Osteoporosis
Bone homeostasis is maintained through a balanced, continuous cycle of cooperation between osteoclasts, which resorb existing bone, and osteoblasts, which create new bone in its place. The key word here is "balance." In a healthy state, a precise equilibrium exists between bone resorption and bone formation. In other words, if new bone is created in proportion to the amount broken down, bone density and overall mass are preserved, maintaining healthy bone health. Unfortunately, due to aging or various diseases, maintaining this balance can become difficult, leading to compromised bone health. As people age, bone formation gradually declines in comparison to bone resorption. Resorption becomes dominant while bone formation becomes delayed or incomplete, resulting in a gradual decrease in bone density. When bone density significantly drops and bones become prone to fractures, this condition is defined as osteoporosis.
Classification of Osteoporosis: Primary vs. Secondary
Osteoporosis can arise due to various factors, including genetic, metabolic, hormonal, and immune imbalances. Based on its cause, osteoporosis is broadly categorized into primary osteoporosis and secondary osteoporosis. Primary osteoporosis is further divided into postmenopausal osteoporosis, caused by decreased estrogen levels in women, and age-related osteoporosis, which affects both men and women due to bone loss with aging.
For osteoclast precursors to differentiate and become activated, RANKL secreted by osteoblasts or osteocytes must bind to RANK receptors on the precursors. Estrogen promotes the expression of OPG in osteoblasts, which intercepts RANKL, preventing it from binding to RANK. As a result, osteoclast differentiation is suppressed. Therefore, estrogen serves to inhibit excessive osteoclastic activity and protects bone. However, during menopause, estrogen levels drop sharply, reducing OPG secretion and relatively increasing RANKL levels. This promotes greater osteoclast differentiation, often leading to osteoporosis.
Aging, in addition to hormonal decline, leads to oxidative stress, telomere shortening, and weakened DNA repair mechanisms, all contributing to cellular senescence. This reduces the differentiation and function of osteoblasts and osteocytes and may alter the rigidity and quality of the bone matrix.
Secondary osteoporosis, on the other hand, arises from other diseases, medications, or lifestyle factors.
Osteoporosis is characterized by greater osteoclastic activity compared to osteoblastic activity, leading to reduced bone mass and strength and a higher risk of fractures. This loss in bone mass may be due to excessive bone resorption or impaired bone formation during the remodeling process. We have previously explored how factors such as estrogen deficiency, vitamin D deficiency, lack of exercise, and reduced mechanical loading contribute to hyperactive osteoclasts.
When osteocytes embedded in the bone matrix detect reduced mechanical loading, they increase the expression of sclerostin and DKK-1 (Dickkopf-1), which inhibit the Wnt/β-catenin signaling pathway. This further activates osteoclasts and suppresses the generation and activity of osteoblasts, resulting in decreased bone density. This explains why astronauts experience reduced bone density in zero gravity and how sedentary lifestyles produce similar effects.
In addition, when parathyroid hormone (PTH) levels rise intermittently, bone formation is stimulated. However, when PTH levels are continuously elevated, the production of RANKL and M-CSF increases, promoting bone resorption. In cases of hypoparathyroidism, such as after thyroid surgery, or with aging-induced receptor decline, PTH signaling may be impaired.
Calcium, collagen, vitamin D, and vitamin K are essential for bone remodeling. Their deficiencies can cause or worsen osteoporosis. When blood calcium levels drop, the body stimulates osteoclast differentiation to retrieve calcium from bone stores. Even if calcium is consumed, a deficiency in vitamin D can impair its absorption through the intestine, ultimately enhancing osteoclastic activity and reducing bone density. Collagen, a primary component of bone, and vitamin K, which is essential for osteocalcin to bind effectively to calcium, are also vital. Deficiency in either leads to poor organic bone scaffolding, reduced structural flexibility, and weakened bone support.
Osteoporosis Treatments
Osteoporosis results when osteoclastic bone resorption exceeds osteoblastic bone formation. Therefore, inhibiting bone resorption or promoting bone formation can improve bone density and mass. Treatments are generally divided into two categories: antiresorptives, which inhibit osteoclast activity, and anabolics, which stimulate osteoblast activity. Understanding the detailed bone remodeling process helps to grasp how these drugs work and where they act. Let us first explore antiresorptives, with anabolics covered in the next article.
Antiresorptives
Antiresorptives target osteoclasts by blocking or inhibiting specific steps in the bone resorption process. This slows the resorption rate or reduces resorption volume, effectively curbing bone loss. However, long-term suppression of osteoclast formation and activity may also suppress the release of osteoclast-mediated coupling factors, reducing osteoblast differentiation and bone formation, which can weaken bone strength.
1. Bisphosphonates
Bisphosphonates are the most widely used first-line treatment for osteoporosis. Chemically similar to pyrophosphate, they are known as inorganic pyrophosphate analogs and bind strongly to hydroxyapatite in bone. Bisphosphonates stick to bone surfaces and are taken up by osteoclasts during bone resorption, where they disrupt osteoclast function. As previously discussed, pyrophosphate limits hydroxyapatite crystal growth and prevents excessive mineralization. Bisphosphonates come in nitrogen-containing and non-nitrogen-containing forms.
Nitrogen vs. Non-Nitrogen Bisphosphonates
Nitrogen-containing bisphosphonates include alendronate, risedronate, and zoledronic acid. Alendronate is the most commonly used osteoporosis drug. These drugs inhibit farnesyl pyrophosphate synthase (FPPS).
To facilitate resorption, osteoclasts reorganize their cytoskeleton, adhere tightly to target sites, and secrete vesicle-packed resorptive substances via their cell membrane. Small GTP-binding proteins like Rho, Rac, and Rab are essential for these processes. These proteins require post-translational prenylation for proper membrane localization, a step dependent on the enzyme FPPS. Thus, inhibiting FPPS disrupts intracellular signaling essential for bone resorption, paralyzing osteoclastic function. In addition, inhibition of the FPPS enzyme leads to excessive accumulation of intracellular IPP and DMAPP upstream of the pathway, and these IPPs are converted into toxic ATP analogs, inducing apoptosis of osteoclasts.
Non-nitrogen bisphosphonates such as etidronate, clodronate, and tiludronate disrupt mitochondrial energy metabolism in osteoclasts, cutting off ATP production and inducing apoptosis.
Bisphosphonates are highly hydrophilic and therefore highly soluble. However, for the same reason, they have difficulty penetrating lipid-containing cell membranes, limiting their bioavailability. Oral administration requires high doses, which can irritate the upper gastrointestinal tract and may also be associated with musculoskeletal pain and cardiovascular risks.
2. RANKL Inhibitors
Denosumab is a fully human monoclonal antibody that was approved in 2010 as a treatment for osteoporosis. It is administered as a 60 mg subcutaneous injection every six months. It is prescribed for patients who do not respond sufficiently to bisphosphonates.
A monoclonal antibody (mAb) refers to an antibody mass-produced after genetically modifying B cells to recognize and bind selectively to a specific antigen. The names of such drugs typically end with “-mab.” Additionally, depending on their origin, further suffixes are added: “-omab” (mouse-derived), “-ximab” (chimeric: mouse-human hybrid), “-zumab” (humanized monoclonal antibody), and “-umab” (100% fully human monoclonal antibody).
Compared to bisphosphonates, denosumab shows a more sustained increase in bone mineral density. However, once treatment is discontinued, the suppression of RANKL is rapidly lifted, leading to a sudden reactivation of osteoclasts. This phenomenon, known as the rebound effect, results in a sharp decrease in bone density. Therefore, when discontinuing denosumab, it is necessary to switch to another antiresorptive agent such as bisphosphonates.
Structural Limitation of Antiresorptive Agents: The Coupling Relationship Between Osteoclasts and Osteoblasts
For example, bisphosphonates interfere with osteoclast cytoskeletal remodeling, adhesion, and vesicular transport or disrupt energy production, eventually leading to osteoclast apoptosis and a reduction in their number. This decrease results in fewer coupling signals to activate osteoblasts, thereby slowing down overall bone remodeling and delaying bone formation. To overcome this limitation, it is often recommended to use anabolic agents alongside antiresorptive drugs, even if only for a short duration, to promote new bone formation and increase bone mass.
3. Estrogen Hormone–Related Treatments
To address this, hormone replacement therapy (HRT) is used to supplement estrogen externally. While HRT has shown effectiveness in preventing bone loss and alleviating menopausal symptoms, it has also been associated with increased risks of breast cancer, endometrial cancer, and cardiovascular disease. As such, it is recommended to use the lowest effective dose for the shortest possible duration and only for the relief of menopausal symptoms. When the goal is osteoporosis treatment, selective estrogen receptor modulators are generally preferred instead.
Selective Estrogen Receptor Modulators (SERMs)
As a lipid-soluble hormone, estrogen easily passes through the cell membrane and enters the cell, where it binds to estrogen receptors (ERs) located in the cytoplasm or nucleus. It then functions as a transcription factor to regulate the transcription of specific genes and stimulate cell growth through division. For this reason, when breast cancer is diagnosed, it is standard practice to first check whether the cancer cells express estrogen receptors. This helps determine whether the tumor is ER-positive (ER⁺) and responsive to estrogen stimulation, or ER-negative (ER⁻) and independent of estrogen.
If the tumor is ER⁺, hormone therapy is effective. If it is ER⁻, hormone therapy is not appropriate, and chemotherapy or targeted therapy must be considered. According to research, approximately 70–80% of breast cancers are ER⁺.[1]
However, estrogen is a hormone that exhibits tissue specificity. After estrogen binds to the estrogen response element (ERE) on DNA in the nucleus, the outcome of gene transcription depends on which co-regulatory proteins are involved. Taking advantage of this property, SERMs are designed to bind to co-activators in bone tissue to promote transcription and protect bone, while in breast tissue they bind to co-repressors to suppress transcription and block the proliferation of cancer cells.
Among SERMs, tamoxifen is known for its anti-estrogenic effects and is used to treat or prevent ER⁺ breast cancer. It also acts like estrogen in bone tissue, helping prevent osteoporosis. However, because tamoxifen acts like estrogen in the endometrium, it may increase the risk of endometrial cancer. Thus, long-term use is generally discouraged due to this risk. On the other hand, raloxifene behaves as an anti-estrogen even in the endometrium, significantly lowering the risk of endometrial cancer, making it more suitable for osteoporosis treatment.
That said, in patients already diagnosed with breast cancer, tamoxifen—which has FDA approval for breast cancer treatment—is the preferred option. For postmenopausal women who wish to avoid the risk of endometrial cancer or who are primarily seeking osteoporosis treatment, raloxifene is often chosen due to its lower risk of uterine side effects and suitability for long-term use.
In the diagram below (not included), one can observe how tamoxifen, despite binding to estrogen receptors, exhibits tissue-specific action. For reference, selective estrogen receptor degraders (SERDs) are drugs that bind to estrogen receptors and destabilize their structure, leading to receptor degradation. These drugs are developed primarily for cancer treatment and are not directly related to the treatment of bone diseases such as osteoporosis.
[Reference]
[1] Hormone Receptor Down-Regulation in Metastatic Breast Cancer After Endocrine Therapy Detected in Oophorectomy: A Case Report and Review of Literature
DOI: 10.7759/cureus.19994
