mild hyperparathyroidism: not need surgery

 

A recent long-term follow-up study suggested that observation was as good as parathyroidectomy in patients with mild primary hyperparathyroidism (see hyperparathyroid surgery no better AIM2022 in dropbox or doi:10.7326/M21-4416)

 

Details: 

-- 191 patients with mild hyperparathyroidism in eight Scandinavian referral centers were randomly assigned to parathyroidectomy (PTX) versus observation (OBS), from 1998 to 2005

-- baseline: mean age 63, 83% women, BP 140/80, prevalent vertebral fractures 7%, history of peripheral fractures 25%

-- history of cardiovascular disease 13%/cancer 4%/kidney stone 3%, mean corrected calcium 10.6 mg/dL, mean PTH 91 ng/L, mean creatinine 0.9 mg/dL (no comment on phosphate level)

-- data and causes of death were obtained from the Swedish and Norwegian registries 10 years after randomization and also after an extended observation period lasting to 2018; morbidity events were prospectively registered annually

-- inclusion criteria: untreated primary hyperparathyroidism with serum albumin corrected calcium levels between 10.4 and 11.2 mg/dL and age between 50 and 80

-- exclusion criteria: hyperparathyroid bone disease, previous operating in the neck, creatinine > 1.47 mg/dL, kidney stones, complicating medical conditions (not explicitly stated), multiple endocrine neoplasia, familial hypocalciuric hypercalcemia

-- spine radiographs were obtained at baseline and at two, five, and 10 years

-- this article presents the 10-year morbidity data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), with extended follow-up to 20 years for mortality

    -- prespecified secondary outcomes: morbidity development, bone mineral density, and quality-of-life were (though no data presented on these)

-- extended period: mean of 15.3 years, with mean age of surviving patients at that time being 77 years

-- outcomes measured: effect of PTX versus OBS on mortality (primary endpoint), and on key morbidities (prespecified secondary endpoints: cardiovascular events, cerebrovascular events, cancer, peripheral fractures, renal stones, and kidney failure)

-- prespecified indications for PTX in the OBS group included hypercalcemia >12 mg/dL at two time points, deteriorating kidney function with creatinine >2.26 mg/dL, kidney stones, parathyroid-associated bone disease, or patient decision

    -- 17 patients in the OBS group had PTX, 4 of  them for prespecified medical indications

 

Results: 

-- all-cause mortality:

    -- after 10 years: eight patients with PTX versus seven in OBS died

    -- within the extended observation (mean of 15.3 years): 24 deaths with PTX versus 20 with OBS

        -- most common causes of deaths: cardiovascular, with eight in PTX and nine in OBS, cerebrovascular disease with five in PTX and three in OBS, and cancer with 4 in each group

-- morbidity events, after 10 years of follow-up: 52 in the PTX group and 49 in the OBS group

    -- peripheral fracture 15 in PTX and 17 in OBS (predominately 15 wrist fractures and nine proximal humerus fractures)

    -- vertebral fractures: seven in each group

    -- cardiovascular events: 10 in each group

    -- cancer: 13 in the PTX and seven in the OBS group, mostly from six breast cancers in the PTX group and one in the OBS group

    -- cerebrovascular events: five in each group

    -- kidney stones: two in the PTX and five in OBS groups

        -- of note, none of the five patients in the OBS group with kidney stones before being included in the study developed new kidney stones

    -- none of these morbidity events were statistically significantly different between the groups

 

--see graphs below: no evidence of splaying of the curves over time

 

 Commentary: 

-- there is concern that mild primary hyperparathyroidism, frequently picked up by hypercalcemia found on routine testing, is associated with arterial stiffness, left ventricular hypertrophy, and endothelial dysfunction, though it is unclear that it is associated with increased mortality and risk for cardiovascular disease. Some epidemiologic studies have shown increased risk for cancer

-- hypercalcemia itself seems to be independently associated with myocardial infarction, perhaps related to calcium deposition in the vasculature. This current study however did not find any evidence of increased cardiovascular disease in people with mild hypercalcemia in the setting of hyperparathyroidism

-- observational studies have suggested that PTX does decrease the risk of vertebral fractures, but there is a remarkable dearth of information by well-conducted studies about optimal management of patients with mild hyperparathyroidism, surprisingly so since this is such a common condition.

     -- BUT, prior to this study, there had been no long-term randomized controlled trials specifically assessing whether parathyroid surgery benefits patients with mild asymptomatic hyperparathyroidism in terms of life expectancy or cardiovascular mortality

-- the data from this study found no increased fracture risk in those with mild hyperparathyroidism who are just observed without surgery, and surgery does not seem to confer any benefits in terms of mortality or morbidity in the medium to long-term, despite prior observational data to the contrary

-- a prior study from this group did find modest improvement in the mental subscales of SF-36 (which measures 8 generic dimensions of health, 4 physical and 4 mental) vs observation, though these differences were minor and of questionable clinical significance (see doi:10.1002/jbmr.4199)

-- as a sideline here: as noted in above study, there was no measurement of phosphate levels. i personally have found a few cases of hyperparathyroidism in patients with normal calcium levels and low phosphate levels. no data on treatment in these cases, though seems reasonable to consider these in the above mild hyperparathyroidism category

 

Limitations:

-- the study was conducted only in northern Europe, so the results may be different from other areas where diet, vitamin D levels, or other things that would affect bone health (e.g. medical comorbidities, exercise, obesity, alcohol or smoking, etc) may be different

-- relatively few men were included in the study, which may limit generalizability of the results to men

-- the results of this study would only apply to those who meet the inclusion criteria, and would not necessarily apply to those with serum calcium levels >11.2 mg/dL, younger than 50 or older than 80, or with the unspecified "underlying serious medical condition"

 

So, a few comments:

-- this study provides strong support for “watchful waiting” in those with mild hyperparathyroidism

    -- which is especially great since the surgery does have potentially serious complications and requires surgeons who have lots of experience (see https://jamanetwork.com/journals/jamasurgery/article-abstract/2791954 )

-- it has actually been my practice for decades to observe patients with mild hyperparathyroidism and not refer to surgery, based on very old studies (all observational and small) that many patients who declined surgery seemed to do very well decades later, both clinically and in terms or fractures and stones/renal function. And I have sent essentially none of these many patients to subsequent surgery.

    -- and the caveat here is that in these patients I avoid meds that increase calcium levels (eg thiazides, but instead using loop diuretics as diuretics including for hypertension), I carefully make sure that vitamin D levels are appropriate for the individual (ie, check D and calcium levels regularly to make sure no increasing hypercalcemia), do routine bone mineral density assessments every couple of years (and prescribe bisphosphonates as needed), and encourage lots of liquids (especially in those with history of renal stones)

 

geoff

 

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