Assessing the Efficacy of Melatonin on Bone Health in Peri-menopausal Women

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.