Actions of Oestrogen and Loading on Bone Structure – The Case for Independence

Jarkko Jokihaara, Ilari Pajamäki, Olli Leppänen, Pekka Kannus, Harri Sievänen, Teppo LN Järvinen
European Musculoskeletal Review, 2011;6(3):162-5
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Abstract

The operating principle of the load-driven feedback system responsible for the mechanical integrity of bones was introduced over a century ago and has become an axiom in skeletal biology – form follows function. The primary endocrine regulator of female bones, oestrogen, has been suggested to exert its influence on skeletal homeostasis by both increasing the sensitivity of this mechanical control system for skeletal integrity and acting directly on bone surfaces. In our series of experiments, we have shown that the anabolic skeletal effects of oestrogen are mainly restricted to accrual of bone mass, whereas the alleged hormonal modulation of the mechanosensitivity and geometry of bones is not direct but rather a consequence of oestrogen-induced increase in mineral mass and the resulting increase in bone rigidity. Our findings also imply that the effects of mechanical loading and oestrogen on bone structure are independent and distinct and, from an evolutionary perspective, in accordance with their respective roles in the evolutionary functions of locomotion and reproduction.
Keywords
Bone, oestrogen, physical activity, mechanosensitivity
Disclosure This study was supported by grants from the AO Research Fund, Switzerland, the Competitive Research Funding of Pirkanmaa Hospital District, Tampere University Hospital, Finland, the Research Council for Physical Education and Sports, Ministry of Education, Finland, the Sigrid Juselius Foundation, Finland and the Academy of Finland. The authors have no conflicts of interest to declare.
Received: April 01, 2011 Accepted August 01, 2011
Correspondence: Teppo LN Järvinen, Department of Surgery, FI-33014 University of Tampere, Finland. E: Teppo.Jarvinen@uta.fi

The Skeleton – A Locomotive Structure
The primary function of the skeleton is locomotion, and bones are mechanically optimised biological systems that reflect the functional demands placed on them.1–3 A bone also protects and comprises vital non-mechanical functions (mineral homeostasis, haematopoiesis) in conjunction with its primary locomotive purpose into a single organ. The skeleton provides sufficient mechanical strength for the prevailing loading environment, which consists of forces caused by muscle contractions, ground impacts and movement against gravity, without restricting its primary function with excessive weight. In terms of locomotion, the continuous maintenance of mechanically optimal bone structure (functional adaptation) materialises through a mechanosensory feedback system that detects load-induced deformations (strains) within bones and subsequently removes existing bone tissue from sites where the concomitant strains are marginal, while forming new bone at sites that experience increased strains (bone mechanoresponsiveness). 4,5 An important feature of bone functional adaptation is the conversion of physical forces into a cellular response (mechanotransduction). It is a multistep process and many systemic factors, such as hormones and growth factors, are believed to modulate this process by altering the sensitivity and response of the mechanosensory feedback system to the incident loading environment.6–8

Skeletal Effects of Oestrogen
Of the possible modulators of bone mechano-responsiveness and nonmechanical factors affecting bone structure, oestrogen has probably received the most attention, which is not surprising given its essential role as a primary origin of post-menopausal osteoporosis.9 The principal targets of oestrogen action are the female reproductive organs, but oestrogen also has direct effects on the bones. In general terms of bone metabolism, oestrogen action is associated with an increased amount of bone mineral and thus oestrogen is considered as a bone-mineralmass- conserving hormone.8 The accrued bone mineral reserve in female bones can be released into the bloodstream during pregnancy and lactation to serve the needs of the foetus and newborn without essentially compromising the mechanical competence of the skeleton. Indeed, during the reproductive years the female skeleton is apparently stronger in terms of bone loading than the male skeleton (i.e. women have puberty-associated higher bone mineral content per lean body mass than men).10,11 In addition to the mineral-packing function, oestrogen influences skeletal architecture by modifying the longitudinal and radial growth of bones.12 According to conventional knowledge, the inhibition of periosteal enlargement at puberty in females13 is assumed to be caused by direct oestrogen-induced inhibition of periosteal bone cells.14–17 Similarly, the expansion of the periosteal envelope after menopause18 (oestrogen-deficient state) is analogously attributed to the removal of this oestrogen-induced constraint on periosteal apposition.19

Effects of Oestrogen on Bone Functional Adaptation – Conventional Wisdom
According to prevailing understanding, the skeletal effects of oestrogen and mechanical loading are coupled as it has been proposed that oestrogen increases the mechano-responsiveness of bone (i.e. sensitises bones to the anabolic effects of loading).6,20–25 However, this permissive role of oestrogen on the osteogenic effects of mechanical loading on bone is based solely on observations of in vitro and transient early-stage load-induced in vivo responses through the proposed involvement of the oestrogen receptor(s) in the mechanosensory pathway of bone cells.26–28

From an evolutionary perspective, one could question why oestrogen, a reproductive hormone, directly controls the set-point(s) of the mechanosensory feedback system of the skeleton and acts directly on bone surfaces? A feedback loop does not exist that would inform any endocrine system about bone structure and rigidity. The mechanical competence of the skeleton and the related bone structure is not crucial to the function of hormones primarily responsible for maintaining calcium homeostasis and coping with physiological needs whenever those emerge.29

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