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Bisphosphonates 4.5 X more likely to work when vitamin D level above 33 ng – Sept 2011

Bisphosphonates Most Effective With Higher Vitamin D Levels

Nancy A. Melville Medscape

September 21, 2011 (San Diego, California) — Bisphosphonate therapy for osteoporosis is much more likely to be effective among patients whose blood serum levels of vitamin D are elevated, according to research presented here at the American Society for Bone and Mineral Research (ASBMR) 2011 Annual Meeting.

For most osteoporosis drug trials, participants are also placed on vitamin D supplementation, and some studies have suggested that the efficacy of bisphosphonates could depend on levels of circulating vitamin D.

To more closely examine the relationship in a real-world setting, researchers evaluated 210 postmenopausal women (mean age, 65 years) with low bone mineral density (BMD), at 2 ambulatory practices in New York City.

The women had been treated with bisphosphonates for approximately 5 years and were followed for drug and vitamin D adherence over at least 18 months, which was the time between their last 2 dual-energy x-ray absorptiometry (DEXA) scans.

About half of the patients were treated with alendronate, a quarter were treated with risedronate, and about 18% were treated with intravenous zoledronate. Vitamin D levels were measured as 25(OH)D serum levels.

Only 99 (47%) of the 210 patients had shown a favorable response to the prolonged treatment with bisphosphonates, and a comparison of the mean 25(OH)D levels between responders and nonresponders showed that patients with a mean 25(OH)D serum level of 33 ng/mL or higher had as much as a 4.5-fold greater odds of bisphosphonate response (estimated odds ratio, 4.5; P < .0001).

In addition, the results showed 25(OH)D level as a continuous variable to be significantly associated with response to bisphosphonates. One 1-ng/mL decrease in 25(OH)D, for instance, was associated with about a 5% decrease in odds of responding (odds ratio, 0.95; 95% confidence interval, 0.92 - 0.98; P = .0007).

"The current study is the first to identify a threshold level of 25(OH)D that defines improved outcome to bisphosphonate therapy such that patients with a mean 25(OH)D ? 33 ng/mL had a substantially greater likelihood of responding to bisphosphonates," the authors wrote.

"This threshold value of ? 33 ng/mL for 25(OH)D is higher than the level considered adequate by the Institute of Medicine report for the general population, arguing that higher levels may be required for specific therapeutic outcomes."

According to coauthor Richard S. Bockman, MD, PhD, the results may help explain discrepancies in responses to bisphosphonates seen in controlled studies compared with the real-world environment.

" 'Real world' patients have not been observed to respond to bisphosphonates at rates comparable to those seen in clinical trials," said Dr. Bockman, a professor of medicine at the Weill Medical College of Cornell University and head of endocrine at the Hospital for Special Surgery in New York, New York.

Yet, "there is a high prevalence of low 25(OH)D levels among 'real world' patients taking bisphosphonates."

Studies typically have other outcome measures, and may not look at bisphosphonates in terms of a favorable maintenance therapy, as the current study was designed to evaluate, he added.

"There are studies reporting no effect of vitamin D and studies showing a vitamin D benefit, but they are not specifically looking at maintenance of bisphosphonate effect, and none specifically correlate outcome based on direct measure of circulating 25(OH) vitamin D levels, which is the gold standard for assessing vitamin D status," Dr. Bockman noted.

Laura A.G. Armas, MD, an assistant professor at Creighton University's Osteoporosis Research Center in Omaha, Nebraska, agreed that the findings are not necessarily surprising considering that efficacy in drug trials is typically based on patients who take vitamin D supplements.

"All the drug trials for bone-saving medications use calcium and vitamin D supplements for all their subjects," explained Dr. Armas, who moderated the session. "We would expect the same level of supplementation would be needed in the 'real world' to have the same decrease in fracture rate."

She noted that previous studies have shown similar minimal thresholds for improvement. "We know there is an increase in calcium absorption with increased 25(OH)D levels. Heaney showed that increased 25(OH)D from 20 ng/mL to 32 ng/mL in postmenopausal women increased calcium absorption by 68%, so this clinical experience fits with our prior knowledge."

Dr. Bockman added that the findings from previous studies were the source for his research team's use of 33 ng/mL as a hypothetical cutoff, and the data validated that level.

"A 25(OH)D equal to or greater than 33 ng/mL was associated with about a 4.5- to 5.0-fold greater odds of maintaining a favorable response," he said.

Dr. Bockman and Dr. Armas have disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2011 Annual Meeting; Abstract #1137. Presented September 18, 2011.

The 25(OH)D level needed to maintain a favorable bisphosphonate response is >33 ng/ml. - Jan 2012

Osteoporos Int. 2012 Jan 12.
Carmel AS, Shieh A, Bang H, Bockman RS.
Department of Internal Medicine, Weill Cornell Medical College, 505 East 68th Street, New York, NY, 10021, USA, als7004 at med.cornell.edu.

Why only some osteoporotic patients maintain response to prolonged bisphosphonate therapy is unknown. We examined bisphosphonate response and its association with serum 25 hydroxy vitamin D (25(OH)D) level in a "real world" setting. Serum 25(OH)D level was strongly associated with maintaining bisphosphonate response arguing that vitamin D may be involved in optimizing prolonged bisphosphonate therapy.

INTRODUCTION: This study examined the maintenance of bisphosphonate response in the "real world" setting and the association between 25(OH)D and bisphosphonate response using an established composite definition of response.

METHODS: Postmenopausal women with low bone mineral density (BMD) treated with bisphosphonates were identified from two New York City practices. Patients were excluded for a history of chronic steroid use, metabolic bone disease, or bisphosphonate non-adherence. Patients were categorized as bisphosphonate non-responders if they had a T-score?<?-3 that persisted between dual-energy X-ray absorptiometry (DEXA) scans, a >3% decrease in BMD, or an incident fracture on bisphosphonate therapy, criteria based on the EUROFORS trial. Demographic and clinical data including mean 25(OH)D levels between DEXA scans were obtained. Mean 25(OH)D levels were compared between responders and non-responders and multiple logistic regression analysis was performed to identify factors associated with non-response.

RESULTS: A total of 210 patients were studied. A favorable response to bisphosphonate therapy was seen in 47% (N?=?99/210).
Patients with a mean 25(OH)D ?33 ng/ml had a ~4.5-fold greater odds of a favorable response (P?<?0.0001).
25(OH)D level was significantly associated with response
a 1 ng/ml decrease in 25(OH)D was associated with ~5% decrease in odds of responding (odds ratio?=?0.95; 95% confidence interval, 0.92-0.98; P?=?0.0006).

CONCLUSIONS: Patients with a mean 25(OH)D ?33 ng/ml had a substantially greater likelihood of maintaining bisphosphonate response. This threshold level of 25(OH)D is higher than that considered adequate by the Institute of Medicine, arguing that higher levels may be required for specific therapeutic outcomes.

PMID: 22237813

Bisphosphonate therapy – consisting of one of the following

  • alendronate
  • risedronate
  • ibandronate
  • zolendronate

Suspect more that improvement would have been >10X if in addition to vitamin D, the people had an adequate level of co-factors

Wonder if Bisphosphonate needed at all for bones: just have Vitamin D and Co-factors: far less expense, virtually no side-effects

See also VitaminDWiki

References of the study

  • Braithwaite RS, Col NF, Wong JB (2003) Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc 51:364–370
  • Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541
  • Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822
  • Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR (2000) Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 85:4118–4124
  • Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352
  • Obermayer-Pietsch BM, Marin F, McCloskey EV, Hadji P, Farrerons J, Boonen S, Audran M, Barker C, Anastasilakis AD, Fraser WD, Nickelsen T (2008) Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res 23:1591–1600
  • Adami S, Isaia G, Luisetto G, Minisola S, Sinigaglia L, Silvestri S, Agnusdei D, Gentilella R, Nuti R (2008) Osteoporosis treatment and fracture incidence: the ICARO longitudinal study. Osteoporos Int 19:1219–1223
  • Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T (2001) A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 86:1212–1221
  • Epstein S (2006) The problem of low levels of vitamin D and osteoporosis: use of combination therapy with alendronic acid and colecalciferol (vitamin D3). Drugs Aging 23:617–625
  • Venning G (2005) Recent developments in vitamin D deficiency and muscle weakness among elderly people. BMJ 330:524–526
  • Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, Petruschke RA, Chen E, de Papp AE (2005) Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90:3215–3224
  • van der Wielen RP, Lowik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, van Staveren WA (1995) Serum vitamin D concentrations among elderly people in Europe. Lancet 346:207–210
  • Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B (2005) Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 293:2257–2264
  • Antoniucci DM, Vittinghoff E, Palermo L, Black DM, Sellmeyer DE (2009) Vitamin D insufficiency does not affect response of bone mineral density to alendronate. Osteoporos Int 20:1259–1266
  • Barone A, Giusti A, Pioli G, Girasole G, Razzano M, Pizzonia M, Palummeri E, Bianchi G (2007) Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trial. J Am Geriatr Soc 55:752–757
  • Ishijima M, Sakamoto Y, Yamanaka M, Tokita A, Kitahara K, Kaneko H, Kurosawa H (2009) Minimum required vitamin D level for optimal increase in bone mineral density with alendronate treatment in osteoporotic women. Calcif Tissue Int 85:398–404
  • Koster JC, Hackeng WH, Mulder H (1996) Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women. Eur J Clin Pharmacol 51:145–147
  • Adami S, Giannini S, Bianchi G, Sinigaglia L, Di Munno O, Fiore CE, Minisola S, Rossini M (2009) Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int 20:239–244
  • Adami S, Isaia G, Luisetto G, Minisola S, Sinigaglia L, Gentilella R, Agnusdei D, Iori N, Nuti R (2006) Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study. J Bone Miner Res 21:1565–1570
  • Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716
  • Holick MF (2007) Optimal vitamin D status for the prevention and treatment of osteoporosis. Drugs Aging 24:1017–1029
  • Morisky DE, Green LW, Levine DM (1986) Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 24:67–74
  • Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383
  • Bonnick SL, Shulman L (2006) Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both? Am J Med 119:S25–S31
  • Cook NR, Buring JE, Ridker PM (2006) The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 145:21–29
  • Bang H, Mazumdar M, Newman G, Bomback AS, Ballantyne CM, Jaffe AS, August PA, Kshirsagar AV (2009) Screening for kidney disease in vascular patients: SCreening for Occult REnal Disease (SCORED) experience. Nephrol Dial Transplant 24:2452–2457
  • Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11:337–349
  • Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the institute of medicine: what clinicians need to know. J Clin Endocrinol Metab 96:53–58
  • Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809
  • Antoniucci DM, Vittinghoff E, Blackwell T, Black DM, Sellmeyer DE (2005) Vitamin D insufficiency does not affect bone mineral density response to raloxifene. J Clin Endocrinol Metab 90:4566–4572
  • Deane A, Constancio L, Fogelman I, Hampson G (2007) The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis. BMC Musculoskelet Disord 8:3
  • Rosen CJ (2011) Clinical practice. Vitamin D insufficiency. N Engl J Med 364:248–254
  • Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938