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J Musculoskel Neuron Interact 2003; 3(1):71-76 Original Article
Bone mineral density in hypoparathyroid
women on LT4 suppressive therapy.
Effect of calcium and 1,25(OH)2 vitamin D3 treatment
F. Hawkins1, F. Escobar-Jiménez2, E. Jfidar1, M.M. Campos2,
M.B. Lfipez Alvarez1, G. Mart›nez D›az-Guerra1
1Service of Endocrinology, University Hospital 12 de Octubre, Madrid 2Service of Endocrinology, University Hospital San Cecilio, Granada, Spain Abstract
Our aim was to study the bone mineral density (BMD) of patients with chronic hypoparathyroidism (hypoPTH) after long- term calcium and vitamin D treatment. Twenty hypoPTH women (mean±SD, aged 50±15 years, IPTH 4±6 pg/ml) and 20matched euparathyroid women (euPTH) after near total thyroidectomy for thyroid cancer, completed with I-131 ablation andon suppressive therapy with L-Thyroxine (LT ), were studied. In addition eight hypoPTH patients who were receiving LT re- placement therapy after surgery for compressive goiter were simultaneously studied. The hypoPTH patients were on calciumand 1,25(OH) vitamin D therapy to normalize serum calcium. Bone mineral density (BMD) (DXA, at the lumbar spine [L - L , LS], femoral neck [FN] and Ward triangle [WT]), serum and urine calcium, serum phosphorus, were measured. Patients with hypoPTH showed greater lumbar BMD than euPTH patients on suppressive therapy (Z-score;1.01±1.34 vs. -0.52±0.70, p<0.05). Serum osteocalcin levels were higher in hypoPTH patients on suppressive therapy comparedto hypoPTH patients on replacement therapy. The LS BMD from hypoPTH patients correlated with calcium supplements(r=0.439; p=0.02), 1,25(OH) D dose (r=0.382; p=0.04) and LT dose (r=0.374; p=0.05). Our data suggest that long-term treat- ment with calcium and 1,25(OH) vitamin D supplements in hypoPTH patients on suppressive LT therapy results in increased BMD when compared with patients with normal PTH levels.
Keywords: Hypoparathyroidism, Thyroid Hormones, Calcium, 1,25(OH) Vitamin D , Bone Density, Bone Markers
Introduction
poPTH) condition could provide protection against age-re-lated cortical and trabecular bone loss, due to the attenuation The adverse effects of L-Thyroxine (LT ) therapy on bone of the high turnover bone loss that occurs after menopause, mass and mineral metabolism are controversial. Although ex- and to the induction of a positive calcium balance6-10.
cess thyroid hormone stimulates bone resorption resulting in The purpose of this study was to assess bone mineral den- increased bone turnover and bone loss1,2, the effect of pro- sity (BMD) and the osteoblastic function of thyroidectomized longed LT suppressive therapy on the skeleton has been re- women with and without hypopararathyroidism, receiving sup- pressive doses of LT due to thyroid cancer, and also to com- ported from being neutral3 to inducing a decrease in axial and pare them with hypoPTH women on LT replacement thera- appendicular bone mass4. Confounding variables such as py after compressive goiter surgery, matched by sex, age, body parathyroid function, menopausal status, and prior history of mass index (BMI) and menopausal status.
hyperthyroidism may be partially responsible for such differ-ences5. On the other hand, the treated hypoparathyroid (hy- Subjects and methods
Corresponding author: Federico Hawkins, Servicio de Endocrinologia, Hospi- tal Universitario 12 de Octubre, Av. Andaluc›a, Km 5.4, Madrid E-28041, SpainE-mail: fhawkins.hdoc@salud.madrid.org Twenty hypoPTH female patients and twenty euparathyroid (euPTH) female patients (matched by age, body mass index F. Hawkins et al.: Ca+ Vit D treatment of hypoparathyroidism on LT4 therapy EuPTH on ST
HypoPTH on ST
HypoPTH on RT
HypoPTH: hypoparathyroid patients; EuPTH: patients with normal parathyroid function.
ST: Suppressive therapy; RT: Replacement therapy. *p<0.05 versus HypoPTH on RT.
Data are expressed as mean ± SD except for % values.
Table 1. Clinical characteristics of patients.
(BMI, calculated as BMI = weight (kg) / height2 (m2)) and ease, alcoholism, osteoporotic fracture, early menopause or menopausal status) after near total thyroidectomy for thyroid any other major medical condition. Patients with previous hy- cancer completed with I-131 ablation and on LT suppressive perthyroidism were excluded. All patients were informed therapy were studied. Eight women with hypoparathyroidism about the nature of the study and gave informed consent. Our secondary to debulking surgery for compressive goiter who ethical committee approved the study.
were receiving LT or replacement therapy were also evalu- ated in the same period. All patients were Caucasians and were regularly followed at our clinic. The study period com-prised six months. All hypoPTH patients were receiving cal- Serum samples were obtained between 08:00 and 09:00 cium (Calcium Sandoz Forte, Novartis) and 1,25(OH) vita- hours after overnight fast and were immediately processed and kept frozen at -20oC until the assays. Basal serum TSH as- min D (Rocaltrol, Roche) therapy to normalize serum calci- say was performed by IRMA (Medgenix Diagnostics, Bel- um. The diagnosis of hypoparathyroidism was based upon low gium; lower detection limit 0.02ÌU/ml) and serum free thy- serum calcium and PTH levels on several different measure- roxine (FT ) by RIA (Diagnostic Products Corporation, USA).
ments, relief of muscular spasms by treatment with calcium Calcium, phosphate, and alkaline phosphatase (ALP) were and vitamin D, and inability to maintain normal serum calci- measured by autoanalyzer (DAX 72 calorimetric method).
um levels with a rapid return of symptoms when treatment Osteocalcin and intact parathyroid hormone (IPTH) were as- was withdrawn. No patient was taking oral contraceptives, sayed by RIA (Nichols Institute Diagnostics, USA). Blood ex- estrogen replacement therapy or any other medications that traction was done the same day that bone densitometry was might affect bone density. None had a history of hepatic dis- F. Hawkins et al.: Ca+ Vit D treatment of hypoparathyroidism on LT4 therapy Figure 1. Bone mineral density (BMD, z-score) in treated hy-
poparathyroid (HypoPTH) and Euparathyroid (EuPTH) women onsuppressive therapy with LT4. LS: Lumbar spine (L1-L4); FN: femoralneck; WT: Ward triangle. *p<0.05 versus EuPTH; Hp<0.05 versus 0.
Bone mineral density (BMD) was measured by dual X-ray absorptiometry using a QDR 1000/w absorptiometer (Hologic Inc., Waltham, MA, USA) in the lumbar spine (L -L ; LS), femoral neck (FN) and Ward triangle (WT). The coefficient of variation for the BMD measurement at our center is 1.31%in the LS and 1.88% in the FN11. One thousand three hundred and thirty-one healthy Spanish females served to establish the mean BMD in the healthy population and to calculate the z-score for each BMD measurement (number of reference pop- ulation standard deviations between the patient’s BMD and the age- and sex-matched reference mean value)12. Results were analyzed using unpaired t-test to compare the mean of LS, FN and WT BMD expressed as z-score versus 0,one way analysis of variance to assess the differences among groups: eu- and hypoPTH patients on LT suppressive thera- py and hypoPTH patients on LT replacement therapy, and Figure 2. Correlation between lumbar spine BMD (LS, L1-L4, z-s-
simple regression analysis or Spearman correlation analysis core) with calcium supplements (CS; r=0.439; p=0.02), 1,25(OH)2vitamin D3 supplements (DS; r=0.382; p=0.04) and LT4 dose (TD; to assess the relationship between BMD and different vari- ables) as appropriate, using SPSS (8.0 for Windows) software(SPSS Inc., Chicago, IL).
er, but these differences did not reach statistical significance.
LT dose was significantly lower in hypoPTH patients on re- The clinical characteristics of the patients are shown in Table 1. As expected from matched selection, hypoPTH and Biochemical and bone mass data are shown in Table 2.
euPTH patients on LT suppressive therapy showed similar Serum calcium, phosphorus, IPTH and 24h urine calcium were age, percentage of posmenopausal women, duration of significantly different between euPTH and hypoPTH patients.
menopause, BMI, LT dose and accumulated LT dose. Hy- HypoPTH patients on LT replacement therapy showed high- poPTH patients on LT replacement therapy were somewhat er TSH and lower osteocalcin levels than the patients on sup- older and the percentage of postmenopausal women was high- pressive therapy. LS and FN BMD were higher in hypoPTH F. Hawkins et al.: Ca+ Vit D treatment of hypoparathyroidism on LT4 therapy EuPTH on ST
HypoPTH on ST
HypoPTH on RT
HypoPTH: hypoparathyroid patients; EuPTH: patients with normal parathyroid function. ST: Suppressive therapy; RT:Replacement therapy. *p<0.05 versus HypoPTH on ST; Hp<0.05 versus HypoPTH on RT; Ip<0.05 versus 0. Referencevalues: Serum Calcium (sCa): 8.4-10.2 mg/dl; serum phosphorus (sP): 2.3-4.6 mg/dl; IPTH 13-54 pg/ml; FT4: 0.85-2.01 ng/dl;TSH: 0.5-5.0 ÌU/ml; osteocalcin: 2.4-10.0 ng/ml; alkaline phosphatase (ALP): 30-115 U/I, 24 hours urine calcium(24hUCa):<250 mg/24h. LS-BMD: Lumbar spinal, FN-BMD: Femoral neck, WT: Ward triangle bone mineral density.
Data are expressed as mean ± SD.
Table 2. Biochemical and densitometrical characteristics of patients.
females on suppressive therapy (95% confidence interval (CI), Discussion
LS: (0.38; 1.64), FN: (0.01;1,08)), whereas LS and WT BMDwere lower in euPTH females on suppressive therapy (95% CI, Up to now, few data are available regarding the bone effects LS: (-0.85; -0.20), WT: (-0.64; -0.02)). HypoPTH females on of calcium and 1,25(OH) vitamin D therapy in hypoPTH.
LT replacement therapy showed normal BMD. When direct We have shown a slightly decreased FN BMD in euPTH comparisons where made, only lumbar bone mass was signif- women on LT suppressive therapy, a normal FN and LS BMD icantly higher in hypoPTH females on LT suppressive ther- in hypoPTH women on LT replacement therapy and an ele- apy compared to euPTH females on LT suppressive therapy vated LS BMD in treated hypoPTH women receiving sup- pressive doses of LT (p<0.05 vs. hypoPTH with suppressive FN BMD from hypoPTH patients significantly correlated LT therapy). These elevated BMD values are probably mul- with the BMI (r=0.367, p=0.05), meanwhile the LS BMD tifactorial in their origin. We confirm, therefore, earlier find- showed positive correlation with calcium supplements ings in patients with primary and secondary hypoPTH after (r=0.439; p=0.02) and 1,25(OH) D supplements (r=0.382; thyroid or parathyroid surgery that have shown higher bone mass when treated with calcium and vitamin D analogs6,7,10,13,14.
F. Hawkins et al.: Ca+ Vit D treatment of hypoparathyroidism on LT4 therapy In hypoPTH menopausal women on LT suppressive ther- cross-sectional, included patients with a long-term therapy pe- apy after total thyroidectomy due to thyroid carcinoma, cal- riod and z-scores were obtained using national standards.
cium and 1-·(OH) vitamin D treatment has been associated In conclusion, long-term treatment with calcium and with higher bone density and lower spinal deformation in- 1,25(OH) vitamin D supplements in hypoPTH women on dex6. It is possible that the accelerated bone loss after LT suppressive therapy results in increased BMD, meanwhile menopause can be attenuated in these patients, indicating a hypoPTH women on LT replacement therapy show normal reduced remodeling rate with this therapy. The hypothetical bone mass and euPTH women on LT suppressive therapy PTH-independent effects of vitamin D analogs to reduce bone show low bone mass. The higher BMD observed in hypoPTH turnover in this setting can not be discarded. In our study, cal- women may be related to a global skeletal effect of LT sup- cium and 1,25(OH) D supplements correlated with LS BMD, pressive and 1,25(OH) vitamin D therapies. Further studies although these correlations are likely to reflect the severity of with longer follow-up and larger samples are probably neces- hypoPTH or other interfering, underlying conditions. In fact, sary to establish if bone loss is reduced in hypoPTH subjects vitamin D receptors have been found in osteoblasts, and, in with LT therapy and combined calcium and vitamin D treat- normal subjects, vitamin D stimulates both the number and ac- tivity of osteoblasts15,16; nevertheless a skeletal anabolic effectin vivo has never been demonstrated. On the other hand, the femoral neck BMD correlated with BMI showing the well- Parts of this study were supported by a grant of Fundacifin para la In- known protective effect of body weight on bone mass17.
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