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Departments of Medicine and Therapeutics (C.C.C., W.B.C., N.N.C., C.S.C.) and Chemical Pathology (M.H.M.C.), The Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong; Department of Medicine, Yan Chai Hospital, Hong Kong (J.K.Y.L.); Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong (G.T.C.K.); and Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong (K.W.L.)
Address all correspondence and requests for reprints to: Dr. C. C. Chow, Department of Medicine and Therapeutics, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. E-mail: ccf193chow{at}cuhk.edu.hk.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Despite largely asymptomatic presentation, the skeleton remains a target organ of concern in the hyperparathyroid disease process. Classically, effects of excess PTH on bone are seen with preferential involvement of the cortical sites, such as the distal forearm, and relative sparing of the cancellous sites, such as the lumber spine (7). The underlying pathophysiology is probably due to increased bone turnover with enhancement in both bone resorption and bone formation (8). An increase in bone mineral density (BMD) has also been observed in patients after parathyroidectomy (9). Paradoxically, the greatest increments have been reported to occur in the cancellous bone, with a 10% increase in lumber spine BMD and a 14% increase in femoral neck BMD after 10 yr, respectively (9). Medical therapy for PHP using sex hormone replacement has previously shown preservation of BMD in postmenopausal women (10, 11). However, compliance with long-term sex hormone replacement has been shown to be poor (12).
Bisphosphonates are analogs of inorganic pyrophosphate that inhibit bone resorption, the driving force of increased bone turnover in patients with PHP (13). Bisphosphonates have been shown to be safe and effective in the treatment of postmenopausal and glucocorticoid-induced osteoporosis (14, 15, 16). Intravenous pamidronate acutely has been shown to be effective in lowering serum calcium in PHP for at least 1–2 wk (17, 18). Several oral bisphosphonates have been used to treat PHP up to 12 wk. These short-term small studies have demonstrated slight reduction of serum calcium, together with decrease in serum alkaline phosphatase activity and urine hydroxyproline, indicating that bone turnover is reduced (19, 20, 21). However, a compensatory rise in the level of PTH may occur, which may limit the use of oral bisphosphonates in PHP (18, 20). There are very limited data available concerning the efficacy and safety of longer duration of bisphosphonate use in patients with PHP. In this double-blind, randomized, placebo-controlled trial, we examined the efficacy of oral alendronate, a potent second-generation bisphosphonate, in the management of postmenopausal women with PHP over a period of 48 wk, with further follow-up of 24 wk after discontinuation of therapy.
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Patients and Methods |
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This is a double-blind, randomized, placebo-controlled trial. Forty postmenopausal women with PHP were recruited. The BMD at femoral neck was chosen as the primary endpoint. Secondary endpoints included BMD at lumber spine and distal radius and serum albumin-adjusted calcium concentration.
PHP was diagnosed by a trained endocrinologist based on a serum albumin-adjusted calcium concentration greater than 2.62 mmol/liter (normal range, 2.15–2.55 mmol/liter) with an inappropriately normal or raised serum PTH concentration. The patients who were recruited were grouped as follows: 1) those who did not reach criteria for surgery according to the NIH guideline (22); 2) those who preferred not to have surgery; 3) those who were considered to be at too high surgical risk; and 4) those who were on the waiting list for surgery. Three had a history of previous fracture. One had fractured neck of the femur, and two had collapsed lumbar spine. All had spinal anatomy suitable for dual-energy x-ray densitometry measurement at three vertebrae from L1–L4 at least. We excluded patients who received bisphosphonates, calcitonin, gallium nitrate, mithramycin, or fluoride treatment within 1 yr of recruitment. We also excluded patients on sex hormone replacement therapy (HRT) and patients who were taking medications that will affect bone metabolism, including steroid, anticonvulsants, vitamin D in excess of 1,000 U/d, and vitamin A in excess of 10,000 U/d. Patients who had underlying diseases that may affect bone metabolism were also excluded. These included Paget’s disease, osteogenesis imperfecta, rheumatoid arthritis, systemic lupus erythematosus, and other collagen vascular diseases. We excluded patients with unstable angina or myocardial infarction within 1 yr before study entry, patients with malignancy within the past 10 yr, patients with significant renal impairment defined as serum creatinine greater than 150 µmol/liter, or other end organ damage that might pose risk or complicate participation in the study. All patients provided written consent, and the study protocol were approved by the University Ethical Committee.
Study design
At the first visit, a full clinical assessment and physical examination were performed. These included demographic data and symptoms of PHP. Fasting blood samples were taken at screening for measurement of serum concentrations of calcium, phosphate, albumin, total alkaline phosphatase activity, and TSH. Patients were seen 4 wk later as wk 0, and were randomized in 1:1 ratio to have either alendronate 10 mg/d or placebo for 48 wk if they fulfilled all inclusion and exclusion criteria. All patients were instructed to take the study drug each morning while fasting, at least 30 min before the first meal, with at least 125 ml of plain water. They were instructed to remain upright for at least 30 min after taking the drug. Throughout the study, the patients were instructed on normal calcium diet and avoiding extra vitamin D supplement. The patients attended for follow-up at wk 4, 12, 24, 36, and 48. At each visit, patients were asked to bring back the remaining test drugs for estimation of compliance by tablet counting. They were also questioned about symptoms of PHP using a standardized questionnaire that included symptoms of bone, joint, gastrointestinal tract, and general well-being. Questions about adverse events other than the above-mentioned aspects were asked in an open fashion manner. Fasting blood samples were taken for measurement of serum concentrations of albumin, calcium, phosphate, osteocalcin, PTH, 25-hydroxyvitamin D, and bone-specific alkaline phosphatase activity (Bone-ALP). Samples of 24-h urine were collected for measurement of daily urinary calcium excretion and concentrations of creatinine and urinary N-telopeptide.
BMD was measured at wk 0, 24, and 48 using dual-density x-ray absorptiometry (model QDR-2000 bone densitometer, Hologic, Inc. Waltham, MA.). Measurements were taken at femoral neck, lumbar spine (L2, L3, and L4), and distal third of the nondominant radius. Vertebrae with deformities and focal sclerosis were excluded from measurement. The CV of these measurements on a phantom spine was 0.4%. After wk 48, the test drug was stopped. The patients were then reassessed at wk 60 and 72. Blood was again taken at these two visits for serum concentrations of albumin, calcium, phosphate, Bone-ALP, and PTH. BMD was measured again at wk 72.
Methods
All blood samples were centrifuged and sera aliquoted immediately after collection. They were deep-frozen at -70 C together with all urine samples until analysis in one single batch. Serum PTH was measured using a two-site sandwich-type chemiluminometric assay (Immulite, Diagnostic Products Corp., Los Angeles, CA) that only detects the intact PTH molecule. The lower limit of detection of the assay was 0.1 pmol/liter, and the assay was capable of detecting PTH in all normal subjects. The interassay CV was 8.6% at 6.2 pmol/liter. Serum total calcium was measured by bichromatic endpoint technique after reacting with o-cresolphthalein (Dimension AR, Dade Behring Inc., Newark, DE). The values were then adjusted with serum albumin concentration using the following formula: Adjusted calcium (in mmol/liter) = Measured calcium (in mmol/liter) + 0.025 x [40 - Measured albumin (in g/liter)] (Ref. 23). Urinary calcium concentration was measured using the bichromatic endpoint technique after reacting with o-cresolphthalein I alkaline solution (Hitachi 911, Roche Diagnostics Corp., Indianapolis, IN). Serum 25-hydroxyvitamin D was measured using a competitive protein-binding assay after extraction (125I RIA kit, DiaSorin, Inc., Stillwater, MN). The interassay CV was 9.4% at 8.6 µg/liter. Bone-ALP was quantified by precipitation with wheat-germ lectin. Osteocalcin (Diagnostic Systems Laboratories Inc., Webster, TX) and urine N-telopeptide (Ostex International, Inc., Seattle, WA) were measured by two-site, sandwich-type, enzyme-linked immunosorbent assay. Urine creatinine (Roche Diagnostics Corp.) concentrations were measured by chemiluminescence immunoassay and kinetic Jaffe reaction. The interassay CV for osteocalcin, Bone-ALP, N-telopeptide, and creatinine measurements were 5.6% at 1.2 µg/liter, 1.8% at 394 IU/liter, 9.2% at 402 nmol/liter, and 2.8% at 8.51 mmol/liter, respectively.
Statistical analysis
The data were analyzed using SPSS 8.0 for Windows (SPSS, Inc., Chicago, IL). The data are expressed in mean ± SD. BMD is expressed as grams per square centimeter, and change in BMD is expressed as percentage change. Baseline data were compared using an unpaired t test. Changes in BMD at 48 wk between two groups were compared using an unpaired t test. Changes in BMD at femoral neck were the prespecified primary endpoint, whereas P values of all other secondary endpoints were adjusted for multiple comparisons (24). Serial changes of serum calcium, phosphate, Bone-ALP, and BMD were analyzed exploratory with ANOVA of repeated measures, with treatment group as the independent variable. We used the Bonferroni method for multiple adjustment. Changes in symptomatology between groups were compared using a 
2 test. Our previous study has shown that the SD of change in BMD at femoral neck was around 3% (our unpublished data). The present study has 90% power to detect a 3% difference in BMD at femoral neck between the two groups.
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Results |
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Forty patients were screened; all were eligible and agreed to participate in the study. The mean (±SD) age of the patients was 70 ± 9.3 yr, with a mean known duration of disease of 1.8 ± 1.4 yr. Only 2.5% had a raised serum Bone-ALP, 30% of the patients had a history of renal calculi, and 12.5% had a history of peptic ulcer or upper gastrointestinal bleeding. The whole group had a high prevalence of concomitant medical illnesses: 65% with hypertension, 32.5% with diabetes mellitus, and 17.5% with ischemic heart disease. There was no significant difference in the clinical characteristics between the two groups (Table 1
).
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BMD
The patients were generally osteoporotic with baseline BMD 0.540 ± 0.112 g/cm2 (T score, -2.07 ± 1.04) at femoral neck, 0.712 ± 0.132 g/cm2 (T score, -2.54 ± 1.25) at lumbar spine, and 0.478 ± 0.086 g/cm2 (T score, -3.58 ± 1.43) at distal third of radius (Table 1
). BMD at the distal radius could not be measured in seven subjects because they were unable to either remain still during scanning or remove a jade bracelet from the wrist. There was no significant difference between the two groups.
At 48 wk, the change in BMD at the femoral neck was statistically different between the two groups (+4.17 ± 6.01% for alendronate vs. -0.25 ± 3.35% for placebo; P = 0.011). BMD in the alendronate group subsequently fell to +3.42 ± 6.29% 24 wk after withdrawal of treatment (P = 0.012 for trend of change over time). The BMD of the placebo group did not show significant changes throughout the study period (P = 0.291). The difference in trend between the two groups was statistically significant (P = 0.005; Fig. 1).
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). There was no difference in change of BMD at the distal third of radius at 48 wk (+1.01 ± 2.32% vs. 0.07 ± 5.50%; P = 0.573) between the two groups (Fig. 1). Calcium and biochemical markers of bone turnover
The change in serum calcium concentration was significantly different between the two groups (-0.09 for alendronate vs. +0.01 mmol/liter for placebo; P = 0.036). In the alendronate group, serum calcium concentration showed significant decrease from a mean of 2.82 mmol/liter at baseline to 2.74 mmol/liter at the end of 48 wk and rose to 2.78 mmol/liter 24 wk after drug withdrawal (P = 0.003 for trend of change over time). Serum calcium did not show significant change in the placebo group (P = 0.484). The trend in change of calcium showed significant difference between the two groups (P = 0.028; Fig. 2). There was no significant change in serum phosphate in either group (data not shown). The change in serum PTH was not significantly different at 48 wk (P = 0.110), and the trend of changes was not significantly different between the two groups (P = 0.110; Fig. 2). Eight of the 40 subjects had a 25-hydroxyvitamin D concentration less than 10 ng/liter, suggesting underlying vitamin D deficiency. However, there was no significant difference in serum calcium concentration between the vitamin D-deficient subjects and the vitamin D-sufficient subjects (2.76 vs. 2.83 mmol/liter; P = 0.301).
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In the alendronate group, urinary N-telopeptide/creatinine ratio showed a significant drop from baseline of 117 ± 86 to 34 ± 18 nmol/nmol (P = 0.004) at 48 wk and rose back to 53 ± 33 nmol/nmol (P = 0.003) 24 wk after withdrawal of treatment (P = 0.008 for trend of change over time). In the placebo group, N-telopeptide/creatinine ratio did not show significant change during the study. The difference in trend between the two groups was statistically significant (P = 0.039; Fig. 3). Twenty-four-hour urinary calcium was not significantly different between groups throughout the study (Fig. 3), although 24-h urinary calcium was significantly lower than baseline at 4 wk (P < 0.001), 12 wk (P = 0.003), and 24 wk (P = 0.015).
Adverse effects
At recruitment, a significant proportion of patients had musculoskeletal symptoms (60%), gastrointestinal symptoms (22.5%), and systemic symptoms (25%). However, no significant change in symptoms was recorded in either group throughout the study. There were 25 adverse events reported in the treatment group, and 24 were reported in the placebo group. Most were upper respiratory tract infections. There were two serious adverse events in the alendronate group. One patient was hospitalized because of dizziness and had a fall, another patient developed methyldopa-induced hemolytic anemia. There were three serious adverse events in the placebo group. One patient sustained a fractured right humerus after a fall. One developed first-degree heart block due to ß-blocker treatment. Another patient was excluded because of ibuprofen-induced gastric ulcer. All were withdrawn from the study. The number of adverse events was comparable between groups.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The optimal management for PHP remains controversial. Surgical intervention has been shown to increase BMD especially at femoral neck and lumbar spine (26). This treatment modality may also lead to improvement in muscle strength and nonspecific symptoms (27). However, many patients with PHP are elderly, with other comorbidities rendering them at increased surgical risk. Currently, there are very limited data in the literature regarding the role of biphosphonates in elderly patients with PHP.
BMD has been shown to be a good predictor of future fracture (28), and alendronate has been shown to be an effective treatment for osteoporosis (14, 15). Fracture at the femoral neck has a large impact on quality of life, with deterioration of functional status even after successful surgery (29). In this context, given the generally osteoporotic bone profile in our PHP cohort, the T score at femoral neck in particular is low (at a mean of -3.15). This implies a theoretical risk of fracture at the femoral neck, and the increase in BMD at the femoral neck with alendronate treatment may be particularly important. Similarly, in our study, an increase in BMD was also detected at the lumbar spine. The lack of improvement in BMD at the distal radius indicates that alendronate does not have a major effect on this site. HRT has also been used to improve BMD in postmenopausal women with PHP, but compliance has generally been unsatisfactory in most surveys. The excellent compliance in our study suggests that alendronate may be a more suitable alternative than HRT in postmenopausal women with PHP.
One theoretical concern with the use of alendronate is a potential increase in PTH concentration in response to lowering of serum calcium (19, 20, 21), because hypercalcemia may exert a feedback suppression on PTH secretion in patients with PHP (30, 31). Short-term administration of pamidronate has been shown to result in an increase in PTH concentration (18). This may result in an increase in urinary calcium excretion and, hence, risk of renal calculi. Reassuringly, this study shows no difference in serum PTH concentration with placebo or alendronate after 48 wk. Furthermore, the urinary calcium excretion also did not change significantly with alendronate therapy.
In this study, serum calcium concentration did drop significantly with alendronate, albeit a small magnitude (-0.09 mmol/liter). Although there is insufficient evidence to support the use of alendronate for normalization of calcium in patients with PHP, it may have a role in stabilizing a modest degree of hypercalcemia. Interestingly, in our study, serum calcium levels rarely increased above 3.0 mmol/liter, an indication for surgery. In contrast, urinary calcium did not change throughout the study. Overall, alendronate should be considered safe and effective in postmenopausal women with PHP with only mild or modest hypercalcemia, at least over a 1-yr period.
In patients with PHP, bone (in particular cortical bone) is reduced by increased bone turnover. It has been shown that serum Bone-ALP, a marker of bone formation, is a predictor of improvement in BMD after parathyroidectomy (32). In this study, alendronate therapy produced a significant decrease in serum Bone-ALP and osteocalcin concentrations, both of which are indices of bone formation. Furthermore, the urinary N-telopeptide/creatinine ratio decreased significantly with alendronate, suggesting a decrease in bone resorptive activity. Short-term use of alendronate has also been shown to decrease other markers of bone resorption in PHP (33). Our study has clearly shown that this effect persists even with longer-term use. We have also demonstrated that the increase in BMD was mainly confined to the femoral neck and lumbar spine. This suggests that the main improvement associated with alendronate was in trabecular bone. The differential improvement at different sites is not well understood. One possible mechanism is that in PHP, the decrease in BMD observed in cortical bone is probably due to an increase in bone diameter rather than true osteoporosis (34). No comment can be made about fracture risk. However, an increase in fracture rate in PHP is not well documented (35, 36). Furthermore, our study was not sufficiently powered to study fracture incidence as a clinical endpoint. Whether oral alendronate given for a longer duration reduces fracture in postmenopausal women with PHP remains undetermined.
In conclusion, alendronate therapy improves BMD at the femoral neck and lumbar spine and has favorable effects on serum calcium concentration and markers of bone turnover in postmenopausal women with PHP over a 1-yr period. Hence, it may be a suitable alternative to surgery, especially in elderly patients who are at increased surgical risk. Its excellent tolerability enhances compliance, making it more superior to HRT in postmenopausal women with PHP. Whether its beneficial effects on bone persist beyond 1 yr requires further investigations.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMD, Bone mineral density; Bone-ALP, bone-specific alkaline phosphatase activity; CV, coefficient(s) of variation; HRT, hormone replacement therapy; PHP, primary hyperparathyroidism.
Received June 7, 2002.
Accepted October 17, 2002.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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