The muscle-bone feedback system undoubtedly pertains
to a complex mechano-biological system that primarily
enables efficient locomotion but is also involved in other
vital physiological functions. It is quite clear that the behav-
iour of such a complex system is qualitatively and quantita-
tively different from what can be inferred from observations
and phenomena in isolated units of the whole system1, e.g.,
in in vitro experiments based on cell cultures or molecules
only. Many of the purported associations and relationships
observed between macroscopic and microscopic properties
may have just been consequences of choices on what partic-
ular microscopic features were evaluated against what
macroscopic features. The scientific value of these
approaches is by no means depreciated, but it is highly like-
ly that the principal laws of the bone-muscle interplay at the
macroscopic (whole body) level cannot be precisely, if at all,
exposed by digging deeper into the microscopic details –
down to cellular, molecular or genetic level.
Rather, the whole musculoskeletal apparatus should be
seen and treated as a "cost-efficient" product of evolution
which integrates several vital functions, along with its pri-
mary locomotive purpose, into a single organ and fills the bill
– at least during the reproductive phase of life and somewhat
beyond that2. This perspective is intended to give a reason-
able picture of the locomotive skeleton and its other vital
functions and particularly to capture factors that are relevant
in understanding the mechanical and physiological function-
ing of the musculoskeletal system as a whole.
Evolutionary and environmental scope
Principal hormones, muscle and bone tissues have co-exist-
ed virtually from the very beginning of the evolution of present
forms of complex life3-7. Given the abundance of time, some
J Musculoskelet Neuronal Interact 2005; 5(3):255-261
Hormonal influences on the muscle-bone feedback system:
Bone Research Group, UKK Institute, Tampere, Finland
Hormones, muscle and bone tissues have co-existed virtually during the whole evolution of vertebrates, and it is obvious
that they constitute a complex system able to cope with needs and challenges arising from a variety of physiological and loco-
motive needs. All body movements are produced by co-ordinated contractions of skeletal muscles, while consequent dynamic
muscle work provides the fundamental source of mechanical loading to the skeleton. Mechanical competence of the skeleton
is principally maintained by a mechanosensory feedback system that senses the loading-induced deformations within the bones
and maintains the skeletal rigidity through structural adaptation. In contrast to the prevalent view suggesting a modulatory
effect of hormones on the sensitivity of the mechanosensory system, a new conceptual scheme is proposed. In particular, it is
argued that the mechanical and hormonal functions in the skeleton are fundamentally independent but can be seemingly inter-
active through hormonally-induced modifications in the bone structure, those basically forming a mineral reservoir for main-
tenance of physiological homeostasis. Whenever needed, utilization of this strategically placed reservoir would not essentially
compromise the mechanical competence and locomotive capability of the skeleton. Although plausible, the present view is
necessarily speculative and awaits corroborative experimental evidence.
Keywords: Bone Mineral, Bone Structure, Estrogen, Evolution, Mechanical Loading, Osteoporosis
The author has no conflict of interest.
Corresponding ·uthor: Dr. Harri Sievänen, Sc.D., Bone Research Group, UKK
Institute, P.O.B 30, FI-33501 Tampere, Finland
Accepted 29 April 2005
H. Sievänen: Hormones and the muscle-bone unit
500 million years, it is obvious that these three physiological
modules have embodied in such a universal biological protocol
that is fit and efficient for virtually all foreseen locomotive and
physiological demands that may occur in various forms of life.
The skeleton is a beautiful example of this evolutionary
process as it provides the body not only with a practical loco-
motive apparatus and protection of internal organs, but also
with a reservoir for minerals needed for physiological functions
– several vital functions integrated within a single organ!
Phylogeny and associated locomotive and loading factors
basically determine the specific functional organization and
features of the skeleton and musculature. All body move-
ments are produced by co-ordinated contractions of skeletal
muscles, while the concomitant dynamic muscle work pro-
vides the fundamental source of mechanical loading to the
skeleton. During locomotion and other movements, the mag-
nitude of body-weight induced reaction forces is usually mul-
tiplied due to moment arms of the musculoskeleton, render-
ing underlying net muscle forces relatively high – multiples of
body weight8. In order to survive, the musculoskeleton must
thus be able to adapt itself to altered loading environments by
adjusting specific characteristics of its functional modules
(bone and muscle) in concordance with each other.
Accordingly, the apparent goal of the mechanosensory con-
trol system is i) to maintain the mechanical competence of the
skeleton in terms of the predominant loading environment
and ii) to keep the loading-induced deformations well below a
specific safety margin in order to avoid failure. It is recalled
here that the load-induced deformations arising from differ-
ent dynamic locomotive activities tend to remain within a spe-
cific range within and between species8, indicating a ubiqui-
tous protocol for bone adaptation to prevalent loading.
The relationship between bone characteristics and
mechanical loading, and particularly the underlying control
system equipped with an elegant ability to sense loading-
induced mechanical deformations (strains) within the affect-
ed bone structure, have been reviewed recently9-13.
Conceptual differences, e.g., regarding the characterization
of the load-induced strains (magnitude, rate, and distribu-
tion) are obvious in these approaches but some features are
common. Without going into details, the common and basic
principle of these approaches is that bone cells located with-
in the mineralized bone matrix (evidently through the inter-
connected osteocyte network14) somehow sense the mechan-
ical forces arising from locomotion (or other movements)
and convert a part of the incident mechanical energy into
biochemical energy (a part of this energy is dissipated into
heat), which eventually results in synthesis of new bone tis-
sue. Reduced loading, in turn, leads to removal of bone tis-
sue from unloaded regions. Particularly noteworthy is that
the sensitivity of bone response to loading is claimed to be
directly modifiable by external factors (e.g., hormones) that
could alter the set-pointaof the mechanosensory feedback
system. Details of the mechanosensory system and associat-
ed pathways from mechanical stimulus to formation or
resorption of bone are sophisticated and not yet fully estab-
lished15, and are beyond the scope of this perspective.
Given the principal role of calcium6,7, the major con-
stituent of bone mineral (in the form of crystalline calcium
hydroxyapatite), in several cellular and biological processes
and functions (e.g., contraction of muscle tissue, gastroin-
testinal and renal functions, reproduction), the mineral
metabolism within a complex organism is rigorously con-
trolled by several parallel and partly complementary physio-
logical feedback systems involving intertwined hormonal
functions. Failure in the regulation of calcium metabolism
would be lethal and the need for redundant systems for ade-
quate safeguard and backup functions is self-evident.
Consequently, many hormones (primarily 1,25-dihydroxy-
cholecalciferol, parathormone and calcitonin) are concerned
with the regulation of calcium metabolism. In addition to
these three hormones affecting calcium metabolism and bone
formation and resorption, adrenal glucocorticoids, growth
hormone and insulin-like growth factors, thyroid hormones
and estrogens are involved and interacting through several
feedback systems securing the physiological homeostasis.
Hormones act through and are regulated by a system of
specific receptors and binding proteins16. Genes, in turn,
encode for nucleid acids and subsequent proteins that carry
out the reactions in living systems and control concomitant
physiological functions. Under normal circumstances
(potential mutations and related peculiarities excluded), the
genetic control of vital functions is pleiotropic (one gene is
linked to a variety of functions or phenotypes) and multi-
genic (several genes are linked to a specific function or phe-
notype), again most likely for apparent safety reasons. Of the
above mentioned arsenal of hormones, estrogen has proba-
bly received the most attention, which is not surprising given
its essential role as a primary cause of postmenopausal
osteoporosis17. In many studies, estrogen has also been sug-
gested to be a central modulator of skeletal response to load-
ing, but the interpretations and conclusions are not consis-
tent18-22, and this topic has aroused a lot of debate23-27.
Distinction between mechanical and hormonal
In this perspective, a conceptually novel scheme for bone-
muscle interplay is presented. The new approach fully agrees
with the previous schemes in that the bone has the ability to
aIn the present context, the set-point should not be strictly consid-
ered a fixed threshold representing a specified magnitude of defor-
mation (e.g., in microstrains) above which the incident deforma-
tions will result in increased bone rigidity and below which
decreased bone rigidity will follow. In fact, the set point denotes a
relatively wide physiological range of deformations within which
the incident deformations would not lead to substantial skeletal
adaptation in either direction, if any. It is also stressed that the set-
point pertains to dynamic loading situations, when not only the
strain magnitude, but also the strain rate play an essential role.
H. Sievänen: Hormones and the muscle-bone unit
sense loading induced deformations (without paying atten-
tion to details of underlying mechanisms or the specific
nature of deformations) and to adapt its structure reason-
ably to an altered loading environment whenever needed,
but essentially disagrees in that the humoral factors (e.g.,
hormones) do not directly modify the sensitivity of the load-
sensing mechanism. It is particularly argued that there is
principally no need for such a complicated adjustment of the
set-point, meaning that an aberrant set-point does not exist
in the mechanosensory control system. It is proposed that
both the mechanical and hormonal functions can be solved
in a straightforward manner without compromising the per-
formance of the musculoskeleton or violating existing clini-
cal or experimental observations.
The seminal observations by Schiessl et al.23and Ferretti
et al.28provide relevant cornerstones to this new proposition.
The former group, using the data readily available in the lit-
erature, incisively exposed that the amount of bone mineral
(bone mass) in relation to muscle mass in post-menarche
(estrogen-replete) girls and women appears to be clearly
higher compared to boys and men23. The latter group further
showed that this excess bone mass seems to disappear after
menopause, indicating that the ratio of bone mass to muscle
mass in estrogen-deplete women returns back to the level in
men of similar age. We revived this paramount idea in our
recent perspective concerning the role of the skeleton in
reproductive and locomotive functions27.
If we assume that bone mass and lean body mass are rea-
sonable surrogates for skeletal rigidity and mechanical load-
ing arising from muscle activity, respectively, the above in
vivo macroscopic observations can be interpreted by two
seemingly plausible but mutually exclusive ways. First, one
can argue that estrogen sensitizes the mechanosensory sys-
tem to loading9,10,13(i.e., compared to an estrogen-deplete sit-
uation, smaller loading-induced deformations would be suffi-
cient to initiate bone formation in estrogen-replete situa-
tions). Customary loading would thus result in greater bone
mass. Conversely, withdrawal of estrogen (due to menopause
or amenorrhea) reduces the sensitivity to loading and leads to
bone loss, as the concurrent loading is not sufficient to count-
er this change in mechanosensitivity. The alternative view is
that at puberty the rise in estrogen levels simply leads to the
deposition of additional bone mass to satisfy the anticipated
physiological needs of the subsequent reproductive period27.
At menopause, this ~20% surplus of bone mineral (com-
pared to men) is removed as unnecessary, which becomes
manifest as postmenopausal bone loss. While both views pro-
vide an equally plausible explanation for the observations, the
latter interpretation constitutes a simpler solution and does
not require a mechanism that could alter the sensitivity of the
mechanosensory feedback system. The new scheme is entire-
ly based on the latter interpretation.
Given the evident causal link between muscle activity-
induced loading and bone characteristics9-13, maintenance of
the mechanical competence of the whole functional organ
(musculoskeletal system) through structural adaptation
remains the major, and most likely, the one and only goal of
the mechanosensory system. In this context, it may be useful
to dispel a common misconception regarding the bone mass
and bone mechanical competence. Despite the fact that the
correlation between bone mass and whole bone strength can
be very high (r up to 0.9 or more), this strong association does
not imply that the bone mass as such equates with the
mechanical competence of a bone. Bone mass simply reflects
the amount of material of which the bone structure is made,
but does not convey any specific information of how reason-
ably, in mechanical terms, the bone mass is spatially distrib-
uted within the bone volume. It is ultimately the bone struc-
ture, characterized by overall size and geometry, cortical
geometry, thickness and porosity, internal trabecular archi-
tecture and organisation, that determines whole bone
mechanical competence (structural rigidity or stiffness, and
strength) in different loading environments - provided that
the material properties are not substantially compromised2,29.
The hormonal control of physiological homeostasis of the
body, in contrast, is only concerned with the access to readi-
ly interchangeable reservoir of minerals (bone mass) that
may be required; e.g., during pregnancy and lactation, nutri-
tional deficiencies, starvation, or diseases - while not criti-
cally jeopardizing the mechanical competence of the skele-
ton and consequent locomotive capability. As there is prob-
ably no feedback loop that would inform any endocrine sys-
tem about bone structure and its rigidity, the latter condition
requires that the bone elements representing the mineral
reservoir are not critically located in terms of mechanical
competence. This means that the excess bone should be
placed on the endosteal surface of cortical bone and on the
surfaces of trabecular bone – next to the bone marrow. And
indeed, premenopausal (estrogen-replete) women are
known to have more cortical bone in relation to bone cross-
sectional area, higher cortical density, as well as higher tra-
becular density at some sites, compared to men30-33. This dif-
ference is also evident between pre- and postmenarcheal
girls34, between pre- and postmenopausal women35, and also
between those postmenopausal women who are on estrogen
replacement therapy or not36. From a mechanical point of
view, it is recalled here that even endocortical thickening of
a cortex, without a change in external diameter, makes the
bone structure stiffer – although not as much as periosteal
expansion does37. A higher cortical density, too, is associated
with increased stiffness of cortical bone37.
All in all, the main skeletal targets from the viewpoint of
loading (mainly induced by muscle activity) and hormones
concern different features of bone. However, since these
basically independent factors act on the same bone structure
and affect the mechanical behaviour of the whole bone
organ, some [secondary] interaction can be expected.
The new conceptual scheme
Figure 1 depicts schematically the muscle-bone feedback
system with the specific feature of including separate feed-
H. Sievänen: Hormones and the muscle-bone unit
back control systems for sensing the loading-induced
mechanical deformations within the rigid bone structures and
for maintaining the physiological homeostasis within the
body. It should be noted that these basically independent
functions share the same bone modelling-remodelling appa-
ratus. Further, distinct from previous schemes9,10,13, the set-
point of the mechanosensory system is considered fixed (i.e.,
not modifiable by hormones), while the set-points of hor-
monally mediated control systems responsible for maintain-
ing the physiological homeostasis can be complex and subject
to potential interplay between hormones, besides being influ-
enced by physiological conditions, health status, nutrition,
age, and genetics. Hormones (e.g., testosterone, growth hor-
mone) can also directly modulate the bone loading through
affecting the muscle performance (force and power) and
indirectly the deformations through the estrogen-induced
mineral reservoir integrated in the bone structure. As men-
tioned before, many other hormones are involved in calcium
metabolism of the body. Since all of these systems readily
exist within the body, the actual situation is not violated.
As argued before, the loading is solely interested in an
adequately rigid skeletal structure (structural rigidity is
closely related to the strength of the whole bone), a pre-req-
uisite for efficient locomotion, while hormones are solely
interested in accessible bone mass (minerals) that can easily
be released for physiological needs. It is recalled that the
bone modelling-remodelling apparatus transforms both the
mechanically or hormonally-induced chemical signals into
activity of bone cells that eventually results in formation or
resorption of bone tissue, as appropriate, for the specific
loading or physiological condition. Specific details concern-
ing the transformation of deformation-induced mechanical
Figure 1. Schematic description of independent and separate feedback control systems for the maintenance of mechanical competence of
the skeleton through structural adaptation of bones and the maintenance of physiological homeostasis of the body through employing a
mineral reservoir embedded in the bone structure. During locomotion and other movements, the load is transmitted to the skeleton main-
ly though dynamic muscle activity. Hormones modulate the loading through affecting the growth and muscle performance and indirectly
through potential changes in the mineral reservoir. See further discussion in the text.
H. Sievänen: Hormones and the muscle-bone unit
energy into chemical signals are not relevant to underpin the
The above noted hormonal modifications in bone struc-
ture30-36inevitably increase the rigidity of the given bone.
This skeletal modulation, attributable to independent hor-
monal effect and evident not only in the relative bone mass
and structure but also indirectly in the mechanical behav-
iour, can be fallaciously interpreted as an increased sensitiv-
ity to loading (equal load causes a more robust bone appear-
ance) - or in line with the present view, as an independent
hormonal addition of interchangeable bone mass to the
endosteal surface and trabecular structure.
Figure 2 illustrates the influence of hormonal modulation
on bone rigidity and strains in a simple bone cylinder.
Compared to a "male-type" bone (without the estrogen
effect), the structural stiffening inherent in a "female-type"
bone (with the estrogen-induced relative cortical thickening at
the endosteal surface and denser cortical bone tissue)
decreases the magnitude of deformations at a given load.
Although the deformations in the "female-type" bone are
somewhat reduced, no disuse-induced bone loss would occur
because the set-point of the mechanosensory system appar-
ently represents a relatively wide physiological window9,10. It is
naturally required that normal physical activities (e.g., walk-
ing) are performed – a complete disuse, long immobilization
and declined physical performance would most likely lead to
bone loss despite the hormonal influence. The removal of
bone mineral from "reservoir" compartments, in turn, would
only marginally affect the structural rigidity of the bone, and
the consequent loading-induced deformations would not devi-
ate from the set-point sufficiently to initiate substantial skele-
tal adaptation. So, in order to gain substantial skeletal adap-
tation, a woman would need to expose her bones to relatively
higher loads than a man. As indicated in Figure 2, in order to
be able to override the effect of estrogen on bone rigidity,
some 20% higher loading would be needed to create defor-
mations that would correspond to typical deformations in the
"male-type" bone in a normal situation.
Fully in line with this argument, male tennis players dis-
play a twice greater average effect in side-to-side differences
between the playing arm and non-playing arm than female
players38,39. Likewise, the bone response to a similar jumping
exercise is significantly higher in premenarcheal girls (with-
out estrogen modulation) than in postmenarcheal girls34.
Figure 2. Theoretical relationship between maximum strain and relative cortical thickness [endosteal diameter (d)/periosteal diameter (D)]
in a bone cylinder subjected to equal bending load [strain · bending moment/EZ, where E denotes the Young’s modulus (material stiffness
· third power of cortical density37) and Z the section modulus calculated according to the standard formula, Z = /32D x (D4– d4)]. For
simplicity, bending moment and cortical density were normalized to one. The strain value of one corresponds to situation when the bone
cylinder is solid (no marrow cavity) and its density is one. The parallel curves show the effect of varied cortical density (±3% in 1% steps)
on the relationship. See further discussion in the text.
H. Sievänen: Hormones and the muscle-bone unit
The above theoretical example and clinical data demon-
strate that regardless of the primary goal of estrogen to store
bone mineral for potential further physiological use, the hor-
mone-induced, indirect structural modification is also
reflected to mechanical behaviour of the whole bone, and
thus indirectly to its mechanical adaptability.
Although this perspective largely dealt with the modula-
tory effect of estrogen only, the following interpretations
regarding the impact of other hormones on the bone-mus-
cle feedback system cannot be ruled out. Hormones, as
such, are not interested in bone structure or mechanical
competence of the skeleton, but they are almost exclusively
concerned in maintaining the calcium homeostasis (through
bone-embedded mineral reservoir) and coping with physio-
logical needs whenever they emerge. As an exception (that
proves the rule), the axial growth of bones and its cessation
is mainly modulated by growth hormone and estrogen.
Otherwise, irrespective of hormonal influence, the bone
would, without loading, remain quite slender in terms of
axial length40. It is also worth noting that hormones (partic-
ularly testosterone and growth hormone) affect muscle
growth and force production capacity of muscles41-43, a fact
that is most likely translated into the bone structure through
concomitant loading of bones, but by no means through
modulating the responsiveness of mechanosensory system.
Dynamic muscle activity incontestably underlies the
mechanical loading of bones, but it is solely the specific
loading environment that becomes beautifully reflected in
the bone structure – e.g., erect bipedal locomotion in the
cortical structure of the femoral neck44, functional features
of the upper and lower extremities in the cross-sections of
humerus and femur during growth45, extreme weight-bear-
ing loading in the structure of the tibia46, not forgetting the
apparent impact of loading on the skull47.
In summary, the goal of the mechanosensory feedback
system is solely to maintain the mechanical competence of
the skeleton in terms of predominant loading environment
through reasonable structural modifications as long as possi-
ble, while bone mineral residing basically in the reservoir
embedded in the bone structure is occasionally or perma-
nently accrued or removed for physiological needs in concert
with incident hormonal control and status. In contrast to the
prevalent view suggesting a modulatory effect of hormones
on the sensitivity of mechanosensory system, it is argued
here that the mechanical and hormonal modules are funda-
mentally independent but can be indirectly interacting
through hormonally-induced modifications in the bone
structure, those being mainly manifest as higher cortical den-
sity, relatively thicker cortices in terms of external diameter,
and higher trabecular apparent density. The present view is
naturally speculative and awaits corroborative experimental
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