Vitamin D deficiency and suggested approach to bone health

A new randomized control trial in younger vitamin D-deficient postmenopausal women found that vit D supplementation led to a reduction in markers of bone turnover (see vit d dec bone turnover postmenop OsteopIntl2018 in dropbox, or doi.org/10.1007/s00198-018-4395-y ).

Details:

--160 menopausal women aged 50-65 and normal bone mineral density (BMD) were randomized to 1000 IU vitamin D3 vs placebo for 9 months

--mean age 59, menopause age 47, BMI 29, dietary calcium intake 750 mg/d, BMD 0.5 spine/0.4 femoral neck, 25(OH)D 16 ng/mL, calcium 9.5, PTH 58, alk phosph 92

Results:

--vitamin D supplement vs placebo, comparing basal levels vs at 9 months (only statistically significant changes noted):

    --25(OH)D levels increased from 15.0 to 27.5 ng/mL (p<0.0001) vs decrease from 16.9 to 13.8

    --PTH levels decreased from 57.8 to 45.5 pg/mL (21.3% reduction, p<0.0001) vs increase from 57.7 to 63.0

    --Alkaline phosph levels: no significant change

    --24-hour urinary calcium excretion: no significant change

    ​--serum C-terminal cross-linked telopeptides of type I collagen (s-CTX) levels decreased from 0.33 to 0.25 ng/mL (24.2% reduction, p<0.0001) vs decrease from 0.28 to 0.27

    --amino-terminal propeptide of type I procollagen (P1NP) decreased from 54.9 to 47.5 ng/mL (13.4% reduction, p=0.003) vs decrease from 52.1 to 51.8

Commentary:

--i certainly acknowledge that the data supporting vitamin D, BMD, and fracture risk are not consistently supportive of vitamin D supplementation, but would argue that many of the studies were pretty flawed (including some where the baseline vitamin D levels were not so bad, and, notably, pretty short timelines for the studies, given that women are likely to live lots longer than the studies lasted). 

--It may be reasonable to use deteriorating surrogate markers (bone turnover rate, BMD) as appropriate individual markers of increased longterm risk, given the slow nature of the process leading to clinical fractures, esp in a low-risk cohort as in the above study). There are lots of studies finding that the rate of bone resorption increases in postmenopausal women, that markers of bone turnover reflect this dynamic bone activity early on, and that high levels of these markers are associated with increased BMD loss. In interpreting the above study, it should be noted that other studies have not consistently found that vitamin D supplementation actually decreases bone turnover markers

--Vitamin D is pretty unique, in that it is uncommonly sufficiently available through foods but mostly by sunlight, which much of the world is pretty deprived of (including Boston)

--i sent out a recent blog on guidelines for length of bisphosphonate therapy (see http://gmodestmedblogs.blogspot.com/2016/01/guidelines-on-length-of-bisphosphonate.html ), and i think the results of this current study may well be relevant here. this blog reviews the array of recommendations, but suggests that if women with osteoporosis are on oral bisphosphonates for 5 years, have no intervening fractures, and hip T score  is better than -2.5, one might consider a drug holiday and reassess in 2-3 years. i do bring up my concerns about this recommendation there, and this new  study reinforces but modifies them some.

--the most important issue here to me is that the longest study on bisphosphonate cessation is 10 years. But, women with menopause at age 47, as in the study above, are pretty likely to live 40-45 years more.

--the basis for stopping alendronate after 5 years vs continuing is based on the FLEX trial (Black DM. JAMA 2006; 296:2927). In this study, after 5 years of alendronate, women were randomized to continuing alendronate (half on 35 and half on 70 mg/week) and half taking placebo. Overall there was no higher fracture risk by discontinuing alendronate, except for clinical vertebral fractures, BUT there were some potentially deleterious trends found in the placebo group during the last 5 years, which might manifest themselves clinically over time:

        --the placebo group did have more bone loss (femoral neck BMD decreased 1.48% vs increasing 0.46% on continued treatment)

        --though there was no difference in nonvertebral or morphometic vertebral fractures by xray in the placebo group, there were more clinical vertebral fractures (5.3 vs 2.4%). which was statistically significant

        ​-- the BMD at the total hip, femoral neck, trochanter and lumbar spine were all better by continuing alendronate therapy (vs switching to placebo); similarly, bone turnover rates did increase with placebo (though no difference in bone turnover markers between those on 35 vs 70mg of alendronate/week).

        --post-hoc analysis of the FLEX trial found that in the group stopping alendronate, the incidence of  any clinical fracture increased from <10% to 30% as the tertile of femoral neck and total hip T-scores decreased (see osteop bisph length amsocbonersch2015 in dropbox, or DOI: 10.1002/jbmr.270 )

        --subgroup analysis found that there was a reduction of nonspine fractures in women who did not have baseline vertebral fractures and had a femoral neck T-score worse than -2.5

        --stopping allendronate does not lead to immediate increase in bone marker turnover (unlike estrogens or raloxifene, PTH treatments), so the increase in bone turnover in this study of 5 years of placebo is likely a significant understatement vs the next 5 years

so, i think this study reinforces the importance of adequate vitamin D levels to preserve bone health. And,  i think it makes sense in younger women to do the following, an approach neither validated nor generally accepted (that i know of):

--check vitamin D levels in all, but especially in women, at a younger age (20's to 30's; i also check them in kids, though the pediatric guidelines recommend routine supplementation, mostly with 400IU of vitamin D). My finding is that these levels are almost always low, especially in the northern latitude of Boston. and that acting on a low level in an individual patient is more likely to succeed than just the global "you should take vitamin D supplements" for at least many people

--i still favor a 25(OH)D goal of 30 ng/mL, since there are studies showing that <30 ng/mL can be associated with secondary hyperparathyroidism (though the Institute of Medicine promoted a goal of 20 ng/mL, probably related to the lack of really rigorous data to the contrary)

--since the 1000 IU size may not really hit the optimal 25-OH vitamin D level (as was found in the above study), and since my own anecdotal experience is that this is often the case, i typically give 2000 IU to those whose 25(OH)D level is <20 ng/mL, but 400-1000 IU depending on how close they are to goal (little harm, no significant change in cost, possible benefit)

--recheck vitamin D and BMD at time of menopause, since this is the time of the greatest bone demineralization, and it is better to prevent than treat osteoporosis (Note: USPSTF suggests screening at age 65, unless "younger women is equal to or greater than that of a 6-years old who has no additional risk factors")

--if BMD is okay, repeat in 5 years or so to monitor for demineralization, reinforce nonpharmacologic measures to prevent further demineralization, and treat with alendronate if BMD meets criteria.

--if on alendronate and BMD is better than -3.5, would repeat BMD after 5 years, stop the alendronate if this BMD is at least as good as the original, and follow patients every 2-3 years with BMD and bone turnover markers, but restart the alendronate if the BMD deteriorates or the bone turnover markers increase. Unclear if one can use 35 mg of alendronate vs 70mg/week (would be useful to know for sure)​

--what, you may ask, will be the cost of this more aggressive diagnostic and therapeutic approach??? i would suggest that the potential quality and quantity of life lost (and the attendant human and monetary cost in taking care of these largely avoidable osteoporotic fractures) pales in comparison to the newest individualized cancer therapies at $1 million a treatment (or pretty much all of the newer therapies). And, besides, we should be preventing more cancer anyway by stricter regulations on chemicals in the water and air and food supply, instead of decreasing regulations on all things environmental, as is currently being done. less i diverge...