Download Osteomalacia and Vitamin D Deficiency among Urban Saudi

Osteomalacia and Vitamin D Deficiency among Urban Saudi Adolescent Girls
Abstract
Objectives
To determine the frequency of clinical osteomalacia caused by vitamin D deficiency
among Saudi adolescent girls in Riyadh, Saudi Arabia.
Methods
Our study evaluated 25(OH)D in 2000 school girls living in Saudi Arabia. This crosssectional study recruited girls ages 12-18 (mean age 16.13±1.77 years)in Riyadh city,
KSA from September 2011 to June 2014. Fasting blood samples were obtained
measuring serum25(OH)D, parathyroid hormone (PTH ) in addition to biomarkers of
bone remodeling. A clinical diagnosis of osteomalacia was considered in subjects with
25(OH)D less than 25 nmol/l in the presence of bone pain , muscle weakness with
elevated alkaline phosphatase , and normal or low serum calcium and phosphorous.
Results
Vitamin D deficiency (Serum 25(OH)D <25nmol/L) associated with bone pains , muscle
weakness , and with elevations in serum alkaline phosphatase consistent with a clinical
diagnosis of osteomalacia was documented in 2.3% of the entire cohort.Vitamin D
deficiency was found to be more prevalent in the summer than in the winter period . Serum
PTH showed a significant inverse association with 25(OH)D at levels below 40nmol/L (r
= -0.21;p<0.001).
Conclusions
Vitamin D deficiency is a common health problem among Saudi adolescent girls. In a
good number of girls, this can progress to osteomalacia. To counteract this deficiency, a
national program should be designed to increase intake of vitamin D rich foods, sun
exposure and supplementation of food with vitamin D.
Acknowledgments
The authors express their appreciation and gratitude to King Abadulaziz City for Science
and Technology (KACST) for funding this study (AR-28-91).
Key Words:Osteomalacia, Parathyroid hormone, Bone turnover, 25 (OH)D.
1
Introduction
Osteomalacia is defined as reduced or incomplete mineralization of normal osteoid tissue
following closure of growth plates 1,2. It results from inadequate exposure to sunlight,
poor intake or reduced absorption of vitamin D. Manifestations include impaired bone
mineralization and in severe cases hypocalcemia and/or hypophosphatemia. Vitamin D
deficiency has re-emerged as a major health concern in the 21st century in both developed
and developing countries 3,4 and remains the most common cause of osteomalacia 5,6.
Vitamin D deficiency may also have extra-skeletal manifestations, which are being
further evaluated in randomized clinical trials. Osteomalacia secondary to vitamin D
deficiency is a common clinical problem encountered in the Saudi population, including
Saudi adolescent females 7,8. The condition is associated with nonspecific generalized
muscle and bone pain as well as gait abnormalities and may be misdiagnosed as
fibromyalgia or arthritis. The presentation of vitamin D deficiency may range from an
asymptomatic state to clinical osteomalacia. This study was undertaken to determine the
frequency of clinical osteomalacia defined as 25OH)D level of ˂ 25nmol/l in the
presence of an elevated alkaline phosphatase and with clinical features of muscle and
bone pain in adolescent girls recruited in intermediate and secondary schools in the entire
city of Riyadh, Saudi Arabia .
Methodology
In this cross- sectional study, a total of 2000 school girls (aged 12-18 years) from
intermediate and secondary schools were recruited during the period September 2011 to
June 2014. The study was conducted in Riyadh city (latitude, 24.6º N). School girls
from southern, northern, central and western parts of Riyadh City were enrolled using the
stratified random technique. Proportional allocation method was used to determine the
number of students recruited from each stratum. Within the stratum, one or more schools
were selected randomly for recruitment. Informed consent from each student's parent or
guardian was obtained through an official letter from the principal investigator and his
team. A written assent was obtained from participants. All consenting subjects completed
a generalized questionnaire, which included basic demographic data, medical history
related to bone health, and lifestyle data. . Direct sun exposure to face and arms in
minutes per day during weekdays and weekend in the last week was recorded. Dietary
intake with emphasis on dietary vitamin D and calcium using the 7-day semi quantitative
food frequency questionnaires were adapted for use from previous local studies. 9,10.
The questionnaire consisted of Saudi food list, definition of portion sizes , and
assignment of frequency of consumption with special emphasis on food items with
calcium – in dairy or non-dairy products- or foods fortified with vitamin D . A specific
section of the questionnaire was used to record vitamin D or calcium supplements intake.
Subjects were asked if they had bone aches and pains. Pain was recorded as "present" or
"absent" as perceived by the adolescent girl. Proximal muscle weakness was tested by
abducting shoulders against resistance. Weakness was reported if muscle strength was
2
less than grade 4 using the medical research council (MRC) system 11. Waddling gait
was reported if while walking on a straight line, there was waddling and exaggerated
lumbar lordosis. Bowing of the legs was identified if there was (outward) bowing of the
lower leg in relation to the thigh. None of the subjects were using calcium or vitamin D
supplements.
Anthropometrics were obtained by a general practitioner. Height in centimeters was
obtained using a standard stadiometer and weight - without shoes – in kilograms was
obtained. Definitions of normal weight, overweight, and obesity in this age group was
according to expert committee recommendations regarding the prevention, assessment,
and treatment of child and adolescent overweight and obesity 12.
Fasting serum samples were obtained during winter months – December to February –
and during summer months – June to end of August - . Blood samples were frozen at – 80
º C. Batches were analyzed within 3 days of receiving samples for the following: serum
calcium, phosphorous, albumin, alkaline phosphatase, creatinine, 25(OH)D and PTH.
Osteocalcin and carboxy- terminal telopeptides of crosslinks of type I collagen (CTX)
were analyzed in 500 girls selected at random.
Vitamin D inadequacy was defined based on the cut-off recommendations by the
European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
(ESCEO)and the Institute of Medicine (IOM) of serum 25(OH)D below 50nmol/l. 13,14.
Osteomalacia was clinically diagnosed in subjects with 25(OH)D deficiency
of<25nmol/l) in the presence of bone pain and muscle weakness as well as the following
biochemical features 15 :elevations in serum alkaline phosphatas,normal or low serum
calcium corrected for albumin,andormal or low serum phosphorous level.
Biochemical assays :The serum levels of calcium, phosphorous, and alkaline phosphatase
were determined using Dimension Xpand Plus autoanalyzer 9Siemens Healthcare
Diagnostics). Serum 25(OH)D was measured using the electrochemiluminescence
binding assay using Roche (Cobas e 411 analyzer) .All measurements were performed in
A RIQAS – Randox International Quality Assessment Scheme- participating laboratory
of King Khalid University Hospital. The intra assay coefficient variation (cv) was 2.2-6.8
while the inter assay cv was 3.4-13 %. Serum PTH was measured using
elecrochemiluminescence assay (Roche-modular E-170).
Bone profile and creatinine were measured using the colorimetric method (Dade
Boehring Dimension RxL Max). CTX and osteocalcin were determined using
electrchemiluminescence immunoassay by the Roche automated system.
Statistical analysis : SPSS version 21 (SPSS Inc., Chicago, IL, USA) was used for data
analysis. Continuous data were presented as means, medians , and standard deviation
while frequencies were presented as percentages (%). Independent T-test was used to
compare differences of normally distributed variables and Mann-Whitney for nonGaussian variables. Chi square test was used to test association between categorical
variables. Person coefficient correlation (R) was used to test correlation between two
continuous variables. Ascatter graph using the linear model was used to display the
correlation. Significance was set at p=0.05.
Results
Table 1 highlights the demographic characteristics of the subjects. Majority of the
adolescents recruited were in secondary education (62.6%). Based on daily sun exposure,
3
face, and arms, more than half of the subjects (55.8%) acknowledged that they expose
themselves to sunlight for less than 10 minutes daily, and only 29.5% expose themselves
for more than 20 minutes. The overall prevalence of obesity (weight of 95 th percentile or
greater) was 5%. Approximately 2 out of 5 subjects (43.5%) reported bone pain and
almost 1 out of 5 subjects (17.8%) reported pain on walking. 40.8% of the girls had
25(OH)D levels ˂ 25 nmol/l in winter , while it was in 63% in summer. Clinical
osteomalacia was identified in 2.3 % of the entire cohort based on the criteria outlined
above. However , there were 69 girls (4.5 %) who had biochemical features of 25(OH)D
˂ 25 nmol/l with elevated alkaline phosphatise , but with no clinical symptoms or signs
suggestive of osteomalacia such as bony pain or muscle weakness. Fresh milk intake was
poor in the present cohort, with 55.5% consuming less than one cup daily. In contrast,
77.4% of the subjects consumed 1-6 cups of carbonated drinks on a daily basis (Table
1).Cream was consumed by 8.6% daily and 16.9 at least once weekly. More than one
third of the girls did not use it (37.5%). White cheese consumption followed the same
pattern where 18.1% used it daily and 16.3% used it at least once weekly. Full cream
yoghurt was used daily by one eighth of the studied girls (12.9%), but only 5.2% used
half cream yoghurt daily. Around one third of the sample (33.8%) did not consume full
cream yoghurt and around one half (51.1%) did not consume half cream one.
31.7% of the girls ate canned fish rarely. One fifth of them (19.7%) ate canned fish 1 -3
times per week, 11.2% ate it daily and 14.9% ate it every once every two weeks. Eggs
were consumed by 7.9% daily, 17.5% 1-3 times per week, and 8.8% once every two
weeks. Around one fourth of the sample did not consume eggs at all.
Daily calcium intake was 691.1 mg in the vitamin D deficient girls - 25(OH)D ˂ 25
nmol/l – while it was 1358.89 mg daily in girls with normal 25(OH)D levels ( p < 0.001).
Table 2 shows the demographics of subjects with a mean age of 16.13±1.77 years; mean
age of menarche was 12.76±1.2 years. Differences in mean biochemical parameters based
on season were also presented in table 2. Circulating 25(OH)D levels were significantly
higher during the winter season – December to end of February - (p<0.001) as well a
significantly higher serum calcium level was observed in the winter months than in the
summer months – June to end of August - (p<0.001) . Of note, serum ALP and PTH were
also significantly lower in the winter group as opposed to the summer group (Table 2).
The mean serum calcium level in winter was 2.29 ± 0.19 mmol/l while summer it was
2.06 ± 0.74 mmol/l. There was negative correlation between serum calcium and alkaline
phosphatse (r=-0.139, p< 0.01). The correlation between 25(OH)D and alkaline
phosphatase was) r=0.051),p >0.05.
Table 3 shows the vitamin D status of subjects stratified and compared according to
different risk factors. Vitamin D deficiency was most prevalent among subjects with no
sun exposure (40.3%) and those with minimal intake of fresh milk (56.7%). Furthermore,
there is a significant difference in the prevalence of vitamin D deficiency in relation to
carbonated drinks consumption, with those consuming more having a higher percentage
of vitamin D deficiency than those who consume less than once per day (p<0.001). It
may be possible that this is due to lower milk intake in those with a high intake of
carbonated drinks. With regards to the weight, vitamin D deficiency was more prevalent
among those with normal weight (80.8%) than (5.7%) in obese subjects. The prevalence
4
of 25(OH)D deficiency was higher among those with normal circulating osteocalcin than
those with elevated levels. The prevalence of 25(OH)D deficiency is significantly higher
in the summer than winter season (p<0.001).
Figure 1 shows that there is a negative correlation between low 25(OH)D level in general
and PTH levels ( r=0.024) but the correlation was not significant (p=0.351). The figure
shows that at levels of 40 nmol/l, the PTH starts to increase. At the level of  40 nmol/l
the negative correlation was r=0.15 and it was statistically significant (p˂0.001).
Discussion
The present study documented a high prevalence of vitamin D deficiency among Saudi
adolescent girls. This confirms many previous reports indicating a strikingly high
prevalence of vitamin D deficiency in the different age groups and in both sexes of the
Saudi population 16-18. The degree of sun exposure was generally minimal in the
majority of the girls and it is difficult to know the time of day that the sun exposure
occurred. Other investigators have previously suggested a certain duration of sun
exposure (including arms and legs for a period of 5 to 30 minutes) considering
differences in the intensity of the sunlight exposure as well as in skin pigmentation. [21].
The UVB necessary for cutaneous conversion of 7-dehadocholesterol to pre-vitamin D3
is 290-315 nm.
The difference in the vitamin D levels between summer and winter was striking and is the
opposite of what has been reported from countries at higher latitudes, which found higher
vitamin D levels during summer months, when people are more likely to be outdoors and
obtaining increased sunlight exposure 19-22. A similar observation to ours was made by
Al-Daghri and his group 23 which suggests that although sun exposure in Middle Eastern
and Gulf States may be minimal, an increase may occur in winter when people may be
more outdoors, and this could raise vitamin D to modest levels. It is to be noted that in
relation to sun exposure, the particular timing of exposure was found to be of importance.
Alshahrani et al found that the optimum time for vitamin D skin formation in people
living in the Riyadh area during summer is from 9:00Am to 10: 30Am and from 2:003:00pm. In winter, it was suggested that the optimal time for sun exposure is from
10:00am-2:00pm 24.
With regards to the seasonal variation, the Canadian Health Measures Survey (CHMS)
examined 25(OH) vitamin D levels in a representative sample of the Canadian
population, and, in 456 girls aged 12-19 years, the mean 25(OH) vitamin D ranged from
60.8 nmol/l (winter, no supplement use) to 76.8 nmol/l (summer, no supplement use)
25.The IOM report suggests osteomalacia and rickets are most likely to be associated
with 25(OH)D levels below 30 nmol/l [14]; and in CHMS, this was found in 3.8% of
Caucasian boys and girls and 17.5% of “non-Caucasian” adolescents aged 12-19 years
(non-Caucasian includes people of Chinese, South Asian, African, Filipino, Latin
American, Southeast Asian, Arab, West Asian, Japanese, Korean, Aboriginal, and other
racial backgrounds). An earlier study of 1753 Québec schoolchildren (871 girls) aged 9,
13, and 16 years, found a larger proportion had low vitamin D status, and in particular,
5
2%, 8%, and 10% of 9-, 13, and 16-year-old girls had frank vitamin D deficiency
(defined as a serum 25(OH)D ≤ 27.5nmol/l) 26.
The nutritional status of the girls, in relation to vitamin D deficiency and osteomalacia,
has revealed that a small number of the girls consume sufficient milk or other dairy
products. This appears to be cultural or related to the currently prevailing dietary habits
of girls in this age group. This low dairy intake was coupled with a relatively high intake
of soft drinks. Worthy to note is that milk in Saudi Arabia is fortified with vitamin D –
400 iu/liter of milk. This could further exacerbate a pre-existing vitamin D insufficient
state possibly present from infancy.
Our study revealed a significant proportion of subjects (2.3%) had vitamin D deficiency
in the presence of elevations in alkaline phosphatase consistent with a clinical diagnosis
of osteomalacia. It is evident that our cohort had variable degrees of vitamin D
insufficiency, with evidence of secondary hyperparathyroidism observed in
approximately10% of subjects. A significant percentage of these individuals may have
had elevations in serum PTH within the normal reference range. 27. Ardawi et al found
no threshold of serum 25(OH)D at which PTH levels plateaued in Saudi men 18.
However, secondary hyperparathyroidism was evident in 18.5 % and 24.6 % in pre and
postmenopausal women with 25(OH)D below 50 nmol/l 17. In our study, the negative
correlation between serum vitamin D levels and PTH appeared at around 40nmol/l. This
is lower than in some other studies. However similar observations have been documented
before. In Chinese premenopausal women, a serum vitamin D level of 40nmol/l was
found to be the optimum level to "suppress" PTH 28. In an older study by Lips, a level of
30 nmol/l was enough to suppress PTH level in elderly subjects 29. Interestingly, in
Finnish adolescent girls, it was observed also that at levels of 25(OH)D of 40 nmol/l or
above, PTH would start to be suppressed 30. This observation in our girls – in contrast to
some other studies-may be a reflection of elevations in serum PTH within the normal
reference range. It is also evident that many girls were having variable degrees of
hypocalcemia in summer, which could contribute to the clinical observation of
osteomalcia. It is also possible- although unlikely- that magnesium deficiency may be
present in our study population , resulting in a blunted rise in PTH due to low
intracellular magnesium31,32. Intracellular reductions in magnesium can result in a
paradoxical block of PTH secretion 33,34 .We did not measure serum magnesium in our
study population and this requires further evaluation. However, hypomagnesaemia is
generally rare, except in severely malnourished elderly individuals or critically ill patients
or those with poor gastrointestinal absorption.
It is also possible that our young subjects displayed a different PTH response in
comparison to the elderly population. This requires further study in well designed
randomized controlled trials. Ethnic differences have been noted in the response of PTH
and BTMs to vitamin D deficiency. Aloia et al found that in African American women,
the PTH does not decline rapidly when serum concentrations of 25(OH)D are more than
40nmol/l 35. Dawson-Hughes et al emphasized the great debate in this subject,but
suggested that the optimum vitamin D level that appears to suppress PTH levels ranges
from 30-99 nmol/l with a cluster in the 75-80 nmol/l range36. A recent meta-analysis by
Bjokrman suggested that responses of PTH to vitamin D supplementation are not only
6
determined by the baseline PTH levels and changes in vitamin D status, but also by age
and mobility of the patients 37. In our population, and particularly in this age group, it
would seem that levels of 40-50nmol/l may be considered sufficient to suppress PTH.
Some studies failed to showa specific correlation between vitamin D and PTH
38,39.Investigators reporting this "lack of association” claimed that PTH secretion is
primarily regulated by extracellular calcium concentrations. Individuals with a blunted
PTH response have shown a lower serum calcium concentration, a reduction in bone
turnover and protection of bone density in comparison with those who have
hypovitaminosis D and secondary hyperparathyroidism. In a study by Barnes et al, there
was no significant effect of vitamin Dsupplementation on bone turnover markers or PTH
concentrations 40.
In short, it would seem that this lack of consistency in the relationship between 25(OH)D
levels and PTH could be related to important confounding factors including age –
especially during puberty -,gender, pre and postmenopausal states, degree of mobility,
status of calcium intake , and ethnic background.
The authors acknowledge these limitations. Boys were not included , as the study
concentrated on females who are at a higher risk for vitamin D deficiency. The diagnosis
of osteomalacia was made clinically and was not confirmed by bone biopsy.
Nevertheless, the present study is the first large scale observation to document the
prevalence of vitamin D inadequacy and clinical osteomalacia amongst Arab adolescent
girls in the region and raises the clinical importance of vitamin D deficiency in this
under- studied population.
In summary, a high prevalence of vitamin D deficiency amongst Saudi adolescent girls
was noted , with a greater frequency of this condition in the summer months than in the
winter months. This may be a reflection of the severe heat in the summer resulting in
girls avoiding the outdoors as much as possible. Subjects with vitamin D deficiency had
lower calcium intake, higher intakes of soft drinks , and had minimum sun exposure.
Vitamin D deficiency was accompanied with subnormal calcium levels and elevated PTH
levels. PTH appears to plateau around 25(OH)D levels of 40nmol/l. A biochemical
diagnosis of osteomalacia was evident in a significant number of Saudi adolescent girls.
Serious attempts should be undertaken to address this serious health care issue and its
consequences in this population. Girls should be encouraged to obtain sun exposure in
schools and homes, even for short time. Morefood fortification with vitamin D for
different dairy products, cereals and flouris needed in Saudi Arabia. Screening for
vitamin D deficiency is necessary in this age group in order to prevent rickets and
osteomalacia.
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Table 1. General Characteristics of Subjects included in the study
Parameter
N
Education
N (%)
2000
11
Intermediate
Secondary
Daily Sun Exposure
<10minutes
11-20 minutes
>20 minutes
Physical Inactivity (%)
Obesity (%)
Bone Pain (%)
Pain on walking (%)
Osteomalacia
Daily Fresh Full Cream Milk Intake
<1 Cup
1-3 Cups
4-6 Cups
Daily Intake of Carbonated Drinks
<1 Cup
1-3 Cups
4-6 Cups
Note: Data presented as frequency (%)
748 (37.4)
1252 (62.6)
1116 (55.8)
294 (14.7)
590 (29.5)
1124 (50.6)
75(5.0)
870 (43.5)
356 (17.8)
33(2.3%)
1110 (55.5)
568 (28.4)
322 (16.1)
452 (22.6)
876 (43.8)
672 (33.6)
12
Table 2. Demographics and Differences in Biochemical Profile of Subjects According to Season
Parameter
Mean ± SD
Age (years)
16.13 ± 1.77
Age at menarche (years)
12.76 ± 1.2
N
25 (OH)D ( 50-125 nmol/l)
Calcium mmol/l ( 2.1 -2.5
Winter
Summer
1529
471
30.6 (3.5-155.0)
21.3 (7.5-131.5)**
2.29 ± 0.19
2.06 ± 0.74**
47.15 ± 10.69
48.16 ± 20.59
98.21±52.45
130.11±100.67**
5.06±5.57
5.98±5.55*
40.29 ± 21.34
38.53 ± 28.15
0.37 ± 0.24
0.37 ± 0.26
mmol/l)
Creatinine µmol/l ( 50-110
µmol/l)
ALP u/l (35-100 u /l )
PTH pmol/l (1.3-6.8pmol/l)
Osteocalcin ng/ml (11.0-43.0
ng/ml)
CTX µg/ml (0.10-5.94 ng/ml)
Note:
#denotes
median
(minimum-maximum);
13
*denotes
p<0.05;
**denotes
p<0.01
Table 3 Prevalence (%) of Vitamin D Deficiency, Insufficiency and Sufficiency According to risk factors
Deficiency
Insufficiency
Sufficiency
Daily Sun Exposure
0 minutes
260 (40.3 )
82 (15.0)
41 (9.6a
1-10minutes
199 (30.9)
240 (44.0)
81 (19.0)
11-20 minutes
87 (13.5)
107 (19.6)
44 (10.3)
21-30 minutes
60 (9.3)
65 (11.9)
238 (55.7)
>30 minutes
39 (6.0)
52 (9.5)
23 (5.4)
Daily Fresh Full Cream Milk Intake
<1 Cup
251 (56.7)
265 (54.9)
76 (53.9b )
1-3 Cups
113 (25.5)
138 (28.6)
52 (36.9)
4-6 Cups
79 (17.8)
80 (16.5)
13 (9.2)
Daily Intake of Carbonated Drinks
<1 Cup
85 (15.5)
164 (27.8)
48 (26.5c )
1-3 Cups
250 (45.7)
257 (43.6)
70 (38.7)
4-6 Cups
212 (38.8)
168 (28.5)
63 (34.8)
Weight
Underweight
21(3.4)
23(3.4)
5(2.4 )ͩ
Normal
497(80.8)
553(82.2)
176(85.4)
Overweight
62(10.1)
62(9.2)
144(9.6)
Obese
35(5.7)
35(5.2)
5(2.4)
270 (40.2)
324 (48.3)
77 (11.5f )
Presence of Bone Pain
Osteocalcin
Elevated
190 (33.5)
189 (28.5)
67 (31.9g )
Normal
377 (66.5)
473 (71.5)
68.1
Season
Summer
317 (63.5)
139 (27.9)
43 (8.6h )
Winter
660 (40.8)
460 (28.4)
498 (30.8)
a
b
c
d
e
f
g
h
p<0.001; p=0.038; p <0.001; p=0.6; p<0.001; p=0.05; p=0.16; p<0.001
14
Figure 1Inversecorrelation between 25(OH)D and PTH (R-0.024; p=0.351)
15