Effect of Two-Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non-obese Younger Adults: a Randomized Clinical Trial

Abstract

Introduction

Caloric restriction (CR) is the most promising intervention for extending healthy lifespan of humans.⁽¹⁾ Data from CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) phase 1 suggested that CR is feasible and could confer ample health benefits.^(2-5) However, there is considerable evidence in the literature linking weight loss with increased bone turnover and reductions in bone mineral density (BMD) in older adults^.(6-12) Conversely, weight loss has not been shown to consistently increase bone turnover and decrease BMD in younger adults.^(13-16) Moreover, findings of bone loss with weight loss mostly come from relatively short-term weight loss studies aiming to reduce body fat in obese adults.^(8-12) There has been little or no scientific study of the possibility that CR initiated with the intent of slowing the aging process in healthy adults could occur at the cost of bone loss. In CALERIE phase 1, one year of CR in older adults (age~57 yrs.; body mass index [BMI]~27 kg/m²) increased bone turnover and decreased BMD by ~3% at the hip and spine,⁽¹⁷⁾ whereas 6 months of CR in younger adults (age~37 yrs.; BMI~26 kg/m²) increased bone turnover but did not change hip BMD.⁽¹⁴⁾ The long-term effects of CR (>1 year) on bone metabolism at the clinically relevant sites of osteoporotic fractures in non-obese younger adults are unknown. Furthermore, the underlying mechanisms behind any changes in BMD need to be elucidated. Such studies could yield important information as to whether CR has adverse effects on bone health and, if so, identify interventions to reduce effects of weight loss on bone.

The purpose of the present study, therefore, was to evaluate the effects of two-year CR on bone metabolism and BMD in non-obese younger adults enrolled in a 24-month, randomized controlled trial (RCT). The data reported here were obtained as secondary outcomes of CALERIE phase 2, which has the overall aim of examining the effects of sustained ~25% CR on slowing aging in non-obese humans.⁽¹⁸⁾

Methods

Results

Body composition and BMD

The CR group relative to AL also had significant reductions in FM and FFM at 12 months, with maintenance of lower FM and FFM at 24 months. The changes in body weight and composition in the CR group were accompanied by significant decreases in BMD relative to the AL group, at the lumbar spine, total hip, femoral neck and other regional hip sites at 12 months and 24 months (Table 2, Figure 1a).

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Figure 1

Mean percent changes ± SEM in bone mineral density (panel a) and biochemical markers of bone turnover (panel b) in non-obese younger adults randomized to ad libitum group (●) or caloric restriction (○). P value significantly different (<0.05) from ad libitum value. Abbreviations: CTX = C-terminal telopeptide of type I collagen; BAP = bone specific alkaline phosphatase; TRAP5b = tartrate-resistant acid phosphatase isoform 5b; PINP = intact N-terminal propeptide of type I

The treatment effects on BMD did not differ between males and females (sex × treatment interaction p>0.05). There were no treatment effects on BMD at the distal radius or whole body.

Discussion

CR could enhance healthy lifespan but it also causes weight loss, which has been associated with a reduction of bone mass in obese older adults.^(6-12) The effects of long-term CR on bone health in non-obese younger adults are unknown. In this two-year RCT, prolonged CR-induced weight loss significantly decreased BMD at the clinically important sites of the lumbar spine, total hip, and femoral neck due to an increase in bone resorption and a decrease in bone formation.

The decreases in spine and hip BMD in our participants, however, were predicted from their decrease in body weight. Weight loss studies in obese older adults also found that bone loss was proportional to the amount of weight loss.^(6-12) The ~2% decrease in spine and hip BMD in our non-obese younger adults is within the range reported in studies of obese older adults who lost a similar amount (~10%) of body weight.^(6-12) Therefore, the effect of weight loss on BMD in non-obese younger adults is similar to that in obese older adults. Conversely, our data are in contrast to studies showing no detrimental bone effects with weight loss in obese younger adults.^(13,15,16) The reason for this discrepancy could be that non-obese younger adults have less FFM than obese younger adults to protect against bone loss.⁽³⁰⁾

BMD decreased at the central sites of the spine and hip but not at the peripheral site of the wrist or whole body. A possible explanation is that the spine and hip contain more trabecular bone, which has a greater rate of turnover than does cortical bone; sites where trabecular bone predominates are more sensitive to factors that alter bone turnover.⁽³¹⁾ Another possible explanation is that the spine and hip are weight-bearing skeleton whereas the wrist is not, which makes these sites more responsive to the unloading effect of weight loss.⁽¹⁷⁾ Although whole body BMD is highly reproducible, it is not sensitive in estimating BMD changes as it averages findings from many areas of the body. Given that spine and hip BMD are used to predict fracture risk and are common sites of osteoporotic fractures,⁽³²⁾ these site-specific effects of CR could have clinical implications.

The transient but marked increases (~30%) in CTX andTRAP5B in the CR participants indicate that bone resorption was stimulated in response to CR-induced weight loss. In fact, the peak increase in bone resorption markers coincided with the peak weight loss (6-12 months). Interestingly, although bone turnover is a tightly coupled process,⁽³³⁾ bone formation markers did not increase following the increase in bone resorption markers, supporting the lower BMD observed at 12 and 24 months. On the contrary, BAP decreased (~8%) whereas PINP did not change during the latter phase when bone resorption markers were reverting towards baseline coincident with weight maintenance. Our results support data from studies in obese older adults, which found that weight loss was associated with disproportionate increase in bone resorption.^(8,17,34) However, our results also suggest that in non-obese younger adults undergoing CR, an absolute decrease in bone formation additionally contributes to bone loss.

Although the precise mechanisms for bone loss during CR are unknown, several contributory factors have been hypothesized.^(30,35,36) Our data showed that CR-induced weight loss was accompanied by changes in body composition (FM, FFM) that could contribute to bone loss.⁽³⁰⁾ Other potential contributors to the higher bone loss were greater increases in cortisol and adiponectin and decreases in leptin and insulin observed in the CR group.^(35,36) Regarding cortisol, serum cortisol increased at 12 months while BMD decreased at 12 and 24 months comparing the CR and AL groups, consistent with known negative effects of cortisol on bone. However, in models confined to the CR group investigating factors that contributed to changes in BMD and bone turnover markers in the setting of CR, we found that cortisol changes over 12 months were positively associated with BMD changes and negatively associated with bone turnover markers in adjusted (Table 5) and unadjusted (Appendix Table 1) models. We are not certain of the reasons for this unexpected finding. We cannot exclude that subjects who had lesser increases in cortisol at 12 months had greater increases in cortisol at 6 months (not measured in this study), consistent with an adaptive CR response.⁽³⁷⁾ The most rapid weight loss in CR participants occurred during the first 6 months. Cortisol levels at 12 months might not accurately reflect cumulative exposure to cortisol over the first year. Thus, future studies might include measurements of serum cortisol at earlier time points to determine if CR-induced changes in cortisol precede and predict the CR-induced bone loss. Although increases in 25OHD were greater in the CR group due to the weight loss,⁽³⁸⁾ changes in PTH or IGF1 did not differ between the CR and AL groups. Another contributing factor is the lower level of physical activity in the CR group although we did not observe group differences in strength. Analyses exploring the factors associated with bone loss suggested that the key factor correlated with changes in hip BMD were changes in FFM. For changes in spine BMD and bone markers, there was no single main predictor but a combination of predictors in the final models accounting for up to 31% of the variance, consistent with the multifactorial nature of the bone loss. Conversely, given that a large proportion of the variance was unexplained, factors not measured could underlie the bone loss with CR. One such factor is sclerostin, a protein secreted by osteocytes in states of unloading (e.g. weight loss) to inhibit Wnt/b-catenin signaling and bone formation.^(39,40) A recent study reported increase in sclerostin with weight loss that was prevented by exercise.⁽⁴¹⁾ It is important to note that physical activity decreased in CR participants since PA has been shown to be osteoprotective during CR;⁽³⁴⁾ this reduction in PA could have also contributed to bone loss. Supporting this premise, CR was associated with FFM loss, a change that can be prevented/attenuated by increased physical activity.⁽⁴²⁾ Given the coupling between muscle and bone during weight loss,⁽⁴³⁾ factors other than sclerostin that mediate muscle-bone interactions could also mediate bone loss during CR⁽⁴⁴⁾ and deserve investigation.

Typically, spine and hip BMD increase until early adulthood and remain stable until age ~50.⁽⁴⁵⁾ Thus, the decreases in spine and hip BMD we observed, although small, are unexpected for adults in this age range (21-50 yrs.). However, we also found that the changes in BMD were consistent with the changes in body weight. Overall, the predicted increase in fracture risk associated with BMD loss with CR appears small. At the femoral neck, the average BMD loss was −0.015 g/cm² (−0.16 T-score units). Using the WHO Fracture Risk Assessment Tool, (⁴⁶) this degree of BMD loss in a 50-year-old woman without risk factors corresponds to <0.5% increase in 10-year risk of fracture. In addition, there was no increased fracture risk in Look AHEAD, a trial testing the effects of a weight loss intervention in overweight and obese adults with type 2 diabetes although the intervention group lost an average of 8.6% of body weight.(⁴⁷) Of course, longer term studies are needed to fully assess the clinical importance of these findings. Follow-up studies in older adults suggest that BMD loss continues after weight reduction(⁴⁸) and/or may not fully recover with weight regain.⁽⁴⁹⁾

The strengths of our study include the RCT design, unique 2-year CR duration in non-obese participants, and comprehensive assessments of bone metabolism. Although we used DXA to monitor bone loss because it is the standard for measuring BMD (≥65% of the variance in bone strength), a limitation is that DXA assesses bone quantity but not bone quality, an additional predictor of fracture risk.⁽⁵⁰⁾ Besides bone markers, we did not measure bone quality (e.g. bone microarchitecture). It is possible that despite BMD loss, CR preserved bone quality as suggested by low BMD but good bone quality noted in persons practicing long-term CR.⁽⁵¹⁾ Another limitation is that changes in BMD after weight loss might be exaggerated because of technical limitations of DXA.⁽⁵²⁾ However, this would primarily affect interpretation of studies examining bone changes after extreme weight loss not after moderate weight loss as in the current study.⁽³⁶⁾ Moreover, our results are consistent with RCTs in older adults showing bone loss with weight loss.^(6-12) Importantly, changes in BMD in the participants were corroborated by changes in bone markers.⁽⁵³⁾ Despite extensive behavioral counseling, participants did not achieve the protocol goal of 25% CR. As discussed,⁽¹⁸⁾ this probably occurred because the target weight loss trajectory based on our pilot studies⁽²³⁾ underestimated the weight loss needed to sustain 25% CR. It may also reflect the inability of most individuals to maintain greater degrees of CR over long periods. Nonetheless, significant CR and weight loss (both ~12%) were achieved throughout the 24-month study, which suggest that even lesser degree of CR has negative effects on bone. Another limitation is that we did not include a standard exercise regime, because the overall goal of CALERIE phase 2 was to determine if CR in humans results in the same beneficial effects as observed in animals subjected to similar levels of CR.(¹⁹) In animals, both CR and exercise improve average survival, but only CR extends maximal life span.⁽⁵⁴⁾ Finally, our study involved a highly motivated population and very intensive behavioral intervention, thus limiting broader inferences of our results.

In conclusion, our results demonstrate that 2-years sustained CR in non-obese younger adults increases bone resorption while decreasing bone formation (i.e. uncoupling of bone turnover) and causes a modest but significant decline in BMD, expected on the basis of the weight lost, at clinically important sites of osteoporotic fractures. Further long-term studies are needed to determine if such bone loss increases fracture risk and whether therapeutic interventions can prevent bone loss that occurs with CR-induced weight loss.

Supplementary Material

Acknowledgement

Footnotes

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