J R Soc Med 2004;97:527-530
doi:10.1258/jrsm.97.11.527
© 2004 Royal Society of Medicine
Biochemical recovery time scales in elderly patients with osteomalacia
S C Allen MD FRCP
S Raut MD MPhil
Department of Medicine and Geriatrics, Royal Bournemouth Hospital, Castle
Lane East, Bournemouth BH7 7DW, UK
Correspondence to: Professor S C AllenE-mail:
stephen.allen{at}rbch-tr.swest.nhs.uk
 |
SUMMARY
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Osteomalacia is not rare in the UK and climatically similar
countries,
particularly in elderly people and those of Asian
descent. Overt clinical
osteomalacia is usually treated with
a loading dose of vitamin D, followed by
a regular supplement.
However, little is known of the time taken to reach a
stable
biochemical state after starting treatment. Such information
would shed
light on the duration of the bone remineralization
phase and guide decisions
on the length of follow-up. To address
this we conducted a 2-year follow-up
study of 42 patients (35
female, mean age 80.8 years) with biopsy proven
osteomalacia
treated with a standard replacement regimen and general
nutritional
support.
Although normocalcaemia was attained within 4 weeks the mean values
continued to rise, to a mid-range plateau at 52 weeks. The phosphate and
alkaline phosphatase values also took at least a year to reach a stable mean,
with a slight further trend towards the mid-range for the entire 104 weeks.
The mean serum albumin also rose throughout the first 52 weeks, indicating an
effective response to the general nutritional support measures.
Our observations suggest that the dynamic relationship between calcium,
phosphate and bone requires at least a year, and probably longer, to reach an
equilibrium after treatment for osteomalacia in elderly patients. The findings
emphasize the need for close medical and social follow-up in this clinical
context.
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INTRODUCTION
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Osteomalacia is a generalized disorder of bone in which impairment
of
mineralization results in the accumulation of unmineralized
osteoid. Vitamin D
deficiency is the major cause, usually as
a result of dietary lack, inadequate
exposure to sunlight, or
both. In childhood this leads to classical rickets,
now rare
in the UK and similar developed northern countries because of
improved
nutrition. Conversely, osteomalacia in adults is not an uncommon
condition,
and there is ample evidence that frail elderly patients are
particularly
at
risk,
1,2
mainly as a result of suboptimal skin exposure to
sun.
3,4
Elderly
Asians living in Britain probably have an even higher prevalence
of
osteomalacia because of an adverse diet, darker skin and
traditional dress
codes.
5 Osteomalacia
predisposes to bone fracture,
skeletal deformity and bone
pain.
4 The
underlying low levels
of active vitamin D also lead to muscle weakness,
myalgia and
symptomatic
hypocalcaemia.
6
Furthermore, less overt manifestations
of vitamin D undernutrition, such as
persistent low-level muscle
aching, can occur in patients over a wide range of
ages and
skin pigmentation levels in northerly
latitudes.
7 Even in
areas
of high average sunlight duration, frail patients and people
with poor
nutrition and low skin exposure are at high
risk.
8
Though osteoporosis is the main risk factor for fracture of the neck of the
femur, a proportion of such patients prove to be osteomalacic—less than
1% in one study where strict histomorphometric criteria were
applied.9 The gold
standard for the diagnosis of osteomalacia is a bone biopsy showing an excess
of osteoid and subnormal number of calcification fronts. The usual criteria
are an osteoid seam width of greater than 13 microns, osteoid surfaces more
than 24% and mineralizing surfaces less than
60%.10 Supportive
biochemical changes include low serum calcium and phosphate concentrations, a
low serum 25-hydroxyvitamin D and high blood levels of parathyroid hormone and
alkaline phosphatase. Patients do not always have all these
findings,11 and the
usefulness of serum 25-hydroxyvitamin D assays in elderly individuals has been
questioned on the grounds that low levels are found in patients with and
without
osteomalacia.12
Nevertheless, there is evidence that vitamin D subnutrition, defined in terms
of an abnormally low serum 25-hydroxyvitamin D, is a predisposing factor for
accelerated osteoporosis in elderly people in developed
countries.13
When a patient is proven to have osteomalacia in the context of fractured
neck of femur it is mandatory to treat the deficient state with vitamin D
replacement. If the deficiency is due to dietary lack and/or low sunlight
exposure the usual regimen is an intramuscular loading dose of 300 000 units
(7.5 mg) vitamin D followed by an oral supplement of 400–800 units
daily, though recommendations vary and large-scale trial evidence is lacking.
Certainly such doses will return serum 25-hydroxyvitamin D concentrations to
the normal range and in most patients normalize the serum calcium and
phosphate
concentrations.14
However, there are no published data about the pattern of recovery of serum
calcium, phosphate and alkaline phosphatase, and the associated symptoms and
mobility, over subsequent months. Such information would help to guide
nutritional support regimens. Therefore, we conducted an open observational
longitudinal study of the rate and duration of the recovery phase of those
biochemical indices in elderly patients with fractured neck of femur and
proven osteomalacia surviving at least 2 years after the fracture while
receiving standard vitamin D replacement and nutritional support.
|
METHODS
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We prospectively studied 42 patients (35 female) with a mean
age of 80.8
years (range 66–99). All were admitted to
hospital urgently for a
fractured neck of femur and underwent
operative management. Patients were
selected consecutively from
a group of patients who had a bone biopsy
performed at the time
of operation for diagnostic purposes because of a
suspicion
of osteomalacia or malignancy. Patients were included in the
study
if they had a biopsy positive for osteomalacia (according
to the criteria
specified in the Introduction), a low serum
calcium (corrected to the
equivalent at a serum calcium of 40
g/L) and a raised serum alkaline
phosphatase at presentation.
For the purposes of analysis, only patients
surviving the 2-year
follow-up were included. The total number of patients
admitted
with a fractured neck of femur was 4050 over a 9-year period,
222
(5.5%) of whom were suspected of being vitamin D deficient
on radiological,
clinical and/or biochemical grounds. 77 (1.9%)
were proven to have
osteomalacia by bone biopsy and 42 (1.03%),
the study group, survived and
attended the 2-year follow-up.
We excluded patients with chronic renal failure
(serum creatinine
>200 µmol/L), coeliac disease or overt malabsorption,
severe
co-pathologies likely to result in an early death, phenytoin
therapy
and known primary parathyroid disorders.
The study group had measurements made of serum calcium, phosphate, albumin,
alkaline phosphatase, haemoglobin, urea, sodium and potassium at presentation
(week 0) and at 2, 4, 6, 8, 12, 24, 36, 52, 76 and 104 weeks, during inpatient
treatment and subsequent follow-up in a day hospital or clinic. The timing of
the follow-up biochemical samples began with the first dose of vitamin D. All
received a starting replacement dose of 7.5 mg (300 000 IU) vitamin D by
intramuscular injection at the beginning of the study period, a mean of 6 days
postoperatively. In most cases this was on clinical suspicion of osteomalacia
while biopsy confirmation was awaited. This was followed by an oral supplement
of 800 IU daily in the form of calcium and vitamin D combined tablets (plain
vitamin D was not available). All were given general nutritional information
and advice, with support in the form of meals-on-wheels, luncheon clubs and
assisted shopping when appropriate, and with reinforcement during follow-up
contacts. All patients proceeded down our usual rehabilitation track for
fractured neck of femur, with a wide range of functional outcomes. We also
obtained narrative data from the case notes and during follow-up about
pre-fracture and post-treatment mobility and symptoms.
The data were analysed by use of SPSS software. A normal parametric
distribution about the mean was assumed and the t test was applied to
identify statistically significant differences.
|
RESULTS
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The blood indices are shown in
Table
1 and the morphology of
the curves over time is illustrated in
Figure 1. The mean value
of
corrected serum calcium rose into the normal reference range
(2.20–2.67
mmol/L) and was significantly higher by week
4, but continued on a rising
trend to reach an apparent plateau
at about 52 weeks. Similarly, the mean
phosphate concentration
rose within the normal range (0.80–1.40 mmol/L),
reaching
a significantly different value at 12 weeks and then showing
a
steadily rising trend throughout the 104 weeks of follow-up.
The alkaline
phosphatase response was more complex. The baseline
levels were high, probably
partly as a result of the underlying
osteomalacia; there was a peak at 6 weeks
in response to the
fracture and the vitamin D loading dose, after which values
declined
gradually into the normal range (25–115 IU/L) by 52 weeks.
A
slight downward trend was still apparent at 104 weeks. Rising
trends with time
were also observed for haemoglobin and albumin,
reaching statistical
significance in the case of albumin at
36 weeks. The low mean haemoglobin at
week 0 was probably due
to blood loss at the time of the trauma and operation;
some
patients received a blood transfusion, hence the higher mean
value by
week 2. Renal function and electrolyte homoeostasis
were remarkably stable
throughout the follow-up, though there
was a slight rising trend in the mean
urea.
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Table 1. Changes in mean (1 SD)* values of various blood indices over time of
patients with osteomalacia after treatment
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Analysis of the narrative data showed that, before the fracture, 66% of
patients had been experiencing bone and muscle pain or aching, mainly in the
legs and pelvis, whereas at the end of the follow-up period the proportion
with such symptoms was only 21%. The figures for independent walking were 59%
and 84% respectively. The fact that the mean body weight rose by only 0.3 kg
in men and 0.1 kg in women from the time of admission to week 104 suggests
that calorie undernutrition was not a major pre-fracture feature in most of
the study group.
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DISCUSSION
|
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We have found that, in elderly patients with osteomalacia, the
serum
calcium returns to the normal range within about 4 weeks
of starting treatment
with a standard vitamin D replacement
regimen. This is consistent with
expectations in this clinical
context.
15 The mean
phosphate concentration was within the normal range
throughout but rose to the
mid-range after treatment. This finding
is in keeping with the observation
that older people tend not
to be as hypophosphataemic as younger people with
osteomalacia,
probably because of the reduced urinary phosphate excretion
in
older age as glomerular filtration rate declines. More interestingly,
we
showed that the mean values of serum calcium, phosphate and
post-fracture
alkaline phosphatase continue to change towards
the mid–normal range for
at least a year after vitamin
D repletion and the start of a general nutrition
programme.
One explanation might be that the initial dose of 300 000 IU
of
vitamin D was too low or that the daily oral dose was inadequate.
This is
unlikely since those doses are known to achieve sustained
normal blood
25-hydroxyvitamin D levels within four months of
the loading
dose.
14 More
likely, the process of establishing
a stable chemical relationship between
bone, calcium, phosphate,
calcitonin and parathyroid hormone requires at least
a year,
and possibly as much as 2 years, in severely vitamin D depleted
individuals
receiving adequate replacement therapy. This is consistent with
a
histomorphometric study which showed a reduction in osteoid
volume over a mean
period of 2 years in patients receiving treatment
for
osteomalacia.
16
Such an explanation is supported by the
observed reduction of transformation
of vitamin D to the active
metabolites in old age and relative resistance to
its effect
in the intestine and on
bone.
17 It could be
argued that our
study should have included measurements of serum
25-hydroxyvitamin
D and parathyroid hormone. These were not available to us
for
routine clinical use when the study began and were omitted for
that
reason. Furthermore, the diagnosis of osteomalacia was
established
histologically, so parathyroid hormone was not required
for that purpose.
Also, the probable unreliability of 25-hydroxyvitamin
D measurement for
confirming the diagnosis of osteomalacia has
been mentioned above. There is no
doubt that an additional insight
into the time-scale of the recovery of bone
metabolism to a
homoeostatic state would have been gained by tracking the
changes
in parathyroid hormone over the 104 week period. The importance
of our
observations to clinical practice lies in the apparently
long duration of the
bone metabolic recovery period in this
context. This indicates that a
sustained attempt to keep osteomalacic
patients adequately nourished and
vitamin D replete is required,
with adequate medical and social follow-up. The
continued rise
in the mean albumin concentration over the first 52 weeks
highlights
the need for general nutritional support of frail elderly
individuals
in these clinical circumstances. The cost of providing vitamin
D
supplements is low in comparison with the potential health
benefits, which are
established for bone risk and mobility.
Furthermore, there is some evidence
that vitamin D deficiency
carries an excess risk of prostate, colon and breast
cancers,
though the explanation for this probably lies with associated
general
nutritional and lifestyle
patterns.
18
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