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Original Studies |
Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Joel S. Finkelstein, M.D., Endocrine Unit, Bulfinch 327, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: finkelstein{at}helix.mgh.harvard.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although currently available therapies produce small increases in bone density in patients with osteoporosis (4), there are no methods to reverse osteoporosis completely once it has developed. Therefore, prevention of osteoporosis is essential. In the United States, only estrogen, alendronate, and raloxifene are approved by the U.S. Food and Drug Administration for the prevention of bone loss in early postmenopausal women. Although these agents prevent bone loss at most skeletal sites, bone loss resumes promptly when therapy with estrogen, and possibly alendronate, is discontinued (5, 6). Thus, it is likely that long term therapy with these agents will be needed to prevent the development of osteoporosis.
Although PTH is usually thought to cause bone resorption, it is now well established that once daily PTH administration increases bone formation and has a powerful anabolic effect on the skeleton (7, 8). In animals, intermittent PTH administration prevents castration-induced bone loss (9, 10, 11) and can completely reverse established osteopenia (10, 12, 13, 14). After PTH administration is stopped, however, bone mineral density (BMD) decreases in ovariectomized rats, so the PTH-induced gains in BMD are subsequently lost (15, 16, 17, 18). We recently reported that daily administration of human (h) PTH-(1–34) prevents bone loss from the proximal femur and total body and actually increases BMD in the lumbar spine in women with endometriosis rendered estrogen deficient by treatment with a long acting GnRH analog (19, 20). The effect of discontinuing daily PTH administration on bone mass in women is currently unknown. To assess the skeletal effects of stopping daily PTH administration, we remeasured BMD at multiple skeletal sites in women previously treated with a GnRH analog with or without daily hPTH-(1–34) 1 yr after active therapy was discontinued.
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Subjects and Methods |
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Patients were recalled 1 yr after completing an initial study in which they received a GnRH analog with or without hPTH-(1–34) for 6–12 months (19, 20). Fifty-one women between the ages of 20–45 yr who had symptomatic, laparoscopically proven endometriosis and participated in the original study returned for this follow-up examination. Thirteen of these 51 women did not meet the entry criteria for the follow-up evaluation (see below). Before entry into the initial study, ovulation was confirmed by a luteal phase serum progesterone level greater than 5 ng/dL (19, 20). All women had normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, free T4 index, and PRL concentrations. Women with disorders or taking medications known to affect bone metabolism were excluded. Oral contraceptives and danazol were discontinued for at least 2 months, and GnRH analog therapy was discontinued for at least 9 months before entry into the initial study (19, 20). Because the goal of the current study was to assess the changes in BMD after discontinuation of nafarelin with or without hPTH-(1–34), women who received a therapy or who developed a medical condition known to affect BMD during the year after active therapy were excluded from the follow-up study. Thirteen such women were excluded for the following reasons: retreatment with a GnRH analog (n = 5), bilateral ovariectomy (n = 4), postpartum lactation (n = 3), and danazol therapy (n = 1). After exclusion of these 13 women, there were 38 women (23 in group 1 and 15 in group 2, see below) in the follow-up study. Because there is little evidence that oral contraceptive use affects BMD in premenopausal women (21, 22, 23), women who were treated with oral contraceptives after the period of nafarelin with or without hPTH-(1–34) were not excluded. The study was approved by the human research committee at Massachusetts General Hospital. All women provided written informed consent.
Protocol for the initial study
The original 51 women were randomly assigned using computer-generated cards to receive the GnRH analog nafarelin acetate (Synarel, Syntex Laboratories, Inc., Palo Alto, CA; 200 µg, intranasally, twice daily) for 6–12 months (group 1; n = 28) or nafarelin acetate plus hPTH-(1–34) [40 µg (500 U), sc, daily] for 6–12 months (group 2; n = 23) (19, 20). Seven women in each group received nafarelin acetate with or without hPTH-(1–34) for 6 months, and the remainder received their assigned therapy for 12 months. The women who received therapy for only 6 months completed therapy before regulatory authorities allowed extension of GnRH analog therapy to 12 months. The remaining women from the original 6-month study agreed to continue in their randomly assigned study groups for an additional 6 months. The hPTH-(1–34) was synthesized by solid phase methods (Bachem, Inc., Torrance, CA), and its potency was determined by bioassay (24). If serum estradiol concentrations remained 40 pg/mL or greater or symptoms of endometriosis were not substantially relieved after 3 months, the nafarelin dose was increased by 200–400 µg daily. In group 2, 24-h urinary calcium excretion and serum calcium were measured 2–4 weeks after starting hPTH-(1–34) therapy. If urinary calcium excretion was above 300 mg/day, dietary calcium intake was decreased by 50%. If the serum calcium level was more than 10.5 mg/dL, the hPTH-(1–34) dose and/or dietary calcium intake were decreased by 30–50%. Serum or urinary calcium measurements were repeated to document normality. Because both we and our local institutional review board believed that the use of placebo PTH injections was inappropriate, no placebo was used. Thus, neither the patients nor the investigators were blinded with respect to treatment.
The women were initially admitted to the General Clinical Research Center (GCRC) at Massachusetts General Hospital (Boston, MA) between days 6–10 of their menstrual cycle and were readmitted every 3 months for 6–12 months. During each admission, the women underwent measurements of radial, spinal, proximal femur, and total body BMD; collection of a fasting second voided urine between 0800–1000 h for measurement of hydroxyproline (OHP) and creatinine excretion; and collection of a fasting blood sample for measurement of serum alkaline phosphatase, osteocalcin (OC), PTH, and estradiol concentrations. Some of these data have been reported previously (19, 20). Blood was drawn just before the morning treatment with nafarelin with or without hPTH-(1–34). Side-effects of therapy and self-reported symptom relief were assessed during each visit and were reported previously (19, 20). Daily calcium intake and body mass index were determined by a research dietitian. The women were asked to maintain a daily calcium intake of approximately 1200 mg through diet or calcium carbonate supplements.
Protocol for the follow-up study
One year after the end of treatment, women were readmitted to the General Clinical Research Center between days 6–10 of their menstrual cycles. Because of ethical considerations, women were allowed to receive any therapy for endometriosis that was recommended by their managing physicians between the end of their nafarelin therapy and their 1-yr follow-up examination, even if that therapy might affect bone metabolism. As noted above, however, women who received a therapy or who developed a medical condition known to affect BMD during the year after active therapy became ineligible for the follow-up study. For the follow-up examination, women underwent measurements of radial, spinal, proximal femur, and total body BMD; collection of a fasting second voided urine between 0800–1000 h for measurement of OHP and creatinine excretion; and collection of a fasting blood sample for measurement of serum alkaline phosphatase, OC, PTH, and estradiol concentrations.
Determination of BMD
BMDs of the proximal radius, lumbar spine, proximal femur, and total body (TBBD) were determined by dual energy x-ray absorptiometry (DXA; QDR-2000, Hologic, Waltham, MA) (25) Measurements of the nondominant radius were made in the diaphysis at the junction of the proximal two thirds and distal one third; the coefficient of variation of this measurement was 1.5% (26). Lumbar spine BMD was assessed in both the anterior-posterior (AP) and lateral projections with the women supine. Lateral spinal BMD estimates trabecular bone mass better than measurements made in the AP projection (25). TBBD was analyzed without contribution from the head region because the head accounts for most of the variability of this measurement (27). SDs for AP and lateral spine measurements were 0.010 and 0.013 g/cm2, respectively, and did not vary with BMD. The coefficients of variation for femoral neck, trochanter, and TBBD measurements were 2.2%, 1.1%, and 1.1%, respectively (28). Follow-up scans were matched to baseline scans to assure measurement of identical bone regions. Vertebrae with obvious deformities or areas of focal sclerosis were not analyzed, and those with visible overlap from ribs or pelvis were eliminated from analysis of lateral spine scans. All bone density scans were read by a physician who was blinded with respect to treatment assignment.
Assays
Serum PTH-(1–84) and OC were measured with immunoradiometric assays (Nichols Institute Diagnostics, San Juan Capistrano, CA). The assay for PTH-(1–84) does not detect hPTH-(1–34). Serum estradiol was determined by RIA (29). Urinary OHP excretion was measured by SmithKline Beecham Clinical Laboratories (Van Nuys, CA) using automated spectrophotometric analysis.
Statistical analyses
The primary end point was the within-group change in BMD between the end of active therapy and the 1-yr follow-up and was assessed using paired t tests. A secondary end point was the within-group net change in BMD from baseline (pretherapy) until the 1-yr follow-up examination and was also assessed using paired t tests. Between-group differences in the percent changes in BMD between the end of active therapy and the 1-yr follow-up visit and from baseline (pretherapy) until the 1-yr follow-up examination were compared using nonpaired t tests. Changes in bone turnover markers were assessed similarly. P < 0.05 was considered significant.
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Results |
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The clinical characteristics of the women at the time of their
1-yr follow-up examination are shown in Table 1
. In group 1, 6 of 23 (26%) women used
oral contraceptives after the end of nafarelin therapy. In group 2, 5
of 15 (33%) women used oral contraceptives after the end of nafarelin
plus hPTH-(1–34) therapy (P = 0.63 vs.
group 1). Serum alkaline phosphatase levels were slightly
(P = 0.051) higher in group 1 than in group 2, but were
well within the normal range in both groups. There were no other
important differences in baseline characteristics between the 2
groups.
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Changes in BMD and bone turnover during nafarelin with or without
hPTH-(1–34) therapy are shown in Table 2. These data have been
reported separately in the past for the women who were treated for only
6 months and the women who were treated for 12 months (19, 20). In
group 1, BMD decreased significantly at all skeletal sites except the
proximal radius during nafarelin therapy (P < 0.001
for the AP spine, lateral spine, femoral neck, and trochanter;
P = 0.005 for TBBD; P = 0.087 for the
proximal radius). In group 2, BMD of the lateral spine increased
significantly (P = 0.002) during nafarelin plus
hPTH-(1–34) therapy. There were no significant changes in BMD at the
other skeletal sites during nafarelin plus hPTH-(1–34) therapy in
group 2.
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Clinical effects of discontinuation of nafarelin plus hPTH-(1–34) therapy
Cyclic menstrual function resumed promptly after discontinuation of nafarelin therapy. In group 1, menses resumed within 2 months in all but two women. In group 2, menses resumed within 2 months in all women. Mean (±SD) serum estradiol levels at the time of the 1-yr follow-up examinations were 105 ± 86 pg/mL in group 1 and 95 ± 65 pg/mL in group 2, values that are normal for days 6–10 of the menstrual cycle.
Effects of discontinuation of nafarelin plus hPTH-(1–34) therapy on BMD
The changes in BMD between the end of active therapy and the 1-yr
follow-up examination are shown in Table 2
and Fig. 1. In group 1, BMD increased
significantly at all sites (P < 0.001 for the AP and
lateral spine; P = 0.014 for the femoral neck;
P = 0.004 for the trochanter), except the proximal
radius (P = 0.065) and TBBD (P =
0.069), after nafarelin therapy was stopped. In group 2, BMD increased
significantly at AP spine (P < 0.001), lateral spine
(P = 0.012), femoral neck (P = 0.002),
and trochanter (P = 0.029) after nafarelin therapy was
stopped.
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and Fig. 2. In group 1, BMD was still
significantly below baseline values at the AP spine (P
< 0.001) and femoral neck (P = 0.006) and tended to be
lower than baseline values at the trochanter (P =
0.057) and TBBD (P = 0.101) at the end of the 1-yr
follow-up period. In group 2, BMD was significantly above baseline
values at the AP and lateral spine (P < 0.001) sites
and was similar to baseline values at the other skeletal sites at the
end of the 1-yr follow-up period.
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and 2. BMD of the spine in
the AP projection increased more in group 2 than in group 1 after
therapy was stopped (P = 0.045). BMD of the femoral
neck also increased more in group 2 than in group 1 after therapy was
stopped, although the difference was not statistically significant
(P = 0.171). Changes in BMD between the end of active
therapy and the follow-up evaluation were similar in groups 1 and 2 at
the other skeletal sites. The overall percent change in BMD was greater
in group 2 than in group 1 for the AP and lateral spine
(P < 0.001), femoral neck (P = 0.005),
and TBBD (P = 0.032) and was borderline for the
trochanter (P = 0.096). Effects of discontinuation of nafarelin and hPTH-(1–34) therapy on bone turnover
The percent change in biochemical markers of bone turnover between
the end of active therapy and the 1-yr follow-up examination are shown
in Fig. 3. All three markers of bone
turnover decreased significantly between the end of active therapy and
the 1-yr follow-up visit in group 1 (P < 0.001 for
alkaline phosphatase and urinary OHP and P = 0.003 for
OC) and group 2 (P < 0.001 for all three markers).
Moreover, all three markers of bone turnover returned to values that
were indistinguishable from pretreatment levels in both groups.
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. In group 1, serum alkaline
phosphatase and OC levels were similar to baseline values, whereas
urinary OHP excretion was lower than at baseline (P =
0.006) at the end of the 1-yr follow-up period. In group 2, all three
markers of bone turnover were similar to baseline values at the end of
the 1-yr follow-up period.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Little is known about the effects of discontinuing PTH administration on bone mass. In ovariectomized rats, PTH administration increases BMD, but BMD decreases rapidly when PTH is stopped (15, 16, 17, 18). Bone mass does not decrease, however, after discontinuation of PTH administration in intact old male rats (15). PTH-induced increases in BMD can be maintained in ovariectomized rats if estrogen, a bisphosphonate, or a raloxifene analog are administered after PTH is stopped (17, 18, 30). No prior studies have examined the consequences of stopping PTH therapy in humans.
The increases in BMD after discontinuation of therapy could be due to the effects of restoration of ovarian steroid secretion, the effects of stopping PTH administration, or both. Numerous studies have demonstrated that BMD increases after GnRH analog therapy is stopped (31, 32, 33), although restoration of bone mass is often incomplete (34, 35, 36). In our study, BMD increased in the women treated with nafarelin alone, although BMD remained below baseline values at several skeletal sites. Thus, it appears that GnRH analog-induced bone loss is only partially reversible in our study population. Importantly, however, BMD of the AP spine (and possibly the femoral neck), increased more after cessation of combined therapy with nafarelin plus PTH than after cessation of therapy with nafarelin alone. It is unknown why the AP spine (and possibly the femoral neck) responded more favorably than other skeletal sites to discontinuation of PTH. Although it is likely that the increases in BMD in the women who received nafarelin plus PTH were in part due to restoration of ovarian steroid secretion, our data suggest that the anabolic effects of PTH on the skeleton in humans may not be fully appreciated until after PTH administration is discontinued.
The mechanism by which bone mass might increase after discontinuation of PTH therapy is unknown. This finding may be related, however, to the technique used to assess bone mass. DXA measures only the mineral content of bone, not the organic bone matrix. PTH increases the rate of bone turnover, and there is typically a lag of several months until newly formed bone matrix becomes fully mineralized. Thus, it is possible that some of the PTH-induced new bone matrix was still incompletely mineralized at the time PTH therapy was stopped. If so, mineralization should continue after PTH therapy was stopped and would ultimately be detected by DXA. This theory is consistent with recent reports that BMD increases markedly in patients with primary hyperparathyroidism after surgical cure (37, 38). It is also possible, however, that additional increases in BMD after discontinuation of PTH administration are due to filling in of the bone remodeling space that was excavated in response to PTH.
Bone loss resumes promptly when therapy with estrogen, and possibly alendronate, is discontinued in postmenopausal women (5, 6). Thus, long term therapy with these agents is probably needed to prevent the development of osteoporosis. In contrast, our data demonstrate that spinal BMD and possibly BMD of the femoral neck actually increase further after PTH therapy is discontinued than after discontinuation of GnRH analog therapy alone. In fact, spinal BMD was 6–8% higher 1 yr after stopping nafarelin plus hPTH-(1–34) therapy than at baseline. Because BMD typically decreases at a rate of 1–4%/yr in postmenopausal women (1), it may be possible to treat estrogen-deficient women with hPTH-(1–34) for 6–12 months and then discontinue therapy for a substantial period of time before BMD decreases to its baseline value. Moreover, prospective cohort studies suggest that changes in BMD of the magnitude observed after discontinuation of PTH are associated with a marked reduction in the risk of osteoporotic fractures (39, 40). In fact, a recent study found a suggestive decrease in the risk of vertebral fractures in estrogen-replete postmenopausal women treated with PTH, although only 34 women were evaluated (41), and animal studies have demonstrated that PTH increases bone strength (41, 42). Further studies are needed to evaluate the effects of periodic PTH administration on bone mass and fractures in postmenopausal women.
In conclusion, we found that BMD increases after discontinuation of GnRH analog therapy with or without concomitant PTH administration. In women treated with a GnRH analog alone, BMD did not return to baseline. In women who received a GnRH analog plus hPTH-(1–34), the final BMD was at or above pretreatment values at all skeletal sites, with substantial increases in the BMD of the lumbar spine. Moreover, spinal BMD increased more after cessation of combined therapy with a GnRH analog plus PTH than after cessation of the GnRH analog alone. These findings suggest that part of the increases in BMD are due to the restoration of ovarian function, whereas additional increases in BMD are due to the anabolic effect of PTH on the skeleton. Studies in PTH-treated women who remain estrogen deficient are needed to clarify the relative contributions of these mechanisms to the changes in bone mass after PTH therapy is stopped.
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Acknowledgments |
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Footnotes |
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Received November 16, 1998.
Revised January 11, 1999.
Accepted January 20, 1999.
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References |
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