Norman H. Bell*
Distinguished
University Professor of Medicine, Strom Thurmond Research Building, 114 Doughty
Street, Medical University of South Carolina, Charleston, SC 29425, USA
*Address correspondence to
author, Distinguished University Professor of Medicine, Strom Thurmond Research
Building, 114 Doughty Street, Medical University of South Carolina, Charleston,
SC 29425, Tel: (843) 876-5162, Fax. (843) 876-5163, e-mail: belln@musc.edu
Abstract:Drugs used to treat osteoporosis act either by inhibiting bone resorption or stimulating bone formation. Osteoclast formation and bone resorption require cell-to-cell contact between osteoblasts and osteoclast precursors and osteoclasts in the marrow. Interaction between the receptor for activation of nuclear factor kappa B (RANK) on the surface of preosteoclasts and osteoclasts and RANK ligand on the surface of osteoblasts is required to stimulate osteoclast formation and activation. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin (OPG), a decoy receptor produced by osteoblasts and marrow stromal cells. Thus, interference in binding of the RANK ligand to RANK by OPG determines the rate of bone resorption. Antiresorptive drugs such as estrogen, raloxifene, bisphosphonates, salmon calcitonin, and osteoprotegerin increase bone mass by inhibiting osteoclast function and bone resorption. Osteoprotegerin is more potent since it also inhibits osteoclast formation. Raloxifene, a selective estrogen receptor modulator (SERM), is a member of a class of compounds that act through estrogen receptors and are agonists for bone, antagonists for breast and uterine tissue and may be cardioprotective. The drug was shown to prevent vertebral fractures. Alendronate and bisphosphonates are the only antiresorptive drugs that have been shown to decrease fracture rates for the hip in addition to spine and other sites. Bone morphogenetic proteins stimulate bone formation at local sites and are being developed to stimulate fracture healing. Parathyroid hormone (1-34) stimulates osteoblastic bone formation, markedly increases bone mass, prevents vertebral fractures and is under development to treat osteoporosis.
Definition
Osteoporosis is a disorder of the skeleton in
which low bone mass and deterioration of bone microarchitecture lead to
increased bone fragility and fracture risk. Biopsies of bone from patients with
osteoporosis show diminished numbers and thinning of trabeculae of cancellous
bone, and scanning electron microscopic photographs of cancellous bone show
trabecular thinning, separation and loss of connectivity compared to normal
bone. Thus, even minor trauma can cause fractures. Since osteoporosis is
usually asymptomatic until fractures occur, early diagnosis and treatment are
essential. Osteoporosis can be prevented with proper treatment and need not be
a consequence of aging.
Bone loss and aging
In a given individual, bone mineral density (BMD) is determined by two factors, peak bone mass or the highest bone mass achieved in adulthood and age-related bone loss. Women lose bone with aging and the rate of bone loss is accelerated during the first decade after the menopause because of a 90 percent decrease in circulating 17b-estradiol [1]. Consequently, women lose 40 to 60 percent of their bone mass by the age of 80 years [2]. Men also experience bone loss with aging but the loss is less since there is no male menopause. However, there are age-related decreases in serum testosterone and increases in serum sex hormone-binding globulin so that the concentration of bioavailable testosterone decreases [3]. Further, testosterone is converted to 17b-estradiol by aromatase primarily in adipose tissue, and serum 17b-estradiol but not serum testosterone correlates with BMD and markers of skeletal remodeling in men [4]. The importance of 17b-estradiol in regulating bone metabolism and turnover in men is emphasized by the observations that men with aromatase deficiency [5] and men with functional impairment of estrogen receptor [6] develop osteoporosis. In aging men and women, low bone BMD and osteoporosis can occur as a consequence of low peak bone mass, increased rate of skeletal remodeling with bone loss or both.
Another important consequence of aging is that the bone loss can occur as a result of altera-tion of vitamin D metabolism. Dermal production of 7-dehydrocholesterol, the precursor of vitamin D3 [7]; dietary intake of vitamin D [8]; production of 25-hydroxyvitamin D [25(OH)D] in response to orally administered vitamin D [8], the concentration of vitamin D receptors in the intestinal mucosa [9]; and renal production of 1,25-dihydroxyvitamin D [1,25(OH)2D] [10], the most biologically active metabolite of the vitamin, decrease with aging. Elderly men and women may be house bound and have limited access to sunlight [11]. Collectively, these changes lead to decreases in intestinal absorption of calcium [12], secondary hyperparathyroidism [13], increases in bone resorption and bone loss [14].
Assessment of bone turnover
Bone turnover is assessed by measuring products produced during bone formation and resorption [15,16]. This is important because bone loss with aging varies with the rate of skeletal remodeling and, in general, the higher the rate of bone remodeling, the higher the rate of bone loss. Circulating markers of bone formation include bone-specific alkaline phosphatase (BSAP), osteo-calcin and propeptide of type I collagen. BSAP is produced by osteoblasts. Osteocalcin is produced by osteoblasts, comprises some 10 to 25 percent of total noncollagenous protein in bone matrix and is released during bone formation. Cleavage of propeptides from procollagen forms collagen and propeptides are products of collagen synthesis. Bone resorption is assessed biochemically by measurement of products of collagen degradation in serum and urine. Products of bone resorption include pyridinium crosslinks and associated peptides; pyridinoline, deoxypyridinoline and telopeptides and hydroxproline [15,16]. The pyridinoline crosslinks in collagen are formed by linkage of two molecules forming pyridinoline and deoxypyridinoline. In women, the rate of skeletal remodeling, determined by measurement of serum or urinary deoxypyridinoline or urinary N-telopeptide of type I collagen, increases at the time of the menopause as a consequence of loss of estrogen by more than 50 percent and remains increased [17], whereas in men, there is little change in the rate of skeletal remodeling with aging [18].
Diagnostic criteria for osteoporosis
At present, measurement of BMD is the cornerstone for determining the presence or absence of osteoporosis. Criteria for diagnosis was developed for this purpose by the World Health Organization [19]. The cutoff point of 2.5 SD or T score below the young adult mean value identifies some 30 percent of postmenopausal women as having osteoporosis by measurements made at the spine, hip and forearm and is consistent with a lifetime risk of a fracture of about 40 percent. This cutoff point is a useful value for treatment of osteoporosis. However, one should keep in mind that age is an independent risk factor for fracture at any given BMD and fracture rate can vary as much as 10 fold in this regard [20]. Prevalent fracture, particularly of the spine, and the rate of bone resorption as assessed by markers of bone resorption, predict fracture risk independently of BMD in women [21]. Prevalent fracture increases the risk of additional fractures.
It is important to establish a cutoff point for prevention of osteoporosis. About 15 percent of perimenopausal women have a BMD of the proximal femur 1 SD or more below the young adult mean value and would have a two-fold or greater risk of fracture compared to women with a higher BMD. Consideration of preventive treatment of such a patient might depend on a number of factors including family history of fracture, body weight of 127 pounds or less, height greater than 5 feet 7 inches, age, and cost, efficacy and safety of treatment [19].
Bone remodeling
Throughout life, the skeleton undergoes continual remodeling in response to hormonal regulation and mechanical stress. Remodeling begins when osteoclasts or bone-resorbing cells are activated by systemic hormones such as parathyroid hormone (PTH), 1,25(OH)2D and local factors such as prostaglandin E2 (PGE2) and cytokines or other biologically active substances [22,23]. Osteoclasts are large, hematopoietically-derived, multi-nucleated cells that attach them-selves by means of a ruffled border to bone and resorb small areas called Howship’s lacunae or resorption pits. Osteoblasts are then recruited and repair the resorbed sites. At any given time, there are some 1 to 2 million resorption pits in a human skeleton. During periods of growth, bone formation is greater, and when bone is lost, bone resorption is predominant. In general, drugs for treatment and prevention of osteoporosis act either to enhance osteoblastic bone forma-tion or to inhibit osteoclastic bone resorption.
Several recent important scientific discoveries at the physiological, cellular and molecular levels have expanded knowledge about how bone is formed and undergoes remodeling and provide new rationales for development of new drugs to treat and prevent osteoporosis. The first important discovery was made independently by two groups: marrow cells and osteoblasts produce a surface protein called osteoclast-differentiating factor (ODF), osteoprotegerin ligand (OPGL) or RANK ligand (RANKL) [24,25] that binds to a receptor for activation of nuclear factor kappa B (RANK) on the surface of preosteoclasts and osteoclasts [26] to stimulate formation and activation of osteoclasts [27]. This process requires cell-to-cell contact. Bone resorption in response to PTH, 1,25(OH)2D, PGE2 and other agents is mediated by ODF/RANKL [28]. Importantly, stromal cells and osteoblasts in the microenvironment of the marrow also produce a secreted decoy receptor protein called osteoclast inhibitory factor (OCIF) or osteoprotegerin (OPG) [28,29] that binds to ODF/RANKL and prevents cell-to-cell surface ODF/RANKL-mediated stimulation of formation and activation of osteoclasts. OCIF/OPG is so powerful in this regard that OCIF knockout mice develop high rates of osteoclastic bone resorption, low bone mass and spontaneous fractures [30], whereas transgenic mice given excess OCIF/OPG develop markedly diminished bone remodeling, greatly increased bone mass, that, due to osteopetrosis, results in loss of bone marrow space [28]. Thus, OPG is a major regulator of skeletal remodeling. Many osteoporosis drug discovery programs are now exploring this new bone turnover regulatory system. RANK, RANK ligand and osteoprotegerin are now established names for the receptor, ligand and decoy receptor, respectively [31]. It is now established that macrophage colony-stimulating factor (M-CSF) and RANK ligand are both required for differentiation of bone marrow monocytes into osteoclasts. In this regard, op/op osteopetrotic mice do not produce M-CSF and treatment with M-CSF rescues the op/op phenotype [32].
The second major discovery is that Cbfa1, a transcription factor, initiates and modulates osteoblast differentiation and bone formation. Mice with Cbfa1 gene knockout develop a carti-lagenous skeleton without osteoblasts, osteoclasts or bone [33,34]. Importantly, it was found that bone morphogenetic protein-2 (BMP-2) increases Cbfa1 expression but the effect may be mediated indirectly [34]. BMP-2 and BMP-7 have been used effectively with matrix scaffolding in animals and patients to repair nonunion fractures and skeletal defects [35]. Both are in the final stages of development for this clinical use.
A third important discovery, also found in mice, is that leptin regulates bone formation centrally, that is, by a pathway that involves the brain and hypothalamus [36]. Leptin is produced by adipocytes and acts centrally to inhibit appetite. Mice that lack leptin (ob/ob mice) or the leptin receptor (db/db mice) are obese and have a skeletal mass that is two to three times normal. These mice have greatly increased bone mass despite the fact that they have hypogonadism and increased secretion of corticosteroids, both of which are known to reduce bone mass. Administration of leptin intracerebroventricularly to ob/ob mice reduces bone mass to normal. Thus, by acting through the central nervous system (CNS) leptin exerts a powerful inhibitory effect on bone formation. This regulatory system may be a means by which marrow and fat cells are protected against over-development by bone. Obese humans have increased bone mass and are less likely to develop osteoporosis. Whether the CNS pathway plays a role in modulating bone formation in man is not yet established. If true, elucidation of this pathway could lead to the development of new means of treating and preventing osteoporosis.
Treatment
Anti-Resorptive Drugs
All drugs currently approved for the treatment and prevention of postmenopausal osteoporosis act to increase bone mass by inhibiting osteoclastic bone resorption. The goal of treatment with antiresorptive drugs is to normalize increased skeletal remodeling, enhance BMD and prevent fractures. Antiresorptive drugs that are approved for treatment of osteoporosis include estrogens, salmon calcitonin, the SERM raloxifene, and the bisphosphonates alendronate and residronate.
Estrogen
Estrogen has been widely used for years to treat osteoporosis. As noted already, bone resorption is increased in postmenopausal women. Estrogen reduces skeletal remodeling by about 50 percent in postmenopausal women as determined by bone markers [37]. Previous epidemiologic studies indicate that estrogen replacement in postmenopausal women decreases the incidence of fractures and coronary artery disease. Despite a large number of clinical studies, however, the mechanism of action of estrogen is still not known.
The ovariectomized rat has proved to be a very useful model for postmenopausal bone loss [38]. T cells have estrogen receptors and modulate T cell function. Studies in rodents show that estrogen deficiency leads to increased production of M-CSF by marrow stromal cells and augmented osteoclastogenesis [39]. Increased osteoclasto-genesis in response to M-CSF and RANKL is mediated by enhanced T-cell production of tumor necrosis factor-a (TNFa) through the TNFa receptor p55 [40]. The importance of this pathway is emphasized by the fact that ovariectomy does not increase osteoclastogenesis and cause bone loss in T-cell deficient mice. Whether T cells and TNFa play a role in bone loss in postmenopausal women is not known.
A large number of studies have shown that estrogen replacement reduces skeletal remodeling and increases BMD but the evidence as regards fractures is conflicting [40]. An open randomized controlled study showed that the estimated risk of new symptomatic fractures in women receiving estrogen was 0.29 (95% CI 0.10-0.90) compared to placebo [41]. A more recent prospective, controlled study in Danish postmenopausal women showed that fracture rate of the forearm of patients on hormone replacement therapy (HRT) evaluated by intent to treat was significantly reduced, RR 0.45 (95% CI 0.22-0.90), whereas fracture rate at other sites was not. However, forearm and overall fracture risk was significantly reduced in women who remained on HRT [42]. In a double-blind, placebocontrol, randomized trial designed to evaluate the effects of HRT on secondary prevention of heart disease, no difference was found in the incidence of hip fracture or any fracture [43]. However, the study was not powered for assessment of hip fracture prevention and fracture reduction was not a primary endpoint. The results of the ongoing Women's Health Initiative in over 20,000 women should provide information about the utility of HRT to prevent fractures and to prevent coronary artery disease as well.
Selective Estrogen Receptor Modulators
SERMs are molecules that have full or partial effects on target tissues of estrogen and likely mediate their effects through estrogen receptors [44]. SERMs were developed because estrogen increases the risk of breast and uterine cancer and causes vaginal bleeding, breast tenderness and bloating [45]. Tamoxifen and raloxifene were the first two to be developed, and, like estrogen, prevent bone loss by inhibiting skeletal remodeling. Whereas both drugs are agonists for estrogen receptors in bone, suppress serum cholesterol and are estrogen receptor antagonists for breast tissue, tamoxifen stimulates growth of uterine tissue and raloxifene does not. Lasofoxifene is a newer, more potent SERM with a profile on target tissues in rodents like that of raloxifene [46] that is undergoing clinical trials in postmenopausal women to determine its efficacy for treatment of osteoporosis. MDL 103,323 is another SERM with a similar raloxifene-like profile on target tissues in rodents [47].
In women treated with raloxifene for 3 years, the RR for vertebral fracture was 0.7 (95% CI 0.5-0.8) at a dose of 60 mg and 0.5 (95% CI, 0.4-0.7) at a dose of 120 mg per day [48]. However, risk reduction of fractures in response to treatment at other sites was not significant. Preliminary results suggest that raloxifene may reduce the risk of breast cancer [49]. Its efficacy is being evaluated in the Study of Tamoxifen and Raloxifene (STAR) multicenter investigation that compares the effects of the two drugs in this regard.
Bisphosphonates
Bisphosphonates are derived from pyrophosphate, a product of cellular cleavage of ATP. Replacement of oxygen by carbon renders them resistant to alkaline phosphatase. Bisphosphonates are poorly absorbed from the gastrointestinal tract. About half of an oral dose is taken up unchanged by bone and the remainder is excreted unchanged in urine. Skeletal deposition is accounted for by the high affinity of the P-C-P structure for hydroxyapatite [50]. Alendronate and other bisphosphonates are potent inhibitors of osteoclastic bone resorption. They are selectively taken up by osteoclasts during bone resorption and inhibit formation of osteoclasts from osteoclast precursors and inhibiti osteoclast function [51,52]. Bisphosphonates also act to inhibit bone resorption by increasing apoptosis of osteoclasts [53]. Alendronate and other bisphosphonates inhibit osteoclastic geranylgeranyl diphosphate synthesis and protein prenylation via the mevalonic pathway [54]. Recent studies indicate that alendronate is a specific inhibitor of farnesyl diphosphate synthase and does not alter function of any of the other enzymes involved in the mevalonic pathway [55]. Further, an associated effect is that alendronate inhibits sterol biosynthesis by this pathway. Nitrogen-containing bisphosphonates prevent incorporation of [14C]-mevalonate into prenylated proteins in purified rabbit osteoclasts [56]. The importance of this pathway in regula-ting osteoclast function is emphasized by the findings that a specific inhibitor of geranylgeranyl transferase I that inhibited protein geranylgeranylation in purified rabbit osteoclasts prevented osteoclast formation in murine bone marrow cultures, disrupted osteoclast cyskeleton, inhibited bone resorption, and induced apoptosis in isolated chick and rabbit osteoclasts in vitro (56). Alendronate and other nitrogen-containing bisphosphonates given in vivo by s.c. injection, were shown to suppress expression of hydroxymethyl-glutaryl-coenzyme A reductase (HMGR) in rat tibia osteoclasts [57]. Simvastatin, a drug previously shown to increase expression of HMGR and inhibit cholesterol synthesis in liver cells [58], prevented the decline in HMGR, indicating feed-back regulation by one or more downstream metabolites. Thus, bisphosphonates diminish bone resorption not only by inhibiting the formation and biologic activity of osteoclasts through inhibition of farnesyl diphosphate synthase in the mevalonate pathway but by reducing their life span as well.
Alendronate and risedronate have been shown to reduce the incidence of vertebral, hip and other nonvertebral fractures in patients with osteoporosis [59-62]. In the FIT study with alendronate, fractures of the spine were reduced by 53 percent, radiographic vertebral by 48 percent, clinical vertebral fractures by 45 percent, hip fractures by 45 percent and all clinical fractures by 30 percent in postmenopausal women with either prevalent vertebral fracture or T score less than -2.5 of the femoral neck, and reductions were significant by 12 months [60]. Over a period of 3 years, risedronate decreased the incidence of nonvertebral fractures by 39 percent, vertebral fractures by 41 percent [61] and hip fractures by 30 percent [62]. Risedronate and alendronate are the only two drugs that have been shown to reduce the incidence of hip fracture in randomized, prospective, placebo-controlled clinical trials [59-62]. It is now established that alendronate is as effective in increased BMD and reducing skeletal remodeling when given once a week as it is when given daily [63]. Thus, 35 mg and 70 mg tablets that can be given weekly instead of 5 mg and 10 mg tablets, respectively, that are given daily are available for prevention and treatment of osteoporosis
Salmon Calcitonin
Calcitonin inhibits bone resorption by decreasing the formation and attachment of osteo-clasts to bone [64,65]. In the PROOF study in postmenopausal women, 200 IU nasal spray salmon calcitonin reduced the incidence of vertebral fractures by 33%. The drug did not signi-ficantly decrease the incidence of fractures in women when given in doses of 100 IU or 400 IU daily [66]. Lumbar spine BMD increased by 1.0 to 1.5%. In the study, there was a 60 percent drop out rate. There is concern about the results of this study because of the lack of significant fracture reduction with the other two doses and the high drop out rate. Nevertheless, salmon calcitonin is approved for treatment of postmenopausal osteoporosis.
Vitamin D and Calcium
As indicated already, vitamin D depletion in older individuals causes secondary hyper-parathyroidism, increased bone resorption and bone loss [7-14]. Treatment of men and women living at home in the Boston, MA, area with vitamin D and calcium for 3 years moderately but significantly increased BMD of the lumbar spine, femoral neck and total body and significantly reduced the incidence of nonvertebral fractures [67]. Thus, it is important to supplement vitamin D and calcium in individuals who are at risk to reduce the incidence of fractures.
avb3 Integrin Receptor Inhibitors
To bring about bone resorption, osteoclasts
attach themselves to Arg-Gly-Asp (RGD) sequences such as those found in
osteopontin, bone sialoprotein, and type I collagen in the extracellular matrix
of bone surface by means of the avb3 vitronectin receptor [68]. The actual
binding molecules for the vitronectin receptor in bone are not known. Small
molecular weight, orally active RGD-mimetics have been developed that inhibit
binding of the vitronectin receptor of osteoclasts and bone resorption [69]. At
least one of these drugs is undergoing clinical trials to assess its possible
utility for treatment of osteoporosis.
Osteoprotegerin
In view of its profound effects in rodents to inhibit skeletal remodeling, OPG is of great potential value in treatment of osteoporosis. The effects of OPG on bone markers were determined in a randomized, prospective, double-blind, placebo-controlled, 85-day, sequential dose-escalation study (0.1, 0.3, 1.0 and 3.0 mg/kg body weight) that involved 52 healthy postmenopausal women.* The drug was given as a single dose by s.c. injection. Urinary NTx had decreased at 12 hours after administration of the OPG and at the highest dose, had decreased by
* Becker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CRJ. J Bone Miner Res 16:348, 2001 (abstract).
80 percent at 4 days and by 14 percent at 6 weeks. In contrast, serum BSAP did not change for 3 weeks and had declined by 30 percent at 6 weeks in response to the highest dose. OPG was well tolerated. These studies indicate that in human subjects osteoprotegerin is a potent inhibitor of osteoclastic bone resorption, reduces the rate of skeletal remodeling and is of potential value for the treatment of osteoporosis.
Anabolic Drugs
Bone Morphogenetic Proteins
As noted already, BMP-2 and BMP-7 are being developed for clinical use to repair fractures [35].
Statins
Statins are drugs that were developed and are widely used to lower serum cholesterol by inhibiting HMG CoA reductase, the rate-limiting enzyme for cholesterol synthesis. Simvastatin was found to increase expression of BMP-2 in bone cells, and lovastatin, simvastatin, mevastatin and fluvastatin were shown to markedly increase bone formation in rodents, both intact and ovariectomized [70]. Thus, statins, particularly newer ones, are of potential value for treatment of osteoporosis.
Parathyroid Hormone
PTH is a physiologic regulator of osteoclastic bone resorption, an effect mediated by RANKL, as indicated already. However, when PTH(1-34), a biologically fully active fragment of PTH, is given daily in low doses, it is known to be a potent stimulator of bone formation and bone mass of the spine in a linear fashion in both experimental animals and human subjects [71]. Available evidence indicates that the action of PTH to promote bone growth is due to its ability to stimulate osteogenic cell proliferation and differentiation. Recombinant expression of BMP-2 and PTH receptor-1 in mesenchymal progenitor C3H10T1/2 cells leads to marked development of osteogenic development [72]. Addition of PTH(1-34) to these cells stimulates early development but suppresses late stages of osteogenic development, effects that appear to be produced by cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway [73]. Histomorphometric stu-dies of trabecular bone in rats indicates that PTH induces c-fos expression and enhances osteoblast proliferation whereas antisense oligonucleotides of c-fos prevent proliferation [74]. This action of PTH is mediated by cAMP [74].
When given by daily subcutaneous injection for one to two years to postmenopausal women with one or more prevalent vertebral fractures, PTH(1-34) was shown to reduce the incidence of vertebral fractures by 65 percent and non-vertebral fractures by almost 50 percent.*
If approved by the FDA, PTH(1-34) will be the first agent to be cleared for treatment of postmenopausal osteoporosis that stimulates bone formation. One advantage that PTH (1-34) would have over other drugs is that it need be given for only a year and a half to two years.
SUMMARY
Osteoporosis is an important disease because of its prevalence and because it is associated with significant morbidity and mortality. As a consequence, development of new means of treating the disease is a major goal of drug companies. A number of new scientific discoveries have provided new rationales for development of new drugs that act either to inhibit bone re-sorption or to stimulate bone formation. These new drugs should greatly expand the therapeutic approach that can be used for treatment of this common disorder in the individual patient.
* Neer, R. M., Arnaud, C., Zanchetta, J.R., Prince, R., Gaich, G.A., Reginster, J.-Y., Hods-man, A.B., Eriksen, E.F., Mellstrom, D., Ish-Shalom, S., Oefjord, E.S., Marcinowska-Suchowierska, A.Z., , Salmi, J., Gaspar, L., Mulder, H., Halse, J., Sawicki, A.Z., Genant, H., Wang, O., Mitlak, B.H. Endocrine Society Program & Abstracts p42 (abstract).
Abbreviations
BMD = Bone mineral density
BMP-2 = Bone morphogenetic protein-2
BSAP = Bone-specific alkaline
phosphatase
CNS = Central nervous system
[1,25(OH)2D] = Cyclic adenosine 3',5'-mon-
ophosphate (cAMP) 1,25-
dihydroxyvitamin D
[25(OH)D] = 25-Hydroxyvitamin D
HRT = Hormone replacement therapy
M-CSF = Macrophage colony-stimulating
factor
ODF = Osteoclast-differentiating factor
OCIF = Osteoclast inhibitory factor
OPG = Osteoprotegerin
OPGL = Osteoprotegerin ligand
PTH = Parathyroid hormone
PGE2 = Prostaglandin E2
RANK = Receptor for activation of
nuclear factor kappa B
RANKL = RANK ligand
SERM = Selective estrogen receptor
modulator
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