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Medical Treatment of Primary Hyperparathyroidism

Medical Treatment of Primary Hyperparathyroidism. F.Hosseinpanah,M.D Obesity Research Center Research Institute for Endocrine Sciences Shahid Beheshti University of Medical Sciences April 14,2016 Tehran. Agenda. Introduction Estrogen-progesterone replacement therapy SERM

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Medical Treatment of Primary Hyperparathyroidism

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  1. Medical Treatment of Primary Hyperparathyroidism F.Hosseinpanah,M.D Obesity Research Center Research Institute for Endocrine Sciences ShahidBeheshti University of Medical Sciences April 14,2016 Tehran

  2. Agenda • Introduction • Estrogen-progesterone replacement therapy • SERM • Bisphosphonate • Calcimimetics • Conclusions

  3. Introduction • Symptomatic HPT • Asymptomatic HPT • The only available definitive therapy is parathyroidectomy

  4. J Clin Endocrinol Metab 99: 3561–3569, 2014)

  5. Clinical scenario for medical management • Patients who meet criteria for surgery(either due to symptoms or to consensus guideline criteria) but whose physicians do not advise parathyroidectomy because of : - Morbidities - Contraindications to surgery - Prior unsuccessful neck exploration - Patients refusal

  6. Agenda • Introduction • Estrogen-progesterone replacement therapy • SERM • Bisphosphonate • Calcimimetics • Conclusions

  7. Design: Double-blind, randomized, placebo-controlled • Participants: postmenopausal women with mild primary hyperparathyroidism ( N=42) • Intervention: conjugated estrogens, 0.625 mg/d, and medroxyprogesterone,5 mg/d, or placebo • Length of F/U: 2 years • Outcomes : BMD, Calcium , Phosphorous, PTH, Bone markers Ann Intern Med. 1996;125:360-368

  8. Hormone replacement therapy did not change levels of serum ionized calcium or intact parathyroid

  9. The between-group differences in bone mineral density at the end of the study ranged from 3.6% to 6.6% and were significant at all sites

  10. Key messages • Although hormone replacement therapy has little effect on serum calcium levels, it suppresses bone turnover, reduces urinary calcium excretion, and increases bone mineral density throughout the skeleton in postmenopausal women with mild primary hyperparathyroidism

  11. Agenda • Introduction • Estrogen-progesterone replacement therapy • SERM • Bisphosphonate • Calcimimetics • Conclusions

  12. Eighteen postmenopausal women with asymptomatic PHPT were randomized to 8wk of raloxifene (60 mg/d) or placebo, followed by a 4-wk washout • Calcium, phosphorous, PTH and bone markers were measured J Clin Endocrinol Metab 88: 1174–1178, 2003

  13. Calcium concentration decreased significantly by 8 wk of raloxifene administration (10.8 ± 0.2 to 10.4 ±0.2 mg/dl; P <0.05)

  14. Markers of bone resorption and formation [osteocalcin11.4 ± 1.6 to 9.9 ±1.6 nmol/liter (P < 0.05); serum N-telopeptide, 21.2±3.4 to 17.3±2.8 nmol bone collagen equivalents/liter (P < 0.05)]

  15. Key messages • The results of this small study demonstrate that raloxifene is associated with reductions in serum calcium levels and markers of bone turnover in postmenopausal women with mild PHPT • There is no alteration in PTH levels and the calcium and bone marker changes return to baseline with discontinuation of raloxifene

  16. Agenda • Introduction • Estrogen-progesterone replacement therapy • SERM • Bisphosphonate • Calcimimetics • Conclusions

  17. There are Four RCTs in this field • Rossini M, Gatti D, Isaia G, et al. Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001; 16:113. • Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ. Alendronate in the treatment of primary hyperparathyroid related osteoporosis: a 2 year study. J ClinEndocrinolMetab 2002; 87:4482. • Chow CC, Chan WB, Li JK, et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J ClinEndocrinolMetab 2003; 88:581. • Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in primary hyperparathyroidism: a double blind, randomized, placebo controlled trial. J ClinEndocrinolMetab 2004; 89:3319.

  18. Objective: To determine whether alendronate (ALN), 10mgdaily, maintains or improves BMD in patients with PHPT • Sample size: Forty-four patients with PHPT who had asymptomatic PHPT and did not meet surgical guidelines or refused surgery • Length of F/U : At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in year 2 • Primary outcome : BMD J Clin Endocrinol Metab 89: 3319–3325, 2004

  19. Alendronate significantly increases BMD at theLS at 12 and 24 months from baseline values Femoral neck Radius Lumbar spine Total Hip

  20. Alendronate was associated with marked reductions in bone turnover markers Urinary NTX BASP

  21. Serum calcium (total and ionized), did not change with alendronate therapy Calcium Ionized calcium

  22. PTH, and urine calcium did not change with alendronate therapy Urinary calcium PTH

  23. Key message • Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD

  24. Agenda • Introduction • Estrogen-progesterone replacement therapy • SERM • Bisphosphonate • Calcimimetics • Conclusions

  25. Multicenter, randomized, double-blind, placebo-controlled study • 12-wk dose-titration phase, a 12-wk maintenance phase during which the primary efficacy endpoint was measured, and a 28-wk follow-up phase to gather additional safety and efficacy information. • Cinacalcet30–50 mg twice daily versus placebo • Proportion of patients achieving a mean serum calcium less than or equal to 10.3 mg/dl and a reduction from baseline of at least 0.5 mg/dl (0.12 mmol/liter) during the maintenance phase

  26. Normalization of serum calcium levels (<10.3 mg/dL) was achieved in 73% of study subjects vs. only 5% of placebo treated patients. ( p < 0.001)

  27. Patients receiving cinacalcet experienced a 7.6% reduction in fasting predoseplasma PTH compared with a 7.7% increase in the placebo group (P < 0.01) during the maintenance phase

  28. At the 52-week end-point of the study, there was no significant change in lumbar spine, total femur and radius BMD

  29. Safety • The two most common adverse events were nausea (28% cinacalcet, 16% placebo) and headache (23% cinacalcet, 41% placebo) • Similar numbers of patients in each group withdrew from the study because of adverse events (eight cinacalcet, six placebo) • Three of these patients from the cinacalcetgroup experienced serum calcium levels less than 8.0 mg/dl while receiving the lowest dose of study drug and, in accordance with the study protocol, were withdrawn from the study

  30. Key messages • In with primary HPT, cinacalcet was highly effective in normalizing serum calcium levels and reducing PTH, and this effect was maintained over long-term administration • The drug was well tolerated and may provide a valuable and effective management option for patients with primary HPT

  31. J Clin Endocrinol Metab 94: 4860–4867, 2009

  32. Mean serum Ca for all subjects remained within the normal range throughout the open-label extension

  33. Predose plasma decreased gradually but never into the normal range

  34. Analysis of Zscores showed no improvements in aBMD at the spine, wrist, femoral neck, and total femur and a nonsignificant trend to increased Z-scores at the lumbar spine

  35. Analysis of Zscores showed no improvements in aBMD at the spine, wrist, femoral neck, and total femur and a nonsignificant trend to increased Z-scores at the lumbar spine

  36. Adverse events were mild to moderate in severity

  37. Key messages • This 4.5-yr open-label extension study describes a favorable safety and efficacy profile of cinacalcet therapy in patients with mild to moderate PHPT • Cinacalcet is useful in the management of PHPT in patients in whom parathyroidectomy is contraindicated or who have failed surgical correction of their PHPT

  38. Conclusions • Limited data suggest that therapy with estrogen in patients with PHPT may reduce bone resorption, improve BMD, without any consistent effects on serum calcium and PTH • There are no fracture data evaluating the effects of estrogen treatment in PHPT • The studies of raloxifene in patients with PHPT are too small and short to reach definitive conclusions or make recommendations

  39. Conclusions… • The RCT data have shown a positive effect of alendronate on BMD at the lumbar spine and hip in PHPT • Bone turnover markers decrease with alendronate therapy • Serum calcium remains stable • There are currently no fracture data with bisphosphonate therapy in PHPT

  40. Conclusions…. • Cinacalcet is effective in lowering, and often normalizing, serum calcium and increasing serum phosphate in patients with PHPT • Its effects on intact serum PTH concentrations are less pronounced • In the few studies that have evaluated the effects of cinacalceton bone turnover markers, the results have been inconsistent • No consistent effects on BMD were observed

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