Presentation on theme: "Hypoparathyroidism: the hormone replacement therapy is close"— Presentation transcript:
1Hypoparathyroidism: the hormone replacement therapy is close H.REZVANIAN MDISFAHAN ENDOCRINE AND METABOLISM RESEARCH CENTER
2IntroductionHypoparathyroidism is due to deficient or absent parathyroid hormone (PTH).The disorder can be congenital or acquiredAcquired hypoparathyroidism is most commonly the result of inadvertent removal of or irreversible damage to all parathyroid glands.
3IntroductionHypoparathyroidism can also be due to immune-mediated destruction of the parathyroid glands, activating mutations in the extracellular calcium-sensing receptor or part of DiGeorge syndrome, a genetic disorder.
4biochemical profileThe typical biochemical constellation in untreated hypoparathyroidism includes low or absent PTH levels in the circulation, hypocalcemia, relatively high urinary calcium excretion, hyperphosphatemia, and reduced levels of 1,25-dihydroxyvitamin D
5Clinical featuresClinical features of the disease include symptoms of hypocalcemia, such as perioral numbness, paresthesias, and carpal/pedal muscle spasms. Laryngeal spasm, tetany, and seizures are serious and potentially life-threatening complications
6diagnosisThe diagnosis of hypoparathyroidism is readily made by the concurrence of hypocalcemia and markedly reduced or absent PTH levels. The only known reversible cause of hypoparathyroidism is associated with marked magnesium deficiency, in which magnesium replenishment can completely reverse the hypoparathyroid state.
8current treatment options For chronic management, current treatment options includeoral calcium,vitamin D (including its metabolites and analogues),thiazide diuretics.In special situations, phosphate binders, low-salt diet, or a low-phosphate diet may be helpful adjuncts.
9goals of chronic management The primary goals of chronic management includemaintaining within an acceptable range the following indexes.(1) serum total calcium (usually in the low-normal range)(2) serum phosphorus (usually in the high-normal range)(3) 24-hour urine calcium excretion (<7.5mmol/d).(4) calcium-phosphate product under 55 mg2/dL2
10Limitations of currently approved treatment options Overall sense of well-beingHypercalcemia and hypercalciuria.HyperphosphatemiaBasal ganglia calcificationsHypokalemia and/or hyponatremia
11Bone density and bone quality in hypoparathyroidism PTH deficiency state has clear consequences on the skeleton.Patients with hypoparathyroidism typically have uniformly increased bone mineral density (BMD) at lumbar spine, hip, and radius sitesIndependent of etiology and well-maintained BMD , bone structure and skeletal dynamics were markedly atypical.
12Bone density and bone quality in hypoparathyroidism Histomorphometric analysis of bone biopsy specimens of patients with hypoparathyroidism show greater cancellous bone volume, trabecular width, and cortical width compared with age- and sex- matched controlsBone turnover markers (BTM) are typically in the lower half of the normal range or frankly low.
16Bone density and bone quality in hypoparathyroidism it seems that the increases in BMD and bone volume were associated with both decreased bone formation and bone resorption rates, theoretically leading to the accumulation of unremodeled or hypermature bone.The common use of vitamin D in both the animal and the human studies permits the conclusion that, without PTH, vitamin D cannot, by itself, restore structure or dynamic properties to the usual state in hypoparathyroidism.
18Use of Parathyroid Hormone in the Treatment of Hypoparathyroidisim Treatment of hypoparathyroidism with PTH is appealing because it provides the hormone that is missing.reducing calcium and calcitriol requirements.Reduced calcium and vitamin D requirements potentially lessen the risk of hypercalcemia and hypercalciuria.
19Use of Parathyroid Hormone in the Treatment of Hypoparathyroidisim An additional possible advantage is that because of its phosphaturic properties, PTH use may reduce the risk of soft tissue deposition of calcium in the kidneys (nephrocalcinosis, nephrolithiasis) and possibly in other soft tissues.
20Use of teriparatide [PTH(1–34)] in hypoparathyroidism single daily subcutaneous injectionmaintained both serum and urinary calcium concentrations in the normal range over a 24-hour period
21PTH 1-34 (teriparatide, Eli Lilly, IN, USA) approval from the US FDA for severe adult osteoporotic patients .approval for the use of recombinant PTH in hypoparathyroidism is still lackingAs long-term supraphysiological doses of teriparatide given to rats with normal functioning parathyroid glands led to osteosarcomas , the product label warned against pediatric use.
22Use of PTH(1–84) in hypoparathyroidism The effects of treatment with PTH(1–84) (100mg in an every- other-day treatment regimen) were studied in 30 hypoparathyroid subjects for 24 months.
23Use of PTH(1–84) in hypoparathyroidism Calcium and vitamin D supplementation with PTH(1–84).Serum and urinary calcium levels with PTH(1–84).Bone mineral density with PTH(1–84)
26Calcium and vitamin D supplementation with PTH(1–84) The reductions in calcium and vitamin D supplementation with PTH(1–84) were notable.Requirements for supplemental calcium fell significantly from 3030 ` 2325 to 1661 ` 1267 mg/d (p<0.05).the number of subjects on calcium supplementation that was greater than 1500 mg/d decreased from 22 (73%) at study entry to only 12 (40%) at study conclusion.
28Calcium and vitamin D supplementation with PTH(1–84) Similarly, calcitriol supplementation declined from the baseline mean of 0.68`0.5 to 0.40`0.5mg/d (p<0.05).Again, fewer patients needed high supplementation.the number of subjects on a dose of 1,25-dihydroxyvitamin D3 that was greater than 0.25 mg/d fell from 25 (83%) at study entry to 15 (50%) at study conclusion.
32Compared with placebo, patients on PTH(1–84) reduced their daily dose of calcium and active vitamin D significantly by 75% and 73%, respectively, without developing hypocalcemia.BMD decreased at the hip , lumbar spine , and whole body, but not at the forearm
33. In conclusion, In contrast to the effect of PTH(1–84) treatment in patients with osteoporosis, PTH-RT in hypoparathyroidism causes a decrease in BMD. This is most likely due to the marked increased bone turnover. Accordingly, PTH-RT counteracts the state of overmineralized bone and, during long-term treatment, may cause a more physiologic bone metabolism.
34Bone mineral density with PTH(1–84) BMD increased at the lumbar spine a site that is enriched in cancellous bone.Along with the increase in lumbar spine BMD, a decrease in the distal 1/3 radius, a site of cortical bone,
38PTH 1-84, developed by NPS Pharmaceuticals (NJ, USA) approved in Europe for the treatment of severe osteoporosis in postmenopausal women,
39PTH(1-84) versus PTH(1-34)The pharmacokinetics of PTH(1-84) are substantially slower than those for PTH(1-34). This may help us to explain why dosing with PTH(1-34) has required multiple injections per day while with PTH(1-84), single daily dosing and every other day dosing appears to provide good results.
40Future directionsThe results with PTH are encouraging with respect to better management of hypoparathyroidism.The biopsy data indicate that the skeletal dynamics are returned toward normal.Since therapy with PTH may well become a long-term management option in hypoparathyroidism, longer-term data are needed.
41Future directionsMore information is needed about the chronic effects of PTH treatment.Is the kidney protected by PTH action?Are there salutary effects on the cardiovascular system?What is the effect of PTH treatment on quality of life?
42Future directionsWhat is the ideal dosing and delivery system to achieve sustained effects on serum calcium and phosphate while protecting the kidney from the potential adverse events?