin D and the Risk of FallsRandomized controlled trials

TrialVit D dose/ preparation

ug (IU)/d

Duration of trial

25(OH)D level achieved

nmol/LOutcome

Muscle performance

SatoPfeiffer

Bischoff

25(1000) D220 (800) D320 (800) D3

3 y2 mo3 mo

846666

+++

Falls

BischoffBroe

FlickerGrant

17.5 (700) D320 (800) D220 (800) D220 (800) D3

3 y5 mo2 y5 y

9975NA62

+++

Null

Dawson-Hughes, Am J Clin Nutr 2008;88(suppl):573S-40S

Vitamin D and Risk of FallsSome observations

Trials assessing impact of vit D on falling more likely to have positive

results when conducted in institutions

Presence of nursing staffMore accurate ascertainment of fallsHigher supplement compliance


Vitamin D and Risk of FallsSome observations

Research has not identified the

minimum 25(OH)D level for maximal

benefit in fall prevention

Trials indicate mean values of 75 nmol/L and 99 nmol/L? higher values might confer benefit




Does supplemental vitamin D reduce fractures and falls?

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Health & Medicine

Vitamin D and Osteoporosis