Osteoporosis is of medical interest only because it increases bone fragility and risk of fracture, and except for relief of symptoms, preventing fracture is the only purpose of intervention. To prevent the first fracture, adequate bone density must be accumulated and conserved, but to prevent subsequent fracture, bone density must be augmented so that the supportive function of the skeleton can be restored. Almost 50 years after the recognition of post menopausal osteoporosis as a clinical entity, not one of the many treatments that have been used has been demonstrated to be efficacious in reducing subsequent fracture risk. My purpose is not to recite this chronicle of disappointment, but to account for it in terms of bone biology, to consider some possible exceptions, and to reiterate the importance of preventing damage to the skeleton rather than belatedly attempting its repair

Parfitt, A. M.

English

NASA Technical Reports Server

N94- 28369
Irreversibility of Advanced Osteoporosis - Limited Role for Pharmacologic
Intervention
A. M. Parfitt, M.B., B. Chir.
Bone and Mineral Research Laboratory
Henry Ford Hospital
Detroit, Michigan
- 52---
66
Introduction
Osteoporosis is of medical interest only because it increases bone fragility and risk of fracture, and
except for relief of symptoms, preventing fracture is the only purpose of intervention. To prevent
the first fracture, adequate bone density must be accumulated and conserved, but to prevent
subsequent fracture, bone density must be augmented so that the supportive function of the
skeleton can be restored [3]. Almost 50 years after the recognition of postmenopausal
osteoporosis as a clinical entity [1], not one of the many treatments that have been used has been
demonstrated to be efficacious in reducing subsequent fracture risk. My purpose is not to recite
this chronicle of disappointment, but to account for it in terms of bone biology, to consider some
possible exceptions, and to reiterate the importance of preventing damage to the skeleton rather
than belatedly attempting its repair.
Bone Remodeling and Bone Loss or Gain
The essence of bone remodeling in the adult human is the focal excavation and repair of
microscopic cavities on bone surfaces. The outcome of each remodeling episode depends upon the
balance between resorption depth, which is an expression of the collective work of a team of
osteoclasts, and wall thickness, which is an expression of the collective work of a team of
osteoblasts. It is an empirical observation that for most of adult life wall thickness on the endosteal
envelope is less than resorption depth, so that each remodeling episode results in a small loss of
bone [22]. There is only a brief window of time during which the osteoblasts needed for complete
repair must be recruited and assembled [26], and when each has exhausted its limited capacity for
matrix synthesis, the remodeling transaction is completed, and its outcome, like that of a completed
financial transaction, is irrevocable. It is in this sense that the loss of bone intrinsic to the
remodeling process on the endosteal envelope is irreversible.
Because of the delay between resorption and formation, there is a temporary mineral deficit
associated with bone remodeling, comprising bone matrix not yet formed and bone matrix formed
but not yet fully mineralized [16]. The magnitude of the deficit is proportional to the rate of bone
turnover, and averages about 2 percent of the total for the whole body, and about 10 percent in
regions of relatively high turnover such as the spine [23]. An increase in the frequency of
remodeling activation and consequent increase in bone turnover will be accompanied by a
corresponding increase in the reversible deficit and reduction in skeletal mineral content.
Conversely, a reduction in remodeling activation will be accompanied by a reduction in the
reversible deficit and a corresponding increase in skeletal mineral content. The reversibility of
bone loss resulting from increased turnover depends upon restoring bone turnover to its previous
level, that is the basis for almost all instances of an increase in bone density as an effect of
treatment in an adequately controlled study [23], or as a consequence of curing the underlying
IRREVERSIBILITY OF ADVANCED OSTEOPOROSIS 169
https://ntrs.nasa.gov/search.jsp?R=19940023866 2020-06-16T15:00:56+00:00Z
disease[28]. Bonegainby this mechanism generally continues only for about 6 months, and in
most patients will not restore bone density to normal.
Reversible bone loss depends upon the number of uncompleted remodeling transactions in
progress at a particular time, whereas irreversible bone loss depends upon the number of
completed remodeling transactions that have accumulated over some period of time. Both types of
bone loss occur in hyperparathyroidism. After successful surgical treatment of primary
hyperparathyroidism, the increase in cortical porosity is reversed but the rise in bone density
continues only for about 6 months and amounts only to about 10 percent of the total deficit [16,
20]. Cortical thinning, due to the cumulative effect of increased resorption depth on the
endocortical surface in conjunction with increased frequency of remodeling activation, is
unaffected. Even the large increase in bone mineral that results from the treatment of osteomalacia
has no effect on the cortical thinning that is due to the associated secondary hyperparathyroidism
[17]. Both types of bone loss also occur in estrogen deficiency, accounting for the different effects
on bone density of estrogen replacement, depending on its timing [10]. If begun before bone
turnover has increased, bone density remains stable with neither loss nor gain. If begun 2 years
later, when bone turnover is still high, there is an initial increase in bone density until the expected
plateau is attained. Finally, if begun 5 years later, when turnover has returned to normal, further
loss is prevented but there is no initial increase.
Other Possible Mechanisms of Bone Gain
During growth, cancellous bone is made by endochondral ossification and cortical bone mainly by
subperiosteal apposition. If osteoporosis occurs during the growth period, and its cause is either
amenable to treatment (as in Cushings syndrome), or subject to spontaneous disappearance (as in
idiopathic juvenile osteoporosis), the remaining potential for growth may allow restitution of an
almost normal skeleton [18], bUr this is rio Io_ pb_gible_in°Tdfili_ End_hondral o_ficati0n'
necessarily stops after epiphysial closure, but periosteal apposition continues slowly throughout
life and may lead to a net gain of bone in subjects older than 90 years, in whom endosteal loss has
become very slow [5]. Periosteal gain can be amplified by an increase in frequency of remodeling
activation for any reason, but the gain is insufficient to offset increased endosteal loss [15].
Periosteal gain is amplified by exercise without endosteal loss [12], but the net effect is of only
modest magnitude. Physiologically excessive strain in response to biomechanical loading [2i] and
prostaglandin administration [4] may both lead to rapid gain of laminar or plexiform bone at the
periosteum, but this would be cosmetically unacceptable, and if generalized, could lead to
compression of nerves as they run through cranial or spinal foramina.
Prevention of fractures is likely to require reversal of the normally inexorable loss of bone from the
endosteal envelope, for which it is both a necessary and a sufficient condition that wall thickness
exceeds resorption depth [22]. Sodium fluoride apparently bypasses the normal remodeling
sequence, with direct transformation of quiescent to forming surfaces, but the bone initially formed
is structurally abnormal, and in controlled trials vertebral fracture rate has not been reduced [8].
Furthermore, axial bone gain can be offset by appendicular bone loss. Coherence therapy has the
potential for adding bone if osteoclast recruitment can be increased and the new osteoclasts
constrained to erode shallower than normal cavities that can be overfilled by normally functioning
osteoblasts, but none of the assumptions underlying this concept have yet been validated [25].
Cyclic administration of human parathyroid hormone in conjunction with calcitriol has led to
impressive gains in spinal bone mineral in a few patients with idiopathic osteoporosis [31], but the
170 IRREVERSIBILITY OF ADVANCED OSTEOPOROSIS
cellular mechanismis unknown, and there have been no measurements of fracture rate and no
controlled trials with this form of treatment.
Architectural Aspects or Bone Loss and Gain--the Necessity for Prevention
Rapid postmenopausal loss of cancellous bone is a reflection of increased resorption depth leading
to perforation of trabecular plates, disruption of structural connectivity, and disproportionate
reduction in compressive strength of the vertebral bodies [21]. The complete removal of a
structural element confers another dimension of irreversibility, since there is no longer a surface on
which the osteoblasts can build. Even the largest attainable increase in thickness of the structural
elements that remain will fail to restore normal connectivity, and so will fail to restore normal bone
strength [19]. It is probably for this reason that the increase in bone density produced by sodium
fluoride does not reduce the risk of fracture. It is conceivable that induction of osseous metaplasia
in the marrow, for example by the local instillation of bone morphogenetic protein [32], might
allow large discontinuities to be bridged, but uncontrolled proliferation of woven bone could
displace hematopoietic tissue, curing osteoporosis at the expense of causing aplastic anemia.
Many patients with postmenopausal osteoporosis have defects in the activation of bone remodeling
and in the recruitment and function of osteoblasts that may prevent adaptation to the initial bone
loss and contribute to bone fragility by compromising the detection and repair of fatigue
microdamage [24]. The sequence of rapid osteoclast-mediated bone loss and decreased
connectivity, followed by slow osteoblast-mediated bone loss and accumulation of bone of
increased age and liability to fatigue damage, occurs also in the osteoporoses of corticosteroid
excess, traumatic osteodystrophy and immobilization, and in some patients with intestinal
malabsorption and hepatobiliary disease [22]. But, even if the osteoblast dysfunction in these
disorders were of known cause and fully correctable by treatment, by the time that the first
spontaneous vertebral fracture had occurred, restoration of normal cancellous bone architecture
would still be impossible.
Prevention of estrogen-dependent bone loss by estrogen replacement therapy reduces the
occurrence of measurable vertebral deformations by at least 90 percent [9], so that the
abnormalities in bone remodeling described earlier will only rarely be of clinical significance unless
the initial osteoclast-mediated loss of bone is allowed to occur. These considerations establish the
cardinal importance of early intervention, long before the first fracture. For women, who should
not or will not take estrogen replacement therapy or who are unable to tolerate it, the discovery of
safe and effective substitutes, and for patients at risk for other forms of osteoporosis, the discovery
of new preventive measures, should become the most important focus of osteoporosis research.
For the immediate future, unless they are still losing cortical bone faster than normal, patients with
established spinal osteoporosis will continue to benefit more from advice than from medication.
Bone Loss and Microgravity
Application of these concepts to the skeletal problems of space flight is unclear because
correspondence between the effects of microgravity and any terrestrial model for microgravity has
not been demonstrated. The available densitometric and metabolic balance data from Skylab are
consistent with the known effects of prolonged bed rest [17], but for neither microgravity nor bed
rest have the bone remodeling mechanisms been adequately studied. The reversibility of bed-rest
induced bone loss [6] and the increase in biochemical markers of bone remodeling [11] indicate
that more frequent activation of bone remodeling and consequent increase in cell team recruitment
is the most likely principal mechanism [22], but the continuous decline in bone density for more
than 6 months [30] suggests an additional effect on differentiated cells. In immobilized monkeys,
IRREVERSIBILITY OF ADVANCED OSTEOPOROSIS 171
there is an increase in depth as well as extent of osteoclastic resorption [13] and in the rat,
microgravity leads to a profound depression of osteoblast function [i4]. Limited data are
consistent with similar effects of bed rest in human subjects [7, 11, 33].
A temporary enhancement of the activity of existing osteoclasts or a temporary interruption or
retardation of the activity of existing osteoblasts are not inconsistent with complete reversibility,
but a persistent increase in the number of osteoclasts or decrease in the number of osteoblasts
recruited for each team would be more likely to cause an irreversible bone deficit [22]. To address
these uncertainties, persons returning from space flight of progressively longer duration must
undergo both sequential bone densitometry and bone biopsy after tetracycline labeling. This advice
has been disregarded since it was first given more than 10 years ago [17], but only when the
pathogenesis of microgravity related bone loss is better understood can preventive measures be
derived and the role of exercise be determined.
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174 IRREVERSIBILITY OF ADVANCED OSTEOPOROSIS


Irreversibility of advanced osteoporosis: Limited role for pharmacologic intervention

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