Our results showed that weight loss among subjects in the diet group was associated with a significant increase in sclerostin levels. However, the increase in sclerostin was prevented by the addition of ET in a similar way that ET prevented bone loss and the increase in markers of bone turnover in the combined diet and exercise group as previously reported.(2)
Likewise, weight loss was associated with deterioration in hip geometry parameters while the addition of ET appeared to result in attenuation of these negative effects. In addition, an inverse relationship was found between the changes in sclerostin and lean body mass highlighting the important influence of mechanical stress on circulating sclerostin levels.
Diet therapy is the cornerstone in every management program designed to reduce weight and treat obesity. However, our group showed that weight loss from diet alone in older adults is associated with loss of bone and muscle mass, which could exacerbate osteopenia and sarcopenia respectively.(3,4,16)
The cause for the weight-loss associated bone loss is multifactorial and complex. Some investigators believed the change in hormone levels is the primary cause for bone loss among these subjects,(17,18)
while others proposed that the reduction in skeletal stress from unloading as a result of weight loss is the main cause for bone loss.(19)
We previously reported that changes in estradiol and leptin in these same subjects are not major determinants of bone loss.(2)
Although there were significant reductions in estradiol and leptin among patients in the weight loss groups, changes in lean body mass and muscle strength as well as bone marker were the only major determinants of bone loss, suggesting that perhaps the relative reduction in skeletal stress from unloading could be the primary driver for bone loss. To date, the exact mediator for bone loss in this setting remains unclear.
The discovery of the canonical Wnt signaling pathway as a key regulator of bone homeostasis has led to an understanding of the mechanism of skeletal adaptation to mechanical loading and unloading.(9,20,21)
Activation of the pathway leads to osteoblastic differentiation, proliferation and activity resulting in enhanced bone formation. This pathway can be antagonized by secreted inhibitors, which include secreted Frizzled-related protein, Dickoff or DKK-1, and sclerostin.(22)
Sclerostin is secreted almost exclusively by the osteocytes, the bone mechanostat, and binds to LRP5/6 to inhibit the canonical Wnt signaling. Sclerostin appears to be the main inhibitor involved in states of mechanical loading and unloading.(9,21)
Animal studies revealed that tail suspension is associated with an increase in sclerostin staining of unloaded hindlimbs in comparison to the exercising forelimbs.(9)
Human studies likewise demonstrated an increase in sclerostin levels in patients immobilized by stroke relative to age-matched subjects.(23)
Our findings of an increase in sclerostin with weight loss in the diet group which was prevented by the addition of ET in the combined diet and exercise group (despite the same amount of weight loss as the diet group) may provide additional proof as to the role of mechanical stress in modulating sclerostin levels. Realizing the effect of sclerostin on bone metabolism, it is possible that the resulting rise in sclerostin levels or lack thereof among subjects in the diet and diet-exercise group, respectively, in turn mediate the skeletal effects of lifestyle interventions in both bone mineral density(2)
and hip geometry parameters in our subjects.
We did not find any correlation between changes in sclerostin and changes in leptin and markers of bone turnover. This is not totally surprising because of mixed results reported in other smaller intervention studies (mostly drug trials). In two studies using teriparatide, one showed a reduction in sclerostin while the other did not.(10,24)
Furthermore, in both studies there was no correlation between changes in sclerostin and markers of bone turnover.(10,24)
Both raloxifene and biphosphonates are antiresorptive agents, but raloxifene was associated with a lowering(25)
while bisphosphonates either had no effect(25)
or increased sclerostin levels.(24)
In addition, a correlation between changes in sclerostin and markers of bone turnover was only reported in the raloxifene-treated patients. Given these conflicting results, data from larger intervention trials may shed light on correlations with changes in sclerostin associated with different types of therapies.
We anticipated a reduction in sclerostin from baseline in the exercise group but found none. A possible explanation is that there may be a floor effect of mechanical loading on the osteocyte’s response in these chronically overloaded obese subjects. On the other hand, a lack of increase in sclerostin levels in response to mechanical loading by exercise has also been reported recently(26)
in younger nonobese subjects. This study considered the effect of an intensive physical training program compared to sedentary lifestyle on sclerostin level.(26)
Despite the substantial body of information on the effect of diet, exercise or both on BMD in the context of lifestyle interventions,(4,19,27,28)
little is known regarding the effect of these interventions on bone quality, most especially in elderly obese. In addition, little information is available on the role of sclerostin as a potential determinant of bone quality in humans. As presented in the results section of this manuscript, there was a significant deterioration in hip geometry parameters among subjects in the diet group. On the other hand, this decline in bone quality at 12 months with weight loss appeared to be prevented by the addition of ET as hip geometry in the diet-exercise group showed no significant change from baseline. Overall, these changes are consistent with the changes in BMD by hologic DXA reported earlier,(2)
indicating that the decline in BMD in the diet group was also associated with negative effects on bone quality. More importantly, however, our data suggest that the addition of ET did not only prevent further bone loss but also resulted in preservation of bone quality as assessed using hip geometry parameters.
Using hip structure analysis, prior studies reported superior bone geometrical parameters in young athletes relative to non-athletic controls.(29,30)
Longitudinal data showed that exercise score was predictive of cortical thickness at both narrow neck and femoral shaft in young women ages 21 and 22 years old.(31)
A 6 year study in boys and girls aged 4 to 12 at the study initiation also showed that moderate and vigorous physical activity was a positive independent predictor of femoral neck cross-sectional area and section modulus.(32)
Our study demonstrates that mechanical loading does have the same positive affect on the skeleton of elderly subjects as it does on younger individuals. Moreover, the significant correlations between changes in sclerostin with changes in certain hip geometry parameters would imply that sclerostin may mediate the deterioration in bone quality from unloading in patients who are undergoing voluntary weight loss and its preservation with the addition of ET.
Our study is the first to report the independent and combined effect of weight loss and ET on sclerostin levels and hip geometry parameters in obese older adults based on a one year randomized controlled trial. As previously reported,(3)
we used comprehensive diet and exercise programs with a high rate of compliance to the interventions. However, this study has some limitations. Given the intensity of the interventions and testings involved, we have relatively small number of subjects per group. In addition, we do not have data on trabecular microarchitecture which directly assesses bone structure, and should be included in future studies. We used HSA to assess hip geometry, which is inherently limited to analyses in a single plane, and, thus, may not fully reflect bone strength.(33)
However, HSA has been found to compare favorably with volumetric QCT, which supports the validity of a projective technique such as DXA to derive hip geometry parameters.(34)
Additional limitations of HSA include sensitivity to variations in the positioning of the patient; and blurred scan images in heavier patients may result in edge detection issues..(35)
We minimized these limitations by ensuring accurate femur positioning (performed by a single expert ISCD certified technician), scanning at a low speed to minimize noise and improve the scan image, and using a state-of-the art Hologic densitometer. Although another limitation of HSA is that it is based on the assumption that average tissue mineralization does not change much through adult life, this is a reasonable assumption in our study.(35)
Besides, because our study is a randomized controlled trial, we would expect any uncertainties related to the method to average out in all the randomized groups. Accordingly, despite equal weight loss (~10%) between the diet group and diet-exercise group, HSA analyses were clearly able to demonstrate that hip geometry deteriorated in the diet group but not in the diet-exercise group, indicating an osteoprotective effect of exercise. More importantly, despite its limitations, HSA-derived hip geometry parameters have been found to be useful noninvasive and inexpensive surrogate measures of bone strength and may predict hip fractures.(36–38)
For instance, investigators from the Study of Osteoporotic Fractures found that cortical thickness and average buckling ratio predicted incident hip fractures equally well as areal BMD.(38)
In summary, our results suggest that sclerostin may partially mediate bone loss and deterioration in bone structure among obese elderly patients undergoing weight loss. Theoretically, the reduction in skeletal stress associated with weight loss leads to an increase in sclerostin production by the mechanostat in bone tissues, the osteocytes. By binding to the LRP5/6 receptors, sclerostin inhibits signaling through the canonical Wnt signaling resulting in an inhibition of osteoblastic differentiation, thus bone formation. Our results indicate that skeletal loading from ET increases BMD and improves bone geometry, and when added to diet, inhibits the weight loss-induced increase in sclerostin, resulting in the attenuation of bone loss and preservation of bone geometry. Increased understanding of the mechanisms for weight loss-induced bone loss could lead to more effective interventions to prevent bone loss most especially in those who already have osteoporosis. An antibody to sclerostin is currently in drug development. In addition to exercise, this agent may be used as a potential tool to counteract weight loss-induced bone loss, in particular, in obese older subjects who may already have low bone mass prior to lifestyle therapy.