Osteoporoz Tedavisinde Güncel Yaklaşımlar

Current Approaches in Osteoporosis Treatment: Conventional Therapy, Novel Agents, and the Research Pipeline

Dr. Sertaç Erarslan

Kütahya Health Sciences University, Faculty of Medicine, Department of Internal Medicine

Introduction and Aim

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and fracture risk (WHO, 1994). It affects more than 500 million people worldwide, carries a lifetime fracture risk exceeding 50% in postmenopausal women, and is associated with a first-year mortality of up to 30% after hip fracture, making it a major public health concern. This review aims to provide a comprehensive, guideline-based overview of osteoporosis management—spanning diagnosis and risk assessment, conventional and novel pharmacological agents, therapies under investigation, and special clinical situations—in light of current guidelines (NOGG 2024, ACP 2023, ASBMR/BHOF 2024).

Diagnosis and Risk Assessment

The diagnostic gold standard is bone mineral density measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and total hip/femoral neck; a T-score ≤ −2.5 defines osteoporosis, while a T-score between −1.0 and −2.5 defines osteopenia. FRAX® is a clinical decision-support tool that estimates an individual's 10-year probability of major osteoporotic fracture and hip fracture using 12 clinical risk factors; pharmacological treatment is recommended when the 10-year hip fracture risk is ≥3% or the major osteoporotic fracture risk is ≥20%. Patients are stratified into moderate, high, and very-high risk categories based on T-score, FRAX result, prior fracture history, and additional risk factors—a classification that directly guides the decision to treat and the choice of agent.

Foundational Treatment and Pharmacological Approaches

Weight-bearing and resistance exercise, adequate protein intake, 1000–1200 mg/day calcium, and 800–2000 IU/day vitamin D form the foundation of care in all patient groups. Among antiresorptive agents, bisphosphonates (alendronate, risedronate, zoledronate, ibandronate) remain first-line therapy in most guidelines; they reduce bone resorption by triggering osteoclast apoptosis, though caution is required in advanced renal impairment and regarding the risks of osteonecrosis of the jaw and atypical femoral fracture. Denosumab, a RANKL-inhibiting monoclonal antibody, is preferred in patients with bisphosphonate intolerance or renal impairment; however, treatment must be continued without interruption, as discontinuation is associated with a marked increase in rebound vertebral fracture risk. The anabolic agents teriparatide (a PTH analog) and abaloparatide (a PTHrP analog) increase bone formation and produce net bone gain in patients at very high fracture risk; treatment duration is limited, and transition to antiresorptive therapy is mandatory afterward. Romosozumab, an anti-sclerostin monoclonal antibody, exerts a unique dual anabolic and antiresorptive effect (ARCH and FRAME trials) but is contraindicated in patients with a history of cardiovascular events.

Therapies Under Investigation

Next-generation therapies include AGA2118, a bispecific antibody that simultaneously targets sclerostin and DKK1 (Phase II ARTEMIS trial); EB613, the first oral PTH analog (Phase II completed, Phase III planned); odanacatib, a cathepsin K inhibitor whose development was discontinued due to cardiovascular adverse effects; and gene therapy/stem cell approaches targeting mesenchymal stem cell osteogenesis. While these agents aim to overcome the limitations of current therapies, most remain in preclinical or early clinical-phase development.

Special Situations

Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary cause of osteoporosis; in patients receiving ≥7.5 mg/day prednisone equivalent, bone-protective therapy should be initiated without delay from the first month, with teriparatide or romosozumab preferred in very-high-risk cases. Male osteoporosis is a frequently overlooked clinical entity in which hip fracture mortality is approximately twice as high as in women; hypogonadism is the most important secondary cause, and the diagnostic and therapeutic approach follows principles similar to those used in women.

Recent Evidence

Notable studies published within the past year include a 2025 NEJM trial showing that just two doses of IV zoledronate (at baseline and year 5) reduced vertebral fracture risk by approximately 44% over 10 years in early postmenopausal women; a review reporting that roughly 7% of patients who discontinue denosumab without sequential antiresorptive therapy develop rebound vertebral fractures; a review confirming that, in very-high-risk patients, an anabolic-to-antiresorptive treatment sequence is more effective than the reverse; and a systematic review noting that the cardiovascular safety profile of romosozumab remains unresolved, though the risk-benefit balance generally favors its use in patients without active cardiovascular disease.

Conclusion

Successful osteoporosis management relies on a stepwise strategy encompassing systematic risk stratification (FRAX + DXA), a calcium–vitamin D–exercise foundation for all patients, individualized agent selection based on risk level (bisphosphonate, denosumab, anabolic agent, or romosozumab), and regular monitoring with DXA and bone turnover markers (P1NP, CTX). The anabolic-first, antiresorptive-second approach in very-high-risk patients is increasingly supported by strong evidence in current guidelines, and gene therapy along with next-generation biologic agents hold the potential to reshape the treatment paradigm within the next 5–10 years.

Keywords: Osteoporosis, FRAX, bisphosphonate, denosumab, romosozumab, anabolic therapy, fracture risk