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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 3  |  Page : 212-223

The molecular etiology and treatment of glucocorticoid-induced osteoporosis

1 Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; Institute of Medical Sciences; School of Medicine, Tzu Chi University, Hualien, Taiwan
2 Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
3 Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; School of Medicine, Tzu Chi University, Hualien, Taiwan
4 Institute of Medical Sciences; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan

Date of Submission07-Sep-2020
Date of Decision19-Nov-2020
Date of Acceptance30-Dec-2020
Date of Web Publication01-Apr-2021

Correspondence Address:
Ming-Der Lin
Department of Molecular Biology and Human Genetics, Tzu Chi University, 701, Section 3, Zhongyang Road, Hualien
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tcmj.tcmj_233_20

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Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, accounting for 20% of osteoporosis diagnoses. Using glucocorticoids for >6 months leads to osteoporosis in 50% of patients, resulting in an increased risk of fracture and death. Osteoblasts, osteocytes, and osteoclasts work together to maintain bone homeostasis. When bone formation and resorption are out of balance, abnormalities in bone structure or function may occur. Excess glucocorticoids disrupt the bone homeostasis by promoting osteoclast formation and prolonging osteoclasts' lifespan, leading to an increase in bone resorption. On the other hand, glucocorticoids inhibit osteoblasts' formation and facilitate apoptosis of osteoblasts and osteocytes, resulting in a reduction of bone formation. Several signaling pathways, signaling modulators, endocrines, and cytokines are involved in the molecular etiology of GIOP. Clinically, adults ≥40 years of age using glucocorticoids chronically with a high fracture risk are considered to have medical intervention. In addition to vitamin D and calcium tablet supplementations, the major therapeutic options approved for GIOP treatment include antiresorption drug bisphosphonates, parathyroid hormone N-terminal fragment teriparatide, and the monoclonal antibody denosumab. The selective estrogen receptor modulator can only be used under specific condition for postmenopausal women who have GIOP but fail to the regular GIOP treatment or have specific therapeutic contraindications. In this review, we focus on the molecular etiology of GIOP and the molecular pharmacology of the therapeutic drugs used for GIOP treatment.

Keywords: Bone remodeling, Glucocorticoid, Osteoblast, Osteoclast, Secondary osteoporosis

How to cite this article:
Peng CH, Lin WY, Yeh KT, Chen IH, Wu WT, Lin MD. The molecular etiology and treatment of glucocorticoid-induced osteoporosis. Tzu Chi Med J 2021;33:212-23

How to cite this URL:
Peng CH, Lin WY, Yeh KT, Chen IH, Wu WT, Lin MD. The molecular etiology and treatment of glucocorticoid-induced osteoporosis. Tzu Chi Med J [serial online] 2021 [cited 2021 Oct 23];33:212-23. Available from: https://www.tcmjmed.com/text.asp?2021/33/3/212/312904

Cheng-Huan Peng and Wen-Ying Lin, Both authors contributed equally to this work.

  Introduction Top

There are >49 million patients with osteoporosis in developed countries, such as the United States, European Union, Australia, and Japan [1]. Patients with osteoporosis tend to develop vertebrae and hip fractures. Vertebrae fractures and fragility fractures at other sites of the body have increased by millions with the population of osteoporosis [2],[3],[4],[5], which causes a heavy financial burden on the country [2],[6]. Moreover, complications may arise in addition to pain and limited mobility, which increases the risk of death in fracture patients and imposes financial burdens on the family and society [7],[8]. Therefore, several countries recognize osteoporosis as a major public health issue, and the World Health Organization has ranked osteoporosis as the second most crucial health care issue worldwide. Osteoporosis can be divided into (1) primary osteoporosis (including postmenopausal osteoporosis and senile osteoporosis) and (2) secondary osteoporosis. Primary osteoporosis is most common in postmenopausal women [9],[10],[11] and elderly persons [12]. Secondary osteoporosis has been associated with various congenital diseases and endocrine disharmony, as well as nutritional status and some medications [13]. The most common form of secondary osteoporosis is glucocorticoid-induced osteoporosis (GIOP) [14], accounting for 20% of all forms of osteoporosis [15]. The majority of these patients have autoimmune diseases (e.g., rheumatoid arthritis and lupus erythematosus), allergic diseases (e.g., asthma and atopic dermatitis), or have undergone organ transplantation. GIOP occurs in two phases: an early phase in which bone mineral density (BMD) declines due to rapid bone resorption and a slow and progressive phase in which BMD declines due to the impaired bone formation [16]. The underlying mechanism of GIOP could be complicated and multifactorial. In this review, we provide an overview of the molecular etiology, assessment, and treatment options in the aspect of molecular pharmacology for GIOP.

  Endogenous glucocorticoid is required for bone homeostasis Top

Bone remodeling is a normal physiological process that involves bone resorption and bone synthesis. Under normal physiological conditions, bone resorption and bone formation are in balance, and many cytokines, hormones, and signaling pathways are involved [17] [Figure 1]. The bone remodeling process undergoes continuously during which osteoclasts absorb aged or damaged bones, whereas osteoblasts and osteocytes are responsible for new bone formation. However, if an imbalance arises, abnormalities in the bone structure or function may occur, resulting in osteometabolic disorders, such as osteopetrosis or osteoporosis [18]. Osteoblasts, osteocytes, and osteoclasts interplay with each other to maintain bone microstructure and homeostasis. Osteoblasts and osteocytes secrete receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) to regulate osteoclasts proliferation and differentiation [16]. On the other way, the activated transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) released from the bone matrix after bone resorption also regulate osteoblasts formation [19],[20]. Moreover, osteoblasts and osteocytes negatively feedback the differentiation of osteoblasts by inhibiting Wingless-related integration site (WNT) signaling through the secretion of WNT antagonists, Sclerostin (SOST), and Dickkopf 1 (DKK1) [21].
Figure 1: Schematic representation of signaling pathways involved in bone remodeling and the formation of osteoblast and osteoclast. WNT, transforming growth factor-beta, bone morphogenetic protein, parathyroid hormone, and estrogen (e) are essential modulators of osteoblast and osteoclast formation. WNT and bone morphogenetic protein enhance the differentiation of osteoblasts. Bone morphogenetic protein, estrogen, and parathyroid hormone could indirectly regulate WNT activity by controlling the expression of Sost, and Dkk1 from osteoblasts and osteocytes. Transforming growth factor-beta enhances bone formation by suppressing the apoptosis of osteoblasts and osteocytes and enhancing the apoptosis of osteoclasts. Moreover, estrogen and WNT also suppress the apoptosis of osteoblasts and osteocytes. Blue lines indicate the effects of signaling molecules or the secreted proteins on the regulation of bone remodeling. Ligands are marked as yellow ovals. Signal modulators or the extracellular matrix proteins are marked as pink ovals. Endocrines are marked as green ovals

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Endogenous glucocorticoid at physiologic concentrations is necessary for osteoblasts to maintain bone homeostasis [22],[23]. The physiological activity of glucocorticoids is regulated by two enzymes, namely 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2), among which 11β-HSD1 activates glucocorticoid, whereas 11β-HSD2 inactivates glucocorticoid [24]. Studies using mouse models elucidate the significance of endogenous glucocorticoids in bone homeostasis. The decrease of glucocorticoid sensitivity in osteoblasts by transgenic expressing of glucocorticoid inactivating enzyme 11β-HSD2 causes a reduction of the bone mass[25],[26]. Mice with conditional knockout of the glucocorticoid receptor in osteoblast lineage also reveal a significant reduction of vertebral bone density and osteoblast activity [27]. These results suggest that endogenous glucocorticoid is necessary for osteoblast activity and bone mineralization. In another way, human diseases causing an imbalance of endogenous glucocorticoid secretion also impair bone metabolism. Cushing's disease, causing an elevation of serum level of endogenous glucocorticoids, is correlated with osteoporosis [28],[29],[30]. Patients with Addison's disease who have a reduced serum level of endogenous glucocorticoids are also associated with a higher risk of hip fracture [31]. In conclusion, evidence from animal models and clinical observations suggests an essential role of endogenous glucocorticoid in maintaining bone remodeling. While the proper regulation of glucocorticoids' physiological concentration is essential for bone homeostasis, excessive glucocorticoids cause bone loss through the dysregulation of osteoblastogenesis and osteoclastogenesis [Figure 2].
Figure 2: Schematic representation of the molecular etiology of glucocorticoid-induced osteoporosis and the effect of anti-osteoporotic drugs. Glucocorticoids (red) induce osteoporosis by inhibiting the differentiation of osteoblasts from mesenchymal stem cell, inducing apoptosis of osteoblasts and osteocytes, increasing the formation of osteoclasts, and prolonging the lifespan of osteoclasts. The effects of anti-osteoporotic drugs (green lines) such as bisphosphonates, teriparatide, denosumab, and raloxifene are indicated. Bisphosphonates inhibit the activity of osteoclast and induce its apoptosis. Bisphosphonates and the intermittent administration of teriparatide decrease the apoptosis of osteoblasts and osteocytes. Raloxifene, only used for postmenopausal women with glucocorticoid-induced osteoporosis, promotes bone formation by stimulating osteogenesis and suppressing osteoblast apoptosis and indirectly inhibits osteoclastogenesis by decreasing the expression of receptor activator of NF-ΚB ligand and increasing the expression of receptor activator of NF-ΚB ligand inhibitor osteoprotegerin. Denosumab inhibits osteoclastogenesis by neutralizing receptor activator of NF-ΚB ligand. Blue lines indicate the signaling affecting osteoclastogenesis

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  The negative impact of excessive glucocorticoids on osteoblast and osteocyte Top

The therapeutic concentration of glucocorticoids reduces the formation and survival of osteoblast and osteocyte. Osteoblasts are differentiated from mesenchymal stem cells (MSCs) which travel through the blood vessel to reach the bone surface [32]. At the bone surface, the WNT signaling promotes the differentiation of MSC into osteoblast progenitor cell [33] and inhibits the differentiation of MSC into chondrocyte or adipocyte [34],[35]. In the modulation of osteogenesis, glucocorticoids facilitate the differentiation of MSCs into adipocytes instead of osteoblast progenitor cells [36],[37],[38].

The differentiation of osteoblast progenitor cells into preosteoblasts and then osteoblasts requires the action of WNT and BMP signaling [39],[40],[41] by which activate the expression of Runt-related transcription factor 2 (Runx2) and Osterix (SP7) transcription factors [42],[43]. Accordingly, excess glucocorticoids exposure suppresses WNT signaling by decreasing Wnt expression [44], bolstering the expression of WNT antagonists, such as Dkk1 [22],[45],[46],[47], Sost [46],[48], and Secreted frizzled-related protein-1 (sFRP-1) [22],[49], and increasing the expression of negative WNT signaling regulator Axin-2 [49]. It is to be noted that the serum concentration of SOST is reduced in humans, which might reflect a compensatory mechanism that remains elucidated [50],[51]. Glucocorticoids also suppress the BMP signaling by inhibiting BMP-2 expression [46],[52] and enhancing the expression of BMP antagonists – Follistatin and Dan [49]. Besides, glucocorticoids suppress both the expression of Runx2 and RUNX2 activity and thus inhibit osteoblast maturation [53],[54].

In addition to WNT and BMP, TGF-β is also involved in regulating osteoblast formation. TGF-β could promote the differentiation of osteoblast progenitor cells from MSCs [55] by enhancing the WNT signaling [56]. On the other hand, TGF-β inhibits osteoblasts and osteocytes' differentiation by decreasing the expression of Runx2 [57],[58],[59],[60],[61],[62]. However, the essentiality of TGF-β in the regulation of osteoblastogenesis can be evident by the study showing that Tgfb1-null mice exhibit a significant loss of trabecular bone density and the reduction of osteoblasts [63]. Even limited literature addresses glucocorticoids' effect on TGF-β signaling; it has been reported that glucocorticoid treatment decreases the mRNA level of TGF-β [64].

Excess glucocorticoids also lead to apoptosis of osteoblasts and osteocytes. The undifferentiated osteoblast usually goes through apoptosis a few months after its formation. WNT [65], TGF-β [66],[67], interleukin-6 (IL-6) [67], and estrogen [68],[69],[70] are reported to suppress the apoptosis of osteoblast. By contrast to osteoblasts' 3-month lifespan, osteocytes are long-lived bone cells that can survive for more than decades [71],[72]. Osteocytes are mechanosensory cells that can sense the microdamage on the bone through their dendritic processes [73] and trigger their apoptosis [73],[74],[75]. While osteocytes undergo apoptosis, the neighboring nonapoptotic osteocytes attract osteoclast precursor cells to the microdamage site by releasing IL-6 and soluble IL-6 receptor [76] and secret RANKL to stimulate the osteoclastogenesis [77]. In the regulation of lifespan of cultured osteoblasts and osteocytes, excess glucocorticoids (≥10−6 M) induced apoptosis [78],[79],[80]. This observation is consistent with the in vivo experiment showing that excess glucocorticoids increase the apoptosis of osteoblasts and osteocytes [81]. Mechanistically, glucocorticoids could induce the apoptosis of osteoblasts by inhibiting the WNT, TGF-β, and IL-6 signaling [64],[65],[82].

  The excessive glucocorticoids promote the differentiation and survival of osteoclast Top

The excessive amount of glucocorticoids promote the proliferation and survival of osteoclast precursor cells. Osteoclasts are originated from hematopoietic stem cells which differentiate into osteoclast precursor cells and then fuse to form multinucleated osteoclasts [83]. During osteoclastogenesis, both macrophage colony-stimulating factor (M-CSF) and RANKL play vital roles [84]. M-CSF is required for the cell survival and proliferation of osteoclast precursor cells, whereas RANK is required for the differentiation of osteoclast precursor cells [85],[86],[87]s. When M-CSF binds to its receptor, colony-stimulating factor 1 receptor (c-Fms), on osteoclast precursor cells, the cell survival and proliferation of osteoclast precursor cells are promoted through the extracellular signal-regulated kinases and Serine/threonine kinase (Akt) signaling pathways [88]. Evidence has shown that glucocorticoids promote the proliferation and survival of osteoclast precursor cells by increasing the expression and half-life of M-CSF produced by osteoblast [89],[90].

Glucocorticoids also promote osteoclast differentiation. RANKL secreted by both osteocytes and osteoblasts binds to the RANK receptor on osteoclast precursor cells and subsequently activates the mitogen-activated protein kinase, Akt, and nuclear factor of activated T-cells, cytoplasmic 1 signaling, which stimulate the differentiation and fusion of osteoclast precursor cells into multinuclear osteoclasts [91],[92],[93]. The activity of RANKL can be neutralized by its decoy receptor OPG secreted by both osteoblasts and osteocytes [94],[95],[96]. When Opg is expressed in large amounts, it hinders the formation of osteoclasts, resulting in osteopetrosis [94]; conversely, osteoporosis can be observed in Opg knockout mice [97],[98]. Therefore, the ratio of RANKL/OPG is recognized as an indicator for the trend of osteoclast differentiation. For example, IL-6 enhances osteoclastogenesis by increasing the Rankl/Opg ratio [99]. Glucocorticoids promote the differentiation of osteoclast precursor cells toward osteoclast by enhancing the expression of Rankl from osteoclasts [100],[101]. In the other way, glucocorticoids indirectly increase the RANKL activity by reducing the expression of its decoy receptor Opg. Glucocorticoids reduce the expression of Opg by directly regulating its expression in osteoblasts [100] or indirectly reduce the expression of Opg through the suppression of WNT signaling, which promotes the secretion of OPG from osteoblasts and osteocytes [102]. It has also been reported that glucocorticoids stimulate osteoclast formation through the activation of IL-6 signaling in osteoblasts [103], although the detailed mechanism is unclear.

The average lifespan of osteoclasts is around 2 weeks in humans [104]. Glucocorticoids act directly on osteoclasts to suppress their apoptosis and thus prolong the lifespan of osteoclasts [105],[106]. On the other hand, glucocorticoids also suppress apoptosis of osteoclast precursor cells by decreasing the expression of Opg [107] and increasing the expression of Rankl [108]. Although glucocorticoids prolonged osteoclasts' lifespan, it was reported that glucocorticoids reduce osteoclast activity by disrupting M-CSF-stimulated cytoskeletal organization in vitro [109].

  The impact of therapeutic glucocorticoids on bone matrix Top

During the process of bone formation, osteoblasts secrete osteoid, the premineralized bone matrix, to prompt bone formation [110] and differentiate into osteocytes embedded in the bone matrix [111]. In osteoid, hydroxyapatite, a complex of calcium and phosphate, is formed within the matrix vesicles that bud from the plasma membrane of osteoblasts [112]. The hydroxyapatite further deposits into the extracellular matrix (ECM) of the bone and interacts with the main fibrous protein, type I Collagen, to form the mineralized collagen essential for maintaining the bone strength [113]. In GIOP patients, glucocorticoids lessen bone mineralization by inhibiting the expression of type I Collagen and increasing the expression of interstitial Collagenase [114],[115],[116].

Osteoblasts also secrete noncollagenous proteins, such as tissue nonspecific alkaline phosphatase (TNAP), osteocalcin (OCN), and osteonectin (ON)/secreted protein acidic and rich in cysteine [117]. These noncollagenous proteins play crucial roles in the bone matrix's mineralization and could be affected by glucocorticoids. TNAP is a membrane-bound enzyme that is localized on the plasma membrane of osteoblasts and the matrix vesicles [118],[119]. TNAP can hydrolyze inorganic pyrophosphate (PPi) to phosphate (Pi) for the formation of hydroxyapatite [120]. OCN is a γ-carboxy glutamic acid-containing protein and has a dual function on bone development. In one way, OCN functions as an inhibitor of bone mineralization by binding to calcium, mediating its association with hydroxyapatite; in the other way, OCN and osteopontin enhance the mechanical properties of the bone [121]. Besides, exogenous supplementation of OCN enhances the differentiation of osteoblasts and increases extracellular calcium levels and TNAP activity [122]. As a calcium-binding matricellular protein, ON triggers the release of the calcium ion by binding to both collagen and hydroxyapatite [123], thereby promoting mineralization of the collagen matrix during bone formation. In addition, ON-null mice have fewer osteoblasts and osteoclasts, leading to a decrease in bone remodeling [124]. As for osteoclast, it also secrets proteolytic enzymes, such as matrix metalloproteinases (MMP) [125] and cathepsins [126],[127], for the degradation of the matrix protein of the ECM during bone resorption. The treatment of glucocorticoids negatively impacts the mineralization of bone matrix by reducing the TNAP activity [128], expression of Ocn [129],[130],[131], and expression of On [132] in osteoblasts. Moreover, glucocorticoids increase the expression of Mmp9, Mmp13, and Cathepsin K by osteoclasts and thus promote the bone reabsorption [78],[132],[133].

  Fracture risk assessment for glucocorticoid-induced osteoporosis Top

For adults ≥40 years of age using glucocorticoids chronically, the fracture risk can be assessed based on BMD and the fragility fracture history. As defined by the World Health Organization in 2008, a BMD T score of <-2.5 standard deviation is considered as osteoporosis. In addition to BMD, the 2017 American College Rheumatology Guideline for the Prevention and Treatment of GIOP recommends using Fracture Risk Assessment Tool (FRAX®, https://www.sheffield.ac.uk/FRAX/) for fracture risk assessment, which is a tool that integrates the information derived from both clinical risk factors and BMD. In the guideline, adults with low FRAX® fracture probability are recommended to take only calcium and Vitamin D, whereas adults with moderate-to-high FRAX® fracture probability (10-year probability of major osteoporotic fracture >10%) are suggested to be treated with additional anti-osteoporosis medication. However, the International Osteoporosis Foundation and the European Calcified Tissue Society suggested that an intervention threshold, instead of the categorization of FRAX® fracture probability, should be determined for clinical practice [134]. Besides, FRAX® fracture probability does not consider the dose of glucocorticoids; therefore, it needs to be adjusted according to the condition of glucocorticoid usage. For example, FRAX® calculations for the 10-year probability of major osteoporotic fracture and hip fracture should be uplifted by 15% and 20%, respectively, when patients take glucocorticoids at doses >7.5 mg/day [135]. In Taiwan, although there is no specific intervention threshold set for GIOP, the 2019 Taiwanese Consensus and Guidelines for the Prevention and Treatment of Adult Osteoporosis suggests using a presumed individual intervention threshold [136]. The presumed individual intervention threshold is defined as the 10-year probability of FRAX®-derived fracture risks for an individual who does not have rheumatoid arthritis, glucocorticoid usage, and other osteoporotic risk factors but has a previous fracture history [136],[137]. By comparing it with the adjusted-FRAX® 10-year probability according to the glucocorticoid dosages, the timing of medical interventions could be determined. Besides, a novel hybrid intervention threshold was established to identify high-risk populations of fragility fractures in Taiwan by considering the FRAX®-derived fracture risks probability, BMD, and presumed individual intervention threshold [138]. However, the intervention threshold for GIOP could vary from country to country, depending on the health policy, economic status, and reimbursement issues.

It is to be noted that the FRAX® calculation is not applicable to determine the fracture risk probability for patients <40 years of age. Although young patients quickly regain bone mass when glucocorticoids are discontinued, the use of glucocorticoids at a dose of >7.5 mg/day for 6 months could still lead to a rapid decrease in bone density in hip or vertebrae (a decrease of >10% in one year) [139]. Therefore, both BMD and prior osteoporotic fracture history should be considered when physicians judge medical intervention for individuals <40 years of age.

  Treatment options for glucocorticoid-induced osteoporosis Top

Calcium and Vitamin D supplements

The evaluation indicators of drug therapy include the dosage and duration of glucocorticoid usage, fragility fracture history, BMD, age, and whether the patient is a postmenopausal woman [140]. In general, prophylaxis and treatment should be initiated in patients using glucocorticoids at a daily dose of 5–7.5 mg for >3 months [139]. Patients treated with glucocorticoids have faced systematic calcium loss caused by reduced gastrointestinal absorption and renal tubular reabsorption [141],[142]. Therefore, it is suggested that adult patients should take adequate calcium (1000–1200 mg/day) and Vitamin D (600–800 IU/day) supplements to reduce calcium loss from bone and increase calcium absorption in the gastrointestinal tract [139]; for adults >50 years of age, a daily intake of 1200 mg calcium with 800–1000 IU Vitamin D is suggested [136].


Bisphosphonates have a nonhydrolyzable P-C-P structure and are analogs of pyrophosphate. Structurally, the bisphosphonates with a nitrogen-containing side chain on the central carbon exhibit substantial therapeutic effects (e.g., alendronate, risedronate, and zoledronate). Bisphosphonates have a high affinity to hydroxyapatite, and thus they could accumulate on surfaces undergoing active resorption. Upon entry into osteoclasts through endocytosis, nitrogen-containing bisphosphonates inhibit the mevalonate pathway's farnesyl pyrophosphate synthase, thereby blocking protein prenylation, inhibiting the function of osteoclasts [143],[144], and inducing osteoclast apoptosis [145],[146]. Apart from the major therapeutic effect of bisphosphonates on inhibiting osteoclasts, bisphosphonates can also increase the lifespan of osteoblasts and osteocytes by inhibiting their apoptosis [147]. In the other way, bisphosphonates decrease the expression of the BMP antagonists Follistatin and Dan, the WNT signaling inhibitors sFRP-1 and axin-2 [49], thus facilitating WNT and BMP signaling and eventually increasing osteoblast formation.

Side effects of bisphosphonates may comprise erosive esophagitis, ulcer bleeding, hypocalcemia, renal function decline, osteonecrosis of the jaw, and atypical femoral fracture [148]. The failure of oral bisphosphonate treatment can be defined as GIOP patients who have new fractures after >18 months of oral bisphosphonates or experienced a significant decrease in BMD (>10% per year) after 1 year of treatment. In such a scenario, follow-up treatment with other osteoporotic drugs, such as denosumab or teriparatide, is suggested [139]. If the failure of oral bisphosphonate treatment is due to poor medical compliance or drug absorption issue caused by gastrointestinal side effects, intravenous bisphosphonates can be considered because of its long dosing interval and infrequent gastrointestinal side effects [149]. Accordingly, a decrease in BMD, new fractures, and other rare side effects, such as osteonecrosis of the jaw and atypical femoral fractures, should be carefully evaluated. For patients who stop using glucocorticoids and have a low risk of fracture, bisphosphonates can be discontinued; however, this is not recommended in patients who have discontinued glucocorticoids but remain at high risk of fracture [139]. It is to be noted that bisphosphonates have a relatively long half-life and tend to be trapped in bones, potentially affecting fetal bones; therefore, they are not recommended for pregnant women [150].

Therapeutic monoclonal antibody

Another commonly used drug in clinical practice is RANKL inhibitor (Denosumab). It is a human monoclonal antibody that binds and neutralizes RANKL, limiting the formation of osteoclasts, thereby inhibiting bone resorption [151]. The clinical trial indicates that GIOP patients take denosumab (60 mg subcutaneously once every six months) has a better therapeutic effect than those take risedronate (5 mg oral per day) in terms of BMD increases in spine and hip after one year of the treatment [152]. The side effects for patients taking denosumab include hypocalcemia, osteonecrosis of the jaw, and a high risk of infection [153],[154]. In addition, the incidence of vertebrae compression fracture also increases rapidly after discontinuation of denosumab [155]. Moreover, there may be a risk of fetal teratogenesis when used in pregnant women [156]. An advantage of denosumab is that no dose adjustment is necessary for patients with renal impairment; however, patients with creatinine clearance <30 mL/min or receiving dialysis are at risk for hypocalcemia. A clinical study has shown that denosumab therapy is well tolerated and improves BMD for patients with solid organ transplant, especially in those with renal function impairment or bisphosphonate intolerance [157]. However, a significant decrease of BMD at the lumbar spine and hip was reported when denosumab was discontinued in renal transplant recipients [158]. Therefore, if denosumab treatment is to be discontinued, an alternative anti-osteoporotic therapy should be considered.

Parathyroid hormone N-terminal active fragment

Teriparatide is an active form of parathyroid hormone (PTH) consisting of the N-terminal 34 amino acids. In the clinical survey, teriparatide significantly increases the expression of bone formation markers and bone mass density of GIOP patients [159],[160],[161]. Intermittent use of teriparatide facilitates osteoblast production, increases TNAP activity [162], and promotes WNT signaling by reducing WNT signaling inhibitors, such as Sost, Dkk1, sFRP-1, and axin-2 [49],[163],[164],[165]. Intermittent administration of teriparatide also inhibits apoptosis of osteoblasts and osteocytes [166],[167], thereby promoting bone formation and increasing bone mass. In addition, teriparatide and WNT can synergistically increase the nuclear translocation of β-catenin by PKA-mediated phosphorylation, thus facilitating WNT signaling [165]. In the absence of WNT binding, PTH-PTH1R complex can also bind to WNT coreceptor LRP6 and trigger WNT signaling in osteoblasts [168]. Teriparatide also decreases the expression of BMP antagonists Follistatin and Dan to facilitate BMP signaling [49]. Besides, PTH exerts an insulin-like growth factor I-mediated anabolic effect on bone formation [169],[170].

However, long-term use of teriparatide may increase Rankl expression and inhibit Opg expression, causing osteoclast differentiation and increasing the number of osteoclasts, leading to bone resorption and bone loss [171],[172]. Furthermore, bone loss and fractures may rapidly occur after teriparatide is discontinued [173]. Accordingly, after teriparatide discontinuation, other osteoporotic drugs should be used. After long-term use of teriparatide, the side effects include a possible cause of osteosarcoma, hypercalcemia, nausea, leg cramps, and dizziness [174].

Selective estrogen receptor modulator

The selective estrogen receptor modulator (SERM), such as raloxifene, lasofoxifene, and bazedoxifene, acts as a tissue-specific agonist and antagonist as it activates estrogen receptors in bone and inhibits estrogen receptors in the uterus and breast [175]. Estrogen facilitates the differentiation of MSCs into osteoblastic lineage [176]. Correspondingly, raloxifene stimulates Runx2 expression to promote the differentiation and proliferation of osteoblasts and suppresses the production of osteoclasts by inhibiting the expression of IL-6 [177]. Estrogen inhibits the expression of Sost by osteocytes and bolsters WNT signaling, leading to increased osteoblast formation [178],[179]. Raloxifene also attenuates the expression of Sost and Dkk1 in mice [180]. In the other way, estrogen could suppress the differentiation of osteoclast precursor cells by decreasing Rankl expression and increasing Opg expression in osteoblasts and osteocytes [181],[182]. Similarly, raloxifene increased the expression of Opg and decreased the expression of Rankl and IL-6 in human osteoblastic MG-63 cells [183]. However, different from the effect of estrogen on the regulation of apoptosis [38],[69],[184], clinical and cell culture studies indicate that raloxifene neither enhances the osteoclast apoptosis [185] nor suppress osteocyte apoptosis [186], except that raloxifene could protect osteoblast from apoptosis induced by sodium nitroprusside [187].

Clinical trials with postmenopausal osteoporotic women indicate that raloxifene [188], lasofoxifene [189], and bazedoxifene [190] are effective for reducing the incidence of vertebral fractures, but not nonvertebral fractures. Among SERMs for the osteoporosis treatment in postmenopausal women, raloxifene is the only SERM approved by the United States Food and Drug Administration (US FDA); the Taiwan FDA approves raloxifene and bazedoxifene. Although the US FDA does not approve the use of raloxifene for GIOP patients, the 2017 American College Rheumatology Guideline for the Prevention and Treatment of GIOP suggests that raloxifene could be used to treat postmenopausal women who have GIOP but fail to respond to regular GIOP treatment or have specific therapeutic contraindications [139]. It is to be noted that women receiving raloxifene might have an increased risk of venous thromboembolism [191].

  Treatment of glucocorticoid-induced osteoporosis in pregnant women and children Top

Because of the lack of comprehensive medication safety assessments for osteoporotic drugs used in pregnant women, there is no treatment recommendation for pregnant GIOP patients. According to the 2017 American College Rheumatology guidelines, oral bisphosphonates are recommended only when female GIOP patients are not planning to become pregnant and have moderate to high risk of fracture; otherwise, only calcium tablets and vitamin D should be used. However, when the female GIOP patients experience side effects from oral bisphosphonates, teriparatide is recommended. Because of safety concerns, denosumab and intravenous injection of high-potency bisphosphonates are only applicable to the female GIOP patients having a high risk of fracture and avoiding pregnancy when other anti-osteoporotic drugs are not applicable [139].

Glucocorticoids are extensively used in children with various indications because of their significant anti-inflammatory and immunomodulatory activity. A study conducted in the United Kingdom found that 1.2% of children received at least one kind of oral glucocorticoid within a year to treat asthma attacks. Asthma is a chronic, obstructive, and inflammatory lung disease requiring long-term treatment with glucocorticoids adjusted according to each child's response to treatment [192]. Other chronic inflammatory diseases in children requiring long-term treatment with glucocorticoid for >3 months include juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, Crohn's disease, and nephrotic syndrome. The glucocorticoids used to control these inflammatory diseases have an additive effect on reducing bone formation and severely compromising children's bone health [193].

An epidemiologic study conducted on the British population (including those aged 4–17 years) showed that oral glucocorticoids used for >4 cycles per year significantly increased fracture risk, with humerus fracture being the most common [194]. Therefore, the treatment of osteoporosis in children (between 4 and 17 years of age) who use glucocorticoids chronically requires a multifaceted approach: (1) Nutritional intake should be actively tracked to prevent obesity and ensure adequate intake of calcium (1000 mg/day), Vitamin D (at least 600 IU/day and exposure to sunlight for approximately 20 min/day), and protein. Furthermore, track the serum concentration of 1, 25-dihydroxyvitamin D every 3–6 months to determine whether the intake dose needs to be adjusted. (2) Regularly perform supervised physical exercises. In addition to controlling ideal body weight, it is also beneficial to maintaining bone and muscle strength. (3) For spontaneous fractures, especially vertebrae fractures (confirmed by pain or height loss), regular radiological examinations are required to rule out the possibility of occult fractures. For patients who have suffered GIOP fractures and continue to use glucocorticoids for >3 months (0.1 mg/kg/day), medical intervention is required [139].

  Conclusion Top

GIOP is the most common type of secondary osteoporosis. It often occurs in patients who used glucocorticoids for a long time, such as those with autoimmune diseases, allergic diseases (e.g., asthma and atopic dermatitis), or organ transplantation. It is an iatrogenic disease in which osteogenesis and osteoclastogenesis are out of balance. Excess glucocorticoids cause rapid bone loss by downregulating bone formation and upregulating bone resorption during the 1st year of glucocorticoid treatment. In addition to direct effects on bone cells, such as osteoblasts, osteoclasts, and osteocytes, glucocorticoids also indirectly cause calcium loss, hypocalcemia, and secondary hyperparathyroidism. Therefore, the dosage and duration of treatment with glucocorticoids should be minimized. Moreover, nonpharmacological treatments, such as appropriate nutrition and exercise, should be combined with pharmacological treatments. For GIOP patients at high risk of fracture, medical intervention is recommended. In the future, more definitive safety studies have to be conducted for the medication of pregnant women and children with GIOP. Due to the limited choices and side effects of the drugs used for GIOP, it is eager to invent more effective and safer therapeutic drugs to meet the best interest of GIOP patients and society.

Financial support and sponsorship

This study was supported by grants from Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TCRD109-53) to C.H.P. and Tzu Chi University (610400239-11) to M.D.L.

Conflicts of interest

Dr. Ing-Ho Chen, an editorial board member at Tzu Chi Medical Journal, had no roles in the peer review process of or decision to publish this article. The other authors declared that they have no conflicts of interest.

  References Top

Wade SW, Strader C, Fitzpatrick LA, Anthony MS, O'Malley CD. Estimating prevalence of osteoporosis: Examples from industrialized countries. Arch Osteoporos 2014;9:182.  Back to cited text no. 1
Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: Medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8:136.  Back to cited text no. 2
Odén A, McCloskey EV, Johansson H, Kanis JA. Assessing the impact of osteoporosis on the burden of hip fractures. Calcif Tissue Int 2013;92:42-9.  Back to cited text no. 3
Watts NB, GLOW investigators. Insights from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Nat Rev Endocrinol 2014;10:412-22.  Back to cited text no. 4
Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726-33.  Back to cited text no. 5
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22:465-75.  Back to cited text no. 6
Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA 2009;302:1573-9.  Back to cited text no. 7
Svedbom A, Hernlund E, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: A compendium of country-specific reports. Arch Osteoporos 2013;8:137.  Back to cited text no. 8
Melton LJ 3rd. How many women have osteoporosis now? J Bone Miner Res 1995;10:175-7.  Back to cited text no. 9
Vestergaard P, Rejnmark L, Mosekilde L. Osteoporosis is markedly underdiagnosed: A nationwide study from Denmark. Osteoporos Int 2005;16:134-41.  Back to cited text no. 10
Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest 2006;116:1186-94.  Back to cited text no. 11
Veldurthy V, Wei R, Oz L, Dhawan P, Jeon YH, Christakos S. Vitamin D, calcium homeostasis and aging. Bone Res 2016;4:16041.  Back to cited text no. 12
Walker-Bone K. Recognizing and treating secondary osteoporosis. Nat Rev Rheumatol 2012;8:480-92.  Back to cited text no. 13
Compston J. Glucocorticoid-induced osteoporosis: An update. Endocrine 2018;61:7-16.  Back to cited text no. 14
Overman RA, Toliver JC, Yeh JY, Gourlay ML, Deal CL. United States adults meeting 2010 American College of Rheumatology criteria for treatment and prevention of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2014;66:1644-52.  Back to cited text no. 15
Chotiyarnwong P, McCloskey EV. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol 2020;16:437-47.  Back to cited text no. 16
Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys 2008;473:201-9.  Back to cited text no. 17
Zaidi M. Skeletal remodeling in health and disease. Nat Med 2007;13:791-801.  Back to cited text no. 18
Oreffo RO, Mundy GR, Seyedin SM, Bonewald LF. Activation of the bone-derived latent TGF beta complex by isolated osteoclasts. Biochem Biophys Res Commun 1989;158:817-23.  Back to cited text no. 19
Huntley R, Jensen E, Gopalakrishnan R, Mansky KC. Bone morphogenetic proteins: Their role in regulating osteoclast differentiation. Bone Rep 2019;10:100207.  Back to cited text no. 20
Ramli FF, Chin KY. A review of the potential application of osteocyte-related biomarkers, fibroblast growth factor-23, sclerostin, and dickkopf-1 in predicting osteoporosis and fractures. Diagnostics (Basel) 2020;10:145.  Back to cited text no. 21
Mak W, Shao X, Dunstan CR, Seibel MJ, Zhou H. Biphasic glucocorticoid-dependent regulation of Wnt expression and its inhibitors in mature osteoblastic cells. Calcif Tissue Int 2009;85:538-45.  Back to cited text no. 22
Kalak R, Zhou H, Street J, Day RE, Modzelewski JR, Spies CM, et al. Endogenous glucocorticoid signalling in osteoblasts is necessary to maintain normal bone structure in mice. Bone 2009;45:61-7.  Back to cited text no. 23
Weinstein RS. Glucocorticoids, osteocytes, and skeletal fragility: The role of bone vascularity. Bone 2010;46:564-70.  Back to cited text no. 24
Yang M, Trettel LB, Adams DJ, Harrison JR, Canalis E, Kream BE. Col3.6-HSD2 transgenic mice: A glucocorticoid loss-of-function model spanning early and late osteoblast differentiation. Bone 2010;47:573-82.  Back to cited text no. 25
Sher LB, Woitge HW, Adams DJ, Gronowicz GA, Krozowski Z, Harrison JR, et al. Transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2 in osteoblasts reveals an anabolic role for endogenous glucocorticoids in bone. Endocrinology 2004;145:922-9.  Back to cited text no. 26
Rauch A, Seitz S, Baschant U, Schilling AF, Illing A, Stride B, et al. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 2010;11:517-31.  Back to cited text no. 27
Kaltsas G, Makras P. Skeletal diseases in Cushing's syndrome: Osteoporosis versus arthropathy. Neuroendocrinology 2010;92(Suppl 1):60-4.  Back to cited text no. 28
Lonser RR, Nieman L, Oldfield EH. Cushing's disease: Pathobiology, diagnosis, and management. J Neurosurg 2017;126:404-17.  Back to cited text no. 29
Belaya ZE, Grebennikova TA, Melnichenko GA, Nikitin AG, Solodovnikov AG, Brovkina OI, et al. Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans. Osteoporos Int 2018;29:211-21.  Back to cited text no. 30
Björnsdottir S, Sääf M, Bensing S, Kämpe O, Michaëlsson K, Ludvigsson JF. Risk of hip fracture in Addison's disease: A population-based cohort study. J Intern Med 2011;270:187-95.  Back to cited text no. 31
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7.  Back to cited text no. 32
Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F. Sequential roles of hedgehog and Wnt signaling in osteoblast development. Development 2005;132:49-60.  Back to cited text no. 33
Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 2005;8:727-38.  Back to cited text no. 34
Kennell JA, MacDougald OA. Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms. J Biol Chem 2005;280:24004-10.  Back to cited text no. 35
Lecka-Czernik B, Gubrij I, Moerman EJ, Kajkenova O, Lipschitz DA, Manolagas SC, et al. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J Cell Biochem 1999;74:357-71.  Back to cited text no. 36
Wu Z, Bucher NL, Farmer SR. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol 1996;16:4128-36.  Back to cited text no. 37
Yang YJ, Zhu Z, Wang DT, Zhang XL, Liu YY, Lai WX, et al. Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARγ2 signaling in GIO rats. Acta Pharmacol Sin 2018;39:633-41.  Back to cited text no. 38
Zhang M, Yan Y, Lim YB, Tang D, Xie R, Chen A, et al. BMP-2 modulates beta-catenin signaling through stimulation of Lrp5 expression and inhibition of beta-TrCP expression in osteoblasts. J Cell Biochem 2009;108:896-905.  Back to cited text no. 39
Rawadi G, Vayssière B, Dunn F, Baron R, Roman-Roman S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 2003;18:1842-53.  Back to cited text no. 40
Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, et al. Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 2013;52:145-56.  Back to cited text no. 41
Gu K, Zhang L, Jin T, Rutherford RB. Identification of potential modifiers of Runx2/Cbfa1 activity in C2C12 cells in response to bone morphogenetic protein-7. Cells Tissues Organs 2004;176:28-40.  Back to cited text no. 42
Shen B, Wei A, Whittaker S, Williams LA, Tao H, Ma DD, et al. The role of BMP-7 in chondrogenic and osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells in vitro. J Cell Biochem 2010;109:406-16.  Back to cited text no. 43
Hildebrandt S, Baschant U, Thiele S, Tuckermann J, Hofbauer LC, Rauner M. Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo. Sci Rep 2018;8:8711.  Back to cited text no. 44
Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: Novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 2004;318:259-64.  Back to cited text no. 45
Yao W, Cheng Z, Busse C, Pham A, Nakamura MC, Lane NE. Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: A longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 2008;58:1674-86.  Back to cited text no. 46
Zhou M, Wu J, Yu Y, Yang Y, Li J, Cui L, et al. Polygonum multiflorm alleviates glucocorticoid-induced osteoporosis and Wnt signaling pathway. Mol Med Rep 2018;17:970-8.  Back to cited text no. 47
Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003;116:2627-34.  Back to cited text no. 48
Hayashi K, Yamaguchi T, Yano S, Kanazawa I, Yamauchi M, Yamamoto M, et al. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: Potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 2009;379:261-6.  Back to cited text no. 49
Thiele S, Hannemann A, Winzer M, Baschant U, Weidner H, Nauck M, et al. Regulation of sclerostin in glucocorticoid-induced osteoporosis (GIO) in mice and humans. Endocr Connect 2019;8:923-34.  Back to cited text no. 50
Jacobsson M, van Raalte DH, Heijboer AC, den Heijer M, de Jongh RT. Short-term glucocorticoid treatment reduces circulating sclerostin concentrations in healthy young Men: A randomized, placebo-controlled, double-blind study. JBMR Plus 2020;4:e10341.  Back to cited text no. 51
Luppen CA, Chandler RL, Noh T, Mortlock DP, Frenkel B. BMP-2 vs. BMP-4 expression and activity in glucocorticoid-arrested MC3T3-E1 osteoblasts: Smad signaling, not alkaline phosphatase activity, predicts rescue of mineralization. Growth Factors 2008;26:226-37.  Back to cited text no. 52
Pereira RC, Delany AM, Canalis E. Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: Correlation with CCAAT-enhancer binding protein expression. Bone 2002;30:685-91.  Back to cited text no. 53
Koromila T, Baniwal SK, Song YS, Martin A, Xiong J, Frenkel B. Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells. J Cell Biochem 2014;115:27-33.  Back to cited text no. 54
Lee KS, Hong SH, Bae SC. Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Oncogene 2002;21:7156-63.  Back to cited text no. 55
Zhou S, Eid K, Glowacki J. Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res 2004;19:463-70.  Back to cited text no. 56
Li J, Tsuji K, Komori T, Miyazono K, Wrana JL, Ito Y, et al. Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells. J Biol Chem 1998;273:31009-15.  Back to cited text no. 57
Alliston T, Choy L, Ducy P, Karsenty G, Derynck R. TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 2001;20:2254-72.  Back to cited text no. 58
Kang JS, Alliston T, Delston R, Derynck R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J 2005;24:2543-55.  Back to cited text no. 59
Hjelmeland AB, Schilling SH, Guo X, Quarles D, Wang XF. Loss of Smad3-mediated negative regulation of Runx2 activity leads to an alteration in cell fate determination. Mol Cell Biol 2005;25:9460-8.  Back to cited text no. 60
Breen EC, Ignotz RA, McCabe L, Stein JL, Stein GS, Lian JB. TGF beta alters growth and differentiation related gene expression in proliferating osteoblasts in vitro, preventing development of the mature bone phenotype. J Cell Physiol 1994;160:323-35.  Back to cited text no. 61
Borton AJ, Frederick JP, Datto MB, Wang XF, Weinstein RS. The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis. J Bone Miner Res 2001;16:1754-64.  Back to cited text no. 62
Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 2009;15:757-65.  Back to cited text no. 63
Li Y, Jie L, Tian AY, Zhong S, Tian MY, Zhong Y, et al. Transforming Growth Factor Beta is regulated by a Glucocorticoid-Dependent Mechanism in Denervation Mouse Bone. Sci Rep 2017;7:9925.  Back to cited text no. 64
Almeida M, Han L, Bellido T, Manolagas SC, Kousteni S. Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. J Biol Chem 2005;280:41342-51.  Back to cited text no. 65
Karsdal MA, Larsen L, Engsig MT, Lou H, Ferreras M, Lochter A, et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J Biol Chem 2002;277:44061-7.  Back to cited text no. 66
Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC. Osteoblast programmed cell death (apoptosis): Modulation by growth factors and cytokines. J Bone Miner Res 1998;13:793-802.  Back to cited text no. 67
Tomkinson A, Gevers EF, Wit JM, Reeve J, Noble BS. The role of estrogen in the control of rat osteocyte apoptosis. J Bone Miner Res 1998;13:1243-50.  Back to cited text no. 68
Bradford PG, Gerace KV, Roland RL, Chrzan BG. Estrogen regulation of apoptosis in osteoblasts. Physiol Behav 2010;99:181-5.  Back to cited text no. 69
Gavali S, Gupta MK, Daswani B, Wani MR, Sirdeshmukh R, Khatkhatay MI. Estrogen enhances human osteoblast survival and function via promotion of autophagy. Biochim Biophys Acta Mol Cell Res 2019;1866:1498-507.  Back to cited text no. 70
Manolagas SC. Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000;21:115-37.  Back to cited text no. 71
Bonewald LF. The amazing osteocyte. J Bone Miner Res 2011;26:229-38.  Back to cited text no. 72
Tresguerres FG, Torres J, López-Quiles J, Hernández G, Vega JA, Tresguerres IF. The osteocyte: A multifunctional cell within the bone. Ann Anat 2020;227:151422.  Back to cited text no. 73
Noble BS, Stevens H, Loveridge N, Reeve J. Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 1997;20:273-82.  Back to cited text no. 74
Verborgt O, Gibson GJ, Schaffler MB. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 2000;15:60-7.  Back to cited text no. 75
Cheung WY, Simmons CA, You L. Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression. Bone 2012;50:104-10.  Back to cited text no. 76
Kennedy OD, Herman BC, Laudier DM, Majeska RJ, Sun HB, Schaffler MB. Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 2012;50:1115-22.  Back to cited text no. 77
Jia J, Yao W, Guan M, Dai W, Shahnazari M, Kar R, et al. Glucocorticoid dose determines osteocyte cell fate. FASEB J 2011;25:3366-76.  Back to cited text no. 78
Li H, Qian W, Weng X, Wu Z, Li H, Zhuang Q, et al. Glucocorticoid receptor and sequential P53 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3-E1 cells. PLoS One 2012;7:e37030.  Back to cited text no. 79
Zhang S, Liu Y, Liang Q. Low-dose dexamethasone affects osteoblast viability by inducing autophagy via intracellular ROS. Mol Med Rep 2018;17:4307-16.  Back to cited text no. 80
O'Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004;145:1835-41.  Back to cited text no. 81
Swolin-Eide D, Ohlsson C. Effects of cortisol on the expression of interleukin-6 and interleukin-1 beta in human osteoblast-like cells. J Endocrinol 1998;156:107-14.  Back to cited text no. 82
Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science 2000;289:1508-14.  Back to cited text no. 83
Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res 2013;92:860-7.  Back to cited text no. 84
Kim JH, Kim N. Signaling Pathways in Osteoclast Differentiation. Chonnam Med J 2016;52:12-7.  Back to cited text no. 85
Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000;103:41-50.  Back to cited text no. 86
Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 2005;202:1261-9.  Back to cited text no. 87
Lee AW, States DJ. Both src-dependent and -independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors. Mol Cell Biol 2000;20:6779-98.  Back to cited text no. 88
Rubin J, Biskobing DM, Jadhav L, Fan D, Nanes MS, Perkins S, et al. Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinology 1998;139:1006-12.  Back to cited text no. 89
Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA. M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 2003;10:1165-77.  Back to cited text no. 90
Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011;17:1231-4.  Back to cited text no. 91
Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345-57.  Back to cited text no. 92
Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med 2011;17:1235-41.  Back to cited text no. 93
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-19.  Back to cited text no. 94
Fei Q, Guo C, Xu X, Gao J, Zhang J, Chen T, et al. Osteogenic growth peptide enhances the proliferation of bone marrow mesenchymal stem cells from osteoprotegerin-deficient mice by CDK2/cyclin A. Acta Biochim Biophys Sin (Shanghai) 2010;42:801-6.  Back to cited text no. 95
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-42.  Back to cited text no. 96
Wagner EF, Karsenty G. Genetic control of skeletal development. Curr Opin Genet Dev 2001;11:527-32.  Back to cited text no. 97
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260-8.  Back to cited text no. 98
Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 2002;169:3353-62.  Back to cited text no. 99
Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: Potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999;140:4382-9.  Back to cited text no. 100
Sivagurunathan S, Muir MM, Brennan TC, Seale JP, Mason RS. Influence of glucocorticoids on human osteoclast generation and activity. J Bone Miner Res 2005;20:390-8.  Back to cited text no. 101
Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005;8:751-64.  Back to cited text no. 102
Udagawa N, Takahashi N, Katagiri T, Tamura T, Wada S, Findlay DM, et al. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med 1995;182:1461-8.  Back to cited text no. 103
Baserga R. The Biology of Cell Reproduction. Cambridge, Mass: Harvard University Press; 1985.  Back to cited text no. 104
Jia D, O'Brien CA, Stewart SA, Manolagas SC, Weinstein RS. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006;147:5592-9.  Back to cited text no. 105
Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 2002;109:1041-8.  Back to cited text no. 106
Liu W, Xu C, Zhao H, Xia P, Song R, Gu J, et al. Osteoprotegerin Induces Apoptosis of Osteoclasts and Osteoclast Precursor Cells via the Fas/Fas Ligand Pathway. PLoS One 2015;10:e0142519.  Back to cited text no. 107
Wu X, Pan G, McKenna MA, Zayzafoon M, Xiong WC, McDonald JM. RANKL regulates Fas expression and Fas-mediated apoptosis in osteoclasts. J Bone Miner Res 2005;20:107-16.  Back to cited text no. 108
Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, et al. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 2006;116:2152-60.  Back to cited text no. 109
Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int 2015;2015:421746.  Back to cited text no. 110
Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat Med 2013;19:179-92.  Back to cited text no. 111
Hasegawa T, Yamamoto T, Tsuchiya E, Hongo H, Tsuboi K, Kudo A, et al. Ultrastructural and biochemical aspects of matrix vesicle-mediated mineralization. Jpn Dent Sci Rev 2017;53:34-45.  Back to cited text no. 112
Weiner S, Traub W. Organization of hydroxyapatite crystals within collagen fibrils. FEBS Lett 1986;206:262-6.  Back to cited text no. 113
Canalis E. Mechanisms of glucocorticoid action in bone. Curr Osteoporos Rep 2005;3:98-102.  Back to cited text no. 114
Delany AM, Gabbitas BY, Canalis E. Cortisol downregulates osteoblast alpha 1 (I) procollagen mRNA by transcriptional and posttranscriptional mechanisms. J Cell Biochem 1995;57:488-94.  Back to cited text no. 115
Delany AM, Jeffrey JJ, Rydziel S, Canalis E. Cortisol increases interstitial collagenase expression in osteoblasts by post-transcriptional mechanisms. J Biol Chem 1995;270:26607-12.  Back to cited text no. 116
Lin X, Patil S, Gao YG, Qian A. The bone extracellular matrix in bone formation and regeneration. Front Pharmacol 2020;11:757.  Back to cited text no. 117
Hoshi K, Amizuka N, Oda K, Ikehara Y, Ozawa H. Immunolocalization of tissue non-specific alkaline phosphatase in mice. Histochem Cell Biol 1997;107:183-91.  Back to cited text no. 118
Miao D, Scutt A. Histochemical localization of alkaline phosphatase activity in decalcified bone and cartilage. J Histochem Cytochem 2002;50:333-40.  Back to cited text no. 119
Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A 2002;99:9445-9.  Back to cited text no. 120
Zoch ML, Clemens TL, Riddle RC. New insights into the biology of osteocalcin. Bone 2016;82:42-9.  Back to cited text no. 121
Carvalho MS, Cabral JM, da Silva CL, Vashishth D. Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties. J Cell Biochem 2019;120:6555-69.  Back to cited text no. 122
Termine JD, Kleinman HK, Whitson SW, Conn KM, McGarvey ML, Martin GR. Osteonectin, a bone-specific protein linking mineral to collagen. Cell 1981;26:99-105.  Back to cited text no. 123
Delany AM, Amling M, Priemel M, Howe C, Baron R, Canalis E. Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest 2000;105:1325.  Back to cited text no. 124
Andersen TL, del Carmen Ovejero M, Kirkegaard T, Lenhard T, Foged NT, Delaissé JM. A scrutiny of matrix metalloproteinases in osteoclasts: Evidence for heterogeneity and for the presence of MMPs synthesized by other cells. Bone 2004;35:1107-19.  Back to cited text no. 125
Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996;271:12511-6.  Back to cited text no. 126
Vizovišek M, Fonović M, Turk B. Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond. Matrix Biol 2019;75-76:141-59.  Back to cited text no. 127
Iu MF, Kaji H, Naito J, Sowa H, Sugimoto T, Chihara K. Low-dose parathyroid hormone and estrogen reverse alkaline phosphatase activity suppressed by dexamethasone in mouse osteoblastic cells. J Bone Miner Metab 2005;23:450-5.  Back to cited text no. 128
Strömstedt PE, Poellinger L, Gustafsson JA, Carlstedt-Duke J. The glucocorticoid receptor binds to a sequence overlapping the TATA box of the human osteocalcin promoter: A potential mechanism for negative regulation. Mol Cell Biol 1991;11:3379-83.  Back to cited text no. 129
Ikeda T, Kohno H, Yamamuro T, Kasai R, Ohta S, Okumura H, et al. The effect of active vitamin D3 analogs and dexamethasone on the expression of osteocalcin gene in rat tibiae in vivo. Biochem Biophys Res Commun 1992;189:1231-5.  Back to cited text no. 130
Morrison N, Eisman J. Role of the negative glucocorticoid regulatory element in glucocorticoid repression of the human osteocalcin promoter. J Bone Miner Res 1993;8:969-75.  Back to cited text no. 131
He H, Wang C, Tang Q, Yang F, Xu Y. Possible mechanisms of prednisolone-induced osteoporosis in zebrafish larva. Biomed Pharmacother 2018;101:981-7.  Back to cited text no. 132
Stoch SA, Wagner JA. Cathepsin K inhibitors: A novel target for osteoporosis therapy. Clin Pharmacol Ther 2008;83:172-6.  Back to cited text no. 133
Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgström F, et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 2012;23:2257-76.  Back to cited text no. 134
Kanis JA, Johansson H, Oden A, McCloskey EV. Guidance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos Int 2011;22:809-16.  Back to cited text no. 135
Hwang JS. 2019 Taiwanese Consensus and Guidelines for the Prevention and Treatment of Adult Osteoporosis. Taipei, Taiwan: The Taiwanese Osteoporosis Association; 2019. p. 37-41.  Back to cited text no. 136
Yu SF, Chen JF, Chen YC, Lai HM, Ko CH, Chiu WC, et al. Beyond bone mineral density, FRAX-based tailor-made intervention thresholds for therapeutic decision in subjects on glucocorticoid: A nationwide osteoporosis survey. Medicine (Baltimore) 2017;96:e5959.  Back to cited text no. 137
Hsu CY, Wu CH, Yu SF, Su YJ, Chiu WC, Chen YC, et al. Novel algorithm generating strategy to identify high fracture risk population using a hybrid intervention threshold. J Bone Miner Metab 2020;38:213-21.  Back to cited text no. 138
Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, et al. 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2017;69:1095-110.  Back to cited text no. 139
Rizzoli R, Biver E. Glucocorticoid-induced osteoporosis: Who to treat with what agent? Nat Rev Rheumatol 2015;11:98-109.  Back to cited text no. 140
Huybers S, Naber TH, Bindels RJ, Hoenderop JG. Prednisolone-induced Ca2+malabsorption is caused by diminished expression of the epithelial Ca2+channel TRPV6. Am J Physiol Gastrointest Liver Physiol 2007;292:G92-7.  Back to cited text no. 141
Reid IR, Ibbertson HK. Evidence for decreased tubular reabsorption of calcium in glucocorticoid-treated asthmatics. Horm Res 1987;27:200-4.  Back to cited text no. 142
Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003;9:2643-58.  Back to cited text no. 143
Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A 2006;103:7829-34.  Back to cited text no. 144
Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10:1478-87.  Back to cited text no. 145
Ito M, Amizuka N, Nakajima T, Ozawa H. Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone 1999;25:447-52.  Back to cited text no. 146
Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 1999;104:1363-74.  Back to cited text no. 147
Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010;363:2027-35.  Back to cited text no. 148
Mottaghi P. Intravenous bisphosphonates for postmenopausal osteoporosis. J Res Med Sci 2010;15:175-84.  Back to cited text no. 149
Marini JC. Do bisphosphonates make children's bones better or brittle? N Engl J Med 2003;349:423-6.  Back to cited text no. 150
Lewiecki EM, Bilezikian JP. Denosumab for the treatment of osteoporosis and cancer-related conditions. Clin Pharmacol Ther 2012;91:123-33.  Back to cited text no. 151
Saag KG, Pannacciulli N, Geusens P, Adachi JD, Messina OD, Morales-Torres J, et al. Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial. Arthritis Rheumatol 2019;71:1174-84.  Back to cited text no. 152
Curtis JR, Xie F, Yun H, Saag KG, Chen L, Delzell E. Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab. Arthritis Rheumatol 2015;67:1456-64.  Back to cited text no. 153
Khan AA, Morrison A, Kendler DL, Rizzoli R, Hanley DA, Felsenberg D, et al. Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ. J Clin Densitom 2017;20:8-24.  Back to cited text no. 154
Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral Fractures After Discontinuation of Denosumab: A Post hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res 2018;33:190-8.  Back to cited text no. 155
Boyce RW, Varela A, Chouinard L, Bussiere JL, Chellman GJ, Ominsky MS, et al. Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period. Bone 2014;64:314-25.  Back to cited text no. 156
Brunova J, Kratochvilova S, Stepankova J. Osteoporosis Therapy With Denosumab in Organ Transplant Recipients. Front Endocrinol (Lausanne) 2018;9:162.  Back to cited text no. 157
Kobel C, Frey D, Graf N, Wuthrich RP, Bonani M. Follow-p of bone mineral density changes in de novo kidney transplant recipients treated with two doses of the receprtor activator of nuclear factor kappaB ligand inhibitor denosumab. Kidney Blood Press Res 2019;44:1285-93.  Back to cited text no. 158
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 1998;102:1627-33.  Back to cited text no. 159
Saag KG, Shane E, Boonen S, Marín F, Donley DW, Taylor KA, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028-39.  Back to cited text no. 160
Hirooka Y, Nozaki Y, Inoue A, Li J, Shiga T, Kishimoto K, et al. Effects of denosumab versus teriparatide in glucocorticoid-induced osteoporosis patients with prior bisphosphonate treatment. Bone Rep 2020;13:100293.  Back to cited text no. 161
Nishida S, Yamaguchi A, Tanizawa T, Endo N, Mashiba T, Uchiyama Y, et al. Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow. Bone 1994;15:717-23.  Back to cited text no. 162
Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone 2005;37:148-58.  Back to cited text no. 163
Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: A novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 2005;146:4577-83.  Back to cited text no. 164
Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, et al. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 2010;11:161-71.  Back to cited text no. 165
Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999;104:439-46.  Back to cited text no. 166
Weinstein RS, Jilka RL, Almeida M, Roberson PK, Manolagas SC. Intermittent parathyroid hormone administration counteracts the adverse effects of glucocorticoids on osteoblast and osteocyte viability, bone formation, and strength in mice. Endocrinology 2010;151:2641-9.  Back to cited text no. 167
Wan M, Yang C, Li J, Wu X, Yuan H, Ma H, et al. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev 2008;22:2968-79.  Back to cited text no. 168
Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60-5.  Back to cited text no. 169
Wang Y, Nishida S, Boudignon BM, Burghardt A, Elalieh HZ, Hamilton MM, et al. IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J Bone Miner Res 2007;22:1329-37.  Back to cited text no. 170
Locklin RM, Khosla S, Turner RT, Riggs BL. Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone. J Cell Biochem 2003;89:180-90.  Back to cited text no. 171
Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 2004;19:235-44.  Back to cited text no. 172
Glüer CC, Marin F, Ringe JD, Hawkins F, Möricke R, Papaioannu N, et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J Bone Miner Res 2013;28:1355-68.  Back to cited text no. 173
Karatoprak C, Kayatas K, Kilicaslan H, Yolbas S, Yazimci NA, Gümüskemer T, et al. Severe hypercalcemia due to teriparatide. Indian J Pharmacol 2012;44:270-1.  Back to cited text no. 174
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Quintanilla Rodriguez BS, Correa R. Raloxifene. Treasure Island, FL: StatPearls; 2020.  Back to cited text no. 175
Zhao JW, Gao ZL, Mei H, Li YL, Wang Y. Differentiation of human mesenchymal stem cells: The potential mechanism for estrogen-induced preferential osteoblast versus adipocyte differentiation. Am J Med Sci 2011;341:460-8.  Back to cited text no. 176
Taranta A, Brama M, Teti A, De luca V, Scandurra R, Spera G, et al. The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 2002;30:368-76.  Back to cited text no. 177
Fujita K, Roforth MM, Demaray S, McGregor U, Kirmani S, McCready LK, et al. Effects of estrogen on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in postmenopausal women. J Clin Endocrinol Metab 2014;99:E81-8.  Back to cited text no. 178
Mödder UI, Clowes JA, Hoey K, Peterson JM, McCready L, Oursler MJ, et al. Regulation of circulating sclerostin levels by sex steroids in women and in men. J Bone Miner Res 2011;26:27-34.  Back to cited text no. 179
Kalam A, Talegaonkar S, Vohora D. Effects of raloxifene against letrozole-induced bone loss in chemically-induced model of menopause in mice. Mol Cell Endocrinol 2017;440:34-43.  Back to cited text no. 180
Taxel P, Kaneko H, Lee SK, Aguila HL, Raisz LG, Lorenzo JA. Estradiol rapidly inhibits osteoclastogenesis and RANKL expression in bone marrow cultures in postmenopausal women: A pilot study. Osteoporos Int 2008;19:193-9.  Back to cited text no. 181
Saika M, Inoue D, Kido S, Matsumoto T. 17beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 2001;142:2205-12.  Back to cited text no. 182
Sun J, Sun WJ, Li ZY, Li L, Wang Y, Zhao Y, et al. Daidzein increases OPG/RANKL ratio and suppresses IL-6 in MG-63 osteoblast cells. Int Immunopharmacol 2016;40:32-40.  Back to cited text no. 183
Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 1996;2:1132-6.  Back to cited text no. 184
Michael H, Härkönen PL, Kangas L, Väänänen HK, Hentunen TA. Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro. Br J Pharmacol 2007;151:384-95.  Back to cited text no. 185
van Essen HW, Holzmann PJ, Blankenstein MA, Lips P, Bravenboer N. Effect of raloxifene treatment on osteocyte apoptosis in postmenopausal women. Calcif Tissue Int 2007;81:183-90.  Back to cited text no. 186
Polunin VS. The problems of developing a healthy life style and the treatment and rehabilitation of the population of the USSR from the viewpoints of the Ayurvedic approaches of the Maharishi. Vopr Kurortol Fizioter Lech Fiz Kult 1992;1:57-8.  Back to cited text no. 187
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-45.  Back to cited text no. 188
Goldstein SR, Neven P, Cummings S, Colgan T, Runowicz CD, Krpan D, et al. Postmenopausal evaluation and risk reduction with lasofoxifene (PEARL) trial: 5-year gynecological outcomes. Menopause 2011;18:17-22.  Back to cited text no. 189
Kaufman JM, Palacios S, Silverman S, Sutradhar S, Chines A. An evaluation of the Fracture Risk Assessment Tool (FRAX®) as an indicator of treatment efficacy: The effects of bazedoxifene and raloxifene on vertebral, nonvertebral, and all clinical fractures as a function of baseline fracture risk assessed by FRAX®. Osteoporos Int 2013;24:2561-9.  Back to cited text no. 190
Kanis JA, Johnell O, Black DM, Downs RW Jr., Sarkar S, Fuerst T, et al. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: A reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone 2003;33:293-300.  Back to cited text no. 191
Horak F, Doberer D, Eber E, Horak E, Pohl W, Riedler J, et al. Diagnosis and management of asthma-Statement on the 2015 GINA Guidelines. Wien Klin Wochenschr 2016;128:541-54.  Back to cited text no. 192
von Scheven E, Corbin KJ, Stagi S, Cimaz R. Glucocorticoid-associated osteoporosis in chronic inflammatory diseases: Epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep 2014;12:289-99.  Back to cited text no. 193
van Staa TP, Cooper C, Leufkens HG, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003;18:913-8.  Back to cited text no. 194


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