Melatonin Osteoporosis Prevention Study
Condition: Osteoporosis; Osteopenia
MeSH terms: Osteoporosis; Bone Diseases, Metabolic
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      BACKGROUND AND SIGNIFICANCE 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.[1] Osteoporosis is
      characterized by low bone mass and microarchitectural disruption, such that fewer, thinner
      bony spicules are present leading to less structural support. These hallmark features of
      osteoporosis lead to increased skeletal fragility and an increased fracture risk.[2] Hip
      fracture specifically has been shown to be a major problem leading to increased morbidity and
      mortality.[3] In addition osteoporotic fractures are responsible for a large portion of
      health care spending. In 1995 $13.8 billion in health care expenditures were attributable to
      osteoporotic fractures.[4] Because the health of older adults often deteriorates after hip
      fracture, efforts to prevent fracture by treating and preventing osteoporosis are critical to
      reducing this common cause of morbidity, mortality and health service utilization.

      The current thinking on the development of osteoporosis is that the changes in bone turnover
      that occur with aging play a major factor. One study which measured markers of bone
      formation, such as osteocalcin (OC), and markers of bone resorption, such as type I collagen
      cross-linked N-telopeptide (NTX), showed that rates of bone formation and resorption are high
      in elderly women. However, bone resorption increases more so than bone formation leading
      resorption to be the major determinant of bone mass.[5] These biochemical markers of bone
      formation and resorption may play an important role in monitoring therapy. In a recent review
      that examined clinical studies in which bone turnover markers were measured after beginning
      treatment with a bisphosphonate, the data showed that suppression of bone turnover markers
      occurred after as little as three months of therapy.[6,7] This suppression in bone turnover
      markers was also associated with reduction in risk for fracture.[6,7] Although dual X-ray
      absorptiometry (DXA) is the gold standard for diagnosis of osteoporosis and osteopenia,
      recent reports are showing that DXA may not be the best method for measuring bone health. For
      example, bone fractures routinely occur despite modest bone mineral density levels and no
      significant reduction in the risk of fracture occurs in patients taking one of the two
      standard medications, one that significantly increases bone mineral density and the other
      that moderately increases it.[6] Thus, it is currently thought that bone quality may not be
      clinically assessed by measures other than the determination of bone metabolism with
      biochemical markers of bone turnover because these markers measure "living" bone cells.[6]
      Many modalities of treatment are used to prevent the bone loss and increased fracture risk
      associated with osteoporosis and osteopenia. One method involves use of calcium and vitamin D
      supplementation such that total calcium intake is approximately 1500 mg/day. Calcium and
      vitamin D supplementation may increase bone mineral density to a small extent, but not nearly
      to the same degree as is seen with other treatment modalities.[8] Therefore, it is often
      combined with another treatment method for better efficacy. Bisphosphonates are being used
      more and more often in postmenopausal women. These antiresorptive agents have been shown to
      prevent bone loss and reduce the incidence of vertebral and nonvertebral fractures.[9]
      Calcitonin has been shown to decrease vertebral fractures, increase bone mineral density at
      the lumbar spine and inhibit bone turnover.[10]

      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.[11]
      Melatonin works through melatonin receptors to form osteoblasts from human mesenchymal stem
      cells[12] and has been shown to inhibit osteoclast activity in rodents.[13] Melatonin levels
      have been correlated with modulating bone markers whereby low nocturnal levels of melatonin
      correlate with in an increase in bone marker metabolism and osteoporosis.[14] The addition of
      exogenous melatonin suppresses bone marker metabolism.[15] Work from my laboratory reveals
      that application of melatonin to human bone stem cells grown in culture enhances alkaline
      phosphatase activity by 50% and calcium deposition by 10-fold.[16]

      HYPOTHESIS AND SPECIFIC AIMS We hypothesize that melatonin will improve bone health,
      menopausal quality of life and sleep compared to placebo in perimenopausal women.

        1. Assess the feasibility of recruiting perimenopausal women willing to be enrolled in a
           randomized, trial of melatonin versus placebo

        2. Assess the effects of melatonin versus placebo on markers of bone health, quality of
           life, and sleep disturbance.

      PRIMARY ENDPOINTS: The primary outcome variables are bone turnover marker status, and
      melatonin levels as measured in blood and bone density as measured by the Achilles method.

      SECONDARY ENDPOINTS:

        1. Quality of life as measured by the MenQOL, a validated scale of menopausal quality of
           life

        2. Sleep, as measured by the Pittsburgh Sleep Questionnaire

      RESEARCH PLAN This study is a longitudinal, cohort trial of 20 subjects who are
      perimenopausal and aged 45 years old or greater who have new onset of irregular menses not
      due to other known causes such as polycystic ovaries or hypothyroidism. Perimenopause is
      defined as the time between the onset of menstrual irregularity and menopause; there is no
      lab test that is diagnostic of perimenopause. Thus, the investigators will include women who,
      according to their age, are likely to be perimenopausal (age 45 or greater) and who have
      symptoms of perimenopause (irregular menses). Once a cohort of 20 subjects is recruited, the
      investigators will randomize volunteers using a computer-generated blocked randomization
      scheme. Five study subjects will receive placebo and 15 study subjects will receive
      melatonin, 3 mg). The women enrolled in the study will be asked to take their treatments by
      mouth at bedtime each day for 6 months to coincide with the nocturnal surge in melatonin each
      day. This dose of melatonin has been chosen because 3 mg melatonin is commonly used to induce
      phase-shifts in circadian rhythms in people.[17] Seeing that this is one of our secondary
      endpoints, this dose is appropriate. Regarding melatonin's effects on bone, there is nothing
      known about its efficacy on forming bone in women. Therefore, the dose of melatonin was
      chosen based on the reported literature using pre-clinical or in vitro culture models that
      showed positive effects on bone formation. These reports show variable effects of melatonin
      ranging from 400 pM in rat [15], to 5 mg melatonin in mouse (unpublished data) to 50 nM on
      human mesenchymal stem cells grown in culture.[12,16] The bioavailability of melatonin is 17%
      in females taking 250 mcg melatonin po.[18] Thus, a 3 mg dose of melatonin taken by mouth
      would result in a nocturnal exogenous level of 2.19 mM. The terminal half-life of melatonin
      is about 41 minutes in females [18], however, accumulation of melatonin in the bone marrow
      occurs [11]. Therefore, these data suggest that our 3 mg dose is appropriate for these
      studies.

      PLANS FOR ASSESSMENT AND STUDY OUTCOMES Our primary outcome will be the levels of bone
      turnover markers, OC and NTX, bone density and melatonin taken at baseline and then after 6
      months of treatment. The change in bone turnover marker levels will be compared between those
      taking melatonin and those taking placebo. Baseline levels of OC and NTX will be calculated.
      For this study the investigators will also visually inspect the data in order to perform
      descriptive analyses of the demographic characteristics of our population, such as age, and
      weight. We will explore characteristics of any individuals who have a significant improvement
      in their bone turnover markers, such as compliance with the treatment, diet, and lifestyle as
      determined by the diary. We will also make note of characteristics such as current or past
      cigarette smoking and alcohol and caffeine consumption as individuals with these risk factors
      may show less improvement in their bone turnover markers. We will use intention to treat as
      our primary analysis. We will attempt to minimize missing data with careful follow-up of
      subjects, maintaining consistent contact with them over the study period, and remunerating
      them for their inconvenience. If a subject drops out of the study, the investigators will
      still attempt to obtain their follow up studies.

      Expected Outcomes.We expect perimenopausal women taking melatonin to show an improvement in
      overall bone health as revealed by an increase in bone density, an increase in OC and a
      decrease in NTX levels when compared to those women taking placebo. We also expect those
      taking melatonin to have better control over their menopausal symptoms, better quality of
      life and less sleep disturbances compared to their placebo controls. The potential benefits
      of participating in this study include the possibility of decreasing bone turnover and
      reducing fracture risk as well as improve sleep regardless, a condition much affected in this
      population of women. The data from these studies may provide novel and alternative uses for
      melatonin for the prevention of osteoporosis and provide women with more options to manage
      diseases associated with menopause.
    

Intervention name(s): melatonin; sugar pill
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 3mg p.o. at bedtime daily; lactose p.o. at bedtime daily
Other intervention name(s): Nature's Bounty Melatonin; Natrol Melatonin; Spring Valley Melatonin; Lactose
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: melatonin; menopause; perimenopause; sleep; osteoporosis; osteopenia; anxiety; depression; hypertension