GLUCOCORTICOID INDUCED OSTEOPOROSIS: EXPLORING ALLOPATHIC THERAPIES AND TRADITIONAL MEDICINE SOLUTIONS

GLUCOCORTICOID INDUCED OSTEOPOROSIS: EXPLORING ALLOPATHIC THERAPIES AND TRADITIONAL MEDICINE SOLUTIONS

C. Senthilkumari *, B. Sagunthala and M. Dev

Department of Pharmacology, K. K. College of Pharmacy, The Tamil Nadu Dr. MGR Medical University, Gerugambakkam, Chennai, Tamil Nadu, India.

ABSTRACT: Osteoporosis is a Skeletal condition that generally develops with aging. The primary osteoporosis is more prevalent in women after menopause which is known as postmenopausal osteoporosis, and it also happens after the age of 75. Secondary osteoporosis is brought on by long-term usage of drugs like glucocorticoids or chronic underlying illnesses. Oral GC use ranges from 0.5 to 0.9% in the community, and it rises to 2.7% among women over 50 years. The key mechanisms by which glucocorticoids directly affect bone formation involve the Wnt/β-catenin signalling pathway and the activation of PPAR-γ. Moreover, glucocorticoids directly contribute to bone resorption by encouraging the production of RANKL, M-CSF and reducing the synthesis of osteoprotegerin ligand by osteocytes and osteoblastic cells. First-line treatments for osteoporosis include weight-bearing physical activity, exercise, and exercises that help with posture and balance, as well as a diet high in calcium and vitamin D, stopping smoking, and consuming alcohol in moderation. Certain medications are required in the second phase such as anabolic, anti-resorptive, and combination drugs. Medicinal plants are essential for preserving health and serve as the main source of ingredients for both conventional and traditional medicine formulations. Traditional therapies, including herbal remedies and natural compounds, may offer benefits such as reducing bone resorption, enhancing bone formation, and minimizing side effects associated with conventional drugs.

Keywords: Osteoporosis, Bone resorption, Anabolic drugs, Anti-resorptive drugs, Herbal remedies

INTRODUCTION: Osteoporosis is a Skeletal condition that generally develops with aging. It is typified by a marked decrease in bone strength, bone mass, or bone mineral density, increasing the risk of fractures for the affected person ¹. Around the world, osteoporosis is the most prevalent illness affecting the bones and joints, particularly in the elderly population. Every ethnicity and gender are impacted by osteoporosis, however, to varying degrees ².

Osteoporosis is often caused by estrogen shortage in older or postmenopausal women, which is important for maintaining bone homeostasis ⁴. An aberrant bone remodelling process between osteoclast and osteoblast is brought on by a female hormone deficiency which results in significant bone loss leading to osteoporosis and osteopenia ⁴. Two types of osteoporosis exist: primary and secondary ¹.

According to the study, osteoporosis affected roughly one in three female and one in five males. Around 20 crore people worldwide are affected with osteoporosis ⁵. The primary osteoporosis is more prevalent in women after menopause which is known as postmenopausal osteoporosis, and it also happens after the age of 75. The ratio of male to female cases is 2:1 ².

Men and women are equally susceptible to secondary osteoporosis, which can develop at any age. Secondary osteoporosis is brought on by long-term usage of drugs like glucocorticoids or chronic underlying illnesses ². Numerous illnesses, such as asthma, autoimmune diseases, ulcerative colitis and rheumatoid arthritis are treated using glucocorticoids ⁸.

The several studies showed that children who got more than four sessions of glucocorticoids had an increased risk of fracture ³. Glucocorticoids treatment increases bone resorption, lowers gastrointestinal absorption of calcium, suppresses gonadal hormones like estrogen, and inhibits osteoblast function, all of which contribute to increased bone loss ⁶. The synthetic glucocorticoid hormone dexamethasone has been shown to promote the synthesis of collagenase while simultaneously suppressing the synthesis of collagen and fibronectin ⁷. Glucocorticoids shorten osteoblasts' and osteocytes' lifespans and suppress osteoblastogenesis ⁹. Apoptosis brought on by dexamethasone is linked to the activation of many caspase gene types ⁷. Because of the long-term negative effects or ineffectiveness of synthetic drugs, scientists and physicians are interested in finding traditional medicines to treat osteoporosis ⁹.

Herbs have been utilized for thousands of years by various civilizations to treat a variety of illnesses ¹⁰. Researches has indicated that a number of naturally occurring substances function as antioxidants to prevent osteoporotic effects ¹¹. Medicinal plants are essential for preserving health and serve as the main source of ingredients for both conventional and traditional medicine formulations ¹². The greatest source of a wide range of medications used to treat serious illnesses in India is medicinal plants ¹². This review aims to highlight how glucocorticoids induce osteoporosis and the effectiveness of herbal plants in treating osteoporosis and to outline conventional medicine for osteoporosis from various scholarly publications.

Composition of Bone: Bone comprises a mixture of extracellular matrix and cells. The extracellular matrix's composition determines bone's mechanical characteristics and the architectural and geometric features brought about by this tissue's spatial distribution. Bone cells are osteocytes, osteoclast, osteoblast and osteoprogenitor cells. The cells create bone and regulate its growth and decomposition. Mineralised and nonmineralized components are present in the extracellular matrix. Calcium hydroxyapatite is a crystalline substance that makes up the mineralised component. Phosphate and calcium ions are the key components of calcium hydroxyapatite. Osteoid refers to the nonmineralized component. Osteoid generates and secretes a non-mineralized substance. Proteins that are collagenous and non-collagenous make up osteoid ¹³.

Osteoporosis Brought on by Glucocorticoids: For many years, clinical practice has employed synthetic glucocorticoids (GCs) to treat gastrointestinal disorders, rheumatism, organ transplants, autoimmune disorders, and cancers ³. Glucocorticoid (GC) exposure in both past and present, raises the risk of bone loss and fracture ¹⁴. Oral GC use ranges from 0.5 to 0.9% common in the community, and it rises to 2.7% among women over 50 years ¹⁴. During the first phase of treatment, chronic oral administration of glucocorticoid medication is linked to dose-related fast reduction in bone mass and an elevated risk of fracture. The risk of fractures stays high while on glucocorticoid medication but decreases when it is stopped, however it is uncertain if it returns to its initial levels ¹⁵. Fractures were 29% less common among individuals who stopped taking glucocorticoids at 60 to182 days ¹⁵. At doses of less than 15 mg per day, the incidence of fracture ranged from 4 to 10 per 1000 person-years; at doses of 15 mg per day, it was 16 and at cumulative doses of more than 5400 mg, it was 13.4 ¹⁵. Despite the availability of several glucocorticoid induced osteoporosis guidelines, a small percentage of patients treated with glucocorticoids are still undergoing prophylactic measures for bone problems ¹⁴.

Pathophysiology: Two types of osteoporosis exist: primary and secondary ¹. The primary osteoporosis is more prevalent in women after menopause which is known as postmenopausal osteoporosis, and it also happens after the age of 75. Men and women are equally susceptible to secondary osteoporosis, which can develop at any age.

Secondary osteoporosis is brought on by long-term usage of drugs like glucocorticoids or chronic underlying illnesses. The annual loss of bone density in men is 0.30%, whereas in women it is 0.50%. Following menopause, bone loss can reach 4–6% annually, especially in the first five years following the commencement ¹³.

When glucocorticoids cause osteoporosis, there is a decline in bone production (osteoblast) together with an early but temporary rise in bone resorption (osteoclast) ¹⁵. The distinction between bone mineral density (BMD) and fracture risk and GCs are characteristics of bone fragility in glucocorticoid induced osteoporosis. The aetiology of glucocorticoid induced osteoporosis explains these two points ¹⁴. External mechanical pressures brought on by physical activity and endogenous hormonal changes both affect bone homeostasis. The capacity of bone to support specific loads is significantly reduced by processes that lower collagen or bone mineral levels. When the maximum stress levels are reached, bones break and fractures happen ¹³.

The key mechanisms by which glucocorticoids directly affect bone formation involve the Wnt/β-catenin signalling pathway and the activation of PPAR-γ (Peroxisome Proliferator-Activated Receptor Gamma). Moreover, glucocorticoids directly contribute to bone resorption by encouraging the production of RANKL (Receptor Activator of Nuclear Factor Kappa-Β Ligand) and M-CSF (Macrophage Colony-Stimulating Factor) and reducing the synthesis of osteoprotegerin ligand (OPG) by osteocytes and osteoblastic cells. This leads to an increase in osteoclast activity and quantity. The impact gradually fades, likely because of a reduction in the number of osteoblasts and osteocytes. And few studies suggesting glucocorticoids influence the shape and mineralisation of osteocytes comes from animal models ¹⁵. Because glucocorticoids cause ROS to accumulate, it causes oxidative stress. ROS triggers RANK/TRAF6/RANKL signalling, which enhances the IκB kinase/ nuclear factor kappa-B (IKK/NF-κB) pathway, nuclear factor of activated T cells of type 1 (NFATc1) expression, and genes unique to osteoclasts, such as acid phosphatase (ACP) activity. Meanwhile, glucocorticoids inhibited the activation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1). Kelch-like ECH-associated protein 1 (Keap1) sequesters Nrf2 and also aids in its proteasomal degradation and ubiquitination within the cytoplasm. But under oxidative stress, the cytoprotective potential begins with Keap1's separation from Nrf2, which then promotes Nrf2 nuclear translocation, modifies ARE-dependent gene expression, and triggers HO-1 production, which is in charge of scavenging oxidative stress and ROS. One major factor contributing to the development and onset of osteoporosis is bone resorption, which is triggered by increased RANKL/RANK signalling and inhibited Nrf2/HO-1 signal ¹⁶.

Sien Lin et al. demonstrated that rats given the maximum dosage of prednisone had considerably lower levels of serum insulin-like growth factor 1 (IGF-1) and longitudinal bone growth (LGR). Drug effects on young patients can be assessed using growing rats as an animal model of glucocorticoid-induced osteoporosis ³. Forough Pirhadi et al. showed that when rats were given dexamethasone, their femoral bone's metaphyseal trabeculae thickness was significantly lower than that of the control group. This resulted in a notable decline in histomorphometric indices, indicating the onset of osteoporosis ¹. Nabil A. Hasona et al showed that reduced catalase activity and a markedly lower hepatic GSH level are signs of enhanced oxidative stress brought on by dexamethasone ¹⁷. Glucocorticoids indirectly produce osteoporosis by decreasing the sex steroid hormone synthesis, and hypogonadism alone can cause increased bone resorption. Increased calcium losses in the kidney and decreased intestinal absorption of calcium¹⁴.

Diagnosis of Osteoporosis: In order to estimate bone mineral density, non-invasive dual-energy X-ray absorptiometry (DEXA) can be used. By using the bone mineral density test's T-score, osteoporosis can be differentiated from osteopenia. A bone mineral density test T-score of -2.500 or less indicates osteoporosis, while a T-score between -1.01 and -2.49 indicates osteopenia. Although it is crucial to remember that the findings of bone mineral density tests do not necessarily correspond with the likelihood of fractures, early detection of low bone mineral density can guide clinical intervention ¹⁸.

Osteoporosis Management: First-line treatments for osteoporosis include weight-bearing physical activity, exercise, and exercises that help with posture and balance, as well as a diet high in calcium and vitamin D, stopping smoking, and consuming alcohol in moderation. Certain medications are required in the second phase. There are three categories of medications: anabolic, anti-resorptive, and combination treatments. Sclerostin inhibitors and parathyroid hormone (PTH) analogues are examples of anabolic medication. Denosumab, SERMs (Selective estrogen receptor modulators), Bisphosphonates and Calcitonin are examples of anti-resorptive medications ^{18, 19, 20}.

Anti-resorptive Drugs: Fractures can be prevented by up to 50% with antiresorptive medication ²⁰. Bisphosphonates are frequently used to raise BMD in primary and secondary osteoporosis, they do have an impact on bone flexibility ¹⁹. Bisphosphonates stop the resorption of bone by blocking the activation of osteoclasts ²⁰. Clodronate, Etidronate, and tiludronate are a few types of first-generation bisphosphonates. Third- and second-generation bisphosphonates include zoledronic acid, pamidronate, ibandronate, risedronate, and alendronate. The way these medications work is by strongly binding to bone mineral and attaching to hydroxyapatite crystals, effectively preventing osteoclast activation and decreasing bone resorption, thereby reducing bone loss. Bisphosphonates can be given intravenously or orally. In postmenopausal women, alendronate reduces the risk of hip, nonvertebral, and vertebral fractures in comparison to vitamin D and calcium supplementation ¹⁸.

Denosumab, a human monoclonal antibody, prevents bone resorption by binding to and blocking RANKL (Receptor Activator of Nuclear Factor Kappa B Ligand), inhibiting the maturation of osteoclast precursors into adult osteoclasts ²¹. Every six months, denosumab is injected subcutaneously ²⁰. Some side effects of denosumab include weakness and fatigue. Calcitonin, a thyroid hormone, is released by the thyroid gland, is recommended for treating osteoporosis in women who have been postmenopausal for at least five years ¹⁸. Calcitonin is administered intranasally. The calcitonin binds to osteoclast precursors' calcitonin receptors which inhibits their maturation and functions ²¹. One SERMs (selective oestrogen receptor modulator) that lessens postmenopausal bone loss is raloxifene. Women who have postmenopausal osteoporosis can use raloxifene instead of denosumab or bisphosphonates. Since raloxifene lowers the risk of breast cancer, it may be taken into consideration for women who are at high risk for the disease. Nevertheless, raloxifene raises the incidence of DVT (deep vein thrombosis) and there is a modest increase in mortality following stroke ²⁰.

Anabolic Drugs: Teriparatide and abaloparatide are two examples of parathyroid hormone or parathormone analogues, which are anabolic treatments given subcutaneously once a day ²¹. Teriparatide is approved to treat osteoporosis resulting from glucocorticoid use in those with a high fracture risk ⁶. Teriparatide and abaloparatide act as an agonist on parathyroid hormone type 1 receptor. When the parathyroid hormone receptor is frequently stimulated, the Wnt pathway is activated, which has a net anabolic effect on bone. Additionally, osteoprotegerin (OPG) transcription is upregulated, which binds to RANKL and has an anti-resorptive impact ²¹. Headaches, nausea, and short-term hypercalcemia are the most frequent side effects of parathormone analogues, occurring more often with teriparatide compared to abaloparatide. A humanized monoclonal antibody, romosozumab is an anabolic agent that prevents the activity of sclerostin. The role of sclerostin is to block Wnt pathway. Thus, romosozumab-induced sclerostin inhibition activates Wnt signalling pathway, resulting in an anabolic action that promotes bone growth and prevents bone resorption. Romosozumab may cause side effects such as injection site discomfort, necrosis of the jaw bone, dermatitis, and cardiovascular complications ^{17, 20, 21}.

Role of Traditional Medicines in Glucocorticoid Induced Osteoporosis: Dieckol markedly changed OPG and RANKL levels and implied a protective effect on bones. Therefore, dieckol showed that it had an anti-osteoporosis effect on rats that had glucocorticoid induced osteoporosis ⁵. Prednisolone-induced osteoporosis in rats was prevented by grape fruit juice, potentially through the RANKL/OPG pathway ⁸. Mollugin could potentially be able to treat glucocorticoid-induced osteoporosis through a mechanism that involves the PI3K/Akt pathway ¹¹. Ethanolic purslane extract and aqueous chicory extract counteracted dexamethasone induced bone deterioration by stimulating the Nrf2/HO-1 signalling pathway and restraining osteoclast differentiation prompted by RANKL ¹⁶. Pinoresinol diglucoside increases bone mass and controls bone metabolism to prevent dexamethasone-induced osteoporosis ²². Korean red ginseng (KRG) inhibited caspase-3 and -9 activation, preventing MC3T3-E1 cells from undergoing apoptosis caused by dexamethasone. Additionally, KRG promoted bone growth in animals with glucocorticoid -induced osteoporosis ²³. The processes that underlie curcumin's ability to prevent osteoporosis caused by dexamethasone include the activation of the Wnt/β-catenin pathway ²⁴. According to a study, annatto tocotrienol may benefit individuals receiving long-term glucocorticoid medication by preventing osteoporosis brought on by glucocorticoids ²⁵. Basil, chicory and parsley aqueous extracts contributed to bone preservation in rats affected by glucocorticoid exposure ²⁶.

CONCLUSION: Glucocorticoid induced osteoporosis (GIOP) presents a major challenge in managing patients on long-term glucocorticoid therapy, requiring effective strategies to prevent bone loss and fractures. While conventional treatments such as bisphosphonates, denosumab, and teriparatide have proven efficacy in managing GIOP, there is growing interest in the role of traditional medicines as complementary or alternative options. Traditional therapies, including herbal remedies and natural compounds, may offer benefits such as reducing bone resorption, enhancing bone formation, and minimizing side effects associated with conventional drugs. However, while some traditional medicines show promise, further clinical studies and rigorous trials are necessary to establish their safety, efficacy, and optimal use in GIOP management. Ultimately, an integrative approach that combines the strengths of both conventional and traditional treatments, under careful medical supervision, could offer a more holistic solution to managing this debilitating condition.

ACKNOWLEDGEMENT: We would like to express our sincere gratitude to Dr. A. Meena, Principal and Dr. A. Shanthi, Vice Principal of K.K. College of Pharmacy, for their constant support, valuable insights, and guidance. Their contributions and expertise have played a crucial role in the success of this article.

CONFLICT OF INTEREST: NIL

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    How to cite this article:

    Senthilkumari C, Sagunthala B and Dev M: Glucocorticoid induced osteoporosis: exploring allopathic therapies and traditional medicine solutions. Int J Pharm Sci & Res 2025; 16(8): 2180-85. doi: 10.13040/IJPSR.0975-8232.16(8).2180-85.

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