Commentary on guidelines on postmenopausal osteoporosis - Indian Menopause Society.

With the demographic and epidemiological transformation in the south Asian region, osteoporosis of women in midlife and beyond needs much attention. Osteoporosis is a silent disease of epidemic proportion which has been under recognized till recently. As a major cause of fractures, it is not only life threatening but also cause many disabilities with resultant loss of quality of life (QoL) of women. The cost of burden of the disease to many millions of menopausal women, their families, and the government; need awareness of public, enhanced knowledge among medical professionals and strategies to diagnose and prevent osteoporosis. It is estimated that 50-70% of postmenopausal women in India are suffering from osteoporosis.[1] In this context, it is timely and praiseworthy that Indian Menopause Society has published Clinical Practice Guidelines on Management of Postmenopausal Osteoporosis. It is a comprehensive publication, updated and best suited not only for India but for whole of south Asia.

Recommended daily requirement of calcium has been the focus of much discussion recently, especially for prevention of osteoporosis of menopausal women. There is evidence that calcium requirement, which is recognized as the intake required to maintain calcium balance and therefore bone health, varies depending on culture, dietary, genetic, and geographical factors. Hence, recommendations for developed countries may not necessarily apply to many developing nations. Calcium balance is determined by relationship of calcium intake, absorption, and excretion. Percentage net absorption depends on the intake, presence of phosphates, phytates in the food, and serum concentration of 1,25-dihydroxyvitamin D (25(OH) D) which controls intestinal absorption. Menopausal status through lowered estrogen concentration has a major influence on calcium absorption. Estrogen deficiency lowers intestinal absorption of calcium.[2] Urinary excretion of calcium is affected by menopausal status, protein, and sodium intake. Dietary protein, especially animal protein has a positive effect on urinary calcium excretion.[3] Protein intake of most south Asian countries is 34-38 g of protein per capita,[4] which is much lower than the western countries. However, sodium administration is known to increase urinary calcium excretion and the average per capita consumption of salt in India is high being 9 g.[56]

What should be the recommended daily requirement of calcium and vitamin D for postmenopausal women in south Asian countries?

In assessing calcium requirement; balance studies, calculation of estimates of requirement, assessment of changes of bone mineral density (BMD), and rates of fractures have been adopted. Many systematic reviews of calcium supplementation and dietary calcium show a positive relationship of calcium with BMD and reduction of vertebral fractures. However, many uncertainties have arisen because of lack of intervention trials that study dose-response relationship. Institute of Medicine (IOM) Committee of 2011 concluded in their report that there is a definite role of calcium and vitamin D in bone health and that dietary reference intake (DRI) of calcium for women over 50 is 1200 mg and recommended daily allowance (RDA) for vitamin D is 600 IU/day.[7]

In the Women’s Health Initiative (WHI) Calcium and Vitamin D Trial, postmenopausal women receiving 1000 mg of calcium and 400 IU of vitamin D had a significant increase of total hip BMD while nonsignificant increases were noted in spine and whole BMD.[8] After a mean follow-up of 7 years, there was a nonsignificant 12% reduction of hip fracture in the study group. A significant 29% reduction was noted in women who were 80% adherent to calcium and vitamin D supplementation and a 21% reduction in women over 60 years. WHI Calcium and Vitamin D Study which is graded as a high quality trial by Institute of Medicine (IOM) and United States Preventive Services Task Force (USPSTF) has used lower dose of 400 IU of vitamin D. A number of studies and meta-analysis have shown a reduction of hip and nonvertebral fractures in postmenopausal women with calcium and vitamin D[9] and vitamin D alone.[10] The recommendation statement by USPSTF in 2012 has caused much concern. It concluded that the current evidence is insufficient to assess balance of benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1,000 mg of calcium for primary prevention of fractures in noninstitutionalized postmenopausal women.[11] Their reports are applicable to the white population in North America, and propose that outcome of fracture reduction with supplementation with higher amounts of vitamin D and calcium needs further research. The task force has used stringent criteria for selection of studies which resulted in many ‘I’ statements where the current evidence was insufficient to come to any conclusions.

In this context, it is pertinent to review IOM report of 2009 which has only a short synopsis about calcium and vitamin D and bone health while dealing extensively with other health matters.[12] While basing mostly on the systematic review by Ottawa Evidence Based Practice Center (EPC) it concluded that supplementation with vitamin D plus calcium is effective in reducing fractures in institutionalized women, but there is inconsistent evidence that supplemental vitamin D reduces falls in postmenopausal women, and this discrepancy is because the mean serum 25(OH) D concentration achieved in trials of institutionalized participants was higher than in the trials on community dwellers.[13] Analysis also showed a significant reduction of falls in postmenopausal women taking calcium and vitamin D supplementation in reducing fractures in institutionalized populations, but there is inconsistent evidence regarding non institutionalized postmenopausal women. This concern is also voiced by USPSTF in their latest report in 2012. IOM statement that skeletal health can be ensured at serum 25(OH) D level of 20 ng/ml has been challenged by many.[14]

Optimum serum level of 25(OH) D below which vitamin D insufficiency occurs has drawn attention. While 30 ng/ml has been suggested by some,[15] Institute of Medicine (IOM) has recommended 20 ng/ml.[16] RDA to maintain this level has been estimated by IOM in 2011 as 600 IU of vitamin D for women below 70 years and 800 IU for those above 70 years.

In a large randomized control trials (RCTs) in UK supplementation with vitamin D in postmenopausal women, raising 25(OH) D level to 29 ng/ml has reduced fracture rate by 33%.[17] Considering that each additional intake of 100 IU per day raises serum 25(OH) D level by only 1%, recommendation by IOM seems inadequate. In a meta-analysis by Bischoff-Ferrari and colleagues,[18] results suggested that for hip and nonvertebral fracture prevention 700-800 IU/day of vitamin D is better than 400 IU/d. and accompanying serum 25(OH) D concentration of 30 ng/l is advantageous. International Osteoporosis Foundation in its position paper in 2010 acknowledges falls reduction with 700-1000 IU of vitamin D per day.

Vitamin D levels in women are lower than that of men and reduce with age. Hence, menopausal women have low levels of vitamin D. Many studies conducted in India have shown low levels of vitamin D in Indian women, in spite of adequate sunshine. In a study among north Indian hospital staff, 78.3% were below 20 ng/ml.[19]

Considering low calcium intake and high phytates in the diet and low serum 25(OH) D concentration in Indian and other south Asian postmenopausal women, and that with increased sweating up to 20 mg of calcium lost per hour; a total intake dietary and supplementary calcium of 1000-1200 mg and 800 IU of vitamin D is suggested, respectively. This amount if insufficient in the diet should be supplemented. Adverse side effects are minimal at these doses. As recommended by the Indian Menopause Society (IMS) committee RCTs in the south Asian region will assist in making final recommendations for our region.