Changes in Bone Resorption Across the Menopause Transition: Effects of Reproductive Hormones, Body Size, and Ethnicity

Sowers, Mary Fran; Zheng, Huiyong; Greendale, Gail A.; Neer, Robert M.; Cauley, Jane A.; Ellis, Jayne E.; Johnson, Sarah; Finkelstein, Joel S.

doi:10.1210/jc.2012-4113

Cited by 106 publications

(69 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased sCD14 levels likely reflect bone resorption due to its presence on cells of the osteoclast lineage. Bone turnover is higher in whites than in African-Americans [49][50][51], and hip fractures are associated with higher bone turnover [52,53]. If sCD14 was simply reflective of bone turnover, one would have assumed, contrary to what we found, that the relationship between sCD14 and hip fractures would be independent of race or diabetes status.…”

Section: Discussioncontrasting

confidence: 81%

Soluble CD14 and fracture risk

et al. 2015

View full text Add to dashboard Cite

Summary Soluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture. Introduction Soluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures. Methods In the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5 years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6 years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender.Results In unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6 ng/mL) and incident hip (HR, 1.26; 95 % CI, 1.17, 1.36) and composite (HR, 1.20; 95 % CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95 % CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women. Conclusions In this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

show abstract

Section: Discussioncontrasting

confidence: 81%

Soluble CD14 and fracture risk

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Specifically, as shown in Figure 1, the decline in serum estradiol levels (and accompanying increase in serum follicle stimulating hormone [FSH] levels) through menopause is closely associated with an increase in osteoclastic bone resorption (urine N-telopeptide of type I collagen [NTx]) (Sowers et al 2013). Conversely, because the postmenopausal ovary continues to produce androgens, serum testosterone or other androgen levels do not change significantly across menopause (Handelsman et al 2016), arguing against a role for androgens in contributing to postmenopausal bone loss.…”

Section: Human Studiesmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Regulation of Bone Metabolism by Sex Steroids

Khosla

Monroe

2017

Cold Spring Harb Perspect Med

207

125

View full text Add to dashboard Cite

Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do play important roles, perhaps in a somewhat compartment-specific (i.e., cancellous vs. cortical bone) manner. This review summarizes our current knowledge of sex steroid action on bone based on human and mouse studies, identifies both agreements and potential discrepancies between these studies, and suggests directions for future research in this important area.

show abstract

“…This period in a woman's life is associated with marked changes in body physiology (1). Bone is lost at the most rapid rate beginning two to three years prior to the cessation of menstruation (2,3).…”

Section: Introductionmentioning

confidence: 99%

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Liu

Yuen

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that the inhibition of FSH reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHβ was found not only to rescue bone loss post-ovariectomy, but also to display marked anti-obesity and pro-beiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance -osteoporosis and obesity -we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHβ. Hf2 has already been shown to reduce body weight, fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on micro-computed tomography.This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild type mice. We also re-confirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat. 3 SIGNIFICANCE STATEMENTWe have addressed the question whether osteoporosis and obesity, which often occur concurrently in postmenopausal women, can be targeted by a single agent. We have shown previously that the reproductive hormone FSH, the levels of which rise after menopause, regulates both body fat and bone mass. We now show that blocking FSH action using two purposefully designed epitope-specific antibodies protects against bone loss in mice. This positions both FSH antibodies as lead molecules for clinical development towards future use in people.

show abstract

Changes in Bone Resorption Across the Menopause Transition: Effects of Reproductive Hormones, Body Size, and Ethnicity

Cited by 106 publications

References 43 publications

Soluble CD14 and fracture risk

Soluble CD14 and fracture risk

Regulation of Bone Metabolism by Sex Steroids

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

Contact Info

Product

Resources

About