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EFFECTS OF CALCITRIOL [ROCALTROL] ON SPINE AND FEMORAL NECK BONE MINERAL DENSITYIN POSTMENOPAUSAL OSTEOPOROSIS

DURU SHAH*, SAFALA SHROFF**, BHAVIN JANKHARIA+, ANAND PARIHAR++

*Honorary Consultant, Nowrosjee Wadia Maternity Hospital, Mumbai 400012, India. **Consultant, Meera Nursing Home, Diamond Garden, Chembur, Mumbai 400071. +Consultant Radiologist, Dr. Jankharia’s Imaging Centre, Mumbai 400 004. ++Mangal Anand Hospital, Chembur, Mumbai 400 071.

Aim: In the present study of postmenopausal women we have investigated the effect of Calcitriol (Rocaltrol) on bone mineral density (BMD) by using dual energy x-ray absorptiometry (DXA) to measure the bone density at the spine and hip. We have also compared the diagnostic findings of DXA of spine and hip with Ultrasonography (USG) of the calcaneus bone at the same time to determine if USG was a reliable indicator of osteoporosis.

Subjects: One hundred and eighty four postmenopausal women (mean age 54.5 years) were recruited into a non- randomized study of the effect of calcitriol on bone density at the Nowrosjee Wadia Maternity Hospital, Osteoporosis Clinic. The women were divided into three groups based on the findings of their DXA done at the start of the study. The first group (group I) consisted of women whose DXA showed osteoporosis and were treated with calcitriol (Rocaltrol) 0.25mg bd/day for one year. The second group (group II) comprised women with osteopenia diagnosed by DXA and were treated with calcium 500 mg twice /day for one year. The third group (group III) were women with normal DXA being studied for natural loss of bone density over one year, this group was treated with vitamins/ haematinics. At the end of one year (study period), DXA of the spine and hip were repeated and the findings compared with the pre-treatment DXA. Biochemical analysis of bone metabolism with markers: alkaline phosphatase, serum calcium and serum phosphorus were also performed during the follow up, which was at 3, 6, 9 and 12 months.


Results: The comparison between the pre and post treatment DXA showed a statistically significant increase in the BMD by 2.71% (SD æ 4.895 ; p=0.01) at the hip and a statistically highly significant increase by 2.14% (SD æ 6.519; p=0.0027) at the lumbar spine with group I (calcitriol). There was a statistically significant decrease in BMD by 1.3 % (SD æ 4.050; p= 0.01) in Group II (calcium) at the hip and a highly significant decrease in BMD by 2.60% (SD æ 2.548; p=0.0027) at the spine. With Group III (Iron / Vitamins) there was a decrease in BMD by 2.3% at both sites.

Ultrasonography of the calcaneus was also done and the diagnosis obtained by ultrasound compared with that obtained by DXA done at the same time. Out of 167 patients studied, 113 were diagnosed to be osteoporotic on the pre treatment DXA giving a prevalence rate of 67.7% in our study. 74 patients (44.3%) showed frank osteoporosis on post treatment DXA where USG had showed osteopenia or was normal. As against this, on ultrasound only 32 (19.2%) patients were diagnosed with frank osteoporosis which correlated with the DXA findings. Others had a normal USG or showed osteopenia thus under diagnosing the condition.

In the calcitriol group, there was a significant reduction in total alkaline phosphatase and no significant change in serum calcium and serum phosphorus. In the control group there was no significant change in any value.

Conclusion: Our study has shown a high prevalence of osteoporosis in Indian women where calcitriol significantly improved bone mineral density at the key sites of spine and hip. We also conclude that USG is not a very reliable tool for diagnosing osteoporosis as it under diagnosed the severity in most cases. In our study only 19.2% patients had comparable results with DXA and USG.

INTRODUCTION


Menopause is accompanied by accelerated bone loss and an increased incidence of fractures. Osteoporosis and osteopenia are the most common metabolic bone diseases in the developed world. Postmenopausal osteoporosis is due to some combinations of a low peak bone density and a high rate of bone loss during the early post - menopausal years. The bone loss is primarily due to oestrogen deficiency, but the pathogenesis is still poorly understood. Vitamin D deficiency is also included as a potential aetiological factor. In older patients, there is more concordant loss of both cortical and cancellous bone. This presumably is a result of age related calcium malabsorption due to a decline in renal production of 1,25 - dihydroxy vitamin D, and decreased response of the intestine to 1,25 - dihydroxy Vitamin D. Based on this theory, a logical course of treatment is the 1,25 dihydroxy vitamin D3 [Calcitriol] therapy.[2]

There is considerable evidence that osteoporotic fractures are preceded by osteopenia and are a direct result of low bone mass. As quantitative measurements of fragility caused by micro- architectural deterioration are unavailable from a practical point of view, osteoporosis is synonymous with reduced bone density. Bone density is a continuous variable, the lower the bone density, the higher the risk for fracture and the need to intervene with treatment.

In the present study of postmenopausal women we have investigated the effect of Calcitriol [Rocaltrol] on bone density by using dual energy x-ray absorptiometry (DXA) to measure the bone mineral density [BMD] at the spine and hip. We have also compared the diagnostic findings of DXA with USG done at the same time to determine if USG was a reliable indicator of osteoporosis where DXA could not be afforded.

MATERIAL AND METHODS

One hundred and eighty four postmenopausal women (mean age 54.5 years) were recruited into a non- randomized study of the effect of calcitriol on bone density at the Nowrosjee Wadia Maternity Hospital, Osteoporosis Clinic (Table 1).


TABLE1
Characteristics of the participants in the study
Characteristic (n=167) mean (range)
Age (years) 54.5 (46 - 63)
Age at menopause (years) 50.0 (44- 56)
Duration of menopause (years) 8.5 (2-15)
Weight (kg) 54.5 (44-65)
Height (m) 1.57 (1.51-1.64)
BMI 22.0

Menopause was defined as one year or more since the last menstrual period. Age at menopause was defined as the age at the last menstrual period. Vasomotor symptoms were recorded as present or absent. Body Mass Index (BMI) was calculated as weight (kg) divided by the square of height (m2). All bone density scans were performed and analyzed by one operator.

The women were divided into three groups based on the findings of their DXA done at the start of the study. The first group (group I) consisted of women whose DXA showed osteoporosis and were treated with calcitriol (Rocaltrol) 0.25 mg bd/day for one year.

The second group (group II) comprised women with osteopenia diagnosed by DXA and were treated with calcium 500 mg twice /day for one year. The third group (group III) were women with normal DXA who were included to study the natural loss of bone over one year and were given vitamins/ haematinics. At the end of one year (study period), DXA of the spine and hip were repeated and the findings compared with the pre-treatment DXA. A statistical analysis using the Kruskal Wallis test was performed for comparison. Biochemical analysis of bone metabolism with markers: alkaline phosphatase, serum. calcium and serum phosphorus were also performed during the follow up which was at 3, 6, 9 and 12 months. During the follow up, patients were evaluated for symptomatic relief with the treatment given, side effects and reasons for discontinuation of therapy if any.

The results of the first and second group reflected the effect of Calcitriol and Calcium respectively on bone density. The third group determined natural loss of bone at the end of one year.

Alongside the bone density evaluation by DXA, quantitative ultrasound was also performed for comparison of results. DXA is the standard non-invasive method to assess BMD, but is not always available. Ultrasound on the other hand is easily available, more affordable and a radiation free method, which is easy to perform. However the radiation levels of DXA are considered to be trivial and too insignificant to be of concern. The main advantage that DXA has over ultrasound is in the precision error for BMD, due to which ultrasound is not considered to be an effective monitoring device for BMD. Furthermore, there are very few clinical studies addressing USG measurements and there is no mention of ultrasound T scores in the WHO census findings. Therefore many physicians are unsure how to treat and monitor a patient based on USG T scores.

RESULTS

Out of 184 post-menopausal women recruited for the study, 167 had continuous follow up. 16 patients were lost or inconsistent hence excluded (3 from the calcitriol group and 14 from the calcium / vitamin group). One patient discontinued calcitriol therapy due to chest pain.

113 patients out of 167 were diagnosed as osteoporotic on the pre treatment DXA analysis, giving a prevalence rate for osteoporosis of 67.7% in our study. It would be pertinent to mention here that this analysis was done on analyzers with standardization for western women, hence the study may not reflect the true prevalence rate for Indian women, as Indian standards have not yet been recognized by the software.

Out of the 167 patients, 113 were initiated on calcitriol therapy 0.25 mg bd / day; 37 on calcium 500 mg twice /day - Group II; 17 on haematinics / vitamins - Group III. The pre and post treatment bone densitometry (DXA) was measured in all groups in a period of one year and the results compared.

The comparison showed a statistically significant increase in the BMD by 2.71% (SD æ 4.895 ; p=0.01) at the hip and a statistically highly significant increase by 2.14% (SD æ 6.519; p=0.0027) at the lumbar spine with group I (calcitriol). There was a statistically significant decrease in BMD by 1.3 % (SD æ 4.050; p= 0.01) with Group II (calcium) at the hip and a highly significant decrease in BMD by 2.60% (SD æ 2.548; p=0.0027) at the spine. With Group III (Iron / Vitamins) there was a decrease in BMD by 2.3% at both sites. Table 2 shows the distribution and number of subjects in the three groups.

TABLE 2
Distribution and number of subjects in the three groups
Site n=167 Group I n=113
Rocaltrol
Group II n=37
Calcium
Group III n=17
Vitamin/Iron

Hip

       
BMD 76 (67.3%) - -
•unchanged BMD 16 (14.1%) 21 (56.8%) 10 (58.8%)
BMD 21 (18.6%) 16 (43.2%) 7 (41.2%)

Spine

     
BMD 73 (64.6%) - -
•unchanged BMD 12 (10.6%) 24 (64.9%) 12 (70.6%)
BMD 18 (24.8%) 13 (35.1%) 5 (29.4%)

Ultrasonography of the calcaneus was also done and the diagnosis obtained by ultrasound compared with that obtained by DXA done at the same time.

Out of 167 patients studied, 74 (44.3%) showed frank osteoporosis on post treatment DXA where USG had showed osteopenia or was normal. As against this, on ultrasound only 32 (19.2%) patients were diagnosed with frank osteoporosis which correlated with the DXA findings. Others had a normal USG or showed osteopenia thus under diagnosing the condition. Table 3 shows the results obtained by comparing USG and DXA among the 167 subjects.

TABLE 3
Shows the results obtained in comparing USG and DXA
No. of patients n=167 Results

32 (19.2%)
Frank osteoporosis on DXA and same on USG
49 (29.3%) Frank osteoporosis on DXA but osteopenia on USG
25 (14.9%) Frank osteoporosis on DXA with normal USG
28 (16.8%) Osteopenia on DXA with normal USG
29 (17.4%) Normal reports in both DXA and USG
1 (0.6%) Osteopenia on DXA with osteoporosis on USG
3 (1.8%) False +ve with USG ie. USG showed Osteopenia but DXA was normal


Blood samples were obtained from all women at the start of the study and at subsequent follow ups at 3, 6, 9 and 12 months. Serum alkaline phosphatase, serum calcium and serum phosphorus were measured and values compared.

In the calcitriol group, there was a significant reduction in total alkaline phosphatase and no significant change in serum calcium and serum phosphorus suggestive of decreased bone turnover. In the control group there was no significant change in any value.

During the trial three women withdrew from the calcitriol group, out of which two did not follow up and one discontinued treatment due to chest pain. In the control group 14 women withdrew. 10 did not follow up and 4 were inconsistent with treatment given.

DISCUSSION

Fractures predispose to more fractures and are associated with increased morbidity and mortality. Bone loss accelerates after 65 years of age with the risk of fracture increasing out of proportion to the accelerating loss of bone, making it necessary to treat as age advances. Men and women age differently. Osteoporosis also develops in the males, but less frequently than in women. Both sexes begin to lose bone mass at about 0.3 to 0.5 per cent per year after about 40 to 50 years of age. Women, however experience a higher rate of bone loss due to menopause. The net result is an average loss of bone of 40 to 50 per cent in women, and 20 to 30 per cent in men. Persons at risk for fracture are identified by bone densitometry. Yet a large number of patients remain uninvestigated and untreated because of lack of awareness about postmenopausal osteoporosis.

It has been well accepted that postmenopausal who are on HRT show an increase in bone mass. However, HRT is not acceptable by a large percentage of Indian women mainly for fear of cancer. Besides HRT may be contraindicated in some women. In such situations, calcitriol would be good drug of choice.

There is compelling evidence to support calcitriol as a major regulator of intestinal calcium absorption.[1] Serum Calcitriol levels have been found to decrease with advancing age in relation to reduced dietary intake or poor intestinal absorption of vitamin D.

Calcium and vitamin D intake in Indians is much lower as compared to other countries and India seems to have the highest prevalence of osteoporosis and osteopenia perhaps equaled by Japan.2 Calcitriol (Rocaltrol), the biologically active form of vitamin D3 increases calcium absorption and has a modest effect on bone mass. One study suggests that calcitriol treatment reduces vertebral fracture rates when compared with a calcium ‘placebo’. [3] Sairanen et al[4] in a 4 year study observed an increase in femoral neck BMD by 3.0% in the calcitriol group and a decrease by 1.6 % in the calcium (control) group and an increase by 2.3% at lumbar spine in the calcitriol group and an increase of 0.9% in the calcium group.

Another recent study [5] shows that continuous treatment of 9 months with calcitriol or calcium in combination with alendronate significantly increased both vertebral and femoral neck density (3.8% to 4.5% and from 0.61% to 2.36% respectively) in osteopenic postmenopausal women. Alendronate plus calcium treatment led to significant increase in lumbar and femoral bone density. Similar results were obtained with calcitriol and alendronate except that femoral BMD did not significantly improve. Thus the effects of combinations proved greater than those achieved by calcium monotherapy. Similar findings were observed in yet another study [6] combining etidronate with calcitriol where the mean % increase in lumbar spine BMD was 5.2% and femoral neck BMD increased by 2.0%. Although further data is needed on fracture efficacy, the above studies suggest that combination therapies have additive therapeutic potential. Also, vitamin D3 treatment represents a useful adjunct in osteoporosis treatment in those women who are intolerant of biphosphonates. The only precaution to be taken is careful monitoring for correct therapeutic dose and to identify potential side effects.

The correct dose of calcitriol reduces the high serum parathyroid hormone (PTH) to normal and increases the low urinary calcium to normal. The most important side effects are increased urinary calcium (increasing the risk for renal stones) and increased serum calcium (hypercalcaemia). Thus serum and urine calcium should be periodically monitored. Hypercalcaemia can be avoided by limiting calcium intake to 800 mg / day.

Biochemical markers such as alkaline phosphatase, urinary excretion of calcium, phosphorus, osteocalcin amongst others are commonly used for predicting bone loss. However, two recent studies [7,8] conclude that these biochemical markers of bone turnover cannot predict bone loss from either spine or the hip with sufficient accuracy to apply in clinical decision making.

CONCLUSION

Hormone replacement therapy remains unacceptable to many women, particularly the elderly. As this group is most at risk for osteoporotic fractures, this presents a real problem in prevention. Our study has shown that calcitriol significantly prevents postmenopausal bone loss at the key sites of spine and hip. The drug is well tolerated, with good patient compliance and no side effects if monitored well, thus having a good potential as a therapeutic agent in prevention of osteoporosis. We also conclude that USG is not a very reliable tool for diagnosing osteoporosis as it under diagnosed the severity in most cases. In our study only 19.2% patients had comparable results with DXA and USG. DXA has been considered as the gold standard for diagnosing osteoporosis and predicting the risk of fracture thus aiding the physician in clinical decision making.

ACKNOWLEDGEMENT

We would like to thank Dr Vandana Walvekar, Dean, Nowrosjee Wadia Maternity Hospital for allowing us to conduct this study. Roche Scientific Company [India] Private limited and Nicholas Piramal India Limited for the financial support of this study. Mr Madhur Kotharay for his assistance with the statistical analysis.


REFERENCES

1.Korbach U. Mechanism of intestinal calcium transport and clinical aspects of disturbed calcium absorption. Dig Dis Sci 1989;7:1-18.

2.Gupta A. Osteoporosis in India - The nutritional hypothesis. The Nat Med J of India 1996; 9 (6).

3.Tilyard MW, Spears GFS, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992;326:357-62.

4.Sairanen S, Karkkainen, Tahtela R et al. Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with calcitriol for four years. Calcif Tissue Int 2000;67(2):122-7.

5.Malavolta N, Zanardi M, Vernesi M et al. Calcitriol and alendronate combination treatment in menopausal women with low bone mass. Int J Tissue React 1999;21(2):51-9.

6.Masud T, Mulcahy B, Thompson AV et al. Effects of cyclical etidronate combined with calcitriol versus etidronate alone on spine and femoral neck bone mineral density in postmenopausal osteoporotic women. Ann Rheum Dis 1998; 57(6):346-9.

7.Yoshimura N, Hashimoto T, Sakata K, et al. Biochemical markers of bone turnover and bone loss at the lumbar spine and femoral neck: The Taiji Study. Calcif Tissue Int 1999; 65(3): 198-202.

8.Keen RW, Nguyen T, Sobnack, et al. Can biochemical markers predict bone loss at the hip and spine ?: 4-year prospective study of 141 early postmenopausal women. Osteoporosis Int 1996; 6(5):399-406.


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