Hypoparathyroidism is a rare endocrine disorder treated with vitamin D analogs and calcium supplements. Although conventional therapy effectively raises serum calcium levels, it does not fully restore normal mineral homeostasis because it bypasses the PTH effects on the kidney and bone and relies entirely on calcium transport across the gastrointestinal tract to normalize blood calcium. Without the renal calcium-retaining effects of PTH, conventional therapy often leads to abnormally elevated urine calcium excretion and long-term complications, including decreased renal function and nephrocalcinosis (1, 2). Hypoparathyroidism is the only classic hormonal insufficiency state where hormonal replacement is not standard therapy. Recently, the full-length molecule, recombinant human PTH (rhPTH) 1–84, has emerged as a potential replacement therapy and is currently approved by the US Food and Drug Administration as an adjunct to conventional therapy for adult patients who are refractory to conventional therapy. Many adults with hypoparathyroidism treated with conventional therapy have health-related quality-of-life (HRQoL) impairments and lower quality-of-life (QoL) scores, using validated tools, compared with reference norms (3–9). Patients treated with conventional therapy have a wide range of complaints, including anxiety, depression, fatigue, muscle weakness, exercise intolerance, and various cognitive deficits (4, 5, 10–12). Controlled studies have examined the impact of PTH 1–84 therapy on QoL but have not demonstrated significant improvements compared with controls receiving exclusively conventional therapy (3, 7). Most studies of PTH effects on HRQoL use the Short Form Health Survey 36 (SF-36), a subjective, self-administered 36-item questionnaire that is divided into eight domains. Two summary measures, physical and mental health component scores, are calculated from the individual domain scores. The SF-36 measures QoL in chronic illness. This questionnaire does not adequately measure cognitive deficits, fatigue, physical endurance, or muscle strength. Therefore, no single instrument can exclusively characterize and precisely measure the burden of disease experienced by patients with hypoparathyroidism. HRQoL deficits, including increased fatigue, anxiety, and decreased muscle strength, may be a feature of PTH deficiency, but the ability to relieve these symptoms with PTH may depend on whether the physiologic replacement regimen adequately restores normal mineral levels with minimal fluctuation throughout the day. Although PTH 1–34 and PTH 1–84 have identical biological effects, studies of these two peptides take two divergent approaches to replacement therapy. From its very early investigative stages (13), synthetic human PTH (hPTH) 1–34 has been given in multiple subcutaneous (SC) injections titrated with small incremental dose changes to normalize both blood and urine calcium levels. This approach allows for lower individual doses and a more steady-state physiologic profile of serum and urine minerals, which is most evident in the later pump studies (14, 15). PTH 1–84, on the other hand, has been given as fixed daily or every-other-day doses as an adjunct to flexible doses of conventional therapy (16). Large, fixed PTH doses may be associated with transient hypercalcemia and hypercalciuria (17–20), which may produce symptoms associated with elevated calcium such as nausea, bone pain, poor concentration, and polyuria. Such recurrent symptoms, however transient, will contribute to decreased well-being. Two studies, which appeared in earlier 2018 issues of JCEM, by Vokes et al. (7) and Palermo et al. (8), explored HRQoL in adults with hypoparathyroidism in response to PTH 1–84 and rhPTH 1–34 therapy, respectively. Both studies used the fixed-dose approach to replacement therapy with little or no titration of the PTH dose. Vokes et al. (7) investigated the impact of PTH 1–84 on HRQoL as measured by the SF-36 during the 6-month double-blind, randomized, controlled multicenter study (16), including predominantly adult patients with postsurgical (70%) hypoparathyroidism. Most patients received PTH 1–84 plus conventional therapy (n = 83) compared with a smaller group randomized to placebo injections (n = 39) plus conventional therapy. A subset of patients had magnesium deficiency and received magnesium supplements. All patients on the PTH treatment arm initially received 50 μg PTH 1–84 daily. The protocol provided the option to titrate the PTH dose up, first to 75 μg and subsequently to 100 μg at preset intervals. SF-36 scores were abnormally low at study baseline. At 24 weeks, there were no significant differences in SF-36 scores between the two treatment arms, PTH 1–84 vs placebo. At 24 weeks, when comparing each treatment arm to baseline, patients receiving PTH 1–84 with conventional therapy had a significant improvement in SF-36 scores in several domains in two (North America and Western Europe) of the three study site geographic areas. Similar improvements were not observed in the patients on conventional therapy and placebo from those same sites. Palermo et al. (8) describe results from a 2-year open-label uncontrolled study of 42 adult subjects (38 women) with postsurgical hypoparathyroidism. Patients with hypomagnesemia were excluded. Patients received fixed doses of rhPTH 1–34, in amounts previously approved for the treatment of osteoporosis (20 μg), by SC injection twice daily. The twice-daily 20-μg rhPTH 1–34 dose remained unchanged for the 2-year duration of the study. HRQoL measures at 6 and 12 months of PTH treatment were improved in all domains compared with baseline. The study results, however, do not inform us if the improved SF-36 scores are a result of the reduction of calcitriol or the addition of rhPTH 1–34 or the synergy of the two regimens. Furthermore, baseline values reflect the results of treatment management by referring physicians, in most cases, not the investigators. Because conventional therapy was not optimized by study investigators prior to starting PTH, the baseline biochemical profile is not an adequate substitute for a conventional therapy control group. Sikjaer et al. (3) examined the effects of PTH 1–84 on muscle function and QoL. Their 6-month randomized controlled study included 62 adult patients with hypoparathyroidism who were randomized to either a daily dose of 100 μg PTH 1–84 by SC injection or to placebo injection; both treatment groups received conventional therapy. At baseline, patients had impaired HRQoL and no evidence of myopathy. At 6 months, PTH 1–84 compared with placebo did not show a beneficial effect on HRQoL and produced a significant decrease in muscle strength in the upper extremities. Intermittent periods of hypercalcemia and PTH excess (17, 18) may explain the apparent myopathy at 6 months because primary hyperparathyroidism is associated with chronic muscle fatigue (21). In a large Norwegian cross-sectional study of HRQoL in hypoparathyroidism, patients with postsurgical hypoparathyroidism had lower SF-36 scores compared with those who had nonsurgical hypoparathyroidism (22). A recent study of nonsurgical hypoparathyroidism (11) reported greater neuropsychiatric dysfunction compared with controls and lower SF-36 scores compared with postsurgical hypoparathyroidsim in three subdomains (physical function, social function, and mental health). Both studies (11, 22) reported no association between the biochemical markers of mineral metabolism and SF-36 scores. These findings suggest that the disordered sense of well-being may result from direct effects of PTH deficiency rather than the effects of abnormal mineral homeostasis. To further understand QoL deficits in patients who had thyroid surgery, Sikjaer et al. (4), in a cross-sectional study, compared three age-matched groups of 22 adult patients with (1) postsurgical hypothyroidism, (2) a combination of postsurgical hypoparathyroidism and hypothyroidism, and (3) healthy controls. Patients with isolated postsurgical hypothyroidism had abnormally low SF-36 scores in several domains, including vitality, pain, and mental health. The combination of hypothyroidism and hypoparathyroidism (treated with conventional therapy) led to more profound deficits in HRQoL and also decreased muscle strength compared with controls. Complaints of muscle weakness and fatigue were common in our patients with hypoparathyroidism when they were referred to us for therapy. We studied fatigue and physical endurance in a subset (seven patients) of a larger controlled study of twice-daily hPTH 1–34 doses compared with conventional therapy in 27 adults with hypoparathyroidism (23). At study baseline, patients had scores on a multifaceted fatigue assessment in the mild-fatigue range. A 9-minute walk test performed at baseline and after 6 months of twice-daily hPTH 1–34 injections revealed no significant differences in endurance comparing hPTH 1-34 vs conventional therapy. At 6 months, two of the four patients in the hPTH 1–34 group showed a 50% improvement in their scores on a self-reported fatigue scale. In a study comparing hPTH 1–34 delivery by an insulin pump compared with twice-daily injections in adults with postsurgical hypoparathyroidism, we showed at baseline, on conventional therapy, decreased muscle strength in eight adults with postsurgical hypoparathyroidism (14). The average maximal isometric strength, measured with Biodex 3 dynamometer (Biodex Medical Systems, Shirley, NY), was only 50% of normal age-matched reference values (14). Paired comparisons of muscle strength, however, revealed no improvement of muscle function in 3 or 6 months after twice-daily SC hPTH 1–34 injections or pump delivery of hPTH 1–34. Recovery of muscle strength likely requires PTH replacement therapy occurring over a longer period of time than that reported in this study. Furthermore, the ability of PTH replacement therapy to overcome deficits may be age or disease duration dependent. It is possible that decreased muscle strength may be related to fatigue and depression, which affect many adult patients with hypoparathyroidism (4, 5, 12). In addition, exercise often triggers symptoms of hypocalcemia, which can lead to the avoidance of even low levels of exercise, thus contributing to muscle weakness and atrophy, not easily reversed during short-term replacement therapy. Although numerous studies examine QoL, muscle weakness, and fatigue, controlled studies do not provide evidence that PTH therapy, compared with controls, reverses these deficiencies. Future studies should investigate effects of PTH 1–84 given alone instead of in combination with conventional therapy, to further demonstrate its efficacy as a replacement therapy. We need long-term safety data (24) and longitudinal studies in which steady-state normal levels of minerals in the blood and urine are achieved and the implementation of more precise, disease-specific techniques to measure QoL. Most important, future studies should be designed in which PTH is given in a physiologic manner with attention to the fine details of calcium homeostasis such as the amount of fluctuation of serum and urine calcium. A device for monitoring calcium to allow for real-time dose adjustments in response to fluctuations in blood calcium would facilitate such titration and give patients a greater sense of control over their health and, perhaps, a greater sense of well-being. Abbreviations: Abbreviations: hPTH synthetic human PTH HRQoL health-related quality of life QoL quality of life rhPTH recombinant human PTH SC subcutaneous SF-36 Short Form Health Survey 36 Acknowledgments Disclosure Summary: The author has nothing to disclose. References 1. 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Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D . Eur J Endocrinol . 2002 ; 146 : 215 – 222 . 6. Cusano NE , Rubin MR , McMahon DJ , Irani D , Tulley A , Sliney J Jr , Bilezikian JP . The effect of PTH(1-84) on quality of life in hypoparathyroidism . J Clin Endocrinol Metab . 2013 ; 98 ( 6 ): 2356 – 2361 . 7. Vokes TJ , Mannstadt M , Levine MA , Clarke BL , Lakatos P , Chen K , Piccolo R , Krasner A , Shoback DM , Bilezikian JP . Recombinant human parathyroid hormone effect on health-related quality of life in adults with chronic hypoparathyroidism . J Clin Endocrinol Metab . 2017 ; 103 ( 2 ): 722 – 731 . 8. Palermo A , Santonati A, Tabacco G , Bosco D , Spada A , Pedone C , Raggiunti B , Doris T , Maggi D , Grimaldi F , Manfrini S , Vescini F . PTH(1-34) for surgical hypoparathyroidism: a 2 year prospective, open-label investigation of efficacy and quality of life . J Clin Endocrinol Metab . 2018 ; 103 ( 1 ): 271 – 280 . 9. Büttner M , Musholt TJ , Singer S . Quality of life in patients with hypoparathyroidism receiving standard treatment: a systematic review . Endocrine . 2017 ; 58 ( 1 ): 14 – 20 . 10. Underbjerg L , Sikjaer T , Mosekilde L , Rejnmark L . The epidemiology of nonsurgical hypoparathyroidism in Denmark: a nationwide case finding study . J Bone Miner Res . 2015 ; 30 ( 9 ): 1738 – 1744 . 11. Underbjerg L , Sikjaer T , Rejnmark L . Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism [published online ahead of print March 9, 2018] . Clin Endocrinol (Oxf) . 12. Underbjerg L , Sikjaer T , Mosekilde L , Rejnmark L . Postsurgical hypoparathyroidism—risk of fractures, psychiatric diseases, cancer, cataract, and infections . J Bone Miner Res . 2014 ; 29 ( 11 ): 2504 – 2510 . 13. Winer KK , Yanovski JA , Sarani B , Cutler GB Jr . A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism . J Clin Endocrinol Metab . 1998 ; 83 ( 10 ): 3480 – 3486 . 14. Winer KK , Zhang B , Shrader JA , Peterson D , Smith M , Albert PS , Cutler GB Jr . Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism . J Clin Endocrinol Metab . 2012 ; 97 ( 2 ): 391 – 399 . 15. Winer KK , Fulton KA , Albert PS , Cutler GB Jr. Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1-34 in children with severe congenital hypoparathyroidism . J Pediatr . 2014 ; 165 : 556 – 563 . 16. Mannstadt M , Clarke BL , Vokes T , Brandi ML , Ranganath L , Fraser WD , Lakatos P , Bajnok L , Garceau R , Mosekilde L , Lagast H , Shoback D , Bilezikian JP . Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study . Lancet Diabetes Endocrinol . 2013 ; 1 ( 4 ): 275 – 283 . 17. Sikjaer T , Rejnmark L , Rolighed L , Heickendorff L , Mosekilde L ; Hypoparathyroid Study Group . The effect of adding PTH(1-84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study . J Bone Miner Res . 2011 ; 26 ( 10 ): 2358 – 2370 . 18. Sikjaer T , Amstrup AK , Rolighed L , Kjaer SG , Mosekilde L , Rejnmark L . PTH(1-84) replacement therapy in hypoparathyroidism: a randomized controlled trial on pharmacokinetic and dynamic effects after 6 months of treatment . J Bone Miner Res . 2013 ; 28 ( 10 ): 2232 – 2243 . 19. Rubin MR , Cusano NE , Fan WW , Delgado Y , Zhang C , Costa AG , Cremers S , Dworakowski E , Bilezikian JP . 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Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: Apr 20, 2018
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