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Original Studies |
Center for Metabolism and Endocrinology, Department of Surgery, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
Address all correspondence and requests for reprints to: Dr. Jörgen Nordenström, Department of Surgery, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden. E-mail: jorgen.nordenstrom{at}karo.ki.se
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Abstract |
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Before surgery, all groups showed a greater reduction of bone mineral density in cortical bone (distal radius) than in predominantly trabecular bone (lumbar spine). In primary symptomatic HPT, the BMD z-score of the distal radius was -1.80 ± 0.21 (±SEM), and the corresponding figures for the total body, femoral neck, and lumbar spine were -0.60 ± 0.15, -0.54 ± 0.14, and -0.53 ± 0.18 compared with those of an age- and sex-matched reference group. In renal HPT BMD z-scores were -2.51 ± 0.38 (hemodialysis patients) and -2.83 ± 0.43 (renal transplant patients) for the distal radius and between -0.81 and -1.46 for the other measured sites.
After parathyroidectomy, BMD increased by 1–8% at all sites in patients with primary symptomatic HPT and HPT associated with renal transplant. The largest increase in bone mass was observed in patients with HPT associated with hemodialysis, in whom the improvement amounted to 7–23%. In patients with primary HPT and HPT associated with hemodialysis, this increase in bone density resulted in virtual recovery from their preoperative bone loss. The majority of patients with asymptomatic primary HPT disease (n = 21) maintained their bone density during the follow-up period and have not shown evidence of increases in serum calcium or PTH levels, but three patients followed conservatively underwent parathyroidectomy due to progressive deterioration of BMD.
We conclude that, regardless of the etiology, a large proportion of HPT patients show reduced bone density. In patients with primary symptomatic HPT and patients with HPT associated with hemodialysis, bone density increases after parathyroidectomy to an extent that largely restores the preoperative bone loss. However, no anabolic effect of parathyroidectomy on bone mass was observed in patients with HPT associated with renal transplant, probably because of their immunosuppressive therapy.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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During the last 3 decades, there has also been a change in the way in which patients present with primary HPT. Severe symptoms that were previously common in these patients are now encountered more rarely, and perhaps as many as half of all newly diagnosed patients may be considered asymptomatic (8). Previously, most, if not all, patients diagnosed with HPT underwent surgery. Nowadays, when HPT is more frequently diagnosed, and a number of patients have few if any symptoms, there is a much greater need to individualize therapy so that those who could benefit from operation could be treated accordingly, whereas those who are not expected to benefit from parathyroidectomy could be spared an operation (9). Recently, there has been an increased interest in the determination of bone mineral density (BMD) in these patients, because this parameter constitutes an objective measurement of disease activity and because patients with primary HPT who have markedly decreased bone mass almost invariably regain bone mass after successful surgery (10, 11, 12, 13).
Patients with renal failure may develop osteitis fibrosa as a result of secondary hyperparathyroidism, and a minority of these patients require parathyroidectomy. The effect of parathyroidectomy on BMD in patients with HPT associated with hemodialysis has not been as well characterized as in patients with primary HPT, and there are studies showing either favorable (11, 14, 15) or disadvantageous (16) effects. Relatively few studies have addressed bone mass changes in patients with hyperparathyroidism associated with renal transplant. In a previous cross-sectional study, we examined the effect of HPT on kidney transplant patients by comparing their bone densities with those of matched normocalcemic kidney transplant patients and found that HPT markedly impaired BMD (17). As a new functioning renal graft eliminates the factors that contribute to secondary HPT, improvement of BMD would be an expected consequence of renal transplantation. There are, however, factors associated with renal transplantation that may adversely affect bone mineralization; most importantly, the necessary immunosuppressive therapy. At present, only sparse information is available regarding the net result of opposing effects on bone mass in kidney transplant patients undergoing parathyroidectomy.
Silverberg and Bilezikian consider measurement of bone density to be instrumental in the management of patients with primary HPT (18). We concur with this recommendation, and we routinely perform bone densitometry in all patients referred to us for consideration of parathyroidectomy. In this study we present the longitudinal effects of parathyroidectomy in patients with primary symptomatic HPT, HPT associated with hemodialysis, and HPT associated with renal transplant as well as the effect of conservative (nonoperative) management in a group of patients with asymptomatic (mild) primary HPT.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One hundred and twenty-eight patients with HPT referred to our
clinic for evaluation and management were included in this study. They
consisted of 4 group of patients: 1) 54 patients with primary
symptomatic HPT, 2) 20 patients with HPT associated with hemodialysis,
3) 30 patients who displayed hypercalcemia and elevated PTH levels
after successful renal transplantation, and 4) 24 patients with primary
asymptomatic (mild) HPT in whom hypercalcemia was detected incidentally
during routine clinical testing. Demographic data for the patients are
presented in Table 1
. The causes of renal
failure in patients with renal HPT were chronic glomerulonephritis
(n = 23), polycystic kidney disease (n = 7), renal hypoplasia
(n = 2), renal tuberculosis (n = 2), congenital
hydronephrosis (n = 2), nephrocalcinosis (n = 1), chronic
pyelonephritis (n = 1), and renal failure of other cause (n =
12). Twenty of about 180 patients undergoing regular dialysis at 4
different dialysis units in Stockholm County were referred to us for
persistent HPT refractory to medical treatment. Patients were dialyzed
3 times/week for an average of 6.8 ± 1.7 (range, 1.2–20) yr,
using a dialysate calcium concentration of 1.50 mmol/L. Patients
received iv calcitriol doses between 0.25–1 µg 3 times weekly at the
end of each dialysis and oral calcium (calcium carbonate; 2–3 g/day)
based on their serum chemistries. Patients with HPT associated with
renal transplant belonged to a group of approximately 1300 patients who
received renal transplants performed at the Department of
Transplantation Surgery, Huddinge University Hospital (Huddinge,
Sweden), during the years 1977–1992. These patients had had
functioning kidney grafts for 4.1 ± 1.0 (range, 0.4–9.0) yr and
had undergone dialysis for 6.3 ± 1.7 (range, 0.8–26) yr before
kidney transplantation. Immunosuppression was maintained with
prednisolone, cyclosporin A, and/or azathioprine. All patients ate a
normal diet and did not receive vitamin D supplementation.
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Parathyroidectomy was performed in 52 patients with primary symptomatic HPT, 19 patients with HPT associated with hemodialysis, and 15 patients with HPT associated with renal transplant. All patients underwent bilateral neck exploration. In patients with primary HPT, the macroscopically enlarged gland(s) was removed, and a biopsy specimen was taken from a macroscopically normal gland. In patients with renal HPT, total parathyroidectomy was performed, with autotransplantation to the forearm of approximately 100 mg parathyroid tissue from the gland with the least abnormal appearance. The histopathological diagnosis was based on the criteria prescribed by Grimelius et al. (19).
Methods
BMD measurements of the total body, lumbar spine, and proximal femur were performed in all patients before parathyroidectomy and were repeated at 6 months, 12 months, and every 12 months thereafter. The hardware used to measure the BMD of the distal radius was not available until 2 yr after inclusion of the first patient, but it was used together with the other bone density measurements from that time on. Dual energy x-ray absorptiometry (DXA) was used for the assessment of BMD using a Lunar DPX-L absorptiometer (Lunar Radiation Corp., Madison, WI). In each patient, separate scans of the whole body, the lumbar spine L2–L4, the proximal femur (femoral neck), and the distal radius (nondominant forearm) were performed and analyzed using the manufacturer’s version 1.3 software. The in vivo measuring precision was assessed by three scans in each of eight volunteers. The coefficients of variation for the different sites were: total body, 0.6%; femoral neck, 2.0%; lumbar spine (L2–L4), 1.0%; and distal radius, 1.0%. The precision (coefficient of variation) based on repeated measurements with the Lunar Spine Phantom was 0.4%.
The reference data for BMD consisted of the data for age- and sex-matched controls obtained from the DXA manufacturer’s reference population. Although this reference population consists of healthy North American individuals, healthy Swedish controls have been shown to have BMDs similar to those of healthy Americans (20).
Blood samples were collected to determine preoperative as well as postoperative serum concentrations of calcium and intact PTH. The serum concentration of calcium was analyzed in accordance with the hospital’s standard procedures, and intact PTH was measured using the Allegro immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Data are expressed as the mean ± SEM. Student’s paired t test was used to compare preoperative bone mass and biochemical values with those obtained after surgery. The unpaired t test and ANOVA were used to compare differences between the various group of patients. Linear regression was used to correlate bone mass at different sites with other variables. The z-score was calculated for each bone density measurement from the mean for the relevant control group (z-score = patient’s value - group mean ÷ group SD). The study was approved by the hospital’s ethics committee, and the informed consent of each patient was obtained.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), and the mean BMD
z-score value at this site was -2.83 ± 0.43 to -1.32 ±
0.33 of that in the age- and sex-matched reference group (Table 2).
BMDs in the total body, lumbar spine, and femoral neck were also lower
than those in matched controls, although not to the extent that was
observed in the distal radius measurements. Furthermore, the extent of
skeletal involvement differed between the different types of HPT, with
a much greater reduction of bone density in renal HPT patients than in
patients with primary HPT (Table 2).
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All patients with HPT had elevated serum calcium and intact PTH levels.
After surgery, serum calcium returned to normal in all patients. The
majority of patients who underwent total parathyroidectomy received
calcium and vitamin D supplementation for prevention and treatment of
postoperative hypocalcemia. Serum intact PTH decreased postoperatively
to normal values in all patients with primary HPT and to normal or
near-normal levels in patients with renal HPT. In primary symptomatic
HPT patients, surgical histopathology showed adenoma in 91% and
hyperplasia in 9%. All patients with renal HPT showed a
histopathological pattern of hyperplasia (of nodular type in 46%,
diffuse and uniform hyperplasia in 20%, and both in 34%).
Parathyroidectomy was associated with increased bone density at all
measured regions regardless of the etiology of the hyperparathyroid
condition. The longitudinal changes in BMD after parathyroidectomy are
presented in Fig. 1. In primary
symptomatic HPT and renal transplant patients, modest, but
statistically significant, increases in bone mass (1–6%) were
observed during the study period. As a group, patients with HPT
associated with hemodialysis showed the most pronounced increases in
bone density. In these patients, BMD in the lumbar spine and femoral
neck had increased by 16–17% 1 yr after parathyroidectomy. This
marked increase was large enough to bring the BMD in the majority of
these patients into the reference range of age- and sex-matched
controls. A similar effect was noted in patients with primary
symptomatic HPT. On the other hand, in patients with HPT associated
with renal transplant, the modest increase at all sites that occurred
after surgery only marginally improved their markedly deranged BMDs. In
patients with primary HPT and HPT associated with hemodialysis, the
greatest bone mineral regain was observed in the patients who had the
lowest preoperative values (Fig. 2).
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. Percent changes were avoided because
not all patients were measured preoperatively at this site. BMD in the
distal radius increased in all groups after parathyroidectomy, and the
increase at this site was also the greatest in patients with HPT
associated with hemodialysis (Fig. 3). Most of the regained bone
density occurred during the first 12 months, except in patients with
HPT associated with renal transplant, who had a slower recovery with
the maximum regain 36 months after surgery (Fig. 3).
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. In these patients, the BMD z-scores
for total body, lumbar spine, and femoral neck were stable during the
3-yr observation period. For the distal radius, however, the mean
z-score tended to be lower at the 2 yr measurement. This decrease in
the z-score was caused by further bone loss in three patients, and as
they no longer fulfilled the criteria for follow-up, they underwent
parathyroidectomy.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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BMD in all groups of HPT patients was lower than the expected values for an age- and sex-matched reference population. This is in accord with the findings of other investigators (6, 7, 12, 13, 14, 15, 21), who have provided bone densitometry or bone biopsy evidence that most, if not all, HPT patients show excess bone resorption whatever the clinical presentation and that they differ from one another only in degree. Almost half of our patients with primary symptomatic HPT displayed a marked reduction (z-score below -2) of bone density in the distal radius. A marked reduction of bone density at other sites was observed in only a few patients with primary HPT. This is in agreement with previous studies showing that HPT patients exhibit a preferential involvement of cortical bone (e.g. the distal radius) and a relatively well maintained bone mass in areas with a greater proportion of trabecular bone (e.g. lumbar spine) (4, 5, 7).
Patients with renal disease have a reduced capacity to synthesize calcitriol, and the parathyroid glands are exposed to stimulation due to hyperphosphatemia and, in the early course of the disease, also to hypocalcemia. Kidney patients who develop overt secondary HPT have a large parathyroid glandular mass and much higher intact PTH levels than patients with primary HPT. These metabolic derangements help explain the much more pronounced reductions in bone mass observed in patients with renal HPT than in patients with primary disease. In fact, 50–75% of the patients with renal HPT showed a marked reduction of bone density in the distal radius, and 25–40% had a z-score below -2 at any of the other measured sites. The degree of skeletal involvement was similar in hemodialysis and renal transplant patients.
Parathyroidectomy resulted in an increased bone mass in all three types of HPT. In patients with primary HPT, bone density in total body, lumbar spine, and femoral neck increased by 2–5% during the first 6–12 months after surgery, with only marginal additional effects on bone density subsequently. The greatest increase in BMD (+8%) was observed in the distal radius, and this improvement resulted in a near normalization of bone density at this site. The observed early postoperative increases are in agreement with our previous findings (11). The increase in bone density observed in our patients was of a magnitude similar to that observed by Silverberg et al. (12) in their parathyroidectomized patients with primary HPT. However, these researchers found the largest increase at sites with predominantly cancellous bone, whereas we observed the most marked regain in areas rich in cortical bone (e.g. the distal radius). The mechanisms underlying this discrepancy is not evident, but in both studies the largest increase in bone density occurred at the sites with the lowest preoperative BMD (12).
The most marked effect of parathyroidectomy on bone density was found in patients with HPT associated with hemodialysis. In these patients, bone density increased by 7–23%, which nearly normalized their reduced bone density. This very marked remineralization of BMD is in agreement with our previous findings (11). Although patients with renal HPT had similar preoperative bone losses, the postoperative regain was much greater in the patients with HPT associated with hemodialysis than in those who had HPT associated with a renal transplant (+7 to +23% vs. +1 to +6%, respectively). Furthermore, the increase in patients with HPT associated with renal transplant occurred at a slower rate, with the maximum regain at the 24 month measurement rather than at 6–12 months as observed in the other groups. The discrepancy between patients with HPT associated with hemodialysis and with renal transplant in bone remineralization could not be explained by differences in disease duration (they had similar durations of dialysis time and kidney failure) or disease activity (PTH levels were markedly higher in HPT associated with hemodialysis patients). The most obvious explanation for the relatively marginal effect on bone remineralization in the HPT associated with renal transplant patients could probably be attributed to the use of steroids and other immunosuppressive drugs. The detrimental effect of long term glucocorticoid use on bone mass is well established (22, 23), and it has been recognized that other immunosuppressive drugs, such as cyclosporine and FK506, induce osteopenia in rats and probably also in humans (24, 25, 26). Aubia et al. (27) reported histological evidence of increased bone turnover osteopenia in cyclosporine-treated kidney transplant patients. Therefore, it seems likely that the potentially anabolic stimulus of parathyroidectomy on bone was curtailed by the inhibitory effects of immunosuppressive drugs given to our kidney transplant patients.
A modification of the NIH consensus statement was used when deciding on operation or observation in patients with primary HPT. The NIH consensus recommends that the bone density in cortical bone should be measured and that surgery should be recommended to patients with a reduction of at least -2 SD compared with the values in age- and sex-matched controls. Subsequent studies have, however, emphasized the importance of also taking bone density at other sites, such as the lumbar spine, into consideration (13). Thus, we took all four measured sites into consideration for the evaluation of primary HPT patients for surgery. All patients with a reduction of -2 SD or more at two different sites were advised to have an operation, but patients with only one site with reduced bone density were not recommended operation if there were no overt clinical symptoms. Consequently, one third of our patients with primary asymptomatic (mild) HPT had a -2 SD or greater reduction of distal radius bone density. During the course of follow-up, 3 of the initially 24 conservatively followed patients displayed a further reduction in bone density after 24 months, and these patients were therefore parathyroidectomized. After surgery, these three patients exhibited the same bone density regain as the patients with symptomatic primary HPT. In the rest of the asymptomatic patients, bone density has remained stable, and they have remained free of clinical symptoms. This is in agreement with our finding in a small group of patients followed by us for more than 2 decades (28) as well as in a large group of patients followed at Columbia-Presbyterian Medical Center (29).
Patients with renal failure are another difficult group to evaluate with regard to symptoms that may be related to HPT. The majority of these patients have fatigue and/or musculoskeletal symptoms that may or may not be related to the presence of HPT. We consider it useful in these patients to measure bone density before deciding whether an operation should be performed. We tend to be more reluctant regarding surgery in patients with renal HPT if BMD is maintained and if no overt clinical symptoms or complications are present. From the patient’s perspective it was reassuring that nearly all subjects who underwent surgery showed bone density increases during the first 6–24 postoperative months. This effect was particularly evident in patients with HPT associated with hemodialysis. Despite a marked decrease in the bone density of patients with HPT associated with renal transplant, bone mass increased only marginally after parathyroidectomy. Therefore, it could be hypothesized that it might be too late, from a bone-preserving perspective, to perform parathyroidectomy on kidney transplant patients taking immunosuppressive medication. If so, parathyroidectomy should preferably be performed at an early, rather than late, stage in patients with renal HPT. Obviously, this hypothesis needs to be tested in a randomized, prospective study.
In conclusion, a reduced BMD was common in patients with HPT regardless of the etiology of the disease. Further bone loss was halted after surgical correction of HPT, and a regain in bone density was observed in the majority of patients. The regain in bone density in patients with primary and HPT associated with hemodialysis was of such a magnitude that in these groups of patients, bone density returned to normal after surgery. The kidney transplant patients with HPT showed only modest increases in bone density after parathyroidectomy, which could be related to their immunosuppressive medication. It is conceivable that parathyroidectomy should preferably be undertaken before rather than after kidney transplantation to achieve greater bone remineralization, but further studies are needed to confirm this hypothesis.
Received February 26, 1998.
Revised June 2, 1998.
Accepted June 10, 1998.
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S. J. Silverberg, E. Shane, T. P. Jacobs, E. Siris, and J. P. Bilezikian A 10-Year Prospective Study of Primary Hyperparathyroidism with or without Parathyroid Surgery N. Engl. J. Med., October 21, 1999; 341(17): 1249 - 1255. [Abstract] [Full Text] [PDF]
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