hypoparathyroidism: the hormone replacement therapy is close h.rezvanian md isfahan endocrine and...

Hypoparathyroidism: the hormone

replacement therapy is close

H.REZVANIAN MDISFAHAN ENDOCRINE AND METABOLISM RESEARCH

CENTER

Hypoparathyroidism is due to deficient or absent parathyroid hormone (PTH).

The disorder can be congenital or acquired

Acquired hypoparathyroidism is most commonly the result of inadvertent removal of or irreversible damage to all parathyroid glands.

Introduction

Hypoparathyroidism 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.

Introduction

The 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

biochemical profile

Clinical 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

Clinical features

The 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.

diagnosis

For chronic management, current treatment options include oral 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.

current treatment options

The primary goals of chronic management include maintaining 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

goals of chronic management

Overall sense of well-being Hypercalcemia and hypercalciuria.

Hyperphosphatemia Basal ganglia calcifications Hypokalemia and/or hyponatremia

Limitations of currently approved treatment options

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 sites

Independent of etiology and well-maintained BMD , bone structure and skeletal dynamics were markedly atypical.

Bone 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 controls

Bone turnover markers (BTM) are typically in the lower half of the normal range or frankly low.

Bone 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.

Bone density and bone quality in hypoparathyroidism

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.

Use 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.

Use of Parathyroid Hormone in the Treatment of Hypoparathyroidisim

single daily subcutaneous injection

maintained both serum and urinary calcium concentrations in the normal range over a 24-hour period

Use of teriparatide [PTH(1–34)] in hypoparathyroidism

approval from the US FDA for severe adult osteoporotic patients .

approval for the use of recombinant PTH in hypoparathyroidism is still lacking

As long-term supraphysiological doses of teriparatide given to rats with normal functioning parathyroid glands led to osteosarcomas , the product label warned against pediatric use.

PTH 1-34 (teriparatide, Eli Lilly, IN, USA)

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.

Use 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)

Use of PTH(1–84) in hypoparathyroidism

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.

Calcium 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.

Calcium and vitamin D supplementation with PTH(1–84)

Compared 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

. 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.

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,

Bone mineral density with PTH(1–84)

approved in Europe for the treatment of severe osteoporosis in postmenopausal women,

PTH 1-84, developed by NPS Pharmaceuticals (NJ,

USA)

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.

PTH(1-84) versus PTH(1-34)

The 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.

Future directions

More 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?

Future directions

What 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?

Future directions