The why and how of sequential and combination therapy in osteoporosis. A review of the current evidence

ABSTRACT It is now well recognized that over the lifetime of a patient with osteoporosis, more than one medication will be needed to treat the disease and to decrease fracture risk. Though current gaps in osteoporosis therapy can be potentially mitigated with sequential and combination regimens, how to move seamlessly amongst the multiple treatments currently available for osteoporosis for sustained efficacy is still unclear. Data from recent studies show that an anabolic agent such as teriparatide or romosozumab followed by an antiresorptive affords maximal gain in BMD and possibly better and earlier fracture risk reduction compared to a regimen which follows the opposite sequence. Sequentially moving to a bisphosphonate such as alendronate from an anabolic agent such as abaloparatide has also been shown to preserve the fracture reduction benefits seen with the latter. This sequence of an anabolic agent followed by an antiresorptive should especially be considered in the high-risk patient with imminent fracture risk to rapidly reduce the risk of subsequent fractures. The data surrounding optimum timing of initiation of bisphosphonate therapy following denosumab discontinuation is still unclear. Though data suggests that combining a bisphosphonate with teriparatide does not provide substantial BMD gains compared to monotherapy, the concomitant administration of denosumab with teriparatide has been shown to significantly increase areal BMD as well as to increase volumetric BMD and estimated bone strength. This narrative review explores the available evidence regarding the various sequential and combination therapy approaches and the potential role they could play in better managing osteoporosis.

Controversies in the treatment of postmenopausal osteoporosis: How long to treat with bisphosphonates?

ABSTRACT Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture leading to an increased risk of fractures. Fragility fractures, especially hip fractures, are associated with a significant reduction in the physical function and quality of life of affected patients, as well as increased mortality, leading to a major financial impact on health care. Many drugs have been registered for the treatment of osteoporosis and very recently, a new anabolic agent, romosozumab, has been approved in some countries. Despite the expansion of efficacious antiresorptive and anabolic therapies in recent years, a concomitant increase in concerns have been raised by physicians, patients and the lay press about the potential for adverse events, especially atypical femoral fractures (AFF) following prolonged use of bisphosphonates. Whatever the mechanism(s) may be, direct or indirect, linking prolonged bisphosphonate use to atypical femoral fractures, this adverse event is very rare in comparison to the magnitude of risk reduction of typical osteoporotic fractures. An estimated 162 osteoporosis-related fractures are prevented for each atypical femoral fracture associated with an anti-resorptive medication. Until a risk calculator for predicting risk of atypical fractures, becomes available in clinical practice, and we view this as an unlikely scenario, it is up to the physician to consider continuing or discontinuing bisphosphonate use after the critical 3-5 year period of treatment with zoledronic acid or alendronate, but close monitoring for the residual bone effects overtime should be planned. For other bisphosphonates, in which no residual effects are expected, drug holiday is usually not applied.

Position Statement: Drug Holiday in Osteoporosis Treatment with Bisphosphonates in South Korea

Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from many placebo-controlled trials demonstrating its efficacy in fracture risk reduction over 3 to 5 years of treatment. Although bisphosphonates are generally safe and well tolerated, concerns have emerged about the adverse effects related to its long-term use, including osteonecrosis of the jaw and atypical femur fractures. Because bisphosphonates are incorporated into the skeleton and continue to exert an anti-resorptive effect for a period of time after the discontinuation of drugs, the concept of a "drug holiday" has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from anti-fracture efficacy. As randomized clinical trial evidence is not yet available on who may qualify for a drug holiday, there is considerable controversy regarding the selection of candidates for the drug holiday and monitoring during a drug holiday, both of which should be based on individual assessments of risk and benefit. This statement will provide suggestions for clinicians in South Korea on the identification of possible candidates and monitoring during a bisphosphonate drug holiday.

Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw

OBJECTIVES: To identify post-treatment prognostic factors for medication-related osteonecrosis of the jaw (MRONJ). MATERIALS AND METHODS: We evaluated 54 MRONJ patients who visited the Department of Dentistry, Ajou University Hospital, from May 2007 to March 2014. Twenty-one patients were surgically managed with debridement or sequestrectomy and 33 patients were conservatively managed using antibiotics. Correlations of age, sex, stage, bisphosphonate duration and type, and drug holiday with the prognosis of MRONJ were investigated. Correlations were verified by logistic regression analysis and t-tests with a significance level of 0.05. RESULTS: Clinical outcomes were evaluated on the basis of both clinical and radiographic findings. Twelve out of 21 surgically managed patients showed a favorable prognosis and nine patients relapsed. Thirty-one of the 33 conservatively managed patients showed no specific change in prognosis, and two patients worsened. Statistical analyses of the conservative management group did not reveal any correlation of the above factors with the prognosis of conservative management. Drug holiday was the only prognostic factor in the surgical management group (P=0.031 in logistic regression analysis, P=0.004 in t-test). CONCLUSION: Drug holiday is a prognostic factor in the surgical management of MRONJ. Because the drug holiday in the patients of the poor prognosis group occurred 1.5 to 4 months prior to surgical management, we recommend a drug holiday more than 4 months before surgery.

Duration of Bisphosphonate Treatment / 대한내과학회지

Large, randomized, controlled trials have demonstrated the efficacy of bisphosphonates (BP) in terms of improving bone mineral density (BMD) and reducing fracture risk. Consequently, bisphosphonates are used widely in the treatment of osteoporosis. Recently, however, several safety issues regarding the long-term use of BP, especially BP-related osteonecrosis of the jaws and atypical fractures, have been noted and have emerged as a limitation of their clinical use. Although the absolute risk is very small, the risks could increase with the long-term use of BP. The anti-fracture efficacy of BP is not sustained after treatment for 5-10 years. Therefore, recommendations suggest that a drug holiday be considered after 5 years of treatment for patients at low risk of fracture. However, as the individual fracture risk varies, the treatment duration should be based on individual clinical risk factors and bone metabolism status. Moreover, recommendations regarding monitoring after discontinuing and reinitiating BP await further studies.

Effects of a 'Drug Holiday' on Bone Mineral Density and Bone Turnover Marker During Bisphosphonate Therapy

BACKGROUND: Recently long-term safety of bisphosphonate raises issues about the duration of therapy. We examined the effects of a drug holiday (DH) on bone mineral density (BMD) and bone turnover markers. METHODS: In Korean, 125 women of 50 years of age or older with T-score or =5 years started DH in 2006. Lumbar (L1-4), left femoral neck, total BMD, serum parameter (beta-crossLaps [CTx], phosphorus, total calcium, total alkaline phosphatase), and urinary parameter (calcium/creatinine ratio) were measured before, the time of starting, and after DH. RESULTS: After DH, lumbar, femoral neck and total BMD did not change significantly (0.757+/-0.093-->0.747+/-0.102, P=0.135, 0.567+/-0.079-->0.560+/-0.082, P=0.351, 0.698+/-0.008-->0.691+/-0.090 g/cm2, P=0.115, respectively). Serum CTx and total alkaline phosphatase were increased significantly (0.205+/-0.120-->0.791+/-0.44 ng/mL, P60.42+/-15.543 IU/L, P=0.001, respectively). Urinary calcium/creatinine ratio increased significantly (0.132+/-0.076-->0.156+/-0.093, P=0.012). CONCLUSIONS: A DH could be cautiously considered in patients with long-term use of bisphosphonate if there is a concern about severe suppression of bone turnover with respect to long-term use because insignificant changes of BMD and significant increase of bone turnover markers are shown during the period.