Changes in Biochemical Markers of Bone Turnover (Serum CTX and PlNP) After Initiation of a "Drug Holiday" From Bisphosphonates

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).

Inclusion Criteria:

1. Postmenopausal women or males >50 years who have taken oral bisphosphonates
(risedronate or alendronate) for five years or more, and in whom it is considered
reasonable to initiate a holiday from the medication, or those who have been on a
holiday for up to 3 months will be eligible for screening visit.

2. Subjects whose 25(0H) D level is above 30 ng/ml (subjects with 25(0H)D from 10-29
ng/ml may be included after supplementation and assessment of serum 25(0H)D) level is
above 30 ng/ml.

Exclusion Criteria:

1. Current steroid treatment at or greater than 5 mg/day prednisone or equivalent.

2. The use of any other bone active medication other than risedronate or alendronate.

3. The use of teriparatide within the past 4 years.

4. A contra-indication to the discontinuation of bisphosphonate (e.g. fracture during
treatment, extremely low t-score).

5. Subjects with fasting serum sCTX less than 100 pg/ml or greater than 300 pg/mL while
taking bisphosphonates.

6. Failure to bring 25(0H)D serum level to 30 ng/ml or greater.

7. Metabolic bone disease other than osteoporosis.

8. Abnormal thyroid function (may be included when thyroid function is shown to be
normal by TSH). Per local lab assessment.

9. Evidence of failure to adhere to bisphosphonate use -