Osteoporosis Clinical Trial
Official title:
Assessing the Efficacy of Melatonin on Bone Health in Peri-menopausal Women
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.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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