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Treatment indications of mild primary hyperparathyroidism in old age; a challenge for research
European Geriatric Medicine 2 (2011) 155–158
Controversies in geriatric medicine
Treatment indications of mild primary hyperparathyroidism in old age; a challenge for research M.P. Bjo¨rkman a,*, R.S. Tilvis a,1, A.J. Sorva b,2 a b
Clinics of Internal Medicine and Geriatrics, Helsinki University Central Hospital, POB 340, FI-00029 HUS, Helsinki, Finland Department of Long-Term Care, Helsinki City Hospital of Laakso, POB 6600, FI-00099 City of Helsinki, Helsinki, Finland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2011 Accepted 10 May 2011 Available online 15 June 2011
Primary hyperparathyroidism (PHPT) is common in older people, but it does not usually develop classical symptoms or long-term complications in the last years of life. The non-specific symptoms are often indistinguishable from age-related complaints and illnesses, and the patients are generally left in surveillance. Trials are needed to show, whether the non-classical symptoms of PHPT so far deemed as contraindications are rather indications for treatment in old age. ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Primary hyperparathyroidism Parathyroidectomy Old people Evidence based medicine
In clinical practice, physicians often encounter mildly hypercalcaemic older patients. In most cases concomitantly elevated concentration of parathyroid hormone (PTH) confirms the diagnosis of primary hyperparathyroidism (PHPT). Several population-based studies have shown that the prevalence of PHPT increases with age, being at least twice as common in women as in men [1]. However, it is not clear how the oldest PHPT patients should be treated and monitored. The diversity of clinical symptoms in older PHPT patients, the poor association of these symptoms with the degree of hypercalcaemia and parathyroid hormone (PTH) levels as well as the uncertainty of treatment results emphasize the need for future trials. 1. The clinical presentation of PHPT has changed At present, PHPT is commonly diagnosed without the classical manifestations such as hypertension, renal calculi, nephrocalcinosis, renal dysfunction, osteopenia or osteoporosis, osteitis fibrosa cystica, and severely altered neurologic function with obtundation, delirium or coma [2]. In fact, case-control studies based on questionnaires have revealed that PHPT patients often report non-specific milder complaints like, weakness, easy fatigability, depression, intellectual weariness, cognitive impairment, loss of initiative, anxiety, irritability, sleep disturbances * Corresponding author. Tel.: +358 5 03 41 40 22. E-mail addresses: mikko.bjorkman@helsinki.fi (M.P. Bjo¨rkman), reijo.tilvis@helsinki.fi (R.S. Tilvis), [email protected] (A.J. Sorva). 1 Reijo S. Tilvis, phone: +358 4 00 69 85 75. 2 Antti J. Sorva, phone: +358 5 04 02 57 13.
and features of somatisation [3]. These patients with milder phenotype of PHPT have been also called ‘‘asymptomatic’’. A third phenotype of the disease, ‘‘normocalcaemic PHPT’’, has been also described [4]. It is defined by elevated PTH concentration, normocalcaemia and sufficient vitamin D status. 2. Effects of parathyroidectomy on non-classical symptoms of PHPT Parathyroidectomy (PTX) is effective and safe also in older patients [5]. PHPT accompanied by frank elevation of serum calcium with obvious clinical symptoms is a clear treatment indication even in the oldest. Moreover, non-classical symptoms of PHPT are being accepted as indication for PTX especially in younger patients. These symptoms often resemble age-related illnesses and aging itself, i.e., ‘‘senility’’, inevitably resulting in delayed or deferred referral of older PHPT patients for PTX [6]. Clinical experience on selected cases and a plethora of sporadic case reports suggest that PTX can sometimes improve this ‘‘pseudosenility’’ [7]. Thus, the effects of PTX on quality of life and functional capacity, particularly, are emphasized in the management of older patients with biochemically mild PHPT. Randomized controlled trials (RCT) addressing the effects of PTX in PHPT were retrieved in April 2011 from Pubmed with the following search phrase: ‘‘Primary hyperparathyroidism AND (parathyroidectomy[title] OR surgery[title] OR surgical[title]) AND (randomly[title/abstract] OR randomized[title/abstract] OR randomised[title/abstract] OR random[title/abstract])’’. The search included 48 papers which were evaluated and their reference lists reviewed. To date three larger and one RCT have addressed the
1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.05.002
M.P. Bjo¨rkman et al. / European Geriatric Medicine 2 (2011) 155–158
156
effects of PTX on quality of life or physical functioning in PHPT patients without classical indications for surgery (Table 1). In these trials PTX improved bone mineral density (BMD), walking distance, some domains of quality of life, and sleep quality [8–13]. However, none of these trials addressed the effectiveness of PTX in old age. Nevertheless, Talpos et al. found that surgery improved social and emotional role functioning [8]. In the extension of the study, a modest benefit was still found [9]. In the series of Bo¨llerslev et al. the patients were collected from primary care in three Scandinavian countries and referred to five surgical centres [10]. The patients did have more neuropsychiatric complaints as compared to the Swedish normative data, but PTX did not improve neuropsychological functions. However, in the single-centre study by Amborgini et al., surgery improved some domains of quality of life such as physical function, bodily pain, general health, mental health, and vitality [11]. One small RCT has shown a clinically meaningful improvement in 6-minute walking distance in the PTX-group [12]. In another report from the same patient group, PTX seemed to improve sleep quality [13]. It should be noted that the placebo effect of surgery cannot be excluded in these studies (Table 1). It is also important to recognize that the patients were highly selected and young in all of these trials. Furthermore, patients with mental disorders and mental symptoms seem to have been often excluded. In fact, also the referral practices in primary care may have been too conventional and conservative leading to under-utilization of surgical possibilities and resulting in surgical study groups with relatively few frail older PHPT patients with ‘‘non-classical’’ symptoms [6].
fractures is increased in young PHPT patients [16], no study has addressed bone fracture risk of oldest PHPT patients. Actually, with advancing age, the fracture incidence of PHPT patients seems to become equal to that of the general population [17], perhaps due to attenuation of disease progression. Thirdly, concerning morbidity and mortality, the prognostic importance of biochemically mild PHPT in old age is unclear. Epidemiologic findings indicate that PHPT increases cardiovascular mortality, which is also decreased by PTX [18]. This evidence from relatively hypercalcaemic patients has been used to advocate PTX in biochemically mild PHPT without classical symptoms. Recently, also mild PHPT has been associated with increased mortality in a population-based cohort of relatively old (mean age = 69 years) PHPT patients [19]. In addition, there are several large-scale prospective studies showing association of elevated PTH with allcause and cardiovascular mortality even in normocalcaemic populations [20]. High PTH has been associated with mortality also in late life [21], but the 17-year follow-up of these older people (age cohorts of 75-, 80-, and 85-year old general population, N = 567) living in Helsinki did not suggest excess mortality of persons with PHPT (Fig. 1). Apart from co-morbidities and disease severity, old age alone diminishes the likelihood of PTX. In contrast to young PHPT patients, older patients with biochemically mild PHPT typically do not develop classical long-term complications [4] and are generally left in surveillance only. However, the actual present-day impact of PHPT on quality of life and activities of everyday living may be far more relevant in the last years of life.
3. Indications for parathyroidectomy in old age are not clear
4. Other treatment options
For several reasons the present trial evidence does not allow normative definitions of indications for surgery in PHPT in old age. Neither serum calcium nor PTH correlates well with severity of symptoms [14]. Thus, treatment decisions solely based on the serum calcium and/or PTH levels seem not to be appropriate. Secondly, old age alters the relative significance of bone disease. The PHPT induced bone loss is partly reverted by PTX which may also prevent fractures [15]. Thus, BMD measurements have been recommended in the follow-up of PHPT patients [3]. However, all older persons have at least osteopenia and the relevance of repeated BMD measurements in surgical decision-making for older PHPT patients remains unclear. Even though PHPT can be associated with neuromuscular weakness and the incidence of
Bisphosphonates can protect bones for years but do not correct hypercalcaemia permanently [22]. The calcimimetics e.g. cinacalcet lower both serum calcium and PTH and thus seem promising in those PHPT patients who are not candidates for PTX [22]. Estrogens or raloxifene, a selective estrogen receptor modulator have not been tested in the treatment of the non-classical symptoms of PHPT, thus far. 5. Future research perspectives Follow-up studies based on calcaemic screening of large unselected older population could shed light on the evolution and natural history of PHPT. Such studies could show that in old
Table 1 Randomized parathyroidectomy vs. observation trials addressing quality of life and physical functioning in primary hyperparathyroidism patients without classical symptoms. Author
Patients
Recruitment population, N
Eligible, N
Mean age, years
Mean calcium, mmol/L
Mean PTH, ng/L
Follow-up
Drop-outs, %
Main positive results related to PTX
Talpos et al. 2000 [8] Rao et al. 2004 [9]
Asymptomatic PHPT patients (USA)
Hypercalcemic patients within computerized health system, 1201
53
65 7
2.59
82
24–64 months
0
BMD, QoL (modest), Anxiety/phobia (modest)
Bo¨llerslev et al. 2007 [10]
Asymptomatic PHPT patients (Sweden, Norway, Denmark)
Referred PHPT patients, N not reported
191
64 7
2.69
97
2 years
48
BMD
Ambrogini et al. 2007 [11]
PHPT patients not meeting guidelines for PTX (Italy)
Referred PHPT patients, 412
50
65 6
2.54
112
1 year
0
BMD, QoL (modest)
Perrier et al. 2009 [12] Morris et al. 2010 [13]
PHPT patients not meeting guidelines for PTX (USA)
Consecutive referred PHPT patients, 54
21
66 10
2.58
122
6 months
14
Walking distance, Day time sleepiness (modest)
PTX: Parathyroidectomy; PHPT: Primary hyperparathyroidism; PTH: parathyroid hormone; BMD: Bone mineral density; QoL: Quality of life.
M.P. Bjo¨rkman et al. / European Geriatric Medicine 2 (2011) 155–158
157
older PHPT patient than to frequently measure BMD and calcaemic status. Worsening general health, declining cognition, increasing confusion, and subsequent risk of permanent institutionalisation are relevant causes for re-evaluation of PTX. Referrals to surgery and decisions to operate should be based on thorough joint discussion not only between the doctor and the patient but often also with the next of kin, at least when the cognitive ability of the patients is compromised. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments This article was written as a joint effort between all three authors based on the previous studies and discussions during their long-term collaboration. Fig. 1. Age and gender adjusted 17-year survival of older Helsinki citizens by parathyroid function. P for model = 0.068.
age, PHPT may in fact often be tertiary caused or enhanced by secondary hyperparathyroidism (SHPT) related to long-standing vitamin D insufficiency [23]. However, sufficient vitamin D levels are individual. Thus, some subjects defined to have ‘‘normocalcaemic PHPT’’ [4], may in fact have SHPT due to their individual higher requirements for vitamin D. If the hypothesis of PHPT in old age being often tertiary was true, PHPT would be relatively rare in vitamin D replete populations and its incidence would be diminished by vitamin D supplementation of vitamin D insufficient populations. Furthermore, it can be speculated that also the positive correlation between PTH and mortality shown in normocalcaemic populations is driven by a subgroup particularly liable to developing autonomous hypersecreting parathyroid cell lines in the presence of chronic vitamin D insufficiency. Compatible with this speculation is the absence of correlation between PTH and mortality in the recent study by Jassal et al. [24]. The subjects in this prospective study of community-dwelling older people had exceptionally high vitamin D levels (mean 25-OHD > 100 nmol/L), assumably high enough to prevent even the liable cells from evolution to hypersecreting adenoma. The time has also come for randomised PTX trials of older PHPT patients with symptoms indistinguishable from aging – studies focusing on symptoms threatening daily activities and independent living outside institutional care. To avoid referral bias, recruitment of patients should optimally be based on screening of older populations (older than 70- or 75-years) and should also focus on symptoms hitherto neglected or deemed as exclusion criteria in PTX studies. To avoid selection bias, inclusion criteria should be wide enough to yield a representative sample of older PHPT patients encountered by physicians in everyday practice. Would the results indicate considerable benefit in functional capacity, quality of life or in postponing institutional care, the relevance of routine calcaemic screening of older populations should be evaluated. In addition, the effects of calcimimetics on non-specific symptoms of older PHPT patients should be similarly addressed. In the calcimimetic study, the willingness to participate would probably be far better than in surgical trials. In short, it remains to be elucidated whether many of the symptoms and signs so far deemed as contraindications are rather indications for treatment in old age. 6. Clinical practice today In the present clinical practice, it seems more important to regularly monitor general health and functional capacity of an
References [1] Christensson T, Hellstro¨m K, Wengle B. Clinical and laboratory findings in subjects with hypercalcaemia. A study including cases with primary hyperparathyroidism detected in a health screening. Acta Med Scand 1976;200:355–60. [2] Mundy GR, Cove DH, Fisken R. Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet 1980;1:1317–20. [3] Bilezikian JP, Khan AA, Potts Jr JT. Third international workshop on the management of asymptomatic primary hyperthyroidism. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009;94:335–9. [4] Silverberg SJ, Bilezikian JP. Incipient’’ primary hyperparathyroidism: a ‘‘forme fruste’’ of an old disease. J Clin Endocrinol Metab 2003;88:5348–52. [5] Tibblin S, Pa˚lsson N, Rydberg J. Hyperparathyroidism in the elderly. Ann Surg 1983;197:135–8. [6] Wu B, Haigh PI, Hwang R, Ituarte PHG, Liu I-LA, Hahn TJ, et al. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2010;95:4324–30. [7] Heath DA, Wright AD, Barnes AD, Oates GD, Dorricott NJ. Surgical treatment of primary hyperparathyroidism in the elderly. Br Med J 1980;280:1406–8. [8] Talpos GB, Bone HG, Kleerekoper M, Phillips ER, Alam M, Honasoge M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery 2000;128:1013–20. [9] Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004;89:5415–22. [10] Bollerslev J, Jansson S, Mollerup CL, Nordenstro¨m J, Lundgren E, Tørring O, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007;92:1687–92. [11] Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007;92:3114–21. [12] Morris GS, Grubbs EG, Hearon CM, Gantela S, Lee JE, Evans DB, et al. Parathyroidectomy improves functional capacity in ‘‘asymptomatic’’ older patients with primary hyperparathyroidism: a randomized control trial. Ann Surg 2010;251:832–7. [13] Perrier ND, Balachandran D, Wefel JS, Jimenez C, Busaidy N, Morris GS, et al. Prospective, randomized, controlled trial of parathyroidectomy versus observation in patients with ‘‘asymptomatic’’ primary hyperparathyroidism. Surgery 2009;146:1116–22. [14] Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608–14. [15] Sankaran S, Gamble G, Bolland M, Reid IR, Grey A. Skeletal effects of interventions in mild primary hyperparathyroidism: a meta-analysis. J Clin Endocrinol Metab 2010;95:1653–62. [16] Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598–602. [17] Mazzuoli GF, D’Erasmo E, Pisani D. Primary hyperparathyroidism and osteoporosis. Aging (Milano) 1998;10:225–31. [18] Hedba¨ck G, Ode´n A. Increased risk of death from primary hyperparathyroidism-an update. Eur J Clin Invest 1998;28:271–6. [19] Yu N, Donnan PT, Flynn RW, Murphy MJ, Smith D, Rudman A, et al. Increased mortality and morbidity in mild primary hyperparathyroid patients. The
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Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf) 2010;73:30–4. [20] Pilz S, Tomaschitz A, Drechsler C, Ritz E, Boehm BO, Grammer TB, et al. Parathyroid hormone level is associated with mortality and cardiovascular events in patients undergoing coronary angiography. Eur Heart J 2010; 31:1591–8. [21] Bjo¨rkman MP, Sorva AJ, Tilvis RS. Elevated serum parathyroid hormone predicts impaired survival prognosis in a general aged population. Eur J Endocrinol 2008;158:749–53.
[22] Khan A, Grey A, Shoback D. Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009;94:373–81. [23] Weaver S, Doherty DB, Jimenez C, Perrier ND. Peer-reviewed, evidence-based analysis of vitamin D and primary hyperparathyroidism. World J Surg 2009;33:2292–302. [24] Jassal SK, Chonchol M, Mu¨hlen DV, Smits G, Barrett-Connor E. Vitamin D, Parathyroid Hormone, and Cardiovascular Mortality in Older Adults: The Rancho Bernardo Study. Am J Med 2010;123:1114–20.
Controversies in geriatric medicine
Treatment indications of mild primary hyperparathyroidism in old age; a challenge for research M.P. Bjo¨rkman a,*, R.S. Tilvis a,1, A.J. Sorva b,2 a b
Clinics of Internal Medicine and Geriatrics, Helsinki University Central Hospital, POB 340, FI-00029 HUS, Helsinki, Finland Department of Long-Term Care, Helsinki City Hospital of Laakso, POB 6600, FI-00099 City of Helsinki, Helsinki, Finland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 January 2011 Accepted 10 May 2011 Available online 15 June 2011
Primary hyperparathyroidism (PHPT) is common in older people, but it does not usually develop classical symptoms or long-term complications in the last years of life. The non-specific symptoms are often indistinguishable from age-related complaints and illnesses, and the patients are generally left in surveillance. Trials are needed to show, whether the non-classical symptoms of PHPT so far deemed as contraindications are rather indications for treatment in old age. ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Primary hyperparathyroidism Parathyroidectomy Old people Evidence based medicine
In clinical practice, physicians often encounter mildly hypercalcaemic older patients. In most cases concomitantly elevated concentration of parathyroid hormone (PTH) confirms the diagnosis of primary hyperparathyroidism (PHPT). Several population-based studies have shown that the prevalence of PHPT increases with age, being at least twice as common in women as in men [1]. However, it is not clear how the oldest PHPT patients should be treated and monitored. The diversity of clinical symptoms in older PHPT patients, the poor association of these symptoms with the degree of hypercalcaemia and parathyroid hormone (PTH) levels as well as the uncertainty of treatment results emphasize the need for future trials. 1. The clinical presentation of PHPT has changed At present, PHPT is commonly diagnosed without the classical manifestations such as hypertension, renal calculi, nephrocalcinosis, renal dysfunction, osteopenia or osteoporosis, osteitis fibrosa cystica, and severely altered neurologic function with obtundation, delirium or coma [2]. In fact, case-control studies based on questionnaires have revealed that PHPT patients often report non-specific milder complaints like, weakness, easy fatigability, depression, intellectual weariness, cognitive impairment, loss of initiative, anxiety, irritability, sleep disturbances * Corresponding author. Tel.: +358 5 03 41 40 22. E-mail addresses: mikko.bjorkman@helsinki.fi (M.P. Bjo¨rkman), reijo.tilvis@helsinki.fi (R.S. Tilvis), [email protected] (A.J. Sorva). 1 Reijo S. Tilvis, phone: +358 4 00 69 85 75. 2 Antti J. Sorva, phone: +358 5 04 02 57 13.
and features of somatisation [3]. These patients with milder phenotype of PHPT have been also called ‘‘asymptomatic’’. A third phenotype of the disease, ‘‘normocalcaemic PHPT’’, has been also described [4]. It is defined by elevated PTH concentration, normocalcaemia and sufficient vitamin D status. 2. Effects of parathyroidectomy on non-classical symptoms of PHPT Parathyroidectomy (PTX) is effective and safe also in older patients [5]. PHPT accompanied by frank elevation of serum calcium with obvious clinical symptoms is a clear treatment indication even in the oldest. Moreover, non-classical symptoms of PHPT are being accepted as indication for PTX especially in younger patients. These symptoms often resemble age-related illnesses and aging itself, i.e., ‘‘senility’’, inevitably resulting in delayed or deferred referral of older PHPT patients for PTX [6]. Clinical experience on selected cases and a plethora of sporadic case reports suggest that PTX can sometimes improve this ‘‘pseudosenility’’ [7]. Thus, the effects of PTX on quality of life and functional capacity, particularly, are emphasized in the management of older patients with biochemically mild PHPT. Randomized controlled trials (RCT) addressing the effects of PTX in PHPT were retrieved in April 2011 from Pubmed with the following search phrase: ‘‘Primary hyperparathyroidism AND (parathyroidectomy[title] OR surgery[title] OR surgical[title]) AND (randomly[title/abstract] OR randomized[title/abstract] OR randomised[title/abstract] OR random[title/abstract])’’. The search included 48 papers which were evaluated and their reference lists reviewed. To date three larger and one RCT have addressed the
1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.05.002
M.P. Bjo¨rkman et al. / European Geriatric Medicine 2 (2011) 155–158
156
effects of PTX on quality of life or physical functioning in PHPT patients without classical indications for surgery (Table 1). In these trials PTX improved bone mineral density (BMD), walking distance, some domains of quality of life, and sleep quality [8–13]. However, none of these trials addressed the effectiveness of PTX in old age. Nevertheless, Talpos et al. found that surgery improved social and emotional role functioning [8]. In the extension of the study, a modest benefit was still found [9]. In the series of Bo¨llerslev et al. the patients were collected from primary care in three Scandinavian countries and referred to five surgical centres [10]. The patients did have more neuropsychiatric complaints as compared to the Swedish normative data, but PTX did not improve neuropsychological functions. However, in the single-centre study by Amborgini et al., surgery improved some domains of quality of life such as physical function, bodily pain, general health, mental health, and vitality [11]. One small RCT has shown a clinically meaningful improvement in 6-minute walking distance in the PTX-group [12]. In another report from the same patient group, PTX seemed to improve sleep quality [13]. It should be noted that the placebo effect of surgery cannot be excluded in these studies (Table 1). It is also important to recognize that the patients were highly selected and young in all of these trials. Furthermore, patients with mental disorders and mental symptoms seem to have been often excluded. In fact, also the referral practices in primary care may have been too conventional and conservative leading to under-utilization of surgical possibilities and resulting in surgical study groups with relatively few frail older PHPT patients with ‘‘non-classical’’ symptoms [6].
fractures is increased in young PHPT patients [16], no study has addressed bone fracture risk of oldest PHPT patients. Actually, with advancing age, the fracture incidence of PHPT patients seems to become equal to that of the general population [17], perhaps due to attenuation of disease progression. Thirdly, concerning morbidity and mortality, the prognostic importance of biochemically mild PHPT in old age is unclear. Epidemiologic findings indicate that PHPT increases cardiovascular mortality, which is also decreased by PTX [18]. This evidence from relatively hypercalcaemic patients has been used to advocate PTX in biochemically mild PHPT without classical symptoms. Recently, also mild PHPT has been associated with increased mortality in a population-based cohort of relatively old (mean age = 69 years) PHPT patients [19]. In addition, there are several large-scale prospective studies showing association of elevated PTH with allcause and cardiovascular mortality even in normocalcaemic populations [20]. High PTH has been associated with mortality also in late life [21], but the 17-year follow-up of these older people (age cohorts of 75-, 80-, and 85-year old general population, N = 567) living in Helsinki did not suggest excess mortality of persons with PHPT (Fig. 1). Apart from co-morbidities and disease severity, old age alone diminishes the likelihood of PTX. In contrast to young PHPT patients, older patients with biochemically mild PHPT typically do not develop classical long-term complications [4] and are generally left in surveillance only. However, the actual present-day impact of PHPT on quality of life and activities of everyday living may be far more relevant in the last years of life.
3. Indications for parathyroidectomy in old age are not clear
4. Other treatment options
For several reasons the present trial evidence does not allow normative definitions of indications for surgery in PHPT in old age. Neither serum calcium nor PTH correlates well with severity of symptoms [14]. Thus, treatment decisions solely based on the serum calcium and/or PTH levels seem not to be appropriate. Secondly, old age alters the relative significance of bone disease. The PHPT induced bone loss is partly reverted by PTX which may also prevent fractures [15]. Thus, BMD measurements have been recommended in the follow-up of PHPT patients [3]. However, all older persons have at least osteopenia and the relevance of repeated BMD measurements in surgical decision-making for older PHPT patients remains unclear. Even though PHPT can be associated with neuromuscular weakness and the incidence of
Bisphosphonates can protect bones for years but do not correct hypercalcaemia permanently [22]. The calcimimetics e.g. cinacalcet lower both serum calcium and PTH and thus seem promising in those PHPT patients who are not candidates for PTX [22]. Estrogens or raloxifene, a selective estrogen receptor modulator have not been tested in the treatment of the non-classical symptoms of PHPT, thus far. 5. Future research perspectives Follow-up studies based on calcaemic screening of large unselected older population could shed light on the evolution and natural history of PHPT. Such studies could show that in old
Table 1 Randomized parathyroidectomy vs. observation trials addressing quality of life and physical functioning in primary hyperparathyroidism patients without classical symptoms. Author
Patients
Recruitment population, N
Eligible, N
Mean age, years
Mean calcium, mmol/L
Mean PTH, ng/L
Follow-up
Drop-outs, %
Main positive results related to PTX
Talpos et al. 2000 [8] Rao et al. 2004 [9]
Asymptomatic PHPT patients (USA)
Hypercalcemic patients within computerized health system, 1201
53
65 7
2.59
82
24–64 months
0
BMD, QoL (modest), Anxiety/phobia (modest)
Bo¨llerslev et al. 2007 [10]
Asymptomatic PHPT patients (Sweden, Norway, Denmark)
Referred PHPT patients, N not reported
191
64 7
2.69
97
2 years
48
BMD
Ambrogini et al. 2007 [11]
PHPT patients not meeting guidelines for PTX (Italy)
Referred PHPT patients, 412
50
65 6
2.54
112
1 year
0
BMD, QoL (modest)
Perrier et al. 2009 [12] Morris et al. 2010 [13]
PHPT patients not meeting guidelines for PTX (USA)
Consecutive referred PHPT patients, 54
21
66 10
2.58
122
6 months
14
Walking distance, Day time sleepiness (modest)
PTX: Parathyroidectomy; PHPT: Primary hyperparathyroidism; PTH: parathyroid hormone; BMD: Bone mineral density; QoL: Quality of life.
M.P. Bjo¨rkman et al. / European Geriatric Medicine 2 (2011) 155–158
157
older PHPT patient than to frequently measure BMD and calcaemic status. Worsening general health, declining cognition, increasing confusion, and subsequent risk of permanent institutionalisation are relevant causes for re-evaluation of PTX. Referrals to surgery and decisions to operate should be based on thorough joint discussion not only between the doctor and the patient but often also with the next of kin, at least when the cognitive ability of the patients is compromised. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments This article was written as a joint effort between all three authors based on the previous studies and discussions during their long-term collaboration. Fig. 1. Age and gender adjusted 17-year survival of older Helsinki citizens by parathyroid function. P for model = 0.068.
age, PHPT may in fact often be tertiary caused or enhanced by secondary hyperparathyroidism (SHPT) related to long-standing vitamin D insufficiency [23]. However, sufficient vitamin D levels are individual. Thus, some subjects defined to have ‘‘normocalcaemic PHPT’’ [4], may in fact have SHPT due to their individual higher requirements for vitamin D. If the hypothesis of PHPT in old age being often tertiary was true, PHPT would be relatively rare in vitamin D replete populations and its incidence would be diminished by vitamin D supplementation of vitamin D insufficient populations. Furthermore, it can be speculated that also the positive correlation between PTH and mortality shown in normocalcaemic populations is driven by a subgroup particularly liable to developing autonomous hypersecreting parathyroid cell lines in the presence of chronic vitamin D insufficiency. Compatible with this speculation is the absence of correlation between PTH and mortality in the recent study by Jassal et al. [24]. The subjects in this prospective study of community-dwelling older people had exceptionally high vitamin D levels (mean 25-OHD > 100 nmol/L), assumably high enough to prevent even the liable cells from evolution to hypersecreting adenoma. The time has also come for randomised PTX trials of older PHPT patients with symptoms indistinguishable from aging – studies focusing on symptoms threatening daily activities and independent living outside institutional care. To avoid referral bias, recruitment of patients should optimally be based on screening of older populations (older than 70- or 75-years) and should also focus on symptoms hitherto neglected or deemed as exclusion criteria in PTX studies. To avoid selection bias, inclusion criteria should be wide enough to yield a representative sample of older PHPT patients encountered by physicians in everyday practice. Would the results indicate considerable benefit in functional capacity, quality of life or in postponing institutional care, the relevance of routine calcaemic screening of older populations should be evaluated. In addition, the effects of calcimimetics on non-specific symptoms of older PHPT patients should be similarly addressed. In the calcimimetic study, the willingness to participate would probably be far better than in surgical trials. In short, it remains to be elucidated whether many of the symptoms and signs so far deemed as contraindications are rather indications for treatment in old age. 6. Clinical practice today In the present clinical practice, it seems more important to regularly monitor general health and functional capacity of an
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