Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency

Background: The beneficial effects of recombinant human GH (rhGH) therapy in GH deficient (GHD) adults are well-established in the short term. However, data documenting the effects during prolonged follow-up are relatively scarce. Objective: To evaluate the reported effects of rhGH replacement (R5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events and mortality. Methods: We conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement. Results: We included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid intima media thickness and bone mineral density. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively, influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased. Conclusion: rhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable.

Section: Introductionmentioning

confidence: 99%

Therapy of Endocrine disease: Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review

Appelman‐Dijkstra

Claessen

Roelfsema

et al. 2013

“…At present, data on long-term efficacy and safety of rhGH replacement are limited and uncontrolled for the effect of aging (5, 6,7,8,9,10,11,12,13,14,15,16,17,18). Recently, we have reported a further increase in BMI and MS prevalence despite 10 years of rhGH replacement (19).…”

Section: Introductionmentioning

confidence: 99%

Abnormal metabolic phenotype in middle-aged GH-deficient adults despite long-term recombinant human GH replacement

Claessen

Appelman‐Dijkstra²,

Pereira³

et al. 2014

Background: Adult GH deficiency (GHD) is associated with increased cardiovascular mortality. Recombinant human GH (rhGH) replacement has beneficial short-term metabolic effects. Although these positive effects sustain during longer follow-up, the prevalence of the metabolic syndrome (MS) remains increased in comparison with population data not adjusted for the higher mean BMI in GHD adults. Objective: To explore whether middle-aged patients with proposed physiological rhGH replacement have been normalized with respect to MS and its individual components in comparison with the general population, adjusted for age, sex, and BMI. Methods: One hundred and sixty-one GHD patients (aged 40-70 years) were studied before the start and after 5 years of rhGH replacement, and were compared with 1671 subjects (aged 45-66 years) from the general population (NEO Study). Results: MS proportion in GHD patients was 41.0% before the start of rhGH suppletion, increasing to 53.4% after 5 years (PZ0.007). Despite chronic rhGH replacement, GHD patients had a 1.3-times higher MS proportion than the general population, independently of age, sex, and BMI (95% CI 1.1-1.5, PZ0.008). The GHD population showed a different metabolic profile than the general population with similar BMI: an increased risk of hypertriglyceridemia (adjusted prevalence ratio (PR) 2.0, 95% CI 1.7-2.3) and low HDL-C (adjusted PR 1.8, 95% CI 1.5-2.2), but less hyperglycemia (adjusted PR 0.5, 95% CI 0.4-0.7). Conclusions: Despite 5 years of rhGH replacement, GHD patients still have a different metabolic profile and more frequently MS than the general population. These differences were independent of BMI, and resemble the unfavorable metabolic profile of untreated GHD patients, pointing to question the long-term benefits of rhGH replacement.

“…The effects of GH therapy on BMD/BMC are also reflected by increased levels of biochemical markers of bone metabolism as well as altered expression of genes in bone, related to a stimulation of bone remodeling (18,33,34,36,38,39,41,42,46,54,59,60,62,(66)(67)(68)(69).…”

Section: Discussionmentioning

confidence: 99%

“…Markers of bone formation, e.g. bonespecific alkaline phosphatase, osteocalcin, and the epitope of C-terminal propeptide (PICP) have similarly been reported to increase significantly from baseline values after 3-24 months of GH therapy (18,33,34,36,38,39,41,42,46,54,59,60,66,67).…”

Section: Discussionmentioning

confidence: 99%

“…The results are summarized in Table 3. Significant increases in BMC compared to baseline were seen mainly in the lumbar spine (20,21,30,35,40,59) and total body measurements (17,21,30,35,40,45,58,59) but also, to a smaller extent, in the femoral neck (35,40,59). The only trial measuring hip BMC reported an insignificant increase from baseline (30).…”

Section: Effect Of Ghd and Gh Replacement On Bonesmentioning

confidence: 99%

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Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis

Klefter¹,

Feldt‐Rasmussen²

2009

Objective: Adult patients with GH deficiency (GHD) are characterized by a reduced muscle mass, but also reduced bone mineral density (BMD) and content (BMC), which have been ascribed to GHD per se.The aim of this study was to investigate if changes in BMD/BMC in adult GHD patients could be due to a muscle modulating effect, and if treatment with GH would primarily increase muscle mass and strength with a secondary increase in BMD/BMC, thus supporting the present physiological concept that mass and strength of bones are mainly determined by dynamic loads from the skeletal muscles. Method: We performed a systematic literature analysis, including 51 clinical trials published between 1996 and 2008, which had studied the development in muscle mass, muscle strength, BMD, and/or BMC in GH-treated adult GHD patients. Results: GH therapy had an anabolic effect on skeletal muscle. The largest increase in muscle mass occurred during the first 12 months of therapy. Most trials measuring BMD/BMC reported significant increases from baseline values. The significant increases in BMD/BMC occurred after 12-18 months of treatment, i.e. usually later than the increases in muscle parameters. Only seven trials studied both muscle and bone variables concomitantly. No trials studied the relationship between the changes in muscle and bone measurements. Conclusion: Although in vitro studies have shown that GH has a direct effect on bone remodeling, present physiological concepts and the results of clinical trials from 1996 to 2008 suggest that the anabolic changes in muscle mass and strength may also contribute to changes in BMD/BMC in GH-treated adult GHD patients.