Glucocorticoid-Induced Osteoporosis: Current Treatments and the Promise of Herbal Medicine

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, deterioration of bone microarchitecture, and increased bone fragility, leading to an elevated risk of fractures. It represents a major public health concern worldwide, particularly among the elderly population, due to its association with chronic pain, physical disability, reduced quality of life, and increased mortality. While primary osteoporosis is commonly linked to aging and postmenopausal hormonal changes, secondary osteoporosis arises from underlying diseases or prolonged exposure to specific medications, among which glucocorticoids are the most significant contributors.¹

Glucocorticoids are widely prescribed for their potent anti-inflammatory and immunosuppressive properties and are essential in the treatment of various chronic conditions, including autoimmune diseases, asthma, rheumatoid arthritis, inflammatory bowel disease, organ transplantation, and certain malignancies. Despite their therapeutic benefits, long-term or high-dose glucocorticoid therapy is associated with a spectrum of adverse effects, with bone loss being one of the most prevalent and clinically significant complications. Even low doses of glucocorticoids, when administered over extended periods, can adversely affect bone metabolism and skeletal integrity.^1-2

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of drug-induced osteoporosis and is characterized by rapid and progressive bone loss, particularly in trabecular-rich skeletal sites such as the spine and hip. Epidemiological studies suggest that up to 30–50% of patients receiving long-term glucocorticoid therapy may experience osteoporotic fractures. Notably, fracture risk increases early during treatment, often within the first three to six months, and may occur even in individuals with normal or moderately reduced bone mineral density, underscoring the unique pathophysiological mechanisms underlying GIOP.²

The clinical consequences of GIOP are substantial, as osteoporotic fractures are associated with significant morbidity, functional impairment, increased healthcare burden, and mortality, particularly in elderly and immunocompromised patients. Vertebral fractures often remain asymptomatic but can lead to chronic pain, spinal deformities, and reduced pulmonary function, whereas hip fractures are associated with prolonged hospitalization, loss of independence, and increased mortality rates. These outcomes highlight the need for early prevention and effective management strategies in patients receiving glucocorticoid therapy.

Although several pharmacological agents are currently available for the prevention and treatment of GIOP, including calcium and vitamin D supplementation, bisphosphonates, and anabolic therapies, their long-term use is frequently limited by adverse effects, contraindications, suboptimal patient adherence, and economic constraints. Consequently, there is a growing interest in identifying safer, cost-effective, and sustainable therapeutic alternatives. In this context, herbal medicine and plant-derived bioactive compounds have gained considerable attention due to their multi-targeted mechanisms, favorable safety profiles, and historical use in bone-related disorders. Exploring the potential role of herbal interventions may offer novel strategies for improving long-term outcomes in the management of glucocorticoid-induced osteoporosis.³

2. Glucocorticoids: Mechanism of Action and Clinical Use

Glucocorticoids are steroid hormones synthesized in the adrenal cortex and play a critical role in regulating metabolism, immune responses, and stress adaptation. Synthetic glucocorticoids, such as prednisolone, dexamethasone, methylprednisolone, and hydrocortisone, are extensively used in clinical practice due to their potent anti-inflammatory and immunosuppressive properties. Despite their therapeutic significance, prolonged use of glucocorticoids is a major risk factor for the development of glucocorticoid-induced osteoporosis.

2.1 Therapeutic Indications of Glucocorticoids

Glucocorticoids are widely prescribed across multiple medical specialties for the management of acute and chronic inflammatory conditions. Their common therapeutic indications include autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis; respiratory diseases including asthma and chronic obstructive pulmonary disease; gastrointestinal conditions such as inflammatory bowel disease; dermatological disorders; and allergic reactions. Additionally, glucocorticoids are frequently used in oncology as part of chemotherapy regimens, in organ transplantation to prevent graft rejection, and in endocrinology for adrenal insufficiency replacement therapy.³

Due to their rapid onset of action and strong efficacy, glucocorticoids are often used long-term in chronic illnesses. However, continuous exposure, especially at moderate to high doses, significantly increases the risk of systemic adverse effects. Among these, skeletal complications, including osteoporosis and fractures, represent one of the most serious and prevalent long-term consequences.

2.2 Molecular Mechanisms of Glucocorticoids

The biological effects of glucocorticoids are primarily mediated through the glucocorticoid receptor (GR), a ligand-activated transcription factor that belongs to the nuclear receptor superfamily. Upon cellular entry, glucocorticoids bind to cytoplasmic GRs, leading to receptor activation, dissociation from heat shock proteins, and translocation into the nucleus. Within the nucleus, the glucocorticoid–GR complex regulates gene expression by binding to glucocorticoid response elements (GREs) in target genes or by interacting with other transcription factors.⁴

Glucocorticoids exert anti-inflammatory effects by suppressing the transcription of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6, while upregulating anti-inflammatory mediators. They also inhibit key signaling pathways, including nuclear factor-κB and activator protein-1, thereby reducing immune cell activation and inflammatory responses. In addition to genomic actions, glucocorticoids produce rapid non-genomic effects through membrane-associated receptors and intracellular signaling cascades.

While these mechanisms account for their therapeutic efficacy, the same molecular pathways also disrupt normal bone remodeling. Glucocorticoids alter gene expression in osteoblasts, osteocytes, and osteoclasts, resulting in an imbalance between bone formation and bone resorption.

2.3 Adverse Skeletal Effects of Long-Term Glucocorticoid Therapy

Long-term glucocorticoid therapy exerts profound detrimental effects on skeletal health by impairing bone remodeling and reducing bone strength. One of the earliest and most prominent effects is the suppression of osteoblast differentiation and activity, leading to decreased bone formation. Glucocorticoids promote apoptosis of osteoblasts and osteocytes, thereby compromising bone matrix production and maintenance of bone microarchitecture.^3-4

Simultaneously, glucocorticoids prolong the lifespan and activity of osteoclasts, resulting in increased bone resorption, particularly during the initial phase of therapy. Additionally, glucocorticoids interfere with calcium homeostasis by reducing intestinal calcium absorption and increasing renal calcium excretion, leading to secondary hyperparathyroidism and further bone loss. They also suppress gonadal hormone production and inhibit the synthesis of insulin-like growth factor-1, both of which are critical for bone formation.

These cumulative effects lead to rapid loss of trabecular bone, reduced bone mineral density, and diminished bone quality, predisposing patients to fractures even at relatively preserved bone density levels. Vertebral and hip fractures are particularly common and may occur early during treatment, emphasizing the need for timely preventive and therapeutic interventions in patients receiving long-term glucocorticoid therapy.⁵

3. Pathophysiology of Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) is a complex, multifactorial disorder resulting from direct and indirect effects of glucocorticoids on bone cells, mineral metabolism, and endocrine regulation. Unlike postmenopausal osteoporosis, GIOP is characterized by a rapid decline in bone strength that may occur even in the presence of modest reductions in bone mineral density. The underlying pathophysiology primarily involves suppression of bone formation, increased bone resorption in the early phase of treatment, and long-term impairment of bone quality.

3.1 Effects on Osteoblasts and Osteocytes

The most profound and sustained effect of glucocorticoids in GIOP is the inhibition of osteoblast function and survival. Glucocorticoids suppress the differentiation of mesenchymal stem cells into osteoblasts while favoring adipogenic lineage commitment. This shift results in reduced osteoblast number and diminished bone matrix synthesis. Additionally, glucocorticoids downregulate the expression of key osteogenic transcription factors such as runt-related transcription factor 2 (Runx2) and osterix, further impairing bone formation.

Glucocorticoids also induce apoptosis of mature osteoblasts and osteocytes. Osteocytes play a pivotal role in mechanotransduction and maintenance of bone microarchitecture; their loss disrupts the bone’s adaptive response to mechanical stress. Increased osteocyte apoptosis compromises the lacunar–canalicular network, leading to reduced bone strength and impaired microstructural integrity, even before significant changes in bone mineral density become evident.^4-5

3.2 Effects on Osteoclasts

In contrast to their inhibitory effects on osteoblasts, glucocorticoids initially enhance osteoclast-mediated bone resorption. This is primarily mediated through increased expression of receptor activator of nuclear factor-κB ligand (RANKL) and reduced production of its decoy receptor osteoprotegerin (OPG) by osteoblasts and stromal cells. The resulting increase in the RANKL/OPG ratio promotes osteoclast differentiation, activation, and survival.

Furthermore, glucocorticoids prolong the lifespan of osteoclasts by inhibiting apoptosis, contributing to accelerated bone resorption, particularly during the early phase of therapy. Although osteoclast activity may decline with prolonged glucocorticoid exposure, the persistent suppression of bone formation leads to a net negative balance in bone remodeling, driving progressive bone loss.⁶

3.3 Alteration in Calcium and Vitamin D Metabolism

Glucocorticoids adversely affect calcium homeostasis by reducing intestinal calcium absorption through antagonism of vitamin D action and downregulation of calcium transport proteins. Simultaneously, they increase renal calcium excretion, resulting in a negative calcium balance. This decrease in circulating calcium levels stimulates parathyroid hormone secretion, leading to secondary hyperparathyroidism.

Elevated parathyroid hormone levels enhance bone resorption to maintain serum calcium levels, further exacerbating bone loss. Additionally, glucocorticoids impair the hepatic and renal activation of vitamin D, reducing its biological availability and effectiveness. These disruptions collectively contribute to decreased bone mineralization and increased fracture susceptibility.

3.4 Role of Inflammatory Cytokines and Oxidative Stress

Although glucocorticoids are potent anti-inflammatory agents, chronic exposure paradoxically contributes to bone loss through complex interactions involving inflammatory cytokines and oxidative stress. Long-term glucocorticoid therapy alters the local bone microenvironment by affecting cytokine signaling pathways related to bone turnover.

Glucocorticoids increase the generation of reactive oxygen species while simultaneously suppressing antioxidant defense mechanisms. Oxidative stress promotes osteoblast and osteocyte apoptosis and enhances osteoclast differentiation. Moreover, oxidative stress interferes with Wnt/β-catenin signaling, a crucial pathway for osteoblast differentiation and bone formation, thereby further impairing skeletal homeostasis.⁷

3.5 Hormonal Dysregulation and Bone Remodeling Imbalance

Glucocorticoids disrupt multiple hormonal axes that are essential for maintaining bone health. They suppress the hypothalamic–pituitary–gonadal axis, leading to reduced estrogen and testosterone levels, both of which play critical roles in inhibiting bone resorption and supporting bone formation. Additionally, glucocorticoids reduce circulating levels of growth hormone and insulin-like growth factor-1, which are key anabolic regulators of bone metabolism.

The combined effects of osteoblast suppression, transient osteoclast activation, calcium imbalance, oxidative damage, and hormonal dysregulation result in a profound imbalance between bone formation and resorption. This imbalance leads to decreased bone mass, impaired microarchitecture, and reduced bone strength, ultimately increasing the risk of fractures in patients receiving long-term glucocorticoid therapy.⁵

Table 1. Pathophysiological Mechanisms Involved in Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) develops due to a combination of drug-related, patient-related, and clinical factors. Early identification of high-risk individuals is essential, as bone loss occurs rapidly—often within the first 3–6 months of therapy. Accurate diagnosis relies on clinical evaluation, bone mineral density measurements, fracture risk assessment tools, and biochemical markers of bone turnover.

4.1 Dose and Duration of Glucocorticoid Therapy⁶

The risk of GIOP is strongly correlated with both the dose and duration of glucocorticoid use.

• Dose-dependent risk: Even low doses (≥2.5 mg/day prednisolone equivalent) administered over several months can cause measurable bone loss. Higher doses (>7.5 mg/day) significantly increase the risk of vertebral and hip fractures.
• Duration-dependent risk: Rapid bone loss occurs in the first 3–6 months, driven by increased osteoclast activity and suppressed osteoblast function. Continued therapy leads to progressive bone deterioration.
• Cumulative exposure: Fracture risk increases with cumulative lifetime glucocorticoid dose, even after therapy ceases.
• Routes of administration: Systemic therapy (oral, IV) carries the highest risk, but inhaled, intra-articular, and topical glucocorticoids also contribute to bone loss with prolonged or high-dose use.

4.2 Patient-Related Risk Factors

Several intrinsic and extrinsic factors modulate an individual's susceptibility to GIOP:

• Age: Older adults have lower baseline bone mass and reduced regenerative capacity.
• Gender: Postmenopausal women are at particularly high risk due to estrogen deficiency.
• Nutritional factors: Low calcium and vitamin D intake, malnutrition, and gastrointestinal disorders impair bone health.
• Lifestyle factors: Smoking, excessive alcohol intake, physical inactivity, and low body mass index reduce bone strength.
• Comorbidities: Chronic inflammatory diseases (rheumatoid arthritis, COPD, IBD), endocrine disorders (hyperthyroidism, hypogonadism), diabetes mellitus, and chronic kidney disease increase susceptibility.
• Genetic predisposition: Family history of osteoporosis or fractures enhances risk.
• Previous fractures: A personal history of fragility fractures strongly predicts future fracture risk, independent of bone mineral density.

Table 2. Risk Factors Associated with Glucocorticoid-Induced Osteoporosis

Accurate diagnosis of GIOP involves integrating clinical history, bone mineral density measurements, fracture risk assessments, and biochemical markers.

Bone Mineral Density (DEXA)

Dual-energy X-ray absorptiometry (DEXA) is the gold standard for assessing bone mineral density (BMD).

• Sites measured: lumbar spine, total hip, femoral neck, and sometimes distal forearm.
• Interpretation:

• T-score ≤ −2.5 indicates osteoporosis.
• T-score between −1.0 and −2.5 indicates osteopenia.

• Limitations: In early GIOP, BMD may remain relatively normal despite increased fracture risk due to rapid microarchitectural deterioration. Therefore, BMD must be interpreted alongside clinical risk factors.

DEXA is recommended at the initiation of glucocorticoid therapy and repeated every 6–12 months depending on dose and clinical status.

FRAX Score

The FRAX (Fracture Risk Assessment) tool estimates the 10-year probability of major osteoporotic and hip fractures.

• Incorporates risk factors such as age, sex, BMI, smoking, alcohol use, prior fractures, rheumatoid arthritis, and glucocorticoid exposure.
• Allows adjustment for glucocorticoid dose:

• Low dose (<2.5 mg/day): lower risk
• Medium dose (2.5–7.5 mg/day): standard FRAX risk
• High dose (>7.5 mg/day): significantly higher risk

• Particularly useful when DEXA values alone underestimate fracture risk.

FRAX is widely used to guide decisions on initiating prophylactic therapy in glucocorticoid users.

Biochemical Markers of Bone Turnover

Biochemical markers provide insights into dynamic bone remodeling changes:

Markers of Bone Formation

• Serum osteocalcin
• Bone-specific alkaline phosphatase (BSAP)
• N-terminal propeptide of type I procollagen (P1NP)

Markers of Bone Resorption

• C-terminal telopeptide of type I collagen (CTX)
• N-terminal telopeptide (NTX)

Key features:

• In early GIOP, resorption markers rise sharply, whereas formation markers decrease due to osteoblast suppression.
• Useful for monitoring treatment response to bisphosphonates, teriparatide, and lifestyle interventions.

Although not diagnostic alone, biochemical markers complement BMD and FRAX in understanding disease progression.⁸

Table 3. Diagnostic Approaches for GIOP

The primary goal of pharmacological management in glucocorticoid-induced osteoporosis (GIOP) is to prevent bone loss, preserve bone strength, and reduce fracture risk. Current treatment strategies focus on correcting glucocorticoid-induced disturbances in bone remodelling and mineral metabolism. Clinical guidelines recommend early initiation of preventive therapy in patients receiving long-term glucocorticoid treatment, particularly those at moderate to high fracture risk.

5.1 Calcium and Vitamin D Supplementation

Calcium and vitamin D supplementation form the cornerstone of GIOP prevention and are recommended for all patients receiving glucocorticoid therapy unless contraindicated. Glucocorticoids impair intestinal calcium absorption and reduce vitamin D activation, leading to negative calcium balance and secondary hyperparathyroidism.

• Calcium: Typically prescribed at doses of 1000–1200 mg/day
• Vitamin D: Administered at doses of 800–1000 IU/day or higher, depending on serum levels

Supplementation helps maintain serum calcium levels, suppress parathyroid hormone secretion, and modestly reduce bone loss. However, calcium and vitamin D alone are insufficient to prevent fractures in high-risk patients and are therefore used as adjunctive therapy alongside pharmacological agents.⁹

5.2 Bisphosphonates

Bisphosphonates are considered first-line therapy for the prevention and treatment of GIOP. Commonly used agents include alendronate, risedronate, ibandronate, and zoledronic acid. These drugs inhibit osteoclast-mediated bone resorption by binding to hydroxyapatite and inducing osteoclast apoptosis.

Clinical trials have demonstrated that bisphosphonates significantly increase bone mineral density at the lumbar spine and hip and reduce the incidence of vertebral fractures in glucocorticoid-treated patients. Both oral and intravenous formulations are effective, making them suitable for patients with gastrointestinal intolerance or poor adherence.

Despite their efficacy, long-term use of bisphosphonates is associated with risks such as atypical femoral fractures, osteonecrosis of the jaw, and gastrointestinal adverse effects, necessitating careful patient selection and monitoring.¹⁰

5.3 Parathyroid Hormone Analogues (Teriparatide)

Teriparatide, a recombinant form of human parathyroid hormone (PTH 1–34), is an anabolic agent that stimulates bone formation by enhancing osteoblast activity and survival. It is particularly beneficial in patients with severe GIOP or those who do not respond adequately to antiresorptive therapy.

Clinical studies have shown that teriparatide produces greater increases in bone mineral density and reduces vertebral fracture risk more effectively than bisphosphonates in patients on chronic glucocorticoid therapy. However, its use is limited to a maximum of 24 months due to safety concerns and is contraindicated in patients with an increased risk of osteosarcoma.

5.4 Denosumab and Other Biologics

Denosumab is a monoclonal antibody that targets receptor activator of nuclear factor-κB ligand (RANKL), thereby inhibiting osteoclast differentiation and activity. It effectively reduces bone resorption and improves bone mineral density in patients with GIOP.

Denosumab is administered subcutaneously every six months and is particularly advantageous for patients who are intolerant to bisphosphonates or have renal impairment. However, discontinuation may result in rapid bone loss and rebound fractures, necessitating transition therapy.¹¹

Other biologic agents targeting bone remodeling pathways, such as sclerostin inhibitors, are under investigation and show potential for future use in glucocorticoid-induced bone loss.

5.5 Selective Estrogen Receptor Modulators (SERMs)

Selective estrogen receptor modulators, such as raloxifene, exert estrogen-like effects on bone while acting as estrogen antagonists in breast and uterine tissue. SERMs reduce bone resorption and modestly increase bone mineral density, particularly in postmenopausal women.

While SERMs may be considered in selected patients with GIOP, their use is limited by an increased risk of venous thromboembolism and lack of robust evidence for fracture risk reduction in glucocorticoid-treated populations.¹²

5.6 Limitations and Side Effects of Existing Therapies

Despite advances in pharmacological management, current therapies for GIOP have several limitations:

• Adverse effects: Gastrointestinal intolerance, renal toxicity, hypocalcemia, and rare but serious complications such as osteonecrosis of the jaw.
• Limited anabolic options: Few agents directly stimulate bone formation.
• Cost and accessibility: Biological therapies are expensive and may limit long-term use.
• Patient adherence: Complex dosing regimens and fear of side effects reduce compliance.
• Long-term safety concerns: Prolonged antiresorptive therapy may impair bone remodeling and bone quality.

These challenges emphasize the need for safer, more affordable, and long-term therapeutic alternatives, supporting increasing interest in complementary approaches such as herbal medicine in the management of glucocorticoid-induced osteoporosis.¹³

Table 4. Pharmacological Agents Used in the Management of GIOP

Herbal medicine has been used for centuries in the prevention and treatment of skeletal disorders and is gaining renewed scientific interest due to its multi-targeted mechanisms and favorable safety profile. In the context of glucocorticoid-induced osteoporosis (GIOP), herbal interventions offer a promising complementary approach by addressing oxidative stress, inflammation, hormonal imbalance, and impaired bone remodeling pathways that are not fully corrected by conventional therapies.

6.1 Rationale for Herbal Interventions

Current pharmacological treatments for GIOP primarily focus on inhibiting bone resorption or stimulating bone formation; however, long-term use is often limited by adverse effects, cost, and patient non-adherence. Herbal medicines provide several theoretical and practical advantages in bone health management:

• Multimodal mechanisms of action: Herbal drugs act on multiple molecular targets simultaneously, including osteoblast stimulation, osteoclast inhibition, antioxidant defense, and cytokine modulation.
• Favorable safety profile: Many medicinal plants have a long history of traditional use with relatively fewer adverse effects when used appropriately.
• Chronic disease suitability: Herbal medicines are particularly suitable for long-term management of chronic conditions such as osteoporosis.
• Synergistic potential: Herbal agents may enhance the efficacy of conventional anti-osteoporotic drugs while minimizing their side effects.
• Cost-effectiveness and accessibility: Plant-based therapies are often more affordable and widely available, especially in developing regions.

These attributes make herbal interventions attractive candidates for adjunctive or alternative therapy in GIOP management.¹⁴

6.2 Traditional Systems of Medicine (Ayurveda, TCM, etc.)

Traditional medical systems have long recognized bone health as a critical component of overall well-being.

• Ayurveda: In Ayurveda, bone tissue (Asthi Dhatu) is maintained through proper nutrition, metabolism, and balance of bodily energies (Doshas). Herbs such as Withania somnifera, Cissus quadrangularis, Terminalia arjuna, and Asparagus racemosus are traditionally used to enhance bone strength, accelerate fracture healing, and prevent age-related bone loss.
• Traditional Chinese Medicine (TCM): TCM associates bone health with kidney function (Shen), and therapies aim to “tonify the kidney” to strengthen bones. Medicinal plants such as Epimedium brevicornum, Drynaria fortunei, and Achyranthes bidentata are commonly used for treating osteoporosis and bone fragility.
• Other traditional systems: Unani, Siddha, and folk medicine also employ calcium-rich plants, adaptogens, and anti-inflammatory herbs for skeletal disorders.

Modern pharmacological research has begun to validate many of these traditional claims, demonstrating significant osteoprotective effects in experimental and clinical settings.

6.3 Phytochemicals with Osteoprotective Potential ^13-14

The therapeutic efficacy of herbal medicines in bone health is largely attributed to their bioactive phytochemicals. These compounds influence bone remodeling by regulating cellular signaling pathways, oxidative balance, and inflammatory responses.

Flavonoids

Flavonoids are polyphenolic compounds widely distributed in plants and are among the most extensively studied phytochemicals for bone protection.

• Promote osteoblast differentiation and mineralization
• Inhibit osteoclast formation by suppressing the RANKL pathway
• Exhibit strong antioxidant and anti-inflammatory properties
• Mimic estrogen-like activity, beneficial in glucocorticoid-related and postmenopausal bone loss

Examples include quercetin, kaempferol, genistein, and icariin.

Saponins

Saponins are glycosides known for their osteoanabolic and antiresorptive effects.

• Enhance osteoblast proliferation and collagen synthesis
• Suppress osteoclast activation and bone resorption
• Improve calcium metabolism and bone mineralization

Steroidal saponins found in plants such as Asparagus, Dioscorea, and Tribulus species have shown promising results in experimental osteoporosis models.

Alkaloids

Alkaloids possess diverse pharmacological activities and contribute to bone health mainly through anti-inflammatory and antioxidant effects.

• Reduce osteoclast-mediated bone resorption
• Protect osteoblasts from glucocorticoid-induced apoptosis
• Modulate cytokines involved in bone remodeling

Certain alkaloids have demonstrated protective effects against oxidative stress–mediated skeletal damage.

Polyphenols

Polyphenols, including phenolic acids and tannins, play a critical role in maintaining bone integrity.

• Neutralize reactive oxygen species and prevent oxidative damage to bone cells
• Inhibit inflammatory mediators that stimulate bone resorption
• Support osteoblast differentiation through Wnt/β-catenin signaling

Curcumin, resveratrol, catechins, and ellagic acid are notable polyphenols with documented osteoprotective activity.¹⁵

Table 6. Molecular Mechanisms of Herbal Medicines in GIOP