Changes in Biochemical Markers of Bone Turnover (Serum CTX and PlNP) After Initiation of a "Drug Holiday" From Bisphosphonates
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02575157|
Recruitment Status : Unknown
Verified October 2015 by National Bone Health Alliance.
Recruitment status was: Recruiting
First Posted : October 14, 2015
Last Update Posted : October 14, 2015
|Condition or disease||Intervention/treatment||Phase|
|Osteoporosis||Other: No intervention||Not Applicable|
Bisphosphonates (BP) are widely used in the prevention and treatment of osteoporosis in postmenopausal women and older men. Recently, there has been concern about the risk of adverse events after several years of using these agents. This has resulted in a publication from the Food and Drug Administration that suggested that, for many individuals, a holiday from bisphosphonates might be considered after 4-5 years of continuous use. In that publication there was little, if any, guidance on how clinicians should proceed after the holiday is initiated.
Bisphosphonates likely work by first binding to the hydroxyapatite crystal, and when the crystal is dissolved in the acid medium created by osteoclasts in the process of bone resorption, the bisphosphonate is released, and is incorporated into the osteoclast where it inhibits farnesyl pyrophosphate synthase and interferes with intracellular protein trafficking. The consequence is loss of osteoclast resorptive activity and in some cases osteoclast apoptosis. Thus the potency of any particular bisphosphonate is dependent on independent processes, such as the binding affinity to hydroxyapatite and the potency of enzyme inhibition. As patients remain on bisphosphonates, it is likely that more and more of the drug will become incorporated into the skeleton. Therefore, when the drugs are discontinued, they gradually leach from the skeleton. The rate at which the effects of the drug wear off ("off-rate"), as evidenced by changes in biochemical markers of bone turnover, should be dependent on the binding affinity. The length of time for which the pharmacologic effect continues will also be dependent on potency of enzyme inhibition. Thus, each bisphosphonate will likely have a unique off-rate. Data from the extensions of some of the clinical trials support the concept of variable off rates, but there are no head to head data to determine this. Furthermore, clinical trial data may have limited utility in patients seen in a practice setting.
Biochemical markers have been shown in a number of studies to be reliable surrogate markers for the overall rate of bone remodeling in the skeleton. After menopause or ovariectomy, serum levels of biochemical markers increase and these increments have been associated with the rate of bone loss as measured by dual x-ray absorptiometry (DXA). As individuals age, fracture risk is determined by both age and bone mineral density (BMD). Trabecular bone score (TBS), an advanced application for DXA, describes the quality of bone microarchitecture, which has been shown to impact bone strength and thus fracture risk.
In clinical trial data where bisphosphonates have been discontinued and subjects continue to be followed, biochemical markers increase after the drug is stopped, and presumably the fracture benefit of the drug will be gradually lost. Concern over possible association of the long term side effects of bisphosphonates (notably osteonecrosis of the jaw and atypical fractures of the femoral shaft) have led to a concept, endorsed by FDA, of a drug holiday. At present there are no guidelines on how patients should be followed when the drugs are discontinued. From the clinical trial data in different subject populations with differing protocols, as well as in vitro data, the inference may be drawn that the off effects will vary with different drugs. It is hypothesized that risedronate will lose its effect more rapidly than alendronate. However, this concept has never been studied in a prospective clinical study. Therefore, the intent in this prospective study is to examine patients who are about to be taken off of 2 different bisphosphonate drugs and compare their off rates using two established biochemical markers (sCTX and P1NP).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||120 participants|
|Intervention Model:||Factorial Assignment|
|Masking:||None (Open Label)|
|Official Title:||Changes in Biochemical Markers of Bone Turnover (Serum CTX and PlNP) After Initiation of a "Drug Holiday" From Bisphosphonates|
|Study Start Date :||June 2015|
|Estimated Primary Completion Date :||June 2016|
|Estimated Study Completion Date :||June 2018|
No Intervention: Discontinuing usage
Patients will discontinue use of bisphosphonates. Bone markers and BMD will be monitored until a need for reinitiation of treatment within 2-years is identified or needed.
Other: No intervention
- Changes in bone turnover markers. [ Time Frame: 2 years ]
- Changes in bone mineral density [ Time Frame: 2 years ]
- Changes in trabecular bone score [ Time Frame: 2 years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02575157
|Contact: Taylor C Wallace, PhDfirstname.lastname@example.org|
|Contact: David Lee, BSemail@example.com|
|United States, District of Columbia|
|Taylor C. Wallace||Recruiting|
|Washington, District of Columbia, United States, 20036|
|Contact: Paul Miller, MD 303-980-9475 firstname.lastname@example.org|
|Contact: Debi Aggers 3039809475 email@example.com|