Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOSITIONS FOR
FOSTERING AND PRESERVING BONE GROWTH
FIELD OF THE INVENTION
The present invention relates generally to methods and compositions for
fostering and
preserving bone growth in a subject. More particularly, the invention
comprises inducing
rapid bone formation at locations such as the site of a bone fracture; in
areas within the
skeleton having diminished bone density; and/or in areas such as the portion
of long bones
lacking cancellous bone structure and thereafter preserving the new bone thus
formed while
fostering the growth of additional bone at any such location by, inter alia,
providing an
internal framework or scaffolding upon which newly produced bone may fasten
and grow.
Anti-resorption agents may optionally be administered for purpose of reducing
the resorption
over time of the newly formed bone.
BACKGROUND OF THE INVENTION
The bones of the skeleton are not entirely solid throughout. The outside,
i.e., cortical,
bone is substantially solid, having only a few small (Haversian) canals.
Located inwardly
from the cortical bone, however, is spongy bone known as cancellous (or
trabecular) bone.
The cancellous bone is composed of a honeycomb network of trabecular bone
defining a
plurality of spaces or cavities filled with fluid bone marrow, stem cells and
some fat cells.
Existing within these bone marrow cavities are, inter alia, various highly
specialized cells
which assist in breaking down existing bone (i.e., osteoclasts) as well as
cells that
correspondingly produce new bone (i.e., osteoblasts) to replace that which is
broken down or
which may be otherwise lost due to factors such as injury or illness.
As indicated above, the physical structure of bone may be compromised for a
variety
of reasons, including injury and disease. One of the most common bone diseases
is
osteoporosis, which is characterized by low bone mass and structural
deterioration of bone
tissue, leading to bone fragility and increased susceptibility to fractures,
particularly of the
hip, spine and wrist. Osteoporosis develops where there is an imbalance such
that the rate of
bone resorption exceeds the rate of bone formation. This is, in part, due to
the fact that it can
require six months for osteoblasts to rebuild the amount of bone destroyed by
osteoclasts in
three days. By age fifty-five, for example, the average woman with
osteoporosis has already
lost thirty percent of her bone mass.
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Osteoporosis is drastically accelerated during menopause and is the third
leading
cause of death of women over seventy. The disease also afflicts men, who
account for twenty
percent of all osteoporosis sufferers. By the age of seventy-five,
approximately ninety percent
of all women and thirty-three percent of all men will suffer from
osteoporosis. The ailment
causes 1.5 million fractures a year, resulting in annual U.S. health care
costs exceeding $18
billion. One in two women and one in eight men over age fifty will have an
osteoporosis-
related fracture in their lifetime. Of those who suffer from hip fractures,
one in five will not
survive more than one year. Currently, less than ten percent of afflicted
persons are treated
for osteoporosis with prescription drugs.
Such prescription drugs typically include at least one bone augmentation
agent. A
`bone augmentation agent', as that term is used herein, includes but is not
limited to bone
anabolic agents, and agents that cause elevated blood levels of an endogenous
bone anabolic
agent to be produced within a subject. Bone augmentation agents, such as bone
anabolic
agents, are well known in the art. Bone anabolic agents commonly include (but
are not
limited to) parathyroid hormone and various parathyroid hormone fragments,
whether
amidated or in the free acid form, as well as PTHrP and analogues thereof,
Prostaglandin E-2,
Bone Morphogenic Proteins, IGF-1, Growth Hormone, fibroblast growth factor TGF
and
others. On the other hand, agents causing increased expression of endogenous
bone anabolic
agent include, but again are not limited to, calcilytic agents as well as
antibodies to sclerostin.
Calcilytic agents typically, but not necessarily, include agents that limit
the binding of
calcium to its receptor, thereby triggering the release of endogenous
parathyroid hormone.
Examples of these materials are set forth in United States Patents 6,362,231;
6,395,919;
6,432,656 and 6,521,667, the contents of which are expressly incorporated
herein by
reference.
Reliance upon the administration of bone augmentation agents such as those
described above, for the purpose of, e.g., increasing bone density, however,
frequently
involves lengthy treatment regimens with accompanying patient compliance
problems.
Additionally, such treatment produces a systemic effect which targets the
entire skeletal
system and thus, it is not and can not be `targeted' to create an effect in
one or more specific
bone(s).
In order, therefore, to provide a faster and more targeted method of inducing
bone
formation in subjects suffering from, e.g., diminished bone mass, and for
aiding in preserving
the retention of the new bone growth so produced, several of the co-inventors
of the present
invention have developed a method for fostering bone formation and
preservation which
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overcomes the deficiencies noted above of the prior art. The method comprises
the steps of
mechanically inducing an increase in osteoblast activity in one or more
`targeted' bones of a
subject in need of additional bone growth, coupled with elevating blood
concentration of at
least one bone anabolic agent in the subject, wherein the above steps may be
performed in
any order but wherein they are carried out in sufficient time proximity that
the elevated
concentration of the bone anabolic agent and the mechanically induced increase
in osteoblast
activity at least partially overlaps. The above methodology is described, for
example, in U.S.
patent application Serial No. 11/128,095 file May 11, 2005 and in U.S.
Continuation-in-part
patent application Serial No. 11/267,987 filed November 7, 2005. The contents
of both of
these applications are incorporated herein by reference. As indicated above,
the method
permits specific targeting of particular bones for effects such as repair,
strengthening,
reshaping and/or remodeling.
Although the above-described method has been found to be particularly
effective in
growing and preserving new bone when the area targeted for such additional
bone growth is
provided with a sufficient amount of cancellous bone to serve as a scaffold
for supporting the
new growth, it has now been determined that the new bone produced by the
action of the
bone anabolic agent alone, whether such agent is endogenous or otherwise, may
not be ideal
for replacement of bone in regions which lack sufficient cancellous bone to
serve as a
scaffold. Furthermore, the use of PTH and other anabolics may not be efficient
at filling gaps
in trabeculae that are perforated due to increased bone resorption. Over time,
some of the
bone produced via augmentation agents (including but not limited to anabolic
agents) may be
lost via such resorption in those areas, as noted above, lacking the bony
scaffolding. Previous
efforts to prevent, or at least minimize such resorption, have involved the
administration of
anti-resorptive agents, which are well-known in the art. These agents include
(but are not
limited to) calcitonins including, for example, human calcitonin, salmon
calcitonin, eel
calcitonin, elkatonin, porcine calcitonin, chicken calcitonin, SERMS
(Selective Estrogen
Receptor Modulators), Bisphosphonates, Strontium Ranelate and combinations
thereof. Such
administration of an antiresorptive agent is able to protect the newly formed
bone. However,
some or all of the new bone formed during the initial growth `spurt'
facilitated due to the
presence of the anabolic agent, may nevertheless be resorbed by the subject.
Thus, the
effectiveness of the new bone, such as increased skeletal strength and/or
support, will be
compromised.
It has been discovered, however, by the present inventors that the addition of
a
biocompatible matrix-forming material in these specific areas will prevent the
new targeted
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bone from being lost since it will serve as a support permitting additional
bone growth. In
addition, the installation of such a biocompatible matrix has been found to
better enable bone
to be synthesized in regions such as the area within the shaft of a long bone,
e.g., the
humerus.
For purposes of illustration, one particular location where bone thinning and
resultant
bone damage, including fracturing, attributable to such thinning is
problematic is in the
vertebrae of the spine. Vertebroplasty and kyphoplasty, which are currently in
common use
in the United States, are surgical procedures for vertebral augmentation that
also treat pain
associated with vertebral compression fractures. Both of these procedures use
x-ray guidance
and a transpedicular or parapedicular technique to access the vertebral body
for injecting
liquid cement therein. The cement then solidifies to augment the weakened and
painful
vertebra. The simplest procedure is vertebroplasty. This technique is
discussed, for example,
in United States Patent No. 6,273,916, the contents of which are incorporated
herein by
reference. A more recent procedure, becoming more common, is kyphoplasty which
involves
the inflation of a balloon to restore height, whereupon a bone cement is
injected into the
cavity created by the balloon.
A highly popular bone cement for use in these procedures is polymethyl
methacrylate
("PMMA"). The use of PIVIMA is described in a variety of professional joumal
articles,
including: (a) "Is Percutaneous Vertebroplasty without Pretreatment Venography
Safe?
Evaluation of 205 Consecutive Procedures", Cristiana Vasconcelos, Philippe
Gailloud,
Norman J. Beauchamp, Donald V. Heck, and Kieran J. Murphy, AJNR Am J
Neuroradiol
23:913-917, June/July 2002 ("Vasconcelos"); (b) "Bone Cements: Review of Their
Physiochemical and Biochemical Properties in Percutaneous Vertebroplasty",
Matthew J.
Provenzano, Kieran P. J. Murphy, and Lee H. Riley III, AJNR Am J
Neuroradio125:1286-
1290, August 2004 ("Provenzano"); (c) "The Chemistry of Acrylic Bone Cements
and
Implications for Clinical Use in Image-Guided Therapy", David A. Nussbaum, M
S, Philippe
Gailloud, MD, and Kieran Murphy, MD., J Vasc Interv Radio12004; 15 Page 1.
("Nussbaum"). The contents of each of these papers is incorporated herein by
reference.
PMMA is an acrylic bone cement. It is not adhesive and it does not integrate
into
bone over time, and yet it is remarkably strong. As an analogy, PMMA can act
like rebar in
cement as used in building construction. The use of PMMA does offer a
significant
drawback, however, in that PMMA is known to remove or reduce forces that
maintain bone
density by supplanting the role of trabecular bone structure in its
neighborhood, thus
removing or reducing the electrical charge that contributes to bone
development.
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Furthermore, the monomer liquid used to dissolve the PMMA powder can be toxic
and has been associated with complications such as death and cardiac arrest
(See the
Nussbaum article). The high compressive strength of PMMA can, in addition,
cause adjacent
vertebral body fractures by exerting high non compliant forces on the adjacent
vertebra, as
the vertebral body is too stiff as a result of the injection of the PMMA.
These adjacent
fractures occur between eight and ten percent of the time.
A promising altemative to PIVAVIA are biologically active bone cements or
biocompatible polymers. Biologically active bone matrices can obviate some of
the
difficulties encountered with the use of PMMA. For example, biologically
active bone
cements can be of lower strength than PMMA, thus causing less stiffness of the
vertebral
body when they are injected. However, there are a number of problems inherent
in their use
in, for example, vertebral augmentation. For example, biologically active bone
cements are
very difficult to inject, they lack natural radio density, and they do not
always integrate well
for months or even years. Further, some biologically active bone cements
require hours
before they solidify and become safe. More generally, there have been deaths
from the use of
some of these cements, which may be related to the pH from the cement injected
or the
lealang of calcium into the circulation, resulting in disseminated clotting.
There is currently
little knowledge, however, of how to use biologically active bone cement for
vertebral
augmentation procedures.
A biologically active cement useful in vertebral augmentation is calcium
phosphate.
Calcium phosphate cements are composed of a powder and a liquid solution that
dissolves the
powder. They are used widely in hip, spine and wrist surgery and also in
cranial restriction.
There are two different families of calcium phosphate cements. One group
undergoes an
exothermic reaction while another undergoes an endothermic reaction. One group
belongs to
a family called bruschite cements. The other group belongs to a family that
ultimately forms
hydroxy apatite, the precursor of bone. When calcium phosphate powders and the
aqueous
solution are mixed, a paste is formed which sets within minutes to hours.
Thus, they are often
poorly injectable and poorly visualized under x-ray guidance, making them
difficult to use for
vertebral augmentation procedures. Further, when they are delivered into the
bone, they are
acted upon by osteoblasts and osteoclasts in the residual trabecular bone
structure. If there is
no residual trabecular bone structure the peripheral bone cement may be
integrated at the
endosteal surface of the bone, but bone cement located within the mass of the
vertebral body
may remain in its unchanged form, a brittle ceramic of low tensile and
compressive strength
with potential long term negative consequences.
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In view of the deficiencies noted above of the prior art, there has been a
long-felt need
by those working in this field for a faster and more effective method of
inducing bone
formation in bones lacking a bony scaffolding comprised of trabecular bone,
coupled with an
enhancement in the degree of retention of the new bone thus produced. The
present
invention, in the manner set forth below, admirably fulfills these desired
functions.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide novel and
unobvious
methods for inducing relatively rapid, targeted bone growth at all locations
in need thereof
while preserving and augmenting the new bone growth thus obtained.
Generally speaking, and as described in further detail below, the present
invention
provides a method of introducing a biocompatible material formed from a
biologically active
cement or other matrix-forming material within an inner portion of a bone and
triggering new
bone growth in the region, thereby integrating the cement or other matrix
material together
with the new bone into the existing bone architecture. In one embodiment of
the invention,
the removal of stromal cells via, e.g., irrigation, serves as a stimulus for
targeted new bone
growth, wherein a bone augmenting composition such as a bone anabolic agent
prolongs the
response, and wherein the matrix-forming material fills in voids where
trabecular bone is
lacking within an inner portion of the bone and serves as a scaffolding for
new bone growth
in regions lacking a sufficient amount of such trabecular bone, as well as in
areas entirely
lacking such trabecular bone. For example, a cyclic treatment paradigm of bone
marrow
irrigation coupled with administration of an anabolic agent in conjunction
with the
installation, within an interior portion of a bone, of a biocompatible matrix,
followed by anti-
resorptive therapy, is envisioned in accordance with the present invention.
The present invention thus provides, in one embodiment, a method for
augmenting
bone in a subject in need thereof wherein the method comprises installing
within an interior
portion of a bone within the subject a sufficient amount of a biocompatible
material to form a
scaffold within the bone interior, the scaffold serving as a support for the
fonnation of new
bone within the bone interior portion; and, administering to the subject a
sufficient amount of
at least one bone augmentation agent to elevate blood concentration of at
least one anabolic
agent in the subject.
In another embodiment, the invention provides a method for augmenting bone in
a
subject in need thereof wherein the method comprises mechanically inducing an
increase in
osteoblast activity within the subject; installing within an interior portion
of a bone within the
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subject where the increase in osteoblast activity has been induced a
sufficient amount of a
biocompatible material to form a scaffold within the bone interior, the
scaffold serving as a
support for formation of new bone within the bone interior portion; and
administering to the
subject a sufficient amount of at least one bone augmentation agent to elevate
blood
concentration of at least one bone anabolic agent in the subject, wherein the
elevation in
blood concentration of the bone anabolic agent in the subject and the increase
in osteoblast
activity therein at least partially overlap in time.
In a further embodiment, the invention is directed to a kit for fostering and
preserving
bone growth in an interior portion of a bone lacking a sufficient trabecular
scaffolding to
substantially prevent resorption of new bone formed therein. The kit comprises
at least one
container having therein at least one biocompatible material adapted for
forming an
additional amount of scaffolding within the inner bone portion; and, at least
one container
having therein a bone augmentation agent.
In a further embodiment the invention is directed to a kit for fostering and
preserving
bone growth in an interior portion of a bone lacking a sufficient trabecular
scaffolding to
substantially prevent resorption of new bone formed therein. The kit comprises
at least one
container having therein at least one biocompatible material adapted for
forming an
additional amount of scaffolding within the inner bone portion; at least one
container having
therein a bone augmentation agent; and, a mechanical alteration device for
altering contents
of a bone marrow cavity in at least one targeted bone.
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BRIEF DESCRIPTION OF THE FIGURES
The present invention will now be explained, by way of example only, with
reference to
certain embodiments and the attached Figures, in which:
Fig. 1A is a section of the mid-shaft of a rat femur following, respectively,
21 and 84 days
of treatment. The groups include: (a) control - no bone marrow ablation
("BMX") or anabolic
agent, (b) BMX - bone marrow ablation alone; and (c) BMX + PTH - bone marrow
ablation plus
treatment for either 21 or 84 days with PTH 1-34 NH2. In addition, the rats
were injected with
calcein, a fluorescent dye, on 9, 8, 2 and 1 day prior to sacrificing the
animals. Calcein becomes
incorporated into bone and serves as a measure of bone growth and
mineralization;
Fig. 1B depicts the results from the same groups of animals using the imaging
technique
known as Micro-CT. This technique provides a high resolution analysis of the
femoral shaft
marrow cavity from the Control, BMX, and the BMX + PTH 1-34 NH2 of rats
treated with PBS
(buffer) or PTH for 21 or 84 days, respectively;
Fig. 2 is a flowchart for depicting a method for augmenting bone in accordance
with one
embodiment of the invention; the procedure entails the administration of a
biocompatible matrix
material, which may be but is not necessarily a biocompatible bone cement, in
conjunction with
the administration of a bone augmentation agent such as a bone anabolic
formulation;
Fig. 3 represents an axial view of a vertebra having an osteoporotic fracture,
wherein the
vertebra is undergoing administration of a biocompatible matrix material
(e.g., a biologically
active bone cement) in the perfonmance of one of the steps identified in Fig.
2. The
biocompatible material is injected into a space devoid of cancellous bone to
provide a scaffold for
permitting persistent bone formation;
Fig. 4 is a representation of the administration of a bone augmentation agent,
such as a
bone anabolic agent, in the performance of one of the steps identified in Fig.
2. The
biocompatible matrix may have an anabolic agent associated with or commingled
with the matrix.
In addition, the anabolic agent may, alternately, be systematically
administered to the subject;
Fig. 5 is a representation of an axial view of a vertebra with an
osteoporosis, wherein the
vertebra is undergoing the administration of a biocompatible matrix slurry, in
the performance of
one of the steps identified in Fig. 2, in accordance with an alternate
embodiment of the invention.
In this instance, there is residual cancellous bone that will respond to the
combined effects of
mechanically inducing an increase in osteoblast activity, e.g., through an
irrigation of at least a
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portion of the marrow cavity, coupled with administration of an anabolic
agent, but for the
regions lacking trabecular integrity the inclusion of the biocompatible
material will fill in the gaps
and provide the necessary framework for persistent new bone growth;
Fig. 6A illustrates the degree of persistent bone growth achieved after 84
days with the
administration of a biocompatible material, in this instance Cementek
(Cementek LV, Non-
stoichiometric hydroxyapatite prepared from the reaction between the acid and
base calcium
phosphates in the presence of an aqueous solution. Teknimid, 65500 VIV en
Biggore, France) or
Pepgen-15 (a high purity anorganic bovine graft material, radiopaque, peptide-
enhanced to mimic
autogeneous bone. Dentsply Friadent CeraMed Lakewood, CO). All samples were
taken from
femurs which had BMX performed on them. The groups included: BMX followed by
84 days
anabolic agent or PBS (buffer) presented in the first row or BMX followed by
insertion of a slurry
of biocompatible matrix (Cementek or Pepgen-15) with our without concomitant
PTH treatment
for 84 days;
Fig. 6B depicts the results obtained from the same groups of animals reported
in Fig. 6A
using the Micro-CT imaging technique. This imaging technique provides a high
resolution
analysis of the femoral shaft marrow cavity from the BMX + PBS or PBX +PTH
treatments,
compared with femurs that had biocompatible materials (Cementek or Pepgen-15)
injected into
the bone marrow cavity following the step (e.g., ablation) resulting in the
inducement of increased
osteoblast activity; and
Figs. 7A and 7B illustrate the effect attributable to administration of the
anti-resorption
agent, Alendronate, in preserving bony tissue formed according to the method
of the invention.
The following treatment modalities are included: (a) BMX + PTH 1-34 NH2 for 21
days + PBS
(buffer) during days 22-84; (b) BMX + PTH 1-34 NH2 for 21 days + calcitonin
during days 22-
84; (c) BMX + PTH 1-34 NH2 for 21 days + Alendronate during days 22-84; and
(d) BMX +
PTH 1-34 NH2 during days 1-84.
Fig. 7B depicts the results from the same groups of animals reported in Fig.
7A using the
Micro-CT imaging technique, which provides a high resolution analysis of the
femoral shaft
marrow cavity.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
As has been pointed out above in the discussion concerning the background of
the present
invention, it has been determined by the inventors that newly formed bone
produced by the action
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of bone augmentation agent(s), such as a bone anabolic agent (e.g.,
parathyroid hormone), in
areas lacking cancellous bone may not be permanent in nature and such bone
may, in fact,
become at least partially resorbed if constant anabolic therapy (alone) is
applied. To address this
issue, the invention describes two distinct approaches for preserving new bone
in marrow cavities
lacking such cancellous bone `scaffolding', i.e., the cycling of a potent
antiresorptive agent, such
as a bisphosphonate or the inclusion of one or more biocompatible material
such as (but not
limited to) a biocompatible bone cement to serve as such scaffolding for
supporting the new bone
growth and fostering its maintenance.
For purposes of convenience in explaining the invention, the materials for
forming a
scaffolding within a targeted bone for facilitating bone growth according to
the present invention
are commonly referred to hereafter as "biocompatible materials" and/or
"biologically active
materials". This term is herein defined to include not only bone cements
(including
biocompatible bone cements) but also alternate materials, such as polymers,
gels and/or foams,
slurries or suspensions of calcium phosphate or hydroxyapatite now know or
subsequently
discovered, which provide the capability for forming the required scaffolding
within the interior
portion of the bone.
It is additionally to be understood that, in regions having sufficient amounts
of cancellous
bone to provide the scaffolding effect, the combination of a mechanical
inducement of an increase
in osteoblast activity, e.g., via bone marrow irrigation, coupled with the
administration of a bone
augmentation agent such as a bone anabolic agent, is sufficient to maintain
new bone growth
during the course of the treatment with the anabolic. However, in bones where
the trabecular
micro-architecture is either lacking (see, e.g., Figs. 1A and IB) or has been
compromised and/or
wherein numerous trabeculae have been perforated, the inclusion of
biocompatible materials -
coupled with the aforementioned bone marrow irrigation and anabolic treatment -
improves the
overall bone augmentation and maintenance. Bone resorption in the diaphysis of
long bones
lacking cancellous bone architecture has been found to occur even in those
instances where the
administration of, e.g., bone anabolic agent is coupled with the inducement of
increased
osteoblast activity in a bone targeted for such additional bone growth, which
technique is
described, for example in application Serial No. 11/128,095 filed May 11, 2005
and application
Serial No. 11/267,987 filed November 7, 2005 which are incorporated above by
reference into
this application.
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As shown for example in Fig. 1A, treatment with PTH for 21 days extends the
bone-
formation phase that follows BMX and leads to additional bone formation. At
day 84, bone
remodeling has taken place, resulting in the resorption of a substantial
portion of the bone that
was present at day 21 in the BMX and BMX + PTH groups. These results suggest
that in regions
of bone lacking the cancellous bone network (i.e., scaffolding), resorption
occurs over time.
In reviewing Fig. 1B, one notes the abundance of newly formed bone in the
marrow cavity
as a result of BMX at Day 21, which is further augmented by treatment with PTH
for 21 days. By
contrast, the marrow cavity from the mid-shaft of BMX-treated femurs from rats
treated with PBS
or PTH for 84 days is no longer undergoing bone formation and, indeed, no
longer contains
substantial amounts of bone. These results confirm the observations obtained
with calcein
labeling as shown in Fig. lA.
Although, as indicated above, bone resorption may be slowed and/or reduced via
the
administration of an anti-resorptive agent, such as calcitonin and/or
alendronate, it remains
desirable for obvious reasons to diminish if not entirely eliminate bone loss
to the degree possible,
as is accomplished with the use of the methods and compositions according to
the present
invention which is useful with long bones, hips, spines and, in fact, any bone
lacking (or having a
diminished) cancellous bone network. The present invention, thus, provides
methods and
compositions for achieving rapid and sustained targeted bone growth, coupled
with a desirable
reduction in loss of the new bone thus produced due to factors such as
resorption in particular
targeted areas of bone.
In one embodiment, illustrated at 100 in Fig. 2, the invention is directed to
a method for
augmenting a bone, including (but not limited to) long bones, e.g., the femur
and humerus, as well
as smaller bones, such as the vertebrae, of an individual. As the term is used
herein, `augment'
or `augmentation' means to increase the amount and/or density of bony tissue
contained within
the bone, while correspondingly reducing or preventing entirely if possible
the subsequent
accelerated resorption of the newly formed bony tissue produced with the use
of the method.
The above is accomplished with the use of a method which comprises, in one
step,
imparting a biologically active material such as a bone cement into an
interior portion of the bone
to be augmented. The biocompatible material, including but not limited to a
bone cement, can
be delivered in a radiographically controlled way or by open surgical
application. Various
biocompatible materials which are effective for use in the method of the
present invention are
described more fully below.
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The biologically active material associates with the trabecular bone structure
located in
an interior portion of a`target' bone to form a scaffolding therein which
serves as a framework
for permitting additional bone growth at that location, so as to permit
restoration of normal bone
functionality and strength in a desired area, e.g., an area where a fracture
has occurred or an area
at risk for a future fracture due, e.g., to a loss of bone density. Over time
in the presence of the
anabolic agent the cement and newly formed bone become integrated into the
existing bone
structures. This is advantageous as normal trabecular bone has sophisticated
weight distribution,
compression shear strength and regenerative properties that cannot be
reproduced with, for
example, the use of bone cements alone.
In the present discussion, augmentation of vertebral bone is frequently relied
upon as a
means of exemplifying the invention. However, the invention is not to be
construed as being
limited to use only with vertebral bones. That is, as indicated above other
bones can be
augmented by means of the methodology described herein, including, but not
limited to, the hip,
the proximal femoral neck, the distal radius, the proximal humerus, the
calcaneus, a rib or ribs,
the tibia, and the sacrum.
Referring now to Fig. 3 provided with this application, a vertebra is
indicated generally at
50. Vertebra 50 has an osteoporotic fracture or a spinal deformity and
exemplifies one type of
bone and a corresponding condition (i.e., a fracture) that can be treated with
the use of method
100. Thus, to treat vertebra 50 using method 100, step 110 is performed which
comprises the
administration of the biologically active material following irrigation for
removing stromal cells.
In certain instances, the introduction into the bone of the biocompatible
material can serve as the
method for removing the stromal cells , but the preferred method involves a
preliminary irrigation
to efficiently removal stromal cells bone marrow.
In the case of a vertebra such as vertebra 50, administration of the
biocompatible material
is typically performed using vertebroplasty or kyphoplasty. In Fig. 2,
vertebra 50 is shown
undergoing a vertebroplasty to effect step 110. The figure thus shows a
vertebroplasty needle 54
inserted along a transpedicular approach, with the tip of needle 54 positioned
within the vertebral
body 58. The irrigation and removal of stromal cells can be accomplished using
the same needle
or a specifically modified needle that provides a better method for irrigation
and collection of the
stromal cells.
It should be understood that the performance of step 110 on vertebra 50 can be
effected
using any presently known or future contemplated vertoblasty techniques, using
appropriate or
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desired needles, image guidance modalities and the like. The type of
biocompatible material (e.g.,
bone cement) 62 will influence such choices and will also be selected as a
means of
complementing the choices used to effect step 120.
As still another means of implementing method 100, the administration of the
biocompatible material and the augmentation agent may be achieved via separate
injections into
the vertebral body. Thus, the cement or other biocompatible matrix material
may be injected into
one pedicle of the vertebral body and the bone augmentation agent could be
injected into the other
pedicle or through an ipsilateral approach through the same pedicle as the
biocompatible material
or it may, instead, be mixed therewith. The anabolic agent can be administered
systemically as
well.
In the method of the invention described herein, it is contemplated that the
biocompatible
material is, in one embodiment of the invention, at least one biologic bone
cement, also referred
to herein as a biologically active bone cement. Suitable biocompatible
materials include, but are
not limited to calcium phosphate, calcium hydroxyapatite, calcium sulphate,
calcium aluminate a
bone morphogenic protein, polymers, fibrinogen, synthetic fibrins, collagen
gels, collagen plus
hydroxyapatite suspensions and various combinations thereof. Particular
examples of these
materials, provided only for the purpose of exemplifying (and not limiting)
the invention, include,
(a) Alpha-BSM Bone Substitute Material, comprising a synthetic bioresorbable
bone substitute
material engineered the chemical composition and crystalline structure of the
crystalline structure
of bone, sold by ETEX Corporation, Cambridge MA; (b) Cortoss Synthetic
Cortical Bone,
comprised of three di-functional cross-linked resins delivered as two mix-on-
demand pastes, sold
by Orthovita Corp., Malveme PA; (c) Cementek LV, a non-stoichiometric
hydroxyapatite
prepared from the reaction between acid and basic calcium phosphates in the
presence of an
aqueous solution, sold by Teknimid located at 65500 VIC en Bigorre, France;
(d) Pepgen P-15, a
high purity anorganic bovine graft material that is radiopaque and is peptide-
enhanced to mimic
autogenous bone, sold by Dentsply Friadent CereaMed Lakewood COP-P; and (e)
Norian SRS
(Skeletal Repair System), which is an injectable, moldable and biocompatible
calcium phosphate
which sets at body temperature into a carbonated apatite, sold by Synthes,
Inc. located in West
Chester, PA.
It may be desired to select combinations of such materials where one or more
cements
provides, for example, short term stability and/or pain relief, while another
provides long term
integration and new bone development. The selection of the biomaterial will be
site specific. For
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example, the biocompatible material used to prevent hip fractures will be
different from the
biomaterial used to support vertebrae during vertoplasty. Additionally, the
biocompatible
material, in most instances, will not be used in an "off the shelf' condition.
That is, its
formulation and/or physical state will be modified as necessary for a
particular application, for
example, by conversion into a suspension, foam or gel and/or by modifying
factors such as the
concentration, size, shape, etc. of the solid particles of which these
materials are comprised.
Enhanced bone cements are also useful in the invention and include a bone
cement as well
as an augmentation agent. Examples of the bone cement used in such enhanced
bone cements
include Cementek and Cementek LV, while examples of the augmentation agent
used in these
enhanced bone cement include (but are not limited to) insulin related growth
factor ("IGF"),
rhPTH, GH, anabolic vitamin D analogs, low density lipoprotein receptor
related protein 5
(LRP5) activator, or an inhibitor of sclerostin binding to LRP5, an activator
of non genomic
estrogen signaling (ANGELS), a bone morphogenic protein, a growth hormone
releasing factor
(GHRF) hepatcyte growth factor (HGF) calcitonin gene related peptide (CGRP)
parathyroid
related peptide (PTHrP) Transforming growth factor (TGF) and/or combinations
thereof.
In accordance with the present invention the embodiment as described herein
additionally
constitutes a further step (i.e., performed in conjunction with the
installation within a target bone
of the biologically active bone cement), which involves the administration to
the subject of a bone
augmentation agent. It is envisioned that the bone augmentation agent will be
administered to the
subject on, e.g., a daily basis for up to six (6) months. The augmentation
agent, such as a bone
anabolic composition for example, assists by facilitating or otherwise
enhancing the growth of
trabecular bone upon the surface of a scaffolding formed by the bone cement
and thereafter
resulting in a diminished degree of bone resorption, at least in comparison to
methods using either
the bone cement or the bone augmentation agent by themselves. The bone
augmentation agent
can be administered in any suitable manner, including by injection,
intravenously ("IV"), peroral
("PO"), transdermally, transnasally or transrectally and at any suitable time
before, during or after
the installation of the bone cement within the interior of the bone.
As indicated above, i.e., in accordance with the recitation of, for example,
trans-dermal
and nasal routes of administration, the agent may be administered systemically
or else directly to
a location where the bone cement is introduced. The timing and method of
administration of the
bone augmentation agent would be well understood by one having ordinary skill
in this field of
art. That is, the steps in method 100 can be performed in a different order
than shown, or
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simultaneously. The bone augmentation agent can be, as indicated above, an
anabolic bone agent
or any other agent that promotes the integration of the injected cement. The
bone augmentation
agent has been found, as indicated above, to produce ajoint effect with that
provided by the bone
cement which helps to convert the biologically active bone cement to actual
bone more rapidly
then is usually achieved in the poor quality trabecular bone of the
osteoporotic patient. In the
absence of the bone anabolic agent the bone cement can be resorbed, thus
diminishing its
effectiveness. Some useful bone augmentation agents are exemplified below.
In a particular embodiment as shown for example in Fig. 4, a sufficient amount
of one
preferred bone anabolic agent, i.e., PTH[1-34]NH2, is administered to patient
68 via, for example,
a needle 72 to achieve, and maintain, a pulsatile blood concentration thereof
in a subject of
between about 50 and about 350 pg/ml, preferably between about 100 and about
200 pg/ml, and
most preferably between about 150 pg/ml. In another embodiment, the blood
concentration of the
PTH[1-34]NHZ in the patient is raised to its preferred level by no later than
seven days following
the performance of step 110. As is well understood by those skilled in the
art, an appropriate
dosage of PTH[1-34]NHZ is determined to achieve the desired blood
concentrations. In the case of
injecting formulations thereof via a needle, the dosage can, though need not
necessarily be, in the
range of between about 10 to about 200 micrograms (" g"), given once per day,
more preferably
between about 20 and about 100 g per dose and more preferably between about
20 and about 50
g per dose, or most preferably between about 20 and about 40 g per dose given
once per day.
Moreover, as would be well understood by one having ordinary skill in this
art, dosage levels of
injectable formulations comprising bone augmentation agents other than PTH[1-
34]NH2, which
are described in further detail below, would be consistent with those noted
herein. If desired,
PTH[1-34]OH could also be used in an identical fashion to that described
above.
Alternate methodologies for implementing method 100 are additionally
contemplated as
being included within the scope of the present invention. Referring now to
FIG. 5, a vertebra is
indicated generally at 50a. Vertebra 50a also has an osteoporotic fracture and
exemplifies one
type of bone (a vertebra) and a corresponding condition (fracture) that can be
treated using
method 100. However, in this embodiment, to treat vertebra 50a using method
100, step 110 and
step 120 are performed substantially simultaneously. FIG. 5 shows an enhanced
or derivatized
bone cement 62a. FIG. 2 shows a vertebroplasty needle 54a inserted along a
transpedicular
approach with the tip of needle 54a positioned within the vertebral body 58a.
Needle 54a is also
shown expressing the enhanced bone cement 62a within vertebral body 58a.
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One example of the embodiment described hereinabove includes a method of
treating an
osteoporotic fracture in the body of an individual in need thereof wherein a
biologically active
bone cement (hereinafter also referred to as, a "biologic material") is
delivered into an inner
portion of the bone and an orally administered bone augmentation agent is used
to assist
integration of the cement from its injected state into a material that is akin
to normal native bone
by promoting bony growth on, in and/or around the particles of the cement such
that the
additional bone thus formed is caused to grow more rapidly, with a markedly
lesser degree of
resorption that methods relying upon either a bone augmentation agent or a
cement used by itself.
Another example includes a method of treating an osteoporotic fracture in the
body of an
individual in need thereof wherein a biologic material is delivered into the
bone and a nasally
administered augmentation agent is used to assist integration and
transformation of the biologic
material from the injected state into a material that is akin to normal native
bone as described
above. Still another example of this embodiment includes a method of treating
an osteoporotic
fracture in the body of an individual in need thereof wherein a biologic
material is delivered into
the bone and a transdermally administered augmentation agent is used to assist
in the integration
and transformation of said biologic material from its injected state into a
material that is akin to
normal native bone.
An additional example involves a method of treating an osteoporotic fracture
in the body
of an individual in need thereof wherein a biologic material is delivered into
the bone and an
injected augmentation agent is used to assist its integration and
transformation from its injected
state into a material that is akin to normal native bone.
A still further example of this embodiment includes a method of treating an
osteoporotic
fracture in the body of an individual in need thereof wherein a biologic
material is delivered into
the bone and parathyroid hormone ("PTH") is used to assist in the integration
and transformation
of the biologic material from its injected state into a material that is akin
to normal native bone.
Another example includes a method of treating an osteoporotic fracture in the
body of an
individual in need thereof wherein a biologic material is delivered into the
bone and recombinant
parathyroid hormone ("rhPTH") is used to assist its integration and
transformation from its
injected state into a material that is akin to normal native bone.
A further example of this embodiment of the invention includes a method of
treating an
osteoporotic fracture in the body of an individual in need thereof wherein a
biologic material is
delivered into the bone and calcitonin is used to assist its integration and
transformation from its
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injected state into a material that is akin to normal native bone.
Still another example of this embodiment includes a method of treating an
osteoporotic
fracture in the body of an individual in need thereof wherein a biologic
material is delivered into
the bone and growth hormone is used to assist its integration and
transformation from its injected
state into a material that is akin to normal native bone.
An additional example includes a method of treating an osteoporotic fracture
in the body
of an individual in need thereof wherein a biologic material is delivered into
the bone and insulin
related growth factor is used to assist its integration and transformation
from its injected state into
a material that is akin to normal native bone. A still further example
includes a method of
treating an osteoporotic fracture in the body of an individual in need thereof
wherein a bone
cement composed of Calcium phosphate is delivered into the bone and a
integration stimulant
used to assist its integration and transformation from its injected state into
a material that is akin
to normal native bone.
Another example includes a method of treating an osteoporotic fracture in the
body of an
individual in need thereof wherein a bone cement composed of Calcium
hydroxyapatite is
delivered into the bone and an integration stimulant used to assist its
integration and
transformation from its injected state into a material that is akin to normal
native bone.
Still another example of the invention includes a method of treating an
osteoporotic
fracture in the body of an individual in need thereof wherein a bone cement
composed of Calcium
sulphate is delivered into the bone and an integration stimulant used to
assist its integration and
transformation from its injected state into a material that is akin to normal
native bone.
Another example includes a method of treating an osteoporotic fracture in the
body of an
individual in need thereof wherein a bone cement composed of Calcium aluminate
is delivered
into the bone and an integration stimulant used to assist its integration and
trans formation from
its -injected state into a material that is akin to normal native bone.
An additional example of this embodiment of the invention includes a method of
treating
an osteoporotic fracture in the body of an individual in need thereof where a
bone cement
composed of bone morphogenic protein is delivered into the bone and a
integration stimulant used
to assist its integration and transformation from its injected state into a
material that is akin to
normal native bone.
Another example includes a method of treating a vertebral fracture in an
individual in need
thereof using cement that has an insulin related growth factor ("IGF")
embedded therein, and
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which is delivered into the vertebrae. The method also includes administering
calcitonin or PTH
or other bone augmentation accelerant using any suitable delivery mechanism,
such as orally,
nasally, injection, transdermally etc.
Still another example includes a method of treating an osteoporotic fracture
in the body of
an individual in need thereof wherein a biologic material is delivered into
the bone and
recombinant parathyroid hormone ("rhPTH") is also delivered into the bone with
the cement as an
accelerant of local bone growth and cement integration and transformation from
its injected state
into a material that is akin to normal native bone.
An additional example of this embodiment of the invention includes a method of
treating
an osteoporotic fracture in the body of an individual in need thereof wherein
a biologic material is
delivered into the bone and recombinant parathyroid hormone ("rhPTH") and
Insulin related
growth factor are also delivered into the bone with the cement as an
accelerant of local bone
growth and cement integration and transformation from its injected state into
a material that is
akin to normal native bone.
Another example includes a method of treating an osteoporotic fracture in the
body of an
individual in need thereof where a biologic material is delivered into the
bone and recombinant
parathyroid hormone ("rhPTH") and Insulin related growth factor are also
delivered into the bone
with the cement as an accelerant of local bone growth and cement integration
and transformation
from its injected state into a material that is akin to normal native bone. At
the same time OraUIV
or some other method of systemic bone anabolic stimulant is delivered to the
patient for a broader
increase in global bone density.
It should be understood that the above-described examples of the invention may
include
an additional step altering the contents of the bone marrow cavities in the
bones so treated so as to
remove all or a portion of the stromal cells from the cavity. The
administration of the
biocompatible material may serve this purpose by forcing the cells from the
marrow cavity, or
else an alternate method, such as irrigation, may instead be used for the
identical purpose.
As shown, for example, in Fig. 6A, the results for bone formation in the
femurs receiving
a biocompatible matrix material and subsequently treated with PTH are markedly
greater than for
buffer (PBS) alone. These results demonstrate that the combination of BMX with
a
biocompatible matrix will foster continuing bone augmentation, and that the
addition of PTH
further improves this response.
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Furthermore, as shown in Fig. 6B, BMX + PTH 1-34 NH2 and either biocompatible
material yielded better results than the use of biocompatible material alone
following BMX. The
results confirm the observations obtained with the use of calcein labeling as
shown in Fig. 1 A.
Fig. 7A illustrates that bone formed in the marrow cavity in response to bone
marrow
ablation (BMX) followed by 21 day treatment with PTH, is protected by
treatment with calcitonin
or alendronate given for the next 63 days, as illustrated by the fluorescent
signal from calcein that
has been incorporated into the mineralizing bone. Alendronate is a powerful
anti-resorptive agent
and, at the dose administered, it had a greater protective effect on the newly
synthesized bone. By
contrast, the ablated marrow cavity of femurs from rats treated for 84 days
with PTH contains a
minimum amount of fluorescent label. Calcein was injected on days 9, 8, 2 and
1 before sacrifice
of the animals.
Furthermore, calcitonin and alendronate protect the bone that forms in
response to marrow
ablation (BMX) and 21 day treatment with PTH. As shown in Fig. 7A, the bone
formed in the
marrow cavity in response to marrow ablation followed by 21 day treatment with
PTH is
protected by calcitonin or alendronate given for the next 63 days, as
demonstrated by the
fluorescent signal from calcien that has been incorporated into mineralizing
bone. By contrast,
the ablated marrow cavity of femurs from rats treated for 84 days with PTH no
longer contains
fluorescent labels.
Furthermore, Fig. 7B illustrates the results obtained by Micro-CT analysis of
the bone
formed in the marrow cavity in response to marrow ablation followed by 21 day
treatment with
PTH followed by subsequent treatment with either of the anti-resorptive drugs
calcitonin or
alendronate, for an additional 63 days. Calcitonin, and to a greater extent,
alendronate, protects
the bone that forms in response to marrow ablation and 21 day treatment with
PTH. By contrast,
the ablated marrow cavity of the diaphysis of femurs from rats treated for 84
days with PTH no
longer contains radio-dense bone. These results confirm that in anatomic
regions lacking a
cancellous network of trabecular bone, continuous treatment with PTH results
in bone resorption.
However, administration of bisphosphonates can preserve the newly formed bone
located at such
a site.
In a preferred embodiment, the method of the invention is utilized with a
human subject.
However, the invention additionally comprises veterinary applications.
In a further alternate embodiment to those heretofore set forth, the invention
includes an
additional step of mechanically inducing an increase in osteoblast activity
within the subject to be
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treated, which inducement is carried out in conjunction with the introduction
of a biocompatible
material such as a bone cement and the administration of a bone augmentation
agent, such as a
bone anabolic agent, to said subject as described above. The various steps may
be performed in
any order, but in sufficient time proximity that an elevated concentration of
the at least one bone
augmentation agent in the bloodstream of the subject and the mechanically
induced increase in
osteoblast activity in said subject at least partially overlaps. In a further,
optional, step an
antiresorptive agent may be administered to the subject for a duration and at
a concentration
sufficient to further reduce resorption of the bone formed due to the
synergistic interaction among
the various method steps. An additional factor preventing such resorption and
thus preserving the
additional bone growth achieved through the use of the method of the invention
is the presence of
the bone cement, which acts as a`scaffold' or support to permit further growth
extending
therefrom. Once an adequate amount of bone has been formed an anti-resorptive
agent can be
administered to protect the bone that has been synthesized.
The mechanical inducement may be, but is not necessarily, achieved through the
use of a
method which comprises mechanically altering the contents of a bone marrow
cavity located
within the bone where it is desired to foster and preserve such additional
bony growth. Various
methods for achieving such an alteration of the bone marrow cavity contents
are described below.
Inducement of bone growth may include, for example, generating new or
additional bone
at locations where such bone growth is not presently taking place and/or
stimulating the growth
(i.e., increasing the rapidity thereof) of bone which is already in the
process of forniation. Without
being bound in any way by theory, applicants believe that the inducement of
bone growth takes
place due to the combined effects of (1) the mechanical inducement of
osteoblast activity in the
subject coupled with (2) an elevation in the blood concentration of at least
one bone anabolic
agent therein. As used throughout this description, the bone described as
being formed by the
process of the invention is not limited solely to trabecular bone and should
also be taken to
include any one or more of the following additional `types' of bone: compact,
cortical and /or
lamellar bone.
Mechanical inducement of an increase in osteoblast activity may be obtained,
in a
preferred embodiment of the invention, by a process of bone marrow irrigation
and ablation.
Again, without being bound in any way by theory, applicants believe that the
bone marrow
irrigation or mechanical process leads to the formation of a blood clot within
the bone marrow
CA 02685407 2009-10-27
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cavity which, through a cascade of biochemical reactions, contributes to
increasing osteoblast
activity in the subject.
In an another embodiment, the increased osteoblast activity may alternately be
obtained by
coupling the mechanical inducement with an additional form of inducement such
as biochemical
inducement. Such biochemical inducement may be obtained by administering to
the subject, for
example, a quantity of a blood factor such as Factor ("F") VH, fibrinogen or
fibrin, Factor VIIa
or a combination thereof. Following tissue or vascular injury clotting is
initiated by the binding of
plasma FVII/FVIIa to tissue factor (tissue thromboplastin). This complex
(FVII/FVIIa +
Thromboplastin) initiates a sequence of events which leads to activation of
the coagulation
cascade ultimately leading to fibrin deposition and platelet activation. This
complex sequence of
events may contribute in part to the stimulation of osteoblasts in the bone
marrow. Factors VII
and VIIa are commercially available from, for example, Novo Nordisk.
The increase in osteoblast activity obtained with the use of the method of the
invention
may be due to a variety of factors including, but not necessarily limited to:
(1) osteoblast
differentiation, i.e., the production of additional osteoblasts, (2)
increasing the activity and/or
effectiveness of osteoblasts which are already present in inducing bone
formation in the subject,
and (3) a combination tliereof. In a preferred embodiment of the invention,
the increase in
osteoblast activity would include all of the above-noted functions.
In one embodiment of the invention the method additionally comprises
"targeting" one or
more specific bones of the subject for inducement of bone growth. This
targeting is accomplished
by mechanically altering the contents of a bone marrow cavity within each
targeted bone so as to
induce the increased osteoblast activity therein.
The method of the invention is thus useful not only for bone repair, i.e., as
in the case of a
bone fracture due to trauma, but also for strengthening bone in a site-
specific manner in the case
of individuals shown by Dual Energy X-Ray Absorptiometry ("DEXA") or other
techniques to
require an increase in bone mass and/or density to prevent bone fractures
(e.g., such as those
afflicted with osteoporosis), or who suffer due to bone weakness from chronic
pain attributable to
conditions such as vertebral cmsh. Moreover, the method of the invention
additionally serves to
provide (and retain) new bone needed to serve as an anchor for prostheses such
as artificial hips,
knees and shoulders and/or for implants such as dental implants. The new bone
growth can be
targeted to bones at risk of fracture to improve strength and thereby reduce
the risk of fracture.
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In one embodiment of the invention, the bone anabolic agent may be
administered to the
subject contemporaneous with the mechanical inducement of osteoblast activity
(whether by
increased osteoblast forrnation and/or by increased bone formation by pre-
existing osteoblasts),
which mechanical inducement may be achieved, e.g., by alteration of the bone
marrow cavity. In
preferred embodiments, marrow and/or other components of the marrow cavity
is/are removed
under pressure (e.g., by altering the relative pressure within versus without
the marrow cavity),
e.g., by irrigating the cavity and removing the stromal cells.
In another embodiment the bone anabolic agent is administered subsequent to
such
mechanical inducement. In another embodiment the bone anabolic agent may be
administered
prior to mechanical inducement such that elevated levels of bone anabolic
agent are already
present at the time of mechanical inducement, which levels may then be
maintained or continued
intermittently for an extended period thereafter.
As indicated in the discussion above, the bone anabolic agent may be
administered orally,
intravenously, intramuscularly, subcutaneously, via implant, transmucosally,
transdermally,
rectally, nasally, by depot injection or by inhalation and pulmonary
absorption. In another
embodiment the bone anabolic agent may be administered once as a time release
formulation, a
plurality of tirries, or over one or more extended periods. It is preferred
that elevated blood levels
of the anabolic agent be maintained at least intermittently for between about
14-365 days, and
more preferably for between about 30-180 days, post-mechanical induction.
Intermittent
administration of parathyroid hormone, e.g., PTH[1-34]-NH2, could occur once
daily or once
weekly resulting in peaks of blood concentration that return to baseline
levels between doses, but
nevertheless result in periodic elevated blood levels of a bone anabolic agent
in a manner that
overlaps the elevated osteoblast activity that is initially induced
mechanically, although thereafter
sustained, at least in part, by the anabolic agent.
In an additional embodiment the anabolic agent is selected from the group
consisting of a
parathyroid hormone (PTH), anabolic Vitamin D analogs, a low-density
lipoprotein receptor-
related protein 5(LR.P5) activator, or an inhibitor of sclerostin binding to
LRP5, an activator of
non-genomic estrogen-like signaling (ANGELS), a bone morphogenic protein
(BMP), an insulin-
like growth factor (IGF), a fibroblast growth factor (FGF), sclerostin,
leptin, a prostaglandin, a
statin, strontium, a growth hormone, a growth hormone releasing factor (GHRF),
hepatocyte
growth factor (HGF), calcitonin gene related peptide (CGRP), parathyroid
hormone related
peptide (PTHrP), transforming growth factor (TGF)-PGE-2 and stable analogs
thereof and
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combinations thereof. As used herein, the term parathyroid hormone includes,
but is not limited to
natural parathyroid hormone, a truncate of natural parathyroid hormone, an
amidated truncate of
natural parathyroid hormone, an amidated natural parathyroid hormone and
combinations thereof.
In one embodiment the bone anabolic agent is truncated PTH[ 1-34] in the free
acid form.
This material is commercially available in an FDA-approved pharmaceutical
formulation from Eli
Lilly & Co. under the trade name Forteo (teriparatide). Other useful bone
anabolic agents for
use with the invention include, but are not limited to, an amidated truncate
of natural parathyroid
hormone, PTH[1-30]NH2, PTH[1-31]NH2, PTH[1-32]NHZ, PTH[1-33]NH2, PTH[1-34]NH2
and
combinations thereof. In one preferred embodiment the bone anabolic agent is
PTH[1-34]NH2.
Methods for the preparation of truncated parathyroid hormones are described in
U.S. Patent No.
6,103,495 to Mehta et al. Moreover, methodologies for amidating such truncated
parathyroid
hormones are provided in, for example, U.S. Patents 5,789,234 to Bertelsen et
al. and 6,319,685
to Gilligan et al. The contents of each of these patents is specifically
incorporated herein by
reference.
In one embodiment of the present method, a sufficient amount of the preferred
truncated
parathyroid hormone (see discussion above) is administered to the subject to
achieve, and
thereafter maintain, a pulsatile blood concentration thereof in the subject of
between about 50 and
350 pg/ml, preferably between about 100 and 200 pg/ml, and most preferably
about 150 pg/ml. In
another embodiment, the blood concentration of the parathyroid hormone in the
subject is raised
to its preferred level by no later than 7 days following mechanical alteration
of the contents of the
bone marrow cavity. As would be well known in this art, an appropriate dosage
of the PTH bone
anabolic agent must be calculated to achieve the above-indicated blood
concentrations. In the case
of injectable formulations, for example, the dose (in pure weight of the
active hormone) given to,
for example, a human subject, may be that taught in the literature relating to
the bone anabolic
activity of these various agents. Such dose, if given by the parenteral route,
may, but does not
necessarily, range between about 10-200 g, given once per day, more
preferably between about
20-100 g per dose and most preferably between about 20-50 g per dose. Dosage
levels of
injectable formulations comprising bone anabolic agents other than the above-
described
parathyroid hormone-based agents would be consistent with the known blood
levels required to
evoke an anabolic response in man.
In a further embodiment of the invention the mechanical induction of
osteoblast activity is
accomplished by inserting, into a bone marrow cavity of a bone targeted for
enhanced bone
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formation, an object configured or adapted to physically alter the contents of
the cavity and
thereby to stimulate the osteoblast activity within the cavity. In another
embodiment the
mechanical alteration may include removal of at least a portion of the cavity
contents. A suitable
method is to irrigate the bone marrow cavity with a solution to remove stromal
cells. In certain
embodiments the application of the biocompatible material may be used to
remove bone marrow
cells and, thereby, for inducing osteoblast activity.
In a still further embodiment, the method of the invention additionally
comprises
administering to the subject an antiresorptive agent for a time and at a
concentration sufficient to
substantially prevent resorption of the new bone produced due to the
osteoblast activity. In one
embodiment the antiresorptive agent may be administered contemporaneous with
the
administration of the bone anabolic agent. In another embodiment the
antiresorptive agent is
administered subsequent to the administration of the bone anabolic agent. In a
further
embodiment the administration of the antiresorptive agent may be commenced
during
administration of the bone anabolic agent and such administration may then be
continued beyond
the termination of administration of the bone anabolic agent.
In another embodiment of the invention a single agent may by administered
having both
bone anabolic and antiresorptive properties. Examples of such materials
include, but are not
limited to estrogen, strontium ranalate and selective estrogen receptor
modulators (SERMS).
In an embodiment of the method of the invention the antiresorptive agent may
be a
calcitonin selected from the group consisting of human calcitonin, salmon
calcitonin ("sCT"), eel
calcitonin, elkatonin, porcine calcitonin, chicken calcitonin, calcitonin gene
related peptide
(CGRP) and combinations thereof. In a preferred embodiment the antiresorptive
agent is salmon
calcitonin. Blood levels of calcitonin, when used as the antiresorptive agent,
preferably range
between about 5-500 pg/ml, more preferably between about 10-250 pg/ml and most
preferably
20-50 pg/ml. Moreover, human dosage levels of the subject calcitonin agents
necessary to achieve
the above blood levels, in the case of, e.g., injectable formulations, may be
those taught in the
literature relating to the use of these materials as anabolic agents. Such
dose may, but does not
necessarily, range between about 5-200 g given once per day, more preferably
between about 5-
50 g and most preferably 8-20 g by weight of the pure drug, administered
daily. Salmon
calcitonin (sCT) administered by alternate routes, i.e., by nasal or oral
administration, would
require higher dosages than those discussed above.
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Alternately, a variety of additional antiresorptive agents (i.e., other than
the calcitonins)
are useful with the method of the present invention. These include, generally,
hormone
replacement therapy (HRT) agents such as selective estrogen receptor
modulators (SERMS),
bisphosphonates, cathepsin-K inhibitors, strontium ranalate and various
combinations thereof.
Specific examples of additional antiresorptive agents include, but are not
limited to, (1)
Premarin available from Wyeth Laboratories, which includes estrogen as the
active ingredient.
A typical accepted dosage is one 0.625 mg tablet daily; (2) Actonel available
from Proctor &
Gamble, which includes, as its active ingredient, risedronate sodium. A
typical accepted dosage is
one 5 mg tablet daily or one 35 mg tablet weekly; (3) Evista sold by Eli
Lilly & Co. which
includes raloxifene HCl as the active ingredient. A typical accepted dosage of
this formulation is
one 60 mg tablet taken daily; and (4) Fosamax available from Merck
Pharmaceuticals, which
includes alendronate as the active ingredient. Typical dosages of this
material are 10 mg/day or 70
mg/week. Additional bisphosphonates include Actonel (Proctor Gamble Aventis),
Ibandronate (GSK Roche) and Zolendronate (Novartis).
Except where otherwise noted or where apparent from the context, dosages
herein refer to
the weight of the active compounds unaffected by pharmaceutical excipients,
diluents, carriers or
other ingredients, although such other ingredients are typically included in
the variety of dosage
forms useful in the method of the invention. Any dosage form (i.e., capsule,
tablet, injection or
the like) commonly used in the pharmaceutical industry is appropriate for use
herein and the
terms "excipient", "diluent" or "carrier" include such non-active ingredients
as are typically
included, together with active ingredients, in the industry. For example,
typical capsules, pills,
enteric coatings, solid or liquid diluents or excipients, flavorants,
preservatives, or the like are
included. Moreover, it is additionally noted that with respect to all of the
dosages recommended
herein, the attending clinician should monitor individual patient response,
and adjust the dosage
accordingly.
The antiresorptive agent may be administered orally, intravenously,
intramuscularly,
subcutaneously, via implant, transmucosally, rectally, nasally, by depot
injection, by inhalation
and pulmonary absorption or transdermally. Moreover, the antiresorptive agent
may be
administered once, a plurality of times, or over one or more extended periods.
Although the present invention has been described in relation to particular
embodiments
thereof, many other variations and modifications and other uses will become
apparent to those
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skilled in the art. The present invention, therefore, is not limited by the
specific disclosure herein,
but only by the claims.
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