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BoneApatite: Attention all night owls

Could it be that watching infomercials in the middle of the night, working the third shift, or continual jet lag among business travelers may be detrimental to our bones? Possibly. In fact, these disruptions of our circadian rhythms may exert an important negative impact on our bone composition. Chronobiology, the study of circadian rhythms, has been a part of bone research for a number of years. Understanding the relationship between circadian rhythms and bone presents an important avenue in which to understand bone homeostatic mechanisms. So what are circadian rhythms? Our circadian rhythms are the physiologic and behavioral functions, which include the release of hormones, expression of certain proteins, regulation of body temperature, and our sleep-wake cycles, that occur over a 24-hour period. These internal rhythms are regulated by a master molecular clock, the suprachiasmatic nucleus (SCN), located in the hypothalamus just above the optic nerve, which also communicates with subcomponents in peripheral tissues such as bone. What is important, though, is that even though our circadian cycles are internally produced, they are influenced by external environmental factors, namely light and darkness. That is, disruption of body's circadian cycles from late night study sessions or shift work has important effects on our health.

So what does this have to do with bone? Well, lots. Since most of the body's homeostatic functions are regulated in a circadian manner, it follows that bone's homeostatic functions are not excluded. For example, both bone formation and resorption markers demonstrate high levels at night and lower levels in the afternoon. Other aspects of bone physiology are also subject to circadian rhythms, specifically, proteins expressed on bone-marrow stromal cells. Recent research led by Dr. Clifford Rosen, of the Jackson Laboratory, has shed light on the circadian-regulated protein, nocturnin (NOC), and the circadian-regulated adipogenic transcription factor, peroxisome proliferator-activated receptor (PPARG2), and their roles in marrow stromal cell osteogenic and adipogenic differentiation (Kawai et al 2010.pdf). What the researchers found was that NOC, highly expressed in bone-marrow stromal cells, adipocytes, and the hypothalamus, interacted with PPARG2 in the differentiation of marrow stromal cells, such that NOC-deficient mice exhibited decreased expression of PPARG2 and in turn, decreased adipogenic differentiation. In contrast, high NOC in cell cultures, induced high PPARG2 expression and greater adipogenesis, suggesting that PPARG2 is modulated by NOC. Thus, disruption of NOC, whose expression peaks in the early evening, may actually increase bone marrow adipogenesis.

The disruption of circadian rhythms, specifically the effect on NOC and PPARG2, present an important vantage point from which to understand bone physiology and the pathogenesis of osteoporosis. PPARG2's role mesenchymal stem cell differentiation may also contribute to age-related osteoporosis, as explained in a recent review by Drs. Alvin Ng and Gustavo Duque (Ng_Duque 2010.pdf). With aging, PPARG2 expression increases while releasing toxic fatty acids, inhibiting osteoblast proliferation and promoting osteoblast apoptosis. The understanding of these, and other, circadian-regulated proteins and transcription factors broaden the potential of populations at risk for osteoporosis. However, this knowledge also presents an opportunity for future research and therapeutic targets in the prevention of osteoporosis. Further, it signals influence of lifestyle factors beyond physical activity and nutrition, such as disrupted sleep-wake cycles on bone health. Sort of makes you rethink that staying awake to watch QVC, doesn't it?

Lesley M. Scibora, D.C.

Bone Apatite: Bisphosphonates and fractures

Last month ABC News reported on an alarming effect of osteoporosis drugs, including Fosamax, Boniva, Reclast, and Actonel - spontaneous femoral fractures. Concern was raised over the atypical fractures subsequent to minimal trauma occurring in women who had taken these bisphosphonate drugs for osteoporosis. Since most of these women had taken the drugs for several years, it raised the question of whether long-term bisphosphonate use was responsible for fracture.

Bisphosphonates are a class of drugs widely used to treat metabolic bone disease, including osteoporosis. They act to diminish bone resorption by inhibiting osteoclastic activity. This disrupts bone's normal remodeling activity, which is designed to remove and replace old and damaged bone tissue. Intuitively, disruption of remodeling could pose a plausible explanation of fracture pathophysiology. First, unchecked microdamage, would allow for the accumulation of microcracks. Unrepaired microcracks likely diminish bone strength through a reduction of bone material properties. Second, uninhibited osteoblasts will continue to form new bone, thereby leading to potential hypermineralization of bone. Like microdamage accumulation, hypermineralization diminishes bone material properties by reducing toughness, and ultimately, bone strength.

While it is nearly impossible to assess which fractures are prevented, one can attempt to assess the risks for increased fracture treatments may be responsible for. In a recent New England Journal of Medicine study, supported by Merck and Novartis, Dr. Dennis Black and colleagues investigated the relationship between subtrochanteric and diaphyseal femoral fractures and bisphosphonate use (Black 2010 NEJM.pdf). Upon analyzing the results of three large-scale, placebo-controlled, randomized trials, the researchers found no association. Across all trials, 14,195 women who had taken the drugs from 3 to 10 years experienced 283 hip or femur fractures. Of those, a total of 12 fractures were pertinent to the analysis, three of which occurred in placebo group women. The researchers concluded that the risk of this type of fracture with bisphosphonate use was extremely low, amounting to an annual rate of 2.3 fractures per 10,000 patient-years.

While the study results suggest there is no increased risk of atypical fracture, it may not have been powered to detect differences of such low incidence. In a recent review of the adverse effects of bisphosphonates (see article link), Dr. Bo Abrahamsen reported that, like osteonecrosis of the jaw, atypical femoral fracture incidence is rare. Citing the relative safety of the drugs in patients who are at a high risk of osteoporotic fracture, he cautions physicians to reassess bone mineral density following treatment course to avoid bisphosphonate use in low-risk patients. Future studies will likely investigate the contribution of other factors, including concurrently used drugs, patient-inherent remodeling abnormalities, patient age, and other concomitant health conditions.

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