SUMMARY
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.
INTRODUCTION
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 arc 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 scam 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 scrum 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
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 lemur 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 scrum calcium of 40g/L) and a raised scrum 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 ostcomalacia 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 crcatinine >200 mol/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
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 s\light rising trend in the mean urea.
Table 1 Changes in mean (1 SD)* values of various blood indices over time of patients with osteomalacia after treatment
Figure 1 Morphology of the curves over time
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 under-nutrition was not a major pre-fracture feature in most of the study group.
DISCUSSION
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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S C Allen MD FRCP S Raut MD MPhil
J R Soc Med 2004;97:527-530
Department of Medicine and Geriatrics, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK
Correspondence to: Professor S C Allen
E-mail: [email protected]
Copyright Royal Society of Medicine Press Ltd. Nov 2004
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