Statins and the Stimulation of Bone Growth -- Do They or Don't They?
by James F. Whitfield, Ph.D., FRSC
| Geriatric Times |
 |
March/April 2002 |
|
Vol. III |
|
Issue 2 |
Aging humans are threatened by a progressive structural weakening and loss
of bone that, depending on how much bone they banked during youth, can end in
osteoporosis. The threat is greater for women in whom the structural weakening
is accelerated by the fading flow of estrogen at menopause. This
osteo-deterioration happens because the shrinking estrogen supply releases the
brakes on osteoclast generation (Whitfield, 2001; Whitfield et al., 2000). The
estrogen decline also shortens the life spans of osteoblasts and perhaps most
importantly osteocytes. Since osteocytes -- locked in the depths of the bone --
send inhibitory signals to bone-lining cells to prevent activation of
bone-repair/remodeling crews (Martin, 2000), their mortality reduces this
inhibitory flow. This mimics the severing of signal transmission lines by
microcracks that activate repair/remodeling crews (Martin, in press; 2000), the
first of which are osteoclasts that dig out the seemingly damaged patch
(Whitfield, 2001; Whitfield et al., 2000). But a growing bone deficit is caused
by fewer shorter-lived osteoblasts to refill the bigger holes (the so-called
"resorption space") that the more numerous osteoclasts dig. Bone fragility and
real microcracking rise, which further increases remodeling activity and bone
turnover by severing more osteocyte-lining cell connections (Martin, in press;
2000). Consequently, a postmenopausal woman's bones become increasingly liable
to fracturing even by her normal body movements.
Osteoporosis is currently treated with bisphosphonates (e.g., alendronate
[Fosamax]), calcitonin or selective estrogen receptor modulators (SERMs) (e.g.,
raloxifene [Evista]). These agents work by reducing osteoclast activity without
affecting osteoblasts, which can then try to refill the existing excavations
and increase bone mineral density (BMD) by extending the mineralization of the
new bone matrix (Boivin et al., 2000; Seeman and Delmas, 2001). But something
more is needed (Seeman and Delmas, 2001; Whitfield, 2001; Whitfield et al.,
2000). That something -- bone anabolic -- would directly stimulate the buildup
of osteoblasts to make structurally strong new bone, reduce microcracking and
expand the osteocyte-lining cell signaling network to restrain excessive
activation of remodeling/repair crews (Martin, in press; 2000).
The most promising anabolics are the 84-amino acid parathyroid hormone
(native PTH) and certain of its fragments (Whitfield, in press; 2001; Whitfield
et al., 2000, 1998). When injected once daily, these molecules directly
stimulate net bone growth and accelerate fracture healing, but if they are
continuously infused or injected at intervals less than an hour apart, they
stimulate net bone resorption. Given properly, these peptides are close to the
ideal anabolics, but they have to be injected subcutaneously (although a PTH
pill may soon be produced [Mehta et al., 2001]). However, in the last six
years, the cholesterol-lowering statins have emerged as possible orally or
topically administered anabolics with an added bonus -- cardiovascular
protection (Mohler et al., 1999; Shepherd, 2000).
The statin-and-bone story began when Wang et al. (1995) reported that
lovastatin (Mevacor) reduced steroid-induced bone loss in New Zealand rabbits.
Further studies showed that atorvastatin (Lipitor), cerivastatin (Baycol
[withdrawn from the market August 2001]), fluvastatin (Lescol), lovastatin and
simvastatin (Zocor) stimulated cultured bone cells to make the osteogenic
bone-morphogenic protein (BMP)-2 (Garrett et al., 2001a, 2001b; Hoffmann and
Gross, 2001; Mundy et al., 1999; Sugiyama et al., 2000). Pravastatin
(Pravachol), which only targets liver cells, had no such effect (Garrett et
al., 2001b). Lovastatin and simvastatin stimulated bone formation in cultured
mouse calvariae and orally gavaged simvastatin (5 mg/kg or 10 mg/kg body
weight) nearly doubled trabecular bone volume and increased bone formation by
50% in ovary-intact and ovariectomized (OVX) rats (Garrett et al., 2001b;
Gasper et al, 2000a, 2000b; Mundy et al., 1999). Lovastatin, either topically
applied or seeping continuously from a polylactide scaffold implanted in the
skin, was 50 to 80 times more effective in rats than when given orally or
injected subcutaneously (Gutierrez et al., 2000; Whang et al., 2000).
Others have reported that topically or systemically administered
cerivastatin, fluvastatin and simvastatin did not stimulate bone growth or
prevent OVX-induced bone loss in mice and rats (Crawford et al., 2001; Sato et
al., 2001; Yao et al., 2001).
Clinical record reviews of the many patients who have taken statins to lower
their blood cholesterol level reported the statins did indeed significantly
reduce fracturing in postmenopausal women (Bauer et el., 1999; Chan et al.,
2000; Chung et al., 2000; Meier et al., 2000). The odds ratios for fracturing
ranged between 0.29 and 0.61 for statin users relative to non-users. Chan et
al. (2001) reported that giving simvastatin (20 mg/day for four weeks) to 17
hypercholesteremic non-osteoporotic patients increased serum osteocalcin level
but not bone-specific alkaline phosphatase activity, both indicators of bone
formation.
Others have found no evidence of statins affecting fracturing. LaCroix et
al. (2000) found no significant reduction of fracture risk for statin users in
the Women's Health Initiative Observational Study survey of postmenopausal
women's health, although Cauley et al. (2000) found that treatment with
atorvastatin and simvastatin for more than three years modestly protected hip
and lumbar vertebral BMD. Other studies also found no evidence in the clinical
databases that statins significantly affect fracture risk (Sirola et al., 2001;
Solomon et al., 2001; van Staa et al., 2000). Cosman et al. (2001) have carried
out a small, short-term experiment on 14 postmenopausal women (mean age=58)
designed specifically to find the effect of a 12-week treatment with 0.4 mg/day
of cerivastatin on bone. Bone-formation markers (type I procollagen propeptide
and osteocalcin) did not change, but the resorption indicators (urinary N- and
C-terminal telopeptides) dropped slightly (<20%) within six weeks in the
cerivastatin-treated group. Unlike Chan et al. (2001), Cosman and colleagues
(2001) concluded that their statin did not detectably stimulate bone formation,
but might have had a modest, bisphosphonate-like antiresorptive action.
Statins should be antiresorptives. They reduce or stop cholesterol synthesis
by inhibiting mevalonate synthesis from acetyl-CoA by
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and downstream
products such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate.
Besides interfering with cholesterol synthesis, a statin such as lovastatin
inhibits osteoclastic activity just like alendronate, a nitrogen-containing
bisphosphonate that specifically targets the FPP enzyme synthase that operates
downstream from HMG-CoA reductase (Benford et al., 1999; Fisher et al., 1999;
Reszka et al., 1999; van Beek et al., 1999). But how could statins have
stimulated the expression of the osteogenic BMP-2 in some experiments when
alendronate does not seem to?
The answer could lie in caveoli, flask-shaped invaginations of cell
membranes that sequester and inactivate enzymes such as constitutive
endothelial cell nitric oxide (NO) synthase (eNOS) (Schlegel and Lisanti, 2001;
van't Hof and Ralston, 2001). Caveolin-1 needs a lot of cholesterol to attach
to membranes and make a caveola (Schlegel and Lisanti, 2001) Therefore,
inhibiting HMG-CoA reductase and cholesterol production with a statin causes
caveolin-1 to separate from the caveoli and go down into the cytoplasm
(Schlegel and Lisanti, 2001). The breakup of the caveolar cages and their
enzyme-binding scaffolds liberates eNOS and causes a surge of the eNOS activity
and NO (Feron et al., 2001), which has been shown to be needed for bone
formation in mice and in cultured mouse calvariae (Armour et al., 2001; Garrett
et al., 2001a).
The dependence of eNOS expression on estrogen may lie at the root of the
conflicting evidence for the statins' osteogenicity in OVX mice and rats and
postmenopausal women (Whitfield, in press). The failures may be due to a lack
of estrogen because eNOS gene expression is positively controlled by it
(Kleinert et al., 1998; Samuels et al., 2001; Tan et al., 1999; Xu et al.,
2001). Thus, for example, OVX reduces eNOS expression in rat vascular cells.
Moreover, eNOS activity is stimulated by Ca2+ surges triggered by estrogen
receptors resident on the cell surface. Therefore, whether the bone's
osteogenic response to a statin is anabolic or only antiresorptive depends on
the extent of the eNOS rundown due to the lack of estrogen.
In conclusion, while statins are at least likely to be antiresorptives like
the nitrogen-containing bisphosphonates, it is far from certain that they are
anabolics like the PTHs. There must be much larger and longer-term experiments
than those reported by Chan et al. (2001) and Cosman et al. (2001) that focus
on the statins' abilities to affect bone growth and fracturing. It is equally
important to find out whether NO made by eNOS mediates statin-induced BMP-2
expression and osteogenicity. If so, the statins, unlike the PTHs, might be
consistently effective anabolics in postmenopausal women only if supplemented
with an estrogen or SERM to have a superthreshold eNOS level.
Dr. Whitfield is principal researcher at the Institute for
Biological Science, National Research Council of Canada.
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