Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology

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Abstract

<p class="first" id="d969036e294">In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic or homeostatic, can be understood in molecular and pharmacokinetic terms. When administered intermittently, PTH increases bone mass, but when present continuously and in excess (e.g. PHPT), bone loss ensues. This dual effect of PTH depends not only on the dosing regimen, continuous or intermittent, but also on how the PTH molecule interacts with various states of its receptor (PTH/PTHrP receptor) influencing downstream signalling pathways differentially. Altering the amino‐terminal end of PTH or PTHrP could emphasize the state of the receptor that is linked to an osteoanabolic outcome. This concept led to the development of a PTHrP analogue that interacts preferentially with the transiently linked state of the receptor, emphasizing an osteoanabolic effect. However, designing PTH or PTHrP analogues with prolonged state of binding to the receptor would be expected to be linked to a homeostatic action associated with the tonic secretory state of the parathyroid glands that is advantageous in treating hypoparathyroidism. Ideally, further development of a drug delivery system that mimics the physiological tonic, circadian, and pulsatile profile of PTH would be optimal. This review discusses basic, translational and clinical studies that may well lead to newer approaches to the treatment of osteoporosis as well as to different PTH molecules that could become more advantageous in treating hypoparathyroidism. </p>

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Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

R M Neer, C Arnaud, J. Zanchetta … (2001)

Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

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The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.

Dennis M. Black, Susan L. Greenspan, Kristine Ensrud … (2003)

Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy. Copyright 2003 Massachusetts Medical Society

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Long-term follow-up of patients with hypoparathyroidism.

Deborah M Mitchell, M Cooley, Jürgen Becker … (2012)

Despite tremendous interest in hypoparathyroidism, large cohort studies describing typical treatment patterns, laboratory parameters, and rates of complications are lacking. Our objective was to characterize the course of disease in a large cohort of hypoparathyroid patients. We conducted a chart review of patients with permanent hypoparathyroidism identified via a clinical patient data registry. Patients were seen at a Boston tertiary-care hospital system between 1988 and 2009. We identified 120 patients. Diagnosis was confirmed by documented hypocalcemia with a simultaneous low or inappropriately normal PTH level for at least 1 yr. Mean age at the end of the observation period was 52 ± 19 (range 2-87) yr, and the cohort was 73% female. We evaluated serum and urine laboratory results and renal and brain imaging. We calculated time-weighted average serum calcium measurements for all patients. The time-weighted average for calcium was between 7.5 and 9.5 mg/dl for the majority (88%) of patients. Using linear interpolation, we estimated the proportion of time within the target calcium range for each patient with a median of 86% (interquartile range 67-98%). Of those with a 24-h urine collection for calcium (n = 53), 38% had at least one measurement over 300 mg/d. Of those with renal imaging (n = 54), 31% had renal calcifications, and 52% of those with head imaging (n = 31) had basal ganglia calcifications. Rates of chronic kidney disease stage 3 or higher were 2- to 17-fold greater than age-appropriate norms. Hypoparathyroidism and its treatment carry a large burden of disease. Renal abnormalities are particularly common.