Melatonin Osteoporosis Prevention Study

NCT01152580 | Completed Phase 1 Results

• 1 other identifier: 07-88
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

Osteoporosis is one of the most common skeletal disorders. Today in the United States, 10 million individuals have osteoporosis and 34 million more have low bone mass or osteopenia, which places them at an increased risk of some day developing osteoporosis. Of the people affected by this problem, 68% are women.The current thinking on the development of osteoporosis is that the changes in bone turnover that occur with aging play a major factor. Many modalities of treatment are used to prevent the bone loss and increased fracture risk associated with osteoporosis and osteopenia. Melatonin supplementation may be another treatment modality that lowers risk of hip fracture in perimenopausal women. Melatonin can remodel bone in animal models and in culture. Melatonin works through melatonin receptors to form osteoblasts from human mesenchymal stem cells and has been shown to inhibit osteoclast activity in rodents. Melatonin levels have been correlated with modulating bone markers; low nocturnal levels of melatonin correlate with in an increase in bone marker metabolism and osteoporosis. It is been shown that women who have worked night-shifts for greater than 20 years have increased risk for wrist and hip fractures. Night-shift workers have lower nocturnal melatonin levels than people who do not work the night-shift. The addition of exogenous melatonin suppresses bone marker metabolism. In human stem cells taken from bone marrow, melatonin increases the activity of bone-forming cells called osteoblasts. It is hypothesized that melatonin will improve bone health, menopausal quality of life and sleep compared to placebo in perimenopausal women. In particular, the investigators expect perimenopausal women taking melatonin to show an improvement in overall bone health as revealed by a reduction in bone marker turnover since bone resorption increases more so than bone absorption in this population compared to those women taking placebo. We also expect that perimenopausal women taking melatonin to have better control over their menopausal symptoms, better quality of life and less sleep disturbances when compared to their placebo controls since melatonin is known to modulate estrogen levels in the body and regulate sleep. The data from these studies may provide novel and alternative uses for melatonin; in particular its use for the prevention and/or treatment of osteoporosis.

Conditions

Osteoporosis; Osteopenia

Keywords

melatonin; menopause; perimenopause; sleep; osteoporosis; osteopenia; anxiety; depression; hypertension

Outcome Measures

Primary Outcomes (3)

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Serum Osteocalcin (OC) Levels in Women After 6 Months, as Compared to Baseline

  Osteocalcin is a measure of osteoblast activity because it is secreted from osteoblasts. Osteocalcin levels were measured in the serum of women at baseline and after 6 months of taking placebo or melatonin (3 mg) and the data are reported as ng/mL. Osteoblasts are bone-forming cells so a more positive mean change in osteoblast activity over time (6 months - baseline) could indicate an improvement in bone mineral density. A more negative mean change in osteocalcin levels over time (6 months - baseline) could indicate a worsening of bone mineral density.

  Baseline and 6 months

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Serum Type-1 Collagen Cross-linked N-telopeptide (NTX) Levels in Women After 6 Months, as Compared to Baseline.

  Type-1 collagen cross-linked N-telopeptide (NTX) levels were measured in the serum of women at baseline and after taking placebo or melatonin (3 mg) nightly for 6 months. NTX, reported as bone collagen equivalents (BCE), is released from bone due to the actions of osteoclasts or bone breakdown cells. A more positive mean change in NTX levels (6 months - baseline) could result in a worsening of bone mineral density due to an increase in bone breakdown whereas a more negative mean change in NTX levels could result in an improvement in bone mineral density due to a decrease in bone breakdown.

  Baseline and 6 months

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Bone Density in Women After 6 Months, as Compared to Baseline.

  The mean change in bone mineral density (BMD), represented by T-scores, was assessed by calcaneal ultrasound in women taking melatonin (3 mg) or placebo nightly at baseline and after 6 months. A T-score is a comparison of a subject's BMD to that of a healthy 30 year old female of the same ethnicity. The more negative the T-score, the worse the BMD. Osteoporosis or brittle bone disease is defined as a T-score -2.5 or less. A more negative mean change in a T-score would indicate a worsening of BMD. A more positive mean change in a T-score would indicate an improvement of BMD.

  Baseline and 6 months

Secondary Outcomes (5)

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Menopause-Specific Quality of Life (MENQOL) Physical Domain Scores in Women After 6 Months, as Compared to Baseline.

  Baseline and 6 mos

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Menopause-Specific Quality of Life (MENQOL) Vasomotor Domain Scores in Women After 6 Months, as Compared to Baseline.

  Baseline and 6 mos

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Menopause-Specific Quality of Life (MENQOL) Psychosocial Domain Scores in Women After 6 Months, as Compared to Baseline.

  Baseline and 6 mos

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in Menopause-Specific Quality of Life (MENQOL) Sexual Domain Scores in Women After 6 Months, as Compared to Baseline.

  Baseline and 6 mos

• The Effect of Melatonin (3 mg) or Placebo on the Mean Change in the Pittsburgh Sleep Quality Index (PSQI) in Women After 6 Months, as Compared to Baseline.

  Baseline and 6 months

Study Arms (2)

Sugar pill

PLACEBO COMPARATOR

Dietary Supplement: sugar pill

melatonin

ACTIVE COMPARATOR

Dietary Supplement: melatonin

Interventions

melatonin DIETARY_SUPPLEMENT

3mg p.o. at bedtime daily

Also known as: Nature's Bounty Melatonin, Natrol Melatonin, Spring Valley Melatonin

melatonin

sugar pill DIETARY_SUPPLEMENT

lactose p.o. at bedtime daily

Also known as: Lactose

Sugar pill

Eligibility Criteria

• Age: 45 Years - 54 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• willingness to participate in the 6-month study, willingness to undergo testing of bone turnover markers before and after the drug therapies and willingness to provide a self-assessment on quality of life and sleep throughout the program.
• Subjects must be willing to take their treatments right before bed and to not to consume alcohol with this medication.

You may not qualify if:

• Those individuals on osteoporotic drugs, hypnotics, CYP1A2 inhibiting drugs, fluvoxamine or those with severe sleep apnea, severe COPD and those with moderate or severe hepatic impairment will also be excluded.
• Individuals who are lactose intolerant will also be excluded because the placebo and melatonin capsules will contain lactose.

Sponsors & Collaborators

• Duquesne University: lead

Study Sites (1)

Duquesne University School of Pharmacy Center for Pharmacy Care

Pittsburgh, Pennsylvania, 15282, United States

Location

Related Publications (19)

• www.osteo.org. Osteoporosis Overview. National Institute of Health Osteoporosis and Related Bone Disease. June 2005.

  BACKGROUND

• Parfitt AM, Villanueva AR, Foldes J, Rao DS. Relations between histologic indices of bone formation: implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res. 1995 Mar;10(3):466-73. doi: 10.1002/jbmr.5650100319.

  PMID: 7785469 BACKGROUND

• Wolinsky FD, Fitzgerald JF, Stump TE. The effect of hip fracture on mortality, hospitalization, and functional status: a prospective study. Am J Public Health. 1997 Mar;87(3):398-403. doi: 10.2105/ajph.87.3.398.

  PMID: 9096540 BACKGROUND

• Ray NF, Chan JK, Thamer M, Melton LJ 3rd. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997 Jan;12(1):24-35. doi: 10.1359/jbmr.1997.12.1.24.

  PMID: 9240722 BACKGROUND

• Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res. 1996 Mar;11(3):337-49. doi: 10.1002/jbmr.5650110307.

  PMID: 8852944 BACKGROUND

• Nishizawa Y, Nakamura T, Ohta H, Kushida K, Gorai I, Shiraki M, Fukunaga M, Hosoi T, Miki T, Chaki O, Ichimura S, Nakatsuka K, Miura M; Committee on the Guidelines for the Use of Biochemical Markers of Bone Turnover in Osteoporosis Japan Osteoporosis Society. Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004). J Bone Miner Metab. 2005;23(2):97-104. doi: 10.1007/s00774-004-0547-6. No abstract available.

  PMID: 15750686 BACKGROUND

• Bonnick SL, Shulman L. Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both? Am J Med. 2006 Apr;119(4 Suppl 1):S25-31. doi: 10.1016/j.amjmed.2005.12.020.

  PMID: 16563938 BACKGROUND

• Riggs BL, O'Fallon WM, Muhs J, O'Connor MK, Kumar R, Melton LJ 3rd. Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res. 1998 Feb;13(2):168-74. doi: 10.1359/jbmr.1998.13.2.168.

  PMID: 9495509 BACKGROUND

• Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P, McClung M, Balske A, Thompson D, Daley M, Yates AJ. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998 Feb 19;338(8):485-92. doi: 10.1056/NEJM199802193380801.

  PMID: 9443925 BACKGROUND

• Chesnut CH 3rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C, Peacock M, Richardson P, Watts N, Baylink D. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000 Sep;109(4):267-76. doi: 10.1016/s0002-9343(00)00490-3.

  PMID: 10996576 BACKGROUND

• Witt-Enderby PA, Radio NM, Doctor JS, Davis VL. Therapeutic treatments potentially mediated by melatonin receptors: potential clinical uses in the prevention of osteoporosis, cancer and as an adjuvant therapy. J Pineal Res. 2006 Nov;41(4):297-305. doi: 10.1111/j.1600-079X.2006.00369.x.

  PMID: 17014686 BACKGROUND

• Radio NM, Doctor JS, Witt-Enderby PA. Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade. J Pineal Res. 2006 May;40(4):332-42. doi: 10.1111/j.1600-079X.2006.00318.x.

  PMID: 16635021 BACKGROUND

• Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res. 2002 Jul;17(7):1219-29. doi: 10.1359/jbmr.2002.17.7.1219.

  PMID: 12096835 BACKGROUND

• Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D. Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. Endocr Regul. 2003 Sep;37(3):163-74.

  PMID: 14986722 BACKGROUND

• Ostrowska Z, Kos-Kudla B, Nowak M, Swietochowska E, Marek B, Gorski J, Kajdaniuk D, Wolkowska K. The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul. 2003 Dec;37(4):211-24.

  PMID: 15106818 BACKGROUND

• Sethi S, Radio NM, Kotlarczyk MP, Chen CT, Wei YH, Jockers R, Witt-Enderby PA. Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res. 2010 Oct;49(3):222-38. doi: 10.1111/j.1600-079X.2010.00784.x. Epub 2010 Jul 6.

  PMID: 20626586 BACKGROUND

• Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol. 2008 Jan 15;586(2):639-47. doi: 10.1113/jphysiol.2007.143180. Epub 2007 Nov 15.

  PMID: 18006583 BACKGROUND

• Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Biopharm Drug Dispos. 2000 Jan;21(1):15-22. doi: 10.1002/1099-081x(200001)21:13.0.co;2-h.

  PMID: 11038434 BACKGROUND

• Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, Balk JL. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012 May;52(4):414-26. doi: 10.1111/j.1600-079X.2011.00956.x. Epub 2012 Jan 6.

  PMID: 22220591 RESULT

Related Links

• Osteoporosis Overview. National Institute of Health Osteoporosis and Related Bone Disease. June 2005
• Melatonin Osteoporosis Prevention Study (MOPS): A Randomized, Double-Blind, Placebo-Controlled Study Examining the Effects of Melatonin on Bone Health and Quality of Life in Perimenopausal Women

MeSH Terms

Conditions

Osteoporosis; Bone Diseases, Metabolic; Anxiety Disorders; Depression; Hypertension

Interventions

Melatonin; Sugars; Lactose

Condition Hierarchy (Ancestors)

Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Mental Disorders; Behavioral Symptoms; Behavior; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Carbohydrates; Disaccharides; Oligosaccharides; Polysaccharides

Limitations and Caveats

Limitations to this study include small sample sizes, length of follow-up, and heterogeneity in terms of stage of perimenopause and prevalence of menopausal symptoms.

Results Point of Contact

• Title: Dr. Paula Witt-Enderby, Professor of Pharmacology and Toxicology
• Organization: Duquesne University

wittp@duq.edu

412-396-4346

Study Officials

• Paula A Witt-Enderby, PhD

  Duquesne University School of Pharmacy

  PRINCIPAL INVESTIGATOR

• Judith L Balk, MD

  Magee-Womens Hospital, University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2010
• First Posted: June 29, 2010
• Study Start: September 1, 2008
• Primary Completion: July 1, 2010
• Study Completion: July 1, 2010
• Last Updated: March 13, 2012
• Results First Posted: March 12, 2012

Record last verified: 2012-03

Locations

US (1)